MEDICATION
After making the diagnosis of endometritis and excluding other sources of infection, broad-spectrum antibiotics should be promptly initiated. Improvement will be noted within 48-72 hours in nearly 90% of women treated with an approved regimen. For mild cases following vaginal delivery, an oral agent may be adequate.
Drug Category: Antibiotics -- A combination therapy with clindamycin and an aminoglycoside is considered the criterion standard by which most antibiotic clinical trials are judged.
A combination regimen of ampicillin, gentamicin, and metronidazole provides coverage against most of the organisms that are encountered in serious pelvic infections.
Doxycycline should be used if Chlamydia is the cause of the endometritis.
Ampicillin sulbactam can be used as monotherapy. Single-agent therapies have been found to be efficacious in 80-90% of patients.
Drug Name
Clindamycin (Cleocin) -- Used in combination with gentamicin. Lincosamide useful as a treatment against serious skin and soft tissue infections caused by most staphylococci strains. Also effective against aerobic and anaerobic streptococci, except enterococci.Inhibits bacterial protein synthesis by inhibiting peptide chain initiation at bacterial ribosome where preferentially binds to the 50S ribosomal subunit, causing bacterial growth inhibition.
Adult Dose
900 mg IV q8h
Pediatric Dose
20-40 mg/kg/d IV divided q6-8h
Contraindications
Documented hypersensitivity; regional enteritis, ulcerative colitis, hepatic impairment, antibiotic-associated colitis
Interactions
Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficileAmerican Academy of Pediatrics states that clindamycin is compatible with breastfeeding
Drug Name
Gentamicin (Gentacidin, Garamycin) -- Aminoglycoside antibiotic used for gram-negative bacterial coverage. Used in combination with either clindamycin or in combination with metronidazole and ampicillin.Dosing regimens are numerous and are adjusted based on creatinine clearance and changes in the volume of distribution. Dose may be given IV or IM.
Adult Dose
1.5 mg/kg IV q8h
Pediatric Dose
2-2.5 mg/kg/d IV q8h
Contraindications
Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions
Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents, thus prolonged respiratory depression may occurCoadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment; data are lacking concerning use while breastfeeding
Drug Name
Ampicillin (Omnipen, Marcillin) -- Used in combination with gentamicin and metronidazole. Interferes with bacterial cell-wall synthesis during active multiplication, causing bactericidal activity against susceptible organisms.
Adult Dose
2 g IV q6h
Pediatric Dose
50-200 mg/kg/d IV divided qid
Contraindications
Documented hypersensitivity
Interactions
Probenecid and disulfiram elevate levels; allopurinol decreases effects and has additive effects on ampicillin rash; may decrease effects of oral contraceptives
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction
Drug Name
Metronidazole (Flagyl) -- Used in combination with gentamicin and ampicillin. Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Appears to be absorbed into the cells and the intermediate-metabolized compounds that are formed bind DNA and inhibit protein synthesis, causing cell death.
Adult Dose
500 mg IV q6h
Pediatric Dose
15-30 mg/kg/d IV divided bid/tid
Contraindications
Documented hypersensitivity
Interactions
May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity; disulfiram reaction may occur with orally ingested ethanol
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathyAmerican Academy of Pediatrics states that metronidazole should be used with caution while breastfeeding
Drug Name
Ampicillin/sulbactam sodium (Unasyn) -- Has been found to be efficacious as monotherapy in 80-90% of patients. Drug combination that uses a beta-lactamase inhibitor with ampicillin. Covers skin, enteric flora, and anaerobes. Not ideal for nosocomial pathogens.
Adult Dose
3 g IV q6h
Pediatric Dose
1.5-3 g IV q8h
Contraindications
Documented hypersensitivity
Interactions
Probenecid and disulfiram elevate ampicillin levels; allopurinol decreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects of oral contraceptives
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction; compatible with breastfeeding
Drug Name
Doxycycline (Bio-Tab, Doryx, Vibramycin) -- Used if Chlamydia is the cause of the endometritis. Inhibits protein synthesis and thus bacterial growth by binding with the 30S and possibly the 50S ribosomal subunits of susceptible bacteria.
Adult Dose
100 mg IV/PO q12h
Pediatric Dose
<8>8 years: 1-2 mg/lb q12h
Contraindications
Documented hypersensitivity; severe hepatic dysfunction
Interactions
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy
D - Unsafe in pregnancy
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one-half of pregnancy through 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclinesAmerican Academy of Pediatrics states that doxycycline is compatible with breastfeeding
Drug Name
Ertapenem (Invanz) -- Bactericidal activity results from inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin binding proteins. Stable against hydrolysis by a variety of beta-lactamases including penicillinases, cephalosporinases, and extended spectrum beta-lactamases. Hydrolyzed by metallo-beta-lactamases.
Adult Dose
1 g qd for 14 d if given IV and 7 d if given IM; infuse over 30 min if given IV
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity to drug or amide type anesthetics
Interactions
Probenecid may reduce renal clearance of ertapenem and increase half-life but benefit is minimum and does not justify coadministration
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Pseudomembranous colitis may occur; seizures and CNS adverse reactions may occur; when using with lidocaine to administer intramuscularly, avoid inadvertent injection into blood vessel FOLLOW-UP
In/Out Patient Meds:
Patient may be discharged home without antibiotic therapy after being afebrile for at least 24 hours and with a benign physical examination.
Further outpatient therapy has proved to be unnecessary.
Complications:
Wound infection
Peritonitis
Adnexal infection
Parametrial phlegmon
Pelvic abscess
Pelvic hematoma
Septic pelvic thrombophlebitis
Prognosis:
Nearly 90% of women treated with an approved regimen note improvement in 48-72 hours. MISCELLANEOUS
Medical/Legal Pitfalls:
Prophylactic antibiotics reduce the incidence of postpartum febrile morbidity in patients undergoing cesarean delivery.
Single-agent cephalosporin therapy of the first- or second-generation type is considered the best choice.
BIBLIOGRAPHY
Tuesday, June 3, 2008
Endometritis 1
INTRODUCTION
Background: Endometritis is an infection of the endometrium or decidua, with extension into the myometrium and parametrial tissues. It is the most common cause of fever during the postpartum period.
Pathophysiology: It is infection of the endometrium or decidua, with extension into the myometrium and parametrial tissues.
Frequency:
In the US: Incidence varies depending on the route of delivery and the patient population. After a vaginal delivery, incidence is 1-3%. Following cesarean delivery, incidence ranges from 13-90%, depending on the risk factors present and whether perioperative antibiotic prophylaxis had been given.
Mortality/Morbidity:
Infection of the genital tract is the most common cause of puerperal morbidity.
Puerperal morbidity is defined as a temperature of 100.4°F (38°C) or higher occurring in any 2 of the first 10 days postpartum, exclusive of the first 24 hours.
In the past, infection accounted for up to 16% of maternal mortality.
Age:
This disorder affects females of reproductive age. CLINICAL
History: Diagnosis usually is based on clinical findings.
Fever
Lower abdominal pain
Foul-smelling lochia
Physical:
Fever, usually occurring within 36 hours of delivery
Lower abdominal pain
Uterine tenderness
Foul-smelling lochia
Malaise
Tachycardia
Causes:
Endometritis is a polymicrobial disease involving, on average, 2-3 organisms.
In the majority of cases, it arises from an ascending infection from organisms found in the normal indigenous vaginal flora.
Common isolated organisms include Ureaplasma urealyticum, Peptostreptococcus, Gardnerella vaginalis, Bacteroides bivius, and group B Streptococcus.
Chlamydia has been associated with late-onset postpartum endometritis.
Enterococcus is identified in up to 25% of women who have received cephalosporin prophylaxis.
Route of delivery is the most important factor in the development of postpartum endometritis.
Major risk factors include cesarean delivery, prolonged rupture of membranes, long labor with multiple vaginal examinations, extremes of patient age, and low socioeconomic status.
Minor contributing factors include maternal anemia, prolonged internal fetal monitoring, prolonged surgery, and general anesthesia. DIFFERENTIALS
Appendicitis
Other Problems to be Considered:
PyelonephritisViral syndromePelvic thrombophlebitis WORKUP
Lab Studies:
Complete blood count: The finding of leukocytosis may be difficult to interpret, secondary to the physiologic leukocytosis of pregnancy.
Blood culture is positive in 10-30%.
Urine culture should be ordered.
Imaging Studies:
Perform imaging studies on patients who fail to respond to adequate antimicrobial therapy in 48-72 hours.
CT scan of the abdomen and pelvis may be helpful for excluding broad ligament masses, septic pelvic thrombophlebitis, ovarian vein thrombosis, and phlegmon.
Sonogram of abdomen and pelvis
Sonographic findings may be normal in patients with a clinical diagnosis of endometritis.
Abnormal findings overlap with those of retained products from conception and intrauterine hematoma. TREATMENT
Medical Care: Most cases of endometritis, including those following cesarean delivery, should be treated in an inpatient setting. For mild cases following vaginal delivery, oral antibiotics in an outpatient setting may be adequate.
Background: Endometritis is an infection of the endometrium or decidua, with extension into the myometrium and parametrial tissues. It is the most common cause of fever during the postpartum period.
Pathophysiology: It is infection of the endometrium or decidua, with extension into the myometrium and parametrial tissues.
Frequency:
In the US: Incidence varies depending on the route of delivery and the patient population. After a vaginal delivery, incidence is 1-3%. Following cesarean delivery, incidence ranges from 13-90%, depending on the risk factors present and whether perioperative antibiotic prophylaxis had been given.
Mortality/Morbidity:
Infection of the genital tract is the most common cause of puerperal morbidity.
Puerperal morbidity is defined as a temperature of 100.4°F (38°C) or higher occurring in any 2 of the first 10 days postpartum, exclusive of the first 24 hours.
In the past, infection accounted for up to 16% of maternal mortality.
Age:
This disorder affects females of reproductive age. CLINICAL
History: Diagnosis usually is based on clinical findings.
Fever
Lower abdominal pain
Foul-smelling lochia
Physical:
Fever, usually occurring within 36 hours of delivery
Lower abdominal pain
Uterine tenderness
Foul-smelling lochia
Malaise
Tachycardia
Causes:
Endometritis is a polymicrobial disease involving, on average, 2-3 organisms.
In the majority of cases, it arises from an ascending infection from organisms found in the normal indigenous vaginal flora.
Common isolated organisms include Ureaplasma urealyticum, Peptostreptococcus, Gardnerella vaginalis, Bacteroides bivius, and group B Streptococcus.
Chlamydia has been associated with late-onset postpartum endometritis.
Enterococcus is identified in up to 25% of women who have received cephalosporin prophylaxis.
Route of delivery is the most important factor in the development of postpartum endometritis.
Major risk factors include cesarean delivery, prolonged rupture of membranes, long labor with multiple vaginal examinations, extremes of patient age, and low socioeconomic status.
Minor contributing factors include maternal anemia, prolonged internal fetal monitoring, prolonged surgery, and general anesthesia. DIFFERENTIALS
Appendicitis
Other Problems to be Considered:
PyelonephritisViral syndromePelvic thrombophlebitis WORKUP
Lab Studies:
Complete blood count: The finding of leukocytosis may be difficult to interpret, secondary to the physiologic leukocytosis of pregnancy.
Blood culture is positive in 10-30%.
Urine culture should be ordered.
Imaging Studies:
Perform imaging studies on patients who fail to respond to adequate antimicrobial therapy in 48-72 hours.
CT scan of the abdomen and pelvis may be helpful for excluding broad ligament masses, septic pelvic thrombophlebitis, ovarian vein thrombosis, and phlegmon.
Sonogram of abdomen and pelvis
Sonographic findings may be normal in patients with a clinical diagnosis of endometritis.
Abnormal findings overlap with those of retained products from conception and intrauterine hematoma. TREATMENT
Medical Care: Most cases of endometritis, including those following cesarean delivery, should be treated in an inpatient setting. For mild cases following vaginal delivery, oral antibiotics in an outpatient setting may be adequate.
Pelvic Inflammatory Disease 2
MEDICATION
See Medical Care for treatment regimens.
Drug Category: Antibiotics -- Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.
Drug Name
Cefoxitin (Mefoxin) -- Second-generation cephalosporin indicated for infections with gram-positive cocci and gram-negative rods. Infections caused by cephalosporin- or penicillin-resistant gram-negative bacteria may respond to cefoxitin.
Adult Dose
2 g IV q6h
Pediatric Dose
80-160 mg/kg/d IV divided q4-6h; higher doses for severe or serious infections; not to exceed 12 g/d
Contraindications
Documented hypersensitivity
Interactions
Probenecid may increase effects; coadministration with aminoglycosides or furosemide may increase nephrotoxicity (closely monitor renal function)
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Bacterial or fungal overgrowth of nonsusceptible organisms may occur with prolonged use or repeated treatment; caution in patients with previously diagnosed colitis
Drug Name
Cefotetan (Cefotan) -- Second-generation cephalosporin indicated for infections caused by susceptible gram-positive cocci and gram-negative rods. Dose and route of administration depend on condition of patient, severity of infection, and susceptibility of causative organism.
Adult Dose
2 g IV q12h
Pediatric Dose
20-40 mg/kg per dose IV/IM q12h for 5-10 d
Contraindications
Documented hypersensitivity
Interactions
Consumption of alcohol within 72 h may produce disulfiramlike reactions; may increase hypoprothrombinemic effects of anticoagulants; coadministration with potent diuretics (eg, loop diuretics) or aminoglycosides may increase nephrotoxicity
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Reduce dosage by one half if CrCl is 10-30 mL/min and by one fourth if CrCl <10 mL/min; bacterial or fungal overgrowth of nonsusceptible organisms may occur with prolonged or repeated therapy
Drug Name
Doxycycline (Vibramycin) -- Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Adult Dose
100 mg PO/IV q12h
Pediatric Dose
<8>8 years: 2-5 mg/kg/d qd or divided bid; not to exceed 200 mg/d
Contraindications
Documented hypersensitivity; severe hepatic dysfunction
Interactions
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy
D - Unsafe in pregnancy
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning facilities; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (<8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
Drug Name
Clindamycin (Cleocin) -- Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose
900 mg IV q8h; if administered with ofloxacin, 450 mg PO qid for 14 d
Pediatric Dose
8-20 mg/kg/d PO as hydrochloride and 8-25 mg/kg/d as palmitate tid/qid20-40 mg/kg/d IV/IM tid/qid
Contraindications
Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Interactions
Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile
Drug Name
Metronidazole (Flagyl) -- Imidazole ring–based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except for C difficile enterocolitis).
Adult Dose
Loading: 15 mg/kg, or 1 g for 70-kg adult, IV over 1 hMaintenance: 6 h following loading dose, infuse 7.5 mg/kg, or 500 mg for 70-kg adult, over 1 h q6-8h; not to exceed 4 g/dIf administered with ofloxacin PO: 500 mg PO bid for 14 d
Pediatric Dose
Administer as in adults
Contraindications
Documented hypersensitivity
Interactions
May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity; disulfiramlike reaction may occur with PO ethanol
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy
Drug Name
Meropenem (Merrem) -- Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell wall synthesis. Effective against most gram-positive and gram-negative bacteria.
Adult Dose
1 g IV q8h
Pediatric Dose
40 mg/kg IV q8h
Contraindications
Documented hypersensitivity
Interactions
Probenecid may inhibit renal excretion of meropenem, increasing meropenem levels
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication
Drug Name
Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum gram-negative activity. Lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins.
Adult Dose
250 mg IM once
Pediatric Dose
50-75 mg/kg/d IV/IM q12h; not to exceed 2 g/d
Contraindications
Documented hypersensitivity
Interactions
Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, or aminoglycosides may increase nephrotoxicity
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in renal impairment; caution in breastfeeding women and in people with allergy to penicillin
Drug Name
Ofloxacin (Floxin) -- Penetrates prostate well and is effective against N gonorrhea and C trachomatis.A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.
Adult Dose
400 mg PO q12h for 14 d
Pediatric Dose
<18>18 years: Administer as in adults
Contraindications
Documented hypersensitivity
Interactions
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal impairment; superinfections may occur with prolonged or repeated antibiotic therapy
Drug Name
Gentamicin (Gentacidin, Garamycin) -- Aminoglycoside antibiotic for gram-negative coverage. Used in combination with an agent against gram-positive organisms and one that covers anaerobes. Dosing regimens are numerous. Adjust dose based on CrCl and changes in volume of distribution. Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing); may draw a peak level 0.5 h after 30-min infusion.
Adult Dose
Loading: 2 mg/kg IV/IMMaintenance: 1.5 mg/kg IV/IM q8h
Pediatric Dose
<5>5 years: 1.5-2.5 mg/kg per dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d
Contraindications
Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions
Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents; thus, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity; irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment Drug Category: Uricosuric agents -- Reduce clearance of some types of antibiotics, increasing their plasma levels.
Drug Name
Probenecid -- Inhibits tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is administered. Adjuvant to therapy with penicillin, ampicillin, methicillin, oxacillin, cloxacillin, or nafcillin. Two- to 4-fold elevation of penicillin plasma levels demonstrated.
Adult Dose
1 g PO once
Pediatric Dose
<2>2 years: Not established
Contraindications
Documented hypersensitivity; blood dyscrasia; uric acid kidney stones; coadministration of ketorolac
Interactions
Salicylates at high dosages and nitrofurantoin may decrease effects; increases levels/toxicity of methotrexate, beta-lactam antibiotics, acyclovir, thiopental, clofibrate, dyphylline, pantothenic acid, ketorolac, benzodiazepines, rifampin, sulfonamide, dapsone, zidovudine, and sulfonylureas
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Crosses placental barrier; caution in history of peptic ulcer FOLLOW-UP
Further Inpatient Care:
Most patients clinically respond within 48-72 hours after medical therapy. If the patient continues to have fever, chills, uterine tenderness, adnexal tenderness, and cervical motion tenderness, consider other possible causes.
Further Outpatient Care:
Perform a follow-up examination 48-72 hours after prescribing outpatient therapy to ensure clinical improvement. If the patient continues to have fevers, chills, uterine tenderness, adnexal tenderness, and cervical motion tenderness, consider hospitalization.
Male sex partners of women with PID should be examined and treated if they have had sexual contact with the patient during the 60 days preceding the onset of symptoms in the patient.
In/Out Patient Meds:
See Medical Care.
Deterrence/Prevention:
Randomized controlled trials suggest that preventing chlamydial infection reduces the incidence of PID. Other methods of preventing PID and STD include reducing the number of sexual partners, avoiding unsafe sexual practices, and using condoms with spermicide. Use of mechanical barriers with spermicide also decreases the risk of acquiring STDs.
Notification of the female sex partners of men infected with Chlamydia trachomatis is recommended.
Complications:
Tuboovarian abscess is one of the major complications of acute PID, and it occurs in up to 15-30% of women requiring hospitalization for treatment of PID.
Prognosis:
Therapy using antibiotics alone is successful in 33-75% of cases. If surgical therapy is warranted, the current trend in therapy is conservation of reproductive potential with simple drainage, adhesiolysis, and copious irrigation or unilateral adnexectomy, if possible. Further surgical therapy is needed in 15-20% of cases so managed.
Chronic pelvic pain occurs in approximately 25% of patients with a history of PID. This pain is thought to be related to cyclic menstrual changes, but it also may be the result of adhesions or hydrosalpinx.
Impaired fertility is a major concern in women with a history of PID. The rate of infertility increases with the number of episodes of infection.
The risk of ectopic pregnancy is increased in women with a history of PID. Ectopic pregnancy is a direct result of damage to the fallopian tube.
Patient Education:
Asking women about high-risk sexual behavior is important.
Encourage screening tests for those at risk.
Ensure that male sex partners are evaluated and treated.
Counsel women about safe sex practices.
MISCELLANEOUS
Medical/Legal Pitfalls:
A frequent cause of litigation is failure to diagnose. The physician should always clearly document the patient's symptoms, as well as the physical examination and results of laboratory and radiological studies. Documenting the diagnosis, treatment plan, and disposition of the case is equally important. If the patient is referred to other services for consultation, a copy of the consulting physician's note should be attached to the medical record.
Special Concerns:
Women with HIV infection who have PID have similar symptoms when compared to women who do not have HIV. However, women with HIV infection are more likely to have tuboovarian abscess.
See Medical Care for treatment regimens.
Drug Category: Antibiotics -- Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.
Drug Name
Cefoxitin (Mefoxin) -- Second-generation cephalosporin indicated for infections with gram-positive cocci and gram-negative rods. Infections caused by cephalosporin- or penicillin-resistant gram-negative bacteria may respond to cefoxitin.
Adult Dose
2 g IV q6h
Pediatric Dose
80-160 mg/kg/d IV divided q4-6h; higher doses for severe or serious infections; not to exceed 12 g/d
Contraindications
Documented hypersensitivity
Interactions
Probenecid may increase effects; coadministration with aminoglycosides or furosemide may increase nephrotoxicity (closely monitor renal function)
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Bacterial or fungal overgrowth of nonsusceptible organisms may occur with prolonged use or repeated treatment; caution in patients with previously diagnosed colitis
Drug Name
Cefotetan (Cefotan) -- Second-generation cephalosporin indicated for infections caused by susceptible gram-positive cocci and gram-negative rods. Dose and route of administration depend on condition of patient, severity of infection, and susceptibility of causative organism.
Adult Dose
2 g IV q12h
Pediatric Dose
20-40 mg/kg per dose IV/IM q12h for 5-10 d
Contraindications
Documented hypersensitivity
Interactions
Consumption of alcohol within 72 h may produce disulfiramlike reactions; may increase hypoprothrombinemic effects of anticoagulants; coadministration with potent diuretics (eg, loop diuretics) or aminoglycosides may increase nephrotoxicity
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Reduce dosage by one half if CrCl is 10-30 mL/min and by one fourth if CrCl <10 mL/min; bacterial or fungal overgrowth of nonsusceptible organisms may occur with prolonged or repeated therapy
Drug Name
Doxycycline (Vibramycin) -- Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Adult Dose
100 mg PO/IV q12h
Pediatric Dose
<8>8 years: 2-5 mg/kg/d qd or divided bid; not to exceed 200 mg/d
Contraindications
Documented hypersensitivity; severe hepatic dysfunction
Interactions
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy
D - Unsafe in pregnancy
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning facilities; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (<8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
Drug Name
Clindamycin (Cleocin) -- Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose
900 mg IV q8h; if administered with ofloxacin, 450 mg PO qid for 14 d
Pediatric Dose
8-20 mg/kg/d PO as hydrochloride and 8-25 mg/kg/d as palmitate tid/qid20-40 mg/kg/d IV/IM tid/qid
Contraindications
Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Interactions
Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile
Drug Name
Metronidazole (Flagyl) -- Imidazole ring–based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except for C difficile enterocolitis).
Adult Dose
Loading: 15 mg/kg, or 1 g for 70-kg adult, IV over 1 hMaintenance: 6 h following loading dose, infuse 7.5 mg/kg, or 500 mg for 70-kg adult, over 1 h q6-8h; not to exceed 4 g/dIf administered with ofloxacin PO: 500 mg PO bid for 14 d
Pediatric Dose
Administer as in adults
Contraindications
Documented hypersensitivity
Interactions
May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity; disulfiramlike reaction may occur with PO ethanol
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy
Drug Name
Meropenem (Merrem) -- Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell wall synthesis. Effective against most gram-positive and gram-negative bacteria.
Adult Dose
1 g IV q8h
Pediatric Dose
40 mg/kg IV q8h
Contraindications
Documented hypersensitivity
Interactions
Probenecid may inhibit renal excretion of meropenem, increasing meropenem levels
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication
Drug Name
Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum gram-negative activity. Lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins.
Adult Dose
250 mg IM once
Pediatric Dose
50-75 mg/kg/d IV/IM q12h; not to exceed 2 g/d
Contraindications
Documented hypersensitivity
Interactions
Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, or aminoglycosides may increase nephrotoxicity
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Adjust dose in renal impairment; caution in breastfeeding women and in people with allergy to penicillin
Drug Name
Ofloxacin (Floxin) -- Penetrates prostate well and is effective against N gonorrhea and C trachomatis.A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.
Adult Dose
400 mg PO q12h for 14 d
Pediatric Dose
<18>18 years: Administer as in adults
Contraindications
Documented hypersensitivity
Interactions
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal impairment; superinfections may occur with prolonged or repeated antibiotic therapy
Drug Name
Gentamicin (Gentacidin, Garamycin) -- Aminoglycoside antibiotic for gram-negative coverage. Used in combination with an agent against gram-positive organisms and one that covers anaerobes. Dosing regimens are numerous. Adjust dose based on CrCl and changes in volume of distribution. Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing); may draw a peak level 0.5 h after 30-min infusion.
Adult Dose
Loading: 2 mg/kg IV/IMMaintenance: 1.5 mg/kg IV/IM q8h
Pediatric Dose
<5>5 years: 1.5-2.5 mg/kg per dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d
Contraindications
Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions
Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents; thus, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity; irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment Drug Category: Uricosuric agents -- Reduce clearance of some types of antibiotics, increasing their plasma levels.
Drug Name
Probenecid -- Inhibits tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is administered. Adjuvant to therapy with penicillin, ampicillin, methicillin, oxacillin, cloxacillin, or nafcillin. Two- to 4-fold elevation of penicillin plasma levels demonstrated.
Adult Dose
1 g PO once
Pediatric Dose
<2>2 years: Not established
Contraindications
Documented hypersensitivity; blood dyscrasia; uric acid kidney stones; coadministration of ketorolac
Interactions
Salicylates at high dosages and nitrofurantoin may decrease effects; increases levels/toxicity of methotrexate, beta-lactam antibiotics, acyclovir, thiopental, clofibrate, dyphylline, pantothenic acid, ketorolac, benzodiazepines, rifampin, sulfonamide, dapsone, zidovudine, and sulfonylureas
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Crosses placental barrier; caution in history of peptic ulcer FOLLOW-UP
Further Inpatient Care:
Most patients clinically respond within 48-72 hours after medical therapy. If the patient continues to have fever, chills, uterine tenderness, adnexal tenderness, and cervical motion tenderness, consider other possible causes.
Further Outpatient Care:
Perform a follow-up examination 48-72 hours after prescribing outpatient therapy to ensure clinical improvement. If the patient continues to have fevers, chills, uterine tenderness, adnexal tenderness, and cervical motion tenderness, consider hospitalization.
Male sex partners of women with PID should be examined and treated if they have had sexual contact with the patient during the 60 days preceding the onset of symptoms in the patient.
In/Out Patient Meds:
See Medical Care.
Deterrence/Prevention:
Randomized controlled trials suggest that preventing chlamydial infection reduces the incidence of PID. Other methods of preventing PID and STD include reducing the number of sexual partners, avoiding unsafe sexual practices, and using condoms with spermicide. Use of mechanical barriers with spermicide also decreases the risk of acquiring STDs.
Notification of the female sex partners of men infected with Chlamydia trachomatis is recommended.
Complications:
Tuboovarian abscess is one of the major complications of acute PID, and it occurs in up to 15-30% of women requiring hospitalization for treatment of PID.
Prognosis:
Therapy using antibiotics alone is successful in 33-75% of cases. If surgical therapy is warranted, the current trend in therapy is conservation of reproductive potential with simple drainage, adhesiolysis, and copious irrigation or unilateral adnexectomy, if possible. Further surgical therapy is needed in 15-20% of cases so managed.
Chronic pelvic pain occurs in approximately 25% of patients with a history of PID. This pain is thought to be related to cyclic menstrual changes, but it also may be the result of adhesions or hydrosalpinx.
Impaired fertility is a major concern in women with a history of PID. The rate of infertility increases with the number of episodes of infection.
The risk of ectopic pregnancy is increased in women with a history of PID. Ectopic pregnancy is a direct result of damage to the fallopian tube.
Patient Education:
Asking women about high-risk sexual behavior is important.
Encourage screening tests for those at risk.
Ensure that male sex partners are evaluated and treated.
Counsel women about safe sex practices.
MISCELLANEOUS
Medical/Legal Pitfalls:
A frequent cause of litigation is failure to diagnose. The physician should always clearly document the patient's symptoms, as well as the physical examination and results of laboratory and radiological studies. Documenting the diagnosis, treatment plan, and disposition of the case is equally important. If the patient is referred to other services for consultation, a copy of the consulting physician's note should be attached to the medical record.
Special Concerns:
Women with HIV infection who have PID have similar symptoms when compared to women who do not have HIV. However, women with HIV infection are more likely to have tuboovarian abscess.
Pelvic Inflammatory Disease 1
Pelvic Inflammatory Disease
INTRODUCTION
Background: Pelvic inflammatory disease (PID) is an inflammatory disorder of the uterus, fallopian tubes, and adjacent pelvic structures. Risk factors for PID include young age at first intercourse, multiple sexual partners, intrauterine device (IUD) insertion, and tobacco smoking. A delay in diagnosis or treatment can result in long-term sequelae such as tubal infertility.
Pathophysiology: In PID, the upper female genital tract is infected by direct spread of microorganisms ascending from the vagina and cervix. The cervix produces mucus that usually protects against upward spread, but bacteria may penetrate the cervical mucus and cause widespread extension of infection.
Frequency:
In the US: PID affects 11% of women of reproductive age. Approximately 1 million women experience an episode of PID per year, and 20% of these women require hospitalization for treatment. The disease produces 2.5 million office visits and 125,000-150,000 hospitalizations yearly.
Internationally: Public health efforts implemented in Scandinavia to decrease incidence of sexually transmitted disease (STD) have been quite effective.
Mortality/Morbidity: A delay in diagnosis or treatment can result in long-term reproductive sequelae, such as tubal infertility. Each repeat episode of PID doubles the risk for tubal factor infertility. Women with a history of PID have a 7- to 10-fold increased risk for ectopic pregnancy (tubal pregnancy) compared with women with no history of PID. Chronic pelvic pain can also follow PID and occurs in 25-75% of women.
Sex: PID is an infection of the female genital tract.
Age: PID may occur more frequently in adolescents (ie, 15-19 y), but it can occur in any patients who are sexually active. Age distributions vary with geographical location and etiology. Young age at first intercourse increases risk for PID.
CLINICAL
History: Patients can present with a variety of symptoms, ranging from lower abdominal pain to dysuria. A direct correlation exists between the incidence of STDs and PID in any given population.
Pain is present in more than 90% of documented cases and is by far the most common presenting symptom.
Usually, pain is described as dull, aching, and constant; it begins a few days after the onset of the last menstrual period and tends to be accentuated by motion, exercise, or coitus.
Pain from PID usually lasts less than 7 days; if pain lasts longer than 3 weeks, the likelihood that PID is the correct diagnosis declines substantially.
Abnormal vaginal discharge is present in approximately 75% of cases.
Unanticipated vaginal bleeding coexists in about 40% of cases.
Temperature higher than 38°C (30%), nausea, and vomiting manifest late in the clinical course of the disease.
Physical: The sensitivity of the pelvic examination is only 60%. The Centers for Disease Control and Prevention (CDC) recommends the following minimal clinical criteria for the diagnosis of PID: lower abdominal tenderness, adnexal tenderness, and cervical motion tenderness.
In addition to the preceding criteria, at least 1 of the following findings also should be present:
Meets the case surveillance definition of chlamydial or gonorrheal infection
Temperature higher than 100.4°F or 38°C
Leukocytosis greater than 10,000 WBC/mm3
Purulent material in the peritoneal cavity obtained by culdocentesis or laparoscopy
Pelvic abscess or inflammatory complex detected by bimanual examination or by sonography
Patient is a sexual contact of a person known to have gonorrhea, Chlamydia infection, or nongonococcal urethritis
Causes: The classic high-risk patient is a menstruating woman younger than 25 years who has multiple sex partners, does not use contraception, and lives in an area with a high prevalence of STD. PID is also more prevalent among unmarried women and individuals who are young at first intercourse. The IUD confers a relative risk of 2.0-3.0 for the first 4 months following insertion, but then it decreases to baseline thereafter. Women who are not sexually active have a very low incidence of upper genital tract infection, as do women who have undergone tubal sterilization.
Chlamydia trachomatis: C trachomatis, an intracellular bacterial pathogen, is the predominant STD organism causing PID. Clinically, infection with this obligate intracellular parasite may manifest as mucopurulent cervicitis.
Cytomegalovirus (CMV): CMV has been found in the upper genital tracts of women with PID, suggesting a potential role of CMV in PID.
Endogenous microflora: In iatrogenically induced infections, the endogenous microflora of the vagina predominate.
Gardnerella vaginalis
Haemophilus influenzae
Enteric gram-negative organisms (Escherichia coli)
Peptococcus species
Streptococcus agalactiae
Bacteroides fragilis: This can cause tubal and epithelial destruction.
Pregnancy: PID is rare in pregnancy.
Neisseria gonorrhea: In the United States, the role of N gonorrhea as the primary cause of PID has decreased. DIFFERENTIALS
Adnexal Tumors Appendicitis Ectopic Pregnancy Endometriosis
Other Problems to be Considered:
Rupture of an adnexal massAdnexal torsionPerihepatic inflammation (Fitz-Hugh and Curtis syndrome)
WORKUP
Lab Studies:
Additional criteria may be used to increase the specificity of the diagnosis as listed below.
Vaginal wet mount - Increased amount of white cells
Erythrocyte sedimentation rate (ESR) - Elevated, nonspecific
C-reactive protein (CRP) - Elevated, nonspecific
CBC count - Elevated white blood cell count
Gonorrhea cultures - Generally used to confirm diagnosis (frequently negative in later stages)
Chlamydial cultures - Generally used to confirm diagnosis (large variability in recovery from cervix [5-56%])
Imaging Studies:
Transvaginal sonography may not be useful in the diagnosis of PID. It has poor sensitivity (81%) and specificity (78%) with mild or atypical PID. It can be used to document an adnexal mass or demonstrate fluid-filled fallopian tubes.
Although the specificity (95%) and sensitivity (95%) of MRI is relatively high, it is costly and rarely indicated in acute PID. If used in the management of PID, MRI can demonstrate thickened fluid-filled tubes with or without free pelvic fluid or tuboovarian complex.
Procedures:
Culdocentesis: With the advent of transvaginal sonography, culdocentesis rarely is performed. In the absence of current technology, insertion of an 18-gauge spinal needle attached to a syringe can be performed. The needle is inserted transvaginally into the cul-de-sac, yielding either purulent fluid or bloody fluid from the peritoneum. TREATMENT
Medical Care:
Most patients are now managed as outpatients, but physicians should consider hospitalization for patients with the following conditions, although no clear data suggest that these patients benefit from hospitalization:
Uncertain diagnosis
Pelvic abscess on ultrasound
Pregnancy
Failure to respond to outpatient management
Inability to tolerate outpatient PO regimen
Severe illness or nausea and vomiting precluding outpatient treatment
Immunodeficiency (eg, HIV with low CD4 count, using immunosuppressive medications)
Failure to improve clinically after 72 hours with outpatient therapy
Inpatient treatment includes the following:
Regimen A: Administer cefoxitin IV or cefotetan IV plus doxycycline PO/IV every 12 hours. Continue this regimen for 48 hours after the patient remains clinically improved, then start doxycycline PO twice daily for a total of 14 days. Administer doxycycline PO when possible because of pain associated with infusion. Bioavailability is similar with PO and IV administrations. IV antibiotics may be discontinued 24 hours after the patient improves clinically, and PO therapy with doxycycline is continued for a total of 14 days. If tuboovarian abscess is present, use clindamycin or metronidazole with doxycycline for more effective anaerobic coverage.
Regimen B: Administer clindamycin IV every 8 hours plus a loading dose of gentamicin IV or IM, followed by a maintenance dose every 8 hours. IV therapy may be discontinued 24 hours after the patient improves clinically, and PO therapy of doxycycline should be continued for a total of 14 days of therapy.
Outpatient treatment
Regimen A: Cefoxitin plus probenecid should be taken PO in a single dose. Alternatively, ceftriaxone (less active against anaerobic bacteria compared to cefoxitin) can be taken once IM with doxycycline PO twice daily for 14 days. Cefoxitin has better anaerobic coverage, and ceftriaxone has better coverage against N gonorrhea.
Regimen B: Ofloxacin should be taken PO for 14 days with either clindamycin or metronidazole, which also are taken PO for 14 days. PO ofloxacin lacks anaerobic coverage but is effective against N gonorrhea and C trachomatis.
Surgical Care: The advantage of laparoscopy is that it allows direct visualization of the pelvis and provides a more accurate and bacteriologic diagnosis if cultures are obtained. However, laparoscopy is not always available in acute PID. In addition, this procedure is costly and requires general anesthesia. It should be used if the diagnosis is in doubt. However, if operative laparoscopy is used early in the course of the disease, copious irrigation and separation of thin adhesions by blunt dissection may prevent later sequelae.
Consultations:
Obstetrician
Gynecologist
Diet: Patients should take nothing by mouth (NPO) if the diagnosis is uncertain or if the patient is scheduled for surgery.
INTRODUCTION
Background: Pelvic inflammatory disease (PID) is an inflammatory disorder of the uterus, fallopian tubes, and adjacent pelvic structures. Risk factors for PID include young age at first intercourse, multiple sexual partners, intrauterine device (IUD) insertion, and tobacco smoking. A delay in diagnosis or treatment can result in long-term sequelae such as tubal infertility.
Pathophysiology: In PID, the upper female genital tract is infected by direct spread of microorganisms ascending from the vagina and cervix. The cervix produces mucus that usually protects against upward spread, but bacteria may penetrate the cervical mucus and cause widespread extension of infection.
Frequency:
In the US: PID affects 11% of women of reproductive age. Approximately 1 million women experience an episode of PID per year, and 20% of these women require hospitalization for treatment. The disease produces 2.5 million office visits and 125,000-150,000 hospitalizations yearly.
Internationally: Public health efforts implemented in Scandinavia to decrease incidence of sexually transmitted disease (STD) have been quite effective.
Mortality/Morbidity: A delay in diagnosis or treatment can result in long-term reproductive sequelae, such as tubal infertility. Each repeat episode of PID doubles the risk for tubal factor infertility. Women with a history of PID have a 7- to 10-fold increased risk for ectopic pregnancy (tubal pregnancy) compared with women with no history of PID. Chronic pelvic pain can also follow PID and occurs in 25-75% of women.
Sex: PID is an infection of the female genital tract.
Age: PID may occur more frequently in adolescents (ie, 15-19 y), but it can occur in any patients who are sexually active. Age distributions vary with geographical location and etiology. Young age at first intercourse increases risk for PID.
CLINICAL
History: Patients can present with a variety of symptoms, ranging from lower abdominal pain to dysuria. A direct correlation exists between the incidence of STDs and PID in any given population.
Pain is present in more than 90% of documented cases and is by far the most common presenting symptom.
Usually, pain is described as dull, aching, and constant; it begins a few days after the onset of the last menstrual period and tends to be accentuated by motion, exercise, or coitus.
Pain from PID usually lasts less than 7 days; if pain lasts longer than 3 weeks, the likelihood that PID is the correct diagnosis declines substantially.
Abnormal vaginal discharge is present in approximately 75% of cases.
Unanticipated vaginal bleeding coexists in about 40% of cases.
Temperature higher than 38°C (30%), nausea, and vomiting manifest late in the clinical course of the disease.
Physical: The sensitivity of the pelvic examination is only 60%. The Centers for Disease Control and Prevention (CDC) recommends the following minimal clinical criteria for the diagnosis of PID: lower abdominal tenderness, adnexal tenderness, and cervical motion tenderness.
In addition to the preceding criteria, at least 1 of the following findings also should be present:
Meets the case surveillance definition of chlamydial or gonorrheal infection
Temperature higher than 100.4°F or 38°C
Leukocytosis greater than 10,000 WBC/mm3
Purulent material in the peritoneal cavity obtained by culdocentesis or laparoscopy
Pelvic abscess or inflammatory complex detected by bimanual examination or by sonography
Patient is a sexual contact of a person known to have gonorrhea, Chlamydia infection, or nongonococcal urethritis
Causes: The classic high-risk patient is a menstruating woman younger than 25 years who has multiple sex partners, does not use contraception, and lives in an area with a high prevalence of STD. PID is also more prevalent among unmarried women and individuals who are young at first intercourse. The IUD confers a relative risk of 2.0-3.0 for the first 4 months following insertion, but then it decreases to baseline thereafter. Women who are not sexually active have a very low incidence of upper genital tract infection, as do women who have undergone tubal sterilization.
Chlamydia trachomatis: C trachomatis, an intracellular bacterial pathogen, is the predominant STD organism causing PID. Clinically, infection with this obligate intracellular parasite may manifest as mucopurulent cervicitis.
Cytomegalovirus (CMV): CMV has been found in the upper genital tracts of women with PID, suggesting a potential role of CMV in PID.
Endogenous microflora: In iatrogenically induced infections, the endogenous microflora of the vagina predominate.
Gardnerella vaginalis
Haemophilus influenzae
Enteric gram-negative organisms (Escherichia coli)
Peptococcus species
Streptococcus agalactiae
Bacteroides fragilis: This can cause tubal and epithelial destruction.
Pregnancy: PID is rare in pregnancy.
Neisseria gonorrhea: In the United States, the role of N gonorrhea as the primary cause of PID has decreased. DIFFERENTIALS
Adnexal Tumors Appendicitis Ectopic Pregnancy Endometriosis
Other Problems to be Considered:
Rupture of an adnexal massAdnexal torsionPerihepatic inflammation (Fitz-Hugh and Curtis syndrome)
WORKUP
Lab Studies:
Additional criteria may be used to increase the specificity of the diagnosis as listed below.
Vaginal wet mount - Increased amount of white cells
Erythrocyte sedimentation rate (ESR) - Elevated, nonspecific
C-reactive protein (CRP) - Elevated, nonspecific
CBC count - Elevated white blood cell count
Gonorrhea cultures - Generally used to confirm diagnosis (frequently negative in later stages)
Chlamydial cultures - Generally used to confirm diagnosis (large variability in recovery from cervix [5-56%])
Imaging Studies:
Transvaginal sonography may not be useful in the diagnosis of PID. It has poor sensitivity (81%) and specificity (78%) with mild or atypical PID. It can be used to document an adnexal mass or demonstrate fluid-filled fallopian tubes.
Although the specificity (95%) and sensitivity (95%) of MRI is relatively high, it is costly and rarely indicated in acute PID. If used in the management of PID, MRI can demonstrate thickened fluid-filled tubes with or without free pelvic fluid or tuboovarian complex.
Procedures:
Culdocentesis: With the advent of transvaginal sonography, culdocentesis rarely is performed. In the absence of current technology, insertion of an 18-gauge spinal needle attached to a syringe can be performed. The needle is inserted transvaginally into the cul-de-sac, yielding either purulent fluid or bloody fluid from the peritoneum. TREATMENT
Medical Care:
Most patients are now managed as outpatients, but physicians should consider hospitalization for patients with the following conditions, although no clear data suggest that these patients benefit from hospitalization:
Uncertain diagnosis
Pelvic abscess on ultrasound
Pregnancy
Failure to respond to outpatient management
Inability to tolerate outpatient PO regimen
Severe illness or nausea and vomiting precluding outpatient treatment
Immunodeficiency (eg, HIV with low CD4 count, using immunosuppressive medications)
Failure to improve clinically after 72 hours with outpatient therapy
Inpatient treatment includes the following:
Regimen A: Administer cefoxitin IV or cefotetan IV plus doxycycline PO/IV every 12 hours. Continue this regimen for 48 hours after the patient remains clinically improved, then start doxycycline PO twice daily for a total of 14 days. Administer doxycycline PO when possible because of pain associated with infusion. Bioavailability is similar with PO and IV administrations. IV antibiotics may be discontinued 24 hours after the patient improves clinically, and PO therapy with doxycycline is continued for a total of 14 days. If tuboovarian abscess is present, use clindamycin or metronidazole with doxycycline for more effective anaerobic coverage.
Regimen B: Administer clindamycin IV every 8 hours plus a loading dose of gentamicin IV or IM, followed by a maintenance dose every 8 hours. IV therapy may be discontinued 24 hours after the patient improves clinically, and PO therapy of doxycycline should be continued for a total of 14 days of therapy.
Outpatient treatment
Regimen A: Cefoxitin plus probenecid should be taken PO in a single dose. Alternatively, ceftriaxone (less active against anaerobic bacteria compared to cefoxitin) can be taken once IM with doxycycline PO twice daily for 14 days. Cefoxitin has better anaerobic coverage, and ceftriaxone has better coverage against N gonorrhea.
Regimen B: Ofloxacin should be taken PO for 14 days with either clindamycin or metronidazole, which also are taken PO for 14 days. PO ofloxacin lacks anaerobic coverage but is effective against N gonorrhea and C trachomatis.
Surgical Care: The advantage of laparoscopy is that it allows direct visualization of the pelvis and provides a more accurate and bacteriologic diagnosis if cultures are obtained. However, laparoscopy is not always available in acute PID. In addition, this procedure is costly and requires general anesthesia. It should be used if the diagnosis is in doubt. However, if operative laparoscopy is used early in the course of the disease, copious irrigation and separation of thin adhesions by blunt dissection may prevent later sequelae.
Consultations:
Obstetrician
Gynecologist
Diet: Patients should take nothing by mouth (NPO) if the diagnosis is uncertain or if the patient is scheduled for surgery.
Menorrhagia 2
INTRODUCTION
Background: Menorrhagia is menstruation at regular cycle intervals but with excessive flow and duration. It is defined clinically as total blood loss exceeding 80 mL per cycle or menses lasting longer than 7 days. Menorrhagia is one of the most common gynecologic complaints in contemporary gynecology. Current gynecological surveys report that 30% of all premenopausal women perceive their menses to be excessive. The World Health Organization recently reported that 18 million women aged 30-55 years perceive their menstrual bleeding to be exorbitant. Reports show that only 10% of these women experience blood loss severe enough to be defined clinically as menorrhagia.
A normal menstrual cycle is 21-35 days in duration, bleeding lasting an average of 7 days, and flow between 25 and 80 mL.
Menorrhagia must be distinguished clinically from other common gynecologic diagnoses. These include metrorrhagia (flow at irregular intervals), menometrorrhagia (frequent, excessive flow), polymenorrhea (bleeding at intervals <21 d), and dysfunctional uterine bleeding (abnormal uterine bleeding without any obvious structural or systemic abnormality).
Nearly 30% of all hysterectomies performed in the United States are performed to alleviate heavy menstrual bleeding. Definitive surgical correction has been the mainstay of treatment for menorrhagia. Modern gynecology dictates the trend toward conservative therapy for cost containment and because many women desire to preserve their uteruses. Alternatives to hysterectomy also are the result of statistics revealing that nearly 50% of uterine pathology findings from hysterectomies for menorrhagia are free of disease and histopathologic abnormalities.
Heavy menstrual bleeding is a subjective finding, making the exact problem definition difficult. Treatment regimens must address the specific facet of the menstrual cycle the patient perceives to be abnormal, (ie, cycle length, quantity of bleeding). Finally, treatment success usually is evaluated subjectively by each patient, making positive outcome measurement difficult.
Pathophysiology: Knowledge of normal menstrual function is imperative in understanding the etiologies of menorrhagia. Four phases constitute the menstrual cycle, follicular, luteal, implantation, and menstrual.
In response to gonadotropin-releasing hormone (GnRH) from the hypothalamus, the pituitary gland synthesizes follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which induce the ovaries to produce estrogen and progesterone.
During the follicular phase, estrogen stimulation results in an increase in endometrial thickness. This also is known as the proliferative phase.
The luteal phase is intricately involved in the process of ovulation. During this phase, also known as the secretory phase, progesterone causes endometrial maturation.
If fertilization occurs, the implantation phase is maintained. Without fertilization, estrogen and progesterone withdrawal results in menstruation.
Etiologic causes are numerous and often unknown. Factors contributing to menorrhagia can be sorted into several categories, including organic, endocrinologic, anatomic, and iatrogenic.
If the bleeding workup does not provide any clues to the etiology of the menorrhagia, a patient often is given the diagnosis of dysfunctional uterine bleeding (DUB). Most cases of DUB are secondary to anovulation. Without ovulation, the corpus luteum fails to form, resulting in no progesterone secretion. Unopposed estrogen allows the endometrium to proliferate and thicken. The endometrium finally outgrows its blood supply and degenerates. The end result is asynchronous breakdown of the endometrial lining at different levels. This also is why anovulatory bleeding is heavier than normal menstrual flow.
Hemostasis of the endometrium is directly related to the functions of platelets and fibrin. Deficiencies in either of these components results in menorrhagia for patients with von Willebrand disease or thrombocytopenia. Thrombi are seen in the functional layers but are limited to the shedding surface of the tissue. These thrombi are known as "plugs" because blood can only partially flow past them. Fibrinolysis limits the fibrin deposits in the unshed layer. Following thrombin plug formation, vasoconstriction occurs and contributes to hemostasis.
Anatomic defects or growths within the uterus can alter either of the aforementioned pathways (endocrinologic/hemostatic), causing significant uterine bleeding. The clinical presentation is dependent on the location and size of the gynecologic lesion.
Organic diseases also contribute to menorrhagia in the female patient. For example, in patients with renal failure, gonadal resistance to hormones and hypothalamic-pituitary axis disturbances result in menstrual irregularities. Most women in this renal state are amenorrheic, but others also develop menorrhagia. If uremic coagulopathy ensues, it usually is due to platelet dysfunction and abnormal factor VIII function. The resulting prolonged bleeding time causes menorrhagia that can be very tenuous to treat.
Due to the overwhelming factors that can contribute to the dysfunction of either the endocrine or hematological pathways, in-depth knowledge of an existing organic disease is just as imperative as understanding the menstrual cycle itself.
Frequency:
In the US: While menorrhagia remains a leading reason for gynecologic office visits, only 10-20% of all menstruating women experience blood loss severe enough to be defined clinically as menorrhagia.
Mortality/Morbidity: Infrequent episodes of menorrhagia usually do not carry severe risks to women’s general health.
Patients who lose more than 80 mL of blood, especially repetitively, are at risk for serious medical sequelae. These women are likely to develop iron-deficiency anemia as a result of their blood loss. Menorrhagia is the most common cause of anemia in premenopausal women. This usually can be remedied by simple ingestion of ferrous sulfate to replace iron stores. If the bleeding is severe enough to cause volume depletion, patients may experience shortness of breath, fatigue, palpitations, and other related symptoms. This level of anemia necessitates hospitalization for intravenous fluids and possible transfusion and/or intravenous estrogen therapy. Patients who do not respond to medical therapy may require surgical intervention to control the menorrhagia.
Other sequelae associated with menorrhagia usually are related to the etiology. For example, with hypothyroidism, patients may experience symptoms associated with a low-functioning thyroid (eg, cold intolerance, hair loss, dry skin, weight gain) in addition to the effects of significant blood loss.
Sex: Only females are affected by menorrhagia.
Age: Any woman of reproductive age who is menstruating may develop menorrhagia. Most patients with menorrhagia are older than 30 years. This is because the most common cause of heavy menses in the younger population is anovulatory cycles, in which bleeding does not occur at regular intervals.
CLINICAL
History: Symptoms related by a patient with menorrhagia often can be more revealing than laboratory tests. Considering the lengthy list of possible etiologies that contribute to menorrhagia, taking a detailed patient history is imperative. Inquiries should include the following:
Exclusion of pregnancy
This is the most common cause of irregular bleeding in women of reproductive age.
Pregnancy should be the first diagnosis to be excluded before further testing or medications are instituted.
Quantity and quality of bleeding
Quantity is a very subjective issue when considering vaginal bleeding. Best estimates usually are the only source clinicians have available to consider. Helpful references for totaling blood loss may include that the average tampon holds 5 mL and the average pad holds 5-15 mL of blood. Asking the patient what type of pad (liner vs overnight) was used and if it was soaked may add some insight into what the patient believes to be heavy bleeding.
Quality of bleeding involves the presence of clots and their size.
Age
Young patients, from menarche to the late-teen years, most commonly have anovulatory bleeding due to the immaturity of their hypothalamic-pituitary axis. If bleeding does not respond to usual therapy in this age group, a bleeding disorder must be considered.
Women aged 30-50 years may have organic or structural abnormalities. Fibroids or polyps are frequent anatomical findings. Organic causes can be anything from thyroid dysfunction to renal failure.
Postmenopausal women with any uterine bleeding should receive an immediate workup for endometrial cancer.
Endometrial hyperplasia must be considered in women who are obese, aged 70 or older, nulliparous, or have diabetes.
Pelvic pain and pathology
Knowing if a patient has any long-standing diagnosis or known pathology (eg, fibroids) is helpful.
Records from other physicians or hospitalizations may prevent redundancy in ordering lab work or diagnostic imaging.
Menses pattern from menarche
If a young patient has had irregular menses since menarche, the most common etiology of her bleeding is anovulation.
Anovulatory bleeding is most common in young girls (aged 12-18 y) and common in obese females of any reproductive age.
If a patient's bleeding normally occurs at regular intervals and the irregularity is new in onset, pathology must be ruled out, regardless of age.
Sexual activity
Simple vaginitis (eg, candidal, bacterial vaginosis) may cause intermenstrual bleeding, while gonorrhea and chlamydia may present with heavier bleeding attributed primarily to the copious discharge mixed with the blood.
Chlamydia is a common cause of postpartum endometritis, leading to vaginal bleeding in the weeks following a delivery.
A postpartum infection (eg, endometritis) also may be due to organisms unrelated to sexual activity.
Contraceptive use (intrauterine device or hormones)
Commonly, an intrauterine device (IUD) causes increased uterine cramping and menstrual flow.
If a patient has recently discontinued birth control pills, she may return to her "natural" menses and report an increase in flow. This actually is normal because most oral birth control pills decrease the flow and duration of a woman's menses.
Presence of hirsutism (polycystic ovarian syndrome)
These patients commonly are obese and in an anovulatory state. When they do have a period, it may be very heavy and cause concern for the patient.
The etiology of this is explained in the Introduction to this article.
Galactorrhea (pituitary tumor): Any patient complaining of a milky discharge from either breast (while not pregnant, postpartum, or breastfeeding) needs a prolactin level to rule out a pituitary tumor.
Systemic illnesses (hepatic/renal failure or diabetes)
As explained in the Introduction, organic diseases may affect either the hormonal or hematologic pathways that are involved in the manifestation of menorrhagia.
If either the hypothalamic-pituitary axis or the coagulation paths are disrupted, heavy bleeding may result.
Symptoms of thyroid dysfunction: The alteration of the hypothalamic-pituitary axis may create either amenorrhea (hyperthyroidism) or menorrhagia (hypothyroidism).
Excessive bruising or known bleeding disorders
This is especially important in a young patient who does not stop bleeding during her first menses.
This is a very common presentation for an undiagnosed bleeding disorder (von Willebrand disease) in a young girl.
Current medications (hormones or anticoagulants)
Any medication that prolongs bleeding time may cause menorrhagia.
A patient treated with any progestin therapy may have a withdrawal bleed after cessation of the medication. This bleeding often is heavy and worrisome to patients if they are not forewarned.
Previous medical or surgical procedures/diagnoses: This also is helpful in preventing duplication of testing.
Physical: The physical examination should be tailored to the differential diagnoses formulated by the results of the patient's history.
Initial inspection should include evaluation for the following:
Signs of severe volume depletion (eg, anemia): This may help confirm the patient's history of very heavy bleeding and/or prompt immediate inpatient care.
Obesity: This is an independent risk factor for endometrial cancer. Adipose tissue is a locale for estrogen conversion. Therefore, the larger the patient, the more increased the risk (and the higher the unopposed estrogen level on the endometrium).
Signs of androgen excess (eg, hirsutism): This usually points to polycystic ovarian syndrome (PCOS), leading to anovulatory bleeding (see Presence of hirsutism).
Ecchymosis: This usually is a sign of trauma or a bleeding disorder.
Purpura: This also is a sign of trauma or a possible bleeding disorder.
Pronounced acne: This is a sign of PCOS.
General examination should include evaluation of the following:
Visual fields
Bleeding gums
Thyroid evaluation
Galactorrhea
Enlarged liver or spleen
Pelvic examination should evaluate for the presence of external genital lesions.
Vaginal/cervical discharge: Look for a copious discharge indicating infection, and confirm the actual site of the bleeding (if present). Assess as follows:
Uterine size, shape, and contour: An enlarged irregularly shaped uterus suggests fibroids if the patient is aged 30-50 years. An enlarged uniformly shaped uterus in a postmenopausal patient with bleeding suggests endometrial cancer until proven otherwise.
Cervical motion tenderness: This is a common symptom of pelvic inflammatory disease (PID) that usually is caused by gonorrhea or chlamydia. This is an important diagnosis to exclude, especially in young nulliparous women, because it can lead to pelvic adhesions and infertility.
Adnexal tenderness or masses: This is especially concerning in patients older than 40 years. Ovarian cancer may present with intermenstrual bleeding as its only symptom. Rare but deadly ovarian tumors also can present in teenage girls. Any suspicion of an adnexal mass should prompt an immediate pelvic ultrasound.
Causes: Etiologies of menorrhagia are divided into 4 categories, organic, endocrinologic, anatomic, and iatrogenic.
Organic causes of menorrhagia include infection, bleeding disorders, and organ dysfunction.
Infections can be of any genitourinary origin. The aforementioned sexually transmitted diseases are of greater concern in the teenage and early adult population. Bleeding from the urethra or rectum always must be considered in the workup, especially in the postmenopausal woman who has negative findings after a workup for vaginal bleeding.
Coagulation disorders can evade diagnosis until menarche, when heavy menstrual bleeding presents as an unrelenting disorder. These include von Willebrand disease; factor II, V, VII, and IX deficiencies; prothrombin deficiency; idiopathic thrombocytopenia purpura (ITP); and thromboasthenia.
Organ dysfunction causing menorrhagia includes hepatic or renal failure. Chronic liver disease impairs production of clotting factors and reduces hormone metabolism (eg, estrogen). Either of these problems may lead to heavy uterine bleeding.
Endocrine causes of menorrhagia include thyroid and adrenal gland dysfunction, pituitary tumors, anovulatory cycles, PCOS, obesity, and vasculature imbalance.
Both hypothyroidism and hyperthyroidism result in menorrhagia. Even subclinical cases of hypothyroidism produce heavy uterine bleeding in 20% of patients. Menorrhagia usually resolves with correction of the thyroid disorder.
Prolactin-producing pituitary tumors cause menorrhagia by disrupting (GnRH) secretion. This leads to decreased LH and FSH levels, which ultimately cause hypogonadism. Interim stages of menorrhagia result until hypogonadism manifests.
The most common etiology of heavy uterine bleeding is anovulatory cycles. The finding of menorrhagia at irregular intervals without any known organic etiology confirms the clinical diagnosis. This is most common in adolescent and perimenopausal populations.
The hallmarks of PCOS are anovulation, irregular menses, obesity, and hirsutism. Insulin resistance is common and increases androgen production by the ovaries.
Hyperinsulinemia is a direct consequence of obesity. This overproduction of insulin leads to ovarian production of androgens, as occurs in PCOS.
Vasculature imbalance is theorized to be the result of a discrepancy between the vasoconstricting and aggregating actions of prostaglandin F2 (alpha) and thromboxane A2 and the vasodilating actions of prostaglandin E2 and prostacyclin on the myometrial and endometrial vasculature.
Anatomic etiologies for menorrhagia include uterine fibroids, endometrial polyps, endometrial hyperplasia, and pregnancy.
Fibroids and polyps are benign structures that distort the uterine wall and/or endometrium. Either may be located within the uterine lining, but fibroids may occur almost anywhere on the uterus.
The mechanism by which endometrial polyps or fibroids cause menorrhagia is not well understood. The blood supply to the fibroid or polyp is different compared to the surrounding endometrium and is thought to function independently. This blood supply is greater than the endometrial supply and may have impeded venous return, causing pooling in the areas of the fibroid. Heavy pooling is thought to weaken the endometrium in that area, and break-through bleeding ensues.
Fibroids located within the uterine wall may inhibit muscle contracture, thereby preventing normal uterine attempts at hemostasis. This also is why intramural fibroids may cause a significant amount of pain and cramping. Fibroids may enlarge to the point that they outgrow their blood supply and undergo necrosis. This also causes a great deal of pain for patients.
Endometrial hyperplasia usually results from unopposed estrogen production, regardless of the etiology. Endometrial hyperplasia can lead to endometrial cancer in 1-2% of patients with anovulatory bleeding, but it is a diagnosis of exclusion in postmenopausal bleeding (average age at menopause is 51 y). If a woman takes unopposed estrogen (without progesterone), her relative risk of endometrial cancer is 2.3 compared to nonusers and 9.5 if taken for 10 years or longer.
Iatrogenic causes of menorrhagia include IUDs, steroid hormones, chemotherapy agents, and medications (eg, anticoagulants).
IUDs can cause increased menstrual bleeding and cramping due to local irritation effects.
Steroid hormones and chemotherapy agents disrupt the normal menstrual cycle, which is restored easily upon cessation of the products.
Anticoagulants decrease clotting factors needed to cease any normal blood flow, including menses. This type of menorrhagia also is easily reversible. DIFFERENTIALS
Abortion Adnexal Tumors Adrenal Adenoma Adrenal Carcinoma Anovulation Cervicitis Endometrial Carcinoma Endometritis Gestational Trophoblastic Neoplasia Hyperprolactinemia Hyperthyroidism Hypothyroidism Obesity Pelvic Inflammatory Disease Pituitary Microadenomas Pregnancy Diagnosis Uterine Cancer Vaginitis
Other Problems to be Considered:
Coagulation disordersEndometrial polypsGenitourinary infectionIntrauterine deviceLiver disease/failureMedicationsRenal disease/failureSteroid hormonesUterine fibroidsVascular imbalance
Background: Menorrhagia is menstruation at regular cycle intervals but with excessive flow and duration. It is defined clinically as total blood loss exceeding 80 mL per cycle or menses lasting longer than 7 days. Menorrhagia is one of the most common gynecologic complaints in contemporary gynecology. Current gynecological surveys report that 30% of all premenopausal women perceive their menses to be excessive. The World Health Organization recently reported that 18 million women aged 30-55 years perceive their menstrual bleeding to be exorbitant. Reports show that only 10% of these women experience blood loss severe enough to be defined clinically as menorrhagia.
A normal menstrual cycle is 21-35 days in duration, bleeding lasting an average of 7 days, and flow between 25 and 80 mL.
Menorrhagia must be distinguished clinically from other common gynecologic diagnoses. These include metrorrhagia (flow at irregular intervals), menometrorrhagia (frequent, excessive flow), polymenorrhea (bleeding at intervals <21 d), and dysfunctional uterine bleeding (abnormal uterine bleeding without any obvious structural or systemic abnormality).
Nearly 30% of all hysterectomies performed in the United States are performed to alleviate heavy menstrual bleeding. Definitive surgical correction has been the mainstay of treatment for menorrhagia. Modern gynecology dictates the trend toward conservative therapy for cost containment and because many women desire to preserve their uteruses. Alternatives to hysterectomy also are the result of statistics revealing that nearly 50% of uterine pathology findings from hysterectomies for menorrhagia are free of disease and histopathologic abnormalities.
Heavy menstrual bleeding is a subjective finding, making the exact problem definition difficult. Treatment regimens must address the specific facet of the menstrual cycle the patient perceives to be abnormal, (ie, cycle length, quantity of bleeding). Finally, treatment success usually is evaluated subjectively by each patient, making positive outcome measurement difficult.
Pathophysiology: Knowledge of normal menstrual function is imperative in understanding the etiologies of menorrhagia. Four phases constitute the menstrual cycle, follicular, luteal, implantation, and menstrual.
In response to gonadotropin-releasing hormone (GnRH) from the hypothalamus, the pituitary gland synthesizes follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which induce the ovaries to produce estrogen and progesterone.
During the follicular phase, estrogen stimulation results in an increase in endometrial thickness. This also is known as the proliferative phase.
The luteal phase is intricately involved in the process of ovulation. During this phase, also known as the secretory phase, progesterone causes endometrial maturation.
If fertilization occurs, the implantation phase is maintained. Without fertilization, estrogen and progesterone withdrawal results in menstruation.
Etiologic causes are numerous and often unknown. Factors contributing to menorrhagia can be sorted into several categories, including organic, endocrinologic, anatomic, and iatrogenic.
If the bleeding workup does not provide any clues to the etiology of the menorrhagia, a patient often is given the diagnosis of dysfunctional uterine bleeding (DUB). Most cases of DUB are secondary to anovulation. Without ovulation, the corpus luteum fails to form, resulting in no progesterone secretion. Unopposed estrogen allows the endometrium to proliferate and thicken. The endometrium finally outgrows its blood supply and degenerates. The end result is asynchronous breakdown of the endometrial lining at different levels. This also is why anovulatory bleeding is heavier than normal menstrual flow.
Hemostasis of the endometrium is directly related to the functions of platelets and fibrin. Deficiencies in either of these components results in menorrhagia for patients with von Willebrand disease or thrombocytopenia. Thrombi are seen in the functional layers but are limited to the shedding surface of the tissue. These thrombi are known as "plugs" because blood can only partially flow past them. Fibrinolysis limits the fibrin deposits in the unshed layer. Following thrombin plug formation, vasoconstriction occurs and contributes to hemostasis.
Anatomic defects or growths within the uterus can alter either of the aforementioned pathways (endocrinologic/hemostatic), causing significant uterine bleeding. The clinical presentation is dependent on the location and size of the gynecologic lesion.
Organic diseases also contribute to menorrhagia in the female patient. For example, in patients with renal failure, gonadal resistance to hormones and hypothalamic-pituitary axis disturbances result in menstrual irregularities. Most women in this renal state are amenorrheic, but others also develop menorrhagia. If uremic coagulopathy ensues, it usually is due to platelet dysfunction and abnormal factor VIII function. The resulting prolonged bleeding time causes menorrhagia that can be very tenuous to treat.
Due to the overwhelming factors that can contribute to the dysfunction of either the endocrine or hematological pathways, in-depth knowledge of an existing organic disease is just as imperative as understanding the menstrual cycle itself.
Frequency:
In the US: While menorrhagia remains a leading reason for gynecologic office visits, only 10-20% of all menstruating women experience blood loss severe enough to be defined clinically as menorrhagia.
Mortality/Morbidity: Infrequent episodes of menorrhagia usually do not carry severe risks to women’s general health.
Patients who lose more than 80 mL of blood, especially repetitively, are at risk for serious medical sequelae. These women are likely to develop iron-deficiency anemia as a result of their blood loss. Menorrhagia is the most common cause of anemia in premenopausal women. This usually can be remedied by simple ingestion of ferrous sulfate to replace iron stores. If the bleeding is severe enough to cause volume depletion, patients may experience shortness of breath, fatigue, palpitations, and other related symptoms. This level of anemia necessitates hospitalization for intravenous fluids and possible transfusion and/or intravenous estrogen therapy. Patients who do not respond to medical therapy may require surgical intervention to control the menorrhagia.
Other sequelae associated with menorrhagia usually are related to the etiology. For example, with hypothyroidism, patients may experience symptoms associated with a low-functioning thyroid (eg, cold intolerance, hair loss, dry skin, weight gain) in addition to the effects of significant blood loss.
Sex: Only females are affected by menorrhagia.
Age: Any woman of reproductive age who is menstruating may develop menorrhagia. Most patients with menorrhagia are older than 30 years. This is because the most common cause of heavy menses in the younger population is anovulatory cycles, in which bleeding does not occur at regular intervals.
CLINICAL
History: Symptoms related by a patient with menorrhagia often can be more revealing than laboratory tests. Considering the lengthy list of possible etiologies that contribute to menorrhagia, taking a detailed patient history is imperative. Inquiries should include the following:
Exclusion of pregnancy
This is the most common cause of irregular bleeding in women of reproductive age.
Pregnancy should be the first diagnosis to be excluded before further testing or medications are instituted.
Quantity and quality of bleeding
Quantity is a very subjective issue when considering vaginal bleeding. Best estimates usually are the only source clinicians have available to consider. Helpful references for totaling blood loss may include that the average tampon holds 5 mL and the average pad holds 5-15 mL of blood. Asking the patient what type of pad (liner vs overnight) was used and if it was soaked may add some insight into what the patient believes to be heavy bleeding.
Quality of bleeding involves the presence of clots and their size.
Age
Young patients, from menarche to the late-teen years, most commonly have anovulatory bleeding due to the immaturity of their hypothalamic-pituitary axis. If bleeding does not respond to usual therapy in this age group, a bleeding disorder must be considered.
Women aged 30-50 years may have organic or structural abnormalities. Fibroids or polyps are frequent anatomical findings. Organic causes can be anything from thyroid dysfunction to renal failure.
Postmenopausal women with any uterine bleeding should receive an immediate workup for endometrial cancer.
Endometrial hyperplasia must be considered in women who are obese, aged 70 or older, nulliparous, or have diabetes.
Pelvic pain and pathology
Knowing if a patient has any long-standing diagnosis or known pathology (eg, fibroids) is helpful.
Records from other physicians or hospitalizations may prevent redundancy in ordering lab work or diagnostic imaging.
Menses pattern from menarche
If a young patient has had irregular menses since menarche, the most common etiology of her bleeding is anovulation.
Anovulatory bleeding is most common in young girls (aged 12-18 y) and common in obese females of any reproductive age.
If a patient's bleeding normally occurs at regular intervals and the irregularity is new in onset, pathology must be ruled out, regardless of age.
Sexual activity
Simple vaginitis (eg, candidal, bacterial vaginosis) may cause intermenstrual bleeding, while gonorrhea and chlamydia may present with heavier bleeding attributed primarily to the copious discharge mixed with the blood.
Chlamydia is a common cause of postpartum endometritis, leading to vaginal bleeding in the weeks following a delivery.
A postpartum infection (eg, endometritis) also may be due to organisms unrelated to sexual activity.
Contraceptive use (intrauterine device or hormones)
Commonly, an intrauterine device (IUD) causes increased uterine cramping and menstrual flow.
If a patient has recently discontinued birth control pills, she may return to her "natural" menses and report an increase in flow. This actually is normal because most oral birth control pills decrease the flow and duration of a woman's menses.
Presence of hirsutism (polycystic ovarian syndrome)
These patients commonly are obese and in an anovulatory state. When they do have a period, it may be very heavy and cause concern for the patient.
The etiology of this is explained in the Introduction to this article.
Galactorrhea (pituitary tumor): Any patient complaining of a milky discharge from either breast (while not pregnant, postpartum, or breastfeeding) needs a prolactin level to rule out a pituitary tumor.
Systemic illnesses (hepatic/renal failure or diabetes)
As explained in the Introduction, organic diseases may affect either the hormonal or hematologic pathways that are involved in the manifestation of menorrhagia.
If either the hypothalamic-pituitary axis or the coagulation paths are disrupted, heavy bleeding may result.
Symptoms of thyroid dysfunction: The alteration of the hypothalamic-pituitary axis may create either amenorrhea (hyperthyroidism) or menorrhagia (hypothyroidism).
Excessive bruising or known bleeding disorders
This is especially important in a young patient who does not stop bleeding during her first menses.
This is a very common presentation for an undiagnosed bleeding disorder (von Willebrand disease) in a young girl.
Current medications (hormones or anticoagulants)
Any medication that prolongs bleeding time may cause menorrhagia.
A patient treated with any progestin therapy may have a withdrawal bleed after cessation of the medication. This bleeding often is heavy and worrisome to patients if they are not forewarned.
Previous medical or surgical procedures/diagnoses: This also is helpful in preventing duplication of testing.
Physical: The physical examination should be tailored to the differential diagnoses formulated by the results of the patient's history.
Initial inspection should include evaluation for the following:
Signs of severe volume depletion (eg, anemia): This may help confirm the patient's history of very heavy bleeding and/or prompt immediate inpatient care.
Obesity: This is an independent risk factor for endometrial cancer. Adipose tissue is a locale for estrogen conversion. Therefore, the larger the patient, the more increased the risk (and the higher the unopposed estrogen level on the endometrium).
Signs of androgen excess (eg, hirsutism): This usually points to polycystic ovarian syndrome (PCOS), leading to anovulatory bleeding (see Presence of hirsutism).
Ecchymosis: This usually is a sign of trauma or a bleeding disorder.
Purpura: This also is a sign of trauma or a possible bleeding disorder.
Pronounced acne: This is a sign of PCOS.
General examination should include evaluation of the following:
Visual fields
Bleeding gums
Thyroid evaluation
Galactorrhea
Enlarged liver or spleen
Pelvic examination should evaluate for the presence of external genital lesions.
Vaginal/cervical discharge: Look for a copious discharge indicating infection, and confirm the actual site of the bleeding (if present). Assess as follows:
Uterine size, shape, and contour: An enlarged irregularly shaped uterus suggests fibroids if the patient is aged 30-50 years. An enlarged uniformly shaped uterus in a postmenopausal patient with bleeding suggests endometrial cancer until proven otherwise.
Cervical motion tenderness: This is a common symptom of pelvic inflammatory disease (PID) that usually is caused by gonorrhea or chlamydia. This is an important diagnosis to exclude, especially in young nulliparous women, because it can lead to pelvic adhesions and infertility.
Adnexal tenderness or masses: This is especially concerning in patients older than 40 years. Ovarian cancer may present with intermenstrual bleeding as its only symptom. Rare but deadly ovarian tumors also can present in teenage girls. Any suspicion of an adnexal mass should prompt an immediate pelvic ultrasound.
Causes: Etiologies of menorrhagia are divided into 4 categories, organic, endocrinologic, anatomic, and iatrogenic.
Organic causes of menorrhagia include infection, bleeding disorders, and organ dysfunction.
Infections can be of any genitourinary origin. The aforementioned sexually transmitted diseases are of greater concern in the teenage and early adult population. Bleeding from the urethra or rectum always must be considered in the workup, especially in the postmenopausal woman who has negative findings after a workup for vaginal bleeding.
Coagulation disorders can evade diagnosis until menarche, when heavy menstrual bleeding presents as an unrelenting disorder. These include von Willebrand disease; factor II, V, VII, and IX deficiencies; prothrombin deficiency; idiopathic thrombocytopenia purpura (ITP); and thromboasthenia.
Organ dysfunction causing menorrhagia includes hepatic or renal failure. Chronic liver disease impairs production of clotting factors and reduces hormone metabolism (eg, estrogen). Either of these problems may lead to heavy uterine bleeding.
Endocrine causes of menorrhagia include thyroid and adrenal gland dysfunction, pituitary tumors, anovulatory cycles, PCOS, obesity, and vasculature imbalance.
Both hypothyroidism and hyperthyroidism result in menorrhagia. Even subclinical cases of hypothyroidism produce heavy uterine bleeding in 20% of patients. Menorrhagia usually resolves with correction of the thyroid disorder.
Prolactin-producing pituitary tumors cause menorrhagia by disrupting (GnRH) secretion. This leads to decreased LH and FSH levels, which ultimately cause hypogonadism. Interim stages of menorrhagia result until hypogonadism manifests.
The most common etiology of heavy uterine bleeding is anovulatory cycles. The finding of menorrhagia at irregular intervals without any known organic etiology confirms the clinical diagnosis. This is most common in adolescent and perimenopausal populations.
The hallmarks of PCOS are anovulation, irregular menses, obesity, and hirsutism. Insulin resistance is common and increases androgen production by the ovaries.
Hyperinsulinemia is a direct consequence of obesity. This overproduction of insulin leads to ovarian production of androgens, as occurs in PCOS.
Vasculature imbalance is theorized to be the result of a discrepancy between the vasoconstricting and aggregating actions of prostaglandin F2 (alpha) and thromboxane A2 and the vasodilating actions of prostaglandin E2 and prostacyclin on the myometrial and endometrial vasculature.
Anatomic etiologies for menorrhagia include uterine fibroids, endometrial polyps, endometrial hyperplasia, and pregnancy.
Fibroids and polyps are benign structures that distort the uterine wall and/or endometrium. Either may be located within the uterine lining, but fibroids may occur almost anywhere on the uterus.
The mechanism by which endometrial polyps or fibroids cause menorrhagia is not well understood. The blood supply to the fibroid or polyp is different compared to the surrounding endometrium and is thought to function independently. This blood supply is greater than the endometrial supply and may have impeded venous return, causing pooling in the areas of the fibroid. Heavy pooling is thought to weaken the endometrium in that area, and break-through bleeding ensues.
Fibroids located within the uterine wall may inhibit muscle contracture, thereby preventing normal uterine attempts at hemostasis. This also is why intramural fibroids may cause a significant amount of pain and cramping. Fibroids may enlarge to the point that they outgrow their blood supply and undergo necrosis. This also causes a great deal of pain for patients.
Endometrial hyperplasia usually results from unopposed estrogen production, regardless of the etiology. Endometrial hyperplasia can lead to endometrial cancer in 1-2% of patients with anovulatory bleeding, but it is a diagnosis of exclusion in postmenopausal bleeding (average age at menopause is 51 y). If a woman takes unopposed estrogen (without progesterone), her relative risk of endometrial cancer is 2.3 compared to nonusers and 9.5 if taken for 10 years or longer.
Iatrogenic causes of menorrhagia include IUDs, steroid hormones, chemotherapy agents, and medications (eg, anticoagulants).
IUDs can cause increased menstrual bleeding and cramping due to local irritation effects.
Steroid hormones and chemotherapy agents disrupt the normal menstrual cycle, which is restored easily upon cessation of the products.
Anticoagulants decrease clotting factors needed to cease any normal blood flow, including menses. This type of menorrhagia also is easily reversible. DIFFERENTIALS
Abortion Adnexal Tumors Adrenal Adenoma Adrenal Carcinoma Anovulation Cervicitis Endometrial Carcinoma Endometritis Gestational Trophoblastic Neoplasia Hyperprolactinemia Hyperthyroidism Hypothyroidism Obesity Pelvic Inflammatory Disease Pituitary Microadenomas Pregnancy Diagnosis Uterine Cancer Vaginitis
Other Problems to be Considered:
Coagulation disordersEndometrial polypsGenitourinary infectionIntrauterine deviceLiver disease/failureMedicationsRenal disease/failureSteroid hormonesUterine fibroidsVascular imbalance
Menorrhagia 3
MEDICATION
Acute menorrhagia requires prompt medical intervention. This is bleeding that will compromise an untreated patient (see Picture 1).
Successful treatment of chronic menorrhagia is highly dependent on a thorough understanding of the exact etiology. For instance, acute bleeding postpartum does not respond to progesterone therapy, while anovulatory bleeding worsens with high-dose estrogen (see Picture 2, Picture 3, and Picture 4).
Drug Category: Nonsteroidal anti-inflammatory drugs -- Block formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation. Prostacyclin is produced in increased amounts in menorrhagic endometrium. Because NSAIDs inhibit blood prostacyclin formation, they might effectively decrease uterine blood flow.
Drug Name
Naproxen (Anaprox, Naprelan, Naprosyn) -- Used for relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
Adult Dose
250-500 mg PO bid; give at last 2 d and first 3 d of cycle, for a total of 5 d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
Interactions
Probenecid may increase toxicity of NSAIDs; coadministration with ibuprofen might decrease effects of loop diuretics; coadministration with anticoagulants might prolong PT (watch for signs of bleeding); might increase serum lithium levels and risk of methotrexate toxicity (eg, stomatitis, bone marrow suppression, nephrotoxicity)
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis might occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and might require discontinuation
Drug Name
Diclofenac (Cataflam) -- Inhibits PG synthesis by decreasing activity of enzyme cyclooxygenase, which in turn decreases formation of PG precursors.
Adult Dose
Initial: 100 mg PO once, then 50 mg PO tid
Pediatric Dose
Not established
Contraindications
Use in persons with allergic reaction to aspirin/NSAIDs, such as swelling, asthma, hives, urticaria, or any forms of angioedema; active GI bleed; active ulcer
Interactions
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors, concomitantly with ACE inhibitors; concomitant administration of low-dose aspirin may result in increased rate of GI ulceration or other complications compared to use of NSAIDs alone; clinical studies and postmarketing observations show that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients, and this response has been attributed to inhibition of renal prostaglandin synthesis; NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
GI bleeding; anaphylaxis; renal or liver injury; pregnancy category D if given at third trimester Drug Category: Combination oral contraceptives -- OCPs containing estrogen and progestin used to treat acute hemorrhagic uterine bleeding.
Drug Name
Ethinyl estradiol and a progestin derivative (Ovral, Ortho-Novum, Ovcon, Genora) -- Reduce secretion of LH and FSH from the pituitary by decreasing amount of GnRH. Reduce pituitary production of gonadotropins and result in reduced LH and FSH with no ovulation.
Adult Dose
1 tab PO qd for 3 wk; followed by a week of inactive pills, during which a withdrawal bleed generally occurs; repeat monthly
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; pregnancy; active or inactive thrombophlebitis or thromboembolic disorders, cerebral vascular disease, myocardial infarction, coronary artery disease, or a past history of these disorders; known or suspected breast cancer; known or suspected genital cancer; history of cholestatic jaundice in pregnancy or jaundice with prior pill use; past or present liver tumors
Interactions
Hepatotoxicity might occur with concurrent administration of cyclosporine; concomitant use of rifampin, barbiturates, phenylbutazone, phenytoin sodium, and, possibly, griseofulvin, ampicillin, and tetracyclines might influence efficacy of oral contraceptives and increase amount of breakthrough bleeding and menstrual irregularity
Pregnancy
X - Contraindicated in pregnancy
Precautions
Complete physical examination, documentation of recent Pap smear test, and family history recommended; pay special attention to blood pressure, breasts, abdomen, and pelvic organs; repeat physical examination annually as long as patient is on hormonal therapyOral contraceptives can cause fluid retention (address any condition aggravated by this factor)Monitor patients with epilepsy, migraine, asthma, or renal or cardiac dysfunctionHistory of psychic depression might be aggravated (observe patient closely)Progestin compounds might elevate LDL levels, making control of hyperlipidemia more difficult (observe closely); certain forms of congenital hypertriglyceridemia might be aggravated by oral contraceptives, with resultant pancreatitisDiscontinue if jaundice developsContact lens wearers with visual changes should be examined by ophthalmologistPatients might develop hypertension secondary to increase in angiotensinogen production (reevaluate blood pressure approximately 3 mo after initiating therapy in all patients) Drug Category: Progestins -- Occasional anovulatory bleeding that is not profuse or prolonged can be treated with progestins, antiestrogens given in pharmacologic doses. Inhibit estrogen-receptor replenishment and activate 17-hydroxysteroid dehydrogenase in endometrial cells, converting estradiol to the less-active estrone.
Drug Name
Medroxyprogesterone (Provera)/megestrol acetate/19-nortestosterone derivative -- Provera: Short-acting synthetic progestin. Works as an antiestrogen by minimizing estrogen effects on target cells. Endometrium is maintained in an atrophic state. Effective against hyperplasia and has modest effects on serum lipids (ie, lowering HDL)Megestrol acetate: May be substituted for Provera. Is active against hyperplasia without significantly altering serum lipid levels.Derivatives of 19-nortestosterone: Potent progestins used in oral contraceptives. Have partial androgenic properties and lower HDL cholesterol levels.
Adult Dose
Provera: 10 mg/d PO for 10 d monthlyProvera for atypical hyperplasia: 10 mg/d PO for 12 d onceMegestrol acetate: 40-80 mg PO for 10 d monthlyMegestrol acetate for atypical hyperplasia: 40-80 mg PO for 12 d onceDerivatives of 19-nortestosterone: Used in oral combination birth control pills; doses vary from 0.075-0.35 mg/pill depending on derivativeDerivatives of 19-nortestosterone for atypical hyperplasia: 5 mg/d for 12 d once
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; cerebral apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction; missed abortion; known or suspected malignancy of breast or genital tract; active or past history of thrombophlebitis, thromboembolic disorders, or cerebral apoplexy (based on past experience with combination oral contraceptive medications; little data suggest that progestin therapy used without estrogen is associated with an increased risk of thrombotic events)
Interactions
Decreases aminoglutethimide efficacy
Pregnancy
X - Contraindicated in pregnancy
Precautions
Caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders; perform complete physical examination, document recent Papanicolaou smear, and take family history before therapy; give special attention to blood pressure, breasts, abdomen, and pelvic organs; repeat physical examination annually; progestins can cause fluid retention (address any condition aggravated by this factor); monitor patients with epilepsy, migraine, asthma, renal or cardiac dysfunction, and history of psychic depression Drug Category: Gonadotropin-releasing hormone agonists -- Work by reducing concentration of GnRH receptors in the pituitary via receptor down-regulation and induction of postreceptor effects, which suppress gonadotropin release. After an initial gonadotropin release associated with rising estradiol levels, gonadotropin levels fall to castrate levels, with resultant hypogonadism. This form of medical castration is very effective in inducing amenorrhea, thus breaking the ongoing cycle of abnormal bleeding in many anovulatory patients.
Drug Name
Leuprolide (Lupron) -- Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.
Adult Dose
3.5-7.5 mg IM monthly for 3-6 mo
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; undiagnosed vaginal bleeding and spinal cord compression
Interactions
None reported
Pregnancy
X - Contraindicated in pregnancy
Precautions
Urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesias; may cause menopauselike symptoms; may cause bone demineralization and/or reduction in HDL cholesterol if given for >6 mo Drug Category: Androgens -- Certain androgenic preparations have been used historically to treat mild-to-moderate bleeding, particularly in ovulatory patients with abnormal uterine bleeding. Use might stimulate erythropoiesis and clotting efficiency. Alters endometrial tissue so that it becomes inactive and atrophic.
Drug Name
Danazol (Danocrine) -- Synthetic steroid analog with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action. Competes with androgen and progesterone at receptor level, resulting in amenorrhea within 3 mo.
Adult Dose
100-400 mg PO qd for 3 mo
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; breastfeeding; seizure disorders; markedly impaired hepatic function or porphyria
Interactions
Prolongation of PT occurs in patients who are on warfarin; carbamazepine levels might rise with concurrent use; might interfere with laboratory determinations of DHEA, androstenedione, and testosterone
Pregnancy
X - Contraindicated in pregnancy
Precautions
Caution in renal, hepatic (may elevate serum transaminase levels), or cardiac insufficiency and in seizure disorders; androgen effects may cause hirsutism, acne, lowering of voice, or decreased breast size Drug Category: Arginine vasopressin derivatives -- Indicated in patients with thromboembolic disorders.
Drug Name
Desmopressin (DDAVP) -- Has been used to treat abnormal uterine bleeding in patients with coagulation defects. Transiently elevates factor VIII and von Willebrand factor.
Adult Dose
0.3 mcg/kg in 50 mL NS IV push (15 min)
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; platelet-type von Willebrand disease
Interactions
Coadministration with demeclocycline and lithium decrease effects; fludrocortisone and chlorpropamide increase effects
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Avoid overhydration in patients using desmopressin to benefit from its hemostatic effects; may cause platelet aggregation in von Willebrand type IIB Drug Category: Estrogens -- Effective in controlling acute, profuse bleeding. Exerts a vasospastic action on capillary bleeding by affecting the level of fibrinogen, factor IV, and factor X in blood and platelet aggregation and capillary permeability. Estrogen also induces formation of progesterone receptors, making subsequent treatment with progestins more effective.
Drug Name
Conjugated equine estrogen (Premarin) -- Only controls bleeding acutely but does not treat underlying cause. Appropriate long-term therapy can be administered once the acute episode has passed.
Adult Dose
Acute bleeding: 25 mg IV q4h for a maximum of 48 h; 2.5 mg PO q6h for a maximum of 48 h
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; known or suspected pregnancy; breast cancer, undiagnosed abnormal genital bleeding, active thrombophlebitis, or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy)
Interactions
May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins
Pregnancy
X - Contraindicated in pregnancy
Precautions
Certain patients may develop undesirable manifestations of excessive estrogenic stimulation (eg, abnormal or excessive uterine bleeding, mastodynia); may cause some degree of fluid retention (exercise caution); prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia
FOLLOW-UP
Complications:
Treatment must be individualized to treat each patient's specific symptoms. Cost, dosing, and patient compliance can play major roles.
If bleeding does not subside within the expected time frame, have the patient keep a menstrual calendar to better assess the resulting bleeding pattern.
If a specific treatment fails, investigate all possibilities, including noncompliance, medication dosing, diagnosis, patient age, and comorbid conditions.
Prognosis:
With proper workup, diagnosis, treatment, and follow-up care, prognosis is excellent.
Patient Education:
Reassure patients that most bleeding stops, but not immediately. Provide literature on the treatment of choice, including expectations and adverse effects.
Many patients appreciate reassurance that they do not have cancer and are not alone in their plight.
Reassure patients who experience a treatment failure that other options are available.
MISCELLANEOUS
Medical/Legal Pitfalls:
Every patient presenting with uterine bleeding should first undergo pregnancy testing. Threatened or incomplete abortion, ectopic pregnancy, or retained products of conception must be considered before any imaging studies may be ordered.
Every high-risk or postmenopausal patient with uterine bleeding first must be evaluated for endometrial or other gynecological malignancy.
When treating patients with progestin therapy of any form, they must be informed that this is not a form of birth control. Pregnancy is possible, especially if ovulation is induced by the cycling of the progesterone.
All medications and procedures must be administered only after informed consent of all benefits and risks.
Acute menorrhagia requires prompt medical intervention. This is bleeding that will compromise an untreated patient (see Picture 1).
Successful treatment of chronic menorrhagia is highly dependent on a thorough understanding of the exact etiology. For instance, acute bleeding postpartum does not respond to progesterone therapy, while anovulatory bleeding worsens with high-dose estrogen (see Picture 2, Picture 3, and Picture 4).
Drug Category: Nonsteroidal anti-inflammatory drugs -- Block formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation. Prostacyclin is produced in increased amounts in menorrhagic endometrium. Because NSAIDs inhibit blood prostacyclin formation, they might effectively decrease uterine blood flow.
Drug Name
Naproxen (Anaprox, Naprelan, Naprosyn) -- Used for relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
Adult Dose
250-500 mg PO bid; give at last 2 d and first 3 d of cycle, for a total of 5 d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
Interactions
Probenecid may increase toxicity of NSAIDs; coadministration with ibuprofen might decrease effects of loop diuretics; coadministration with anticoagulants might prolong PT (watch for signs of bleeding); might increase serum lithium levels and risk of methotrexate toxicity (eg, stomatitis, bone marrow suppression, nephrotoxicity)
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis might occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and might require discontinuation
Drug Name
Diclofenac (Cataflam) -- Inhibits PG synthesis by decreasing activity of enzyme cyclooxygenase, which in turn decreases formation of PG precursors.
Adult Dose
Initial: 100 mg PO once, then 50 mg PO tid
Pediatric Dose
Not established
Contraindications
Use in persons with allergic reaction to aspirin/NSAIDs, such as swelling, asthma, hives, urticaria, or any forms of angioedema; active GI bleed; active ulcer
Interactions
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors, concomitantly with ACE inhibitors; concomitant administration of low-dose aspirin may result in increased rate of GI ulceration or other complications compared to use of NSAIDs alone; clinical studies and postmarketing observations show that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients, and this response has been attributed to inhibition of renal prostaglandin synthesis; NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
GI bleeding; anaphylaxis; renal or liver injury; pregnancy category D if given at third trimester Drug Category: Combination oral contraceptives -- OCPs containing estrogen and progestin used to treat acute hemorrhagic uterine bleeding.
Drug Name
Ethinyl estradiol and a progestin derivative (Ovral, Ortho-Novum, Ovcon, Genora) -- Reduce secretion of LH and FSH from the pituitary by decreasing amount of GnRH. Reduce pituitary production of gonadotropins and result in reduced LH and FSH with no ovulation.
Adult Dose
1 tab PO qd for 3 wk; followed by a week of inactive pills, during which a withdrawal bleed generally occurs; repeat monthly
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; pregnancy; active or inactive thrombophlebitis or thromboembolic disorders, cerebral vascular disease, myocardial infarction, coronary artery disease, or a past history of these disorders; known or suspected breast cancer; known or suspected genital cancer; history of cholestatic jaundice in pregnancy or jaundice with prior pill use; past or present liver tumors
Interactions
Hepatotoxicity might occur with concurrent administration of cyclosporine; concomitant use of rifampin, barbiturates, phenylbutazone, phenytoin sodium, and, possibly, griseofulvin, ampicillin, and tetracyclines might influence efficacy of oral contraceptives and increase amount of breakthrough bleeding and menstrual irregularity
Pregnancy
X - Contraindicated in pregnancy
Precautions
Complete physical examination, documentation of recent Pap smear test, and family history recommended; pay special attention to blood pressure, breasts, abdomen, and pelvic organs; repeat physical examination annually as long as patient is on hormonal therapyOral contraceptives can cause fluid retention (address any condition aggravated by this factor)Monitor patients with epilepsy, migraine, asthma, or renal or cardiac dysfunctionHistory of psychic depression might be aggravated (observe patient closely)Progestin compounds might elevate LDL levels, making control of hyperlipidemia more difficult (observe closely); certain forms of congenital hypertriglyceridemia might be aggravated by oral contraceptives, with resultant pancreatitisDiscontinue if jaundice developsContact lens wearers with visual changes should be examined by ophthalmologistPatients might develop hypertension secondary to increase in angiotensinogen production (reevaluate blood pressure approximately 3 mo after initiating therapy in all patients) Drug Category: Progestins -- Occasional anovulatory bleeding that is not profuse or prolonged can be treated with progestins, antiestrogens given in pharmacologic doses. Inhibit estrogen-receptor replenishment and activate 17-hydroxysteroid dehydrogenase in endometrial cells, converting estradiol to the less-active estrone.
Drug Name
Medroxyprogesterone (Provera)/megestrol acetate/19-nortestosterone derivative -- Provera: Short-acting synthetic progestin. Works as an antiestrogen by minimizing estrogen effects on target cells. Endometrium is maintained in an atrophic state. Effective against hyperplasia and has modest effects on serum lipids (ie, lowering HDL)Megestrol acetate: May be substituted for Provera. Is active against hyperplasia without significantly altering serum lipid levels.Derivatives of 19-nortestosterone: Potent progestins used in oral contraceptives. Have partial androgenic properties and lower HDL cholesterol levels.
Adult Dose
Provera: 10 mg/d PO for 10 d monthlyProvera for atypical hyperplasia: 10 mg/d PO for 12 d onceMegestrol acetate: 40-80 mg PO for 10 d monthlyMegestrol acetate for atypical hyperplasia: 40-80 mg PO for 12 d onceDerivatives of 19-nortestosterone: Used in oral combination birth control pills; doses vary from 0.075-0.35 mg/pill depending on derivativeDerivatives of 19-nortestosterone for atypical hyperplasia: 5 mg/d for 12 d once
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; cerebral apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction; missed abortion; known or suspected malignancy of breast or genital tract; active or past history of thrombophlebitis, thromboembolic disorders, or cerebral apoplexy (based on past experience with combination oral contraceptive medications; little data suggest that progestin therapy used without estrogen is associated with an increased risk of thrombotic events)
Interactions
Decreases aminoglutethimide efficacy
Pregnancy
X - Contraindicated in pregnancy
Precautions
Caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders; perform complete physical examination, document recent Papanicolaou smear, and take family history before therapy; give special attention to blood pressure, breasts, abdomen, and pelvic organs; repeat physical examination annually; progestins can cause fluid retention (address any condition aggravated by this factor); monitor patients with epilepsy, migraine, asthma, renal or cardiac dysfunction, and history of psychic depression Drug Category: Gonadotropin-releasing hormone agonists -- Work by reducing concentration of GnRH receptors in the pituitary via receptor down-regulation and induction of postreceptor effects, which suppress gonadotropin release. After an initial gonadotropin release associated with rising estradiol levels, gonadotropin levels fall to castrate levels, with resultant hypogonadism. This form of medical castration is very effective in inducing amenorrhea, thus breaking the ongoing cycle of abnormal bleeding in many anovulatory patients.
Drug Name
Leuprolide (Lupron) -- Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.
Adult Dose
3.5-7.5 mg IM monthly for 3-6 mo
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; undiagnosed vaginal bleeding and spinal cord compression
Interactions
None reported
Pregnancy
X - Contraindicated in pregnancy
Precautions
Urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesias; may cause menopauselike symptoms; may cause bone demineralization and/or reduction in HDL cholesterol if given for >6 mo Drug Category: Androgens -- Certain androgenic preparations have been used historically to treat mild-to-moderate bleeding, particularly in ovulatory patients with abnormal uterine bleeding. Use might stimulate erythropoiesis and clotting efficiency. Alters endometrial tissue so that it becomes inactive and atrophic.
Drug Name
Danazol (Danocrine) -- Synthetic steroid analog with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action. Competes with androgen and progesterone at receptor level, resulting in amenorrhea within 3 mo.
Adult Dose
100-400 mg PO qd for 3 mo
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; breastfeeding; seizure disorders; markedly impaired hepatic function or porphyria
Interactions
Prolongation of PT occurs in patients who are on warfarin; carbamazepine levels might rise with concurrent use; might interfere with laboratory determinations of DHEA, androstenedione, and testosterone
Pregnancy
X - Contraindicated in pregnancy
Precautions
Caution in renal, hepatic (may elevate serum transaminase levels), or cardiac insufficiency and in seizure disorders; androgen effects may cause hirsutism, acne, lowering of voice, or decreased breast size Drug Category: Arginine vasopressin derivatives -- Indicated in patients with thromboembolic disorders.
Drug Name
Desmopressin (DDAVP) -- Has been used to treat abnormal uterine bleeding in patients with coagulation defects. Transiently elevates factor VIII and von Willebrand factor.
Adult Dose
0.3 mcg/kg in 50 mL NS IV push (15 min)
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; platelet-type von Willebrand disease
Interactions
Coadministration with demeclocycline and lithium decrease effects; fludrocortisone and chlorpropamide increase effects
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Avoid overhydration in patients using desmopressin to benefit from its hemostatic effects; may cause platelet aggregation in von Willebrand type IIB Drug Category: Estrogens -- Effective in controlling acute, profuse bleeding. Exerts a vasospastic action on capillary bleeding by affecting the level of fibrinogen, factor IV, and factor X in blood and platelet aggregation and capillary permeability. Estrogen also induces formation of progesterone receptors, making subsequent treatment with progestins more effective.
Drug Name
Conjugated equine estrogen (Premarin) -- Only controls bleeding acutely but does not treat underlying cause. Appropriate long-term therapy can be administered once the acute episode has passed.
Adult Dose
Acute bleeding: 25 mg IV q4h for a maximum of 48 h; 2.5 mg PO q6h for a maximum of 48 h
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; known or suspected pregnancy; breast cancer, undiagnosed abnormal genital bleeding, active thrombophlebitis, or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy)
Interactions
May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins
Pregnancy
X - Contraindicated in pregnancy
Precautions
Certain patients may develop undesirable manifestations of excessive estrogenic stimulation (eg, abnormal or excessive uterine bleeding, mastodynia); may cause some degree of fluid retention (exercise caution); prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia
FOLLOW-UP
Complications:
Treatment must be individualized to treat each patient's specific symptoms. Cost, dosing, and patient compliance can play major roles.
If bleeding does not subside within the expected time frame, have the patient keep a menstrual calendar to better assess the resulting bleeding pattern.
If a specific treatment fails, investigate all possibilities, including noncompliance, medication dosing, diagnosis, patient age, and comorbid conditions.
Prognosis:
With proper workup, diagnosis, treatment, and follow-up care, prognosis is excellent.
Patient Education:
Reassure patients that most bleeding stops, but not immediately. Provide literature on the treatment of choice, including expectations and adverse effects.
Many patients appreciate reassurance that they do not have cancer and are not alone in their plight.
Reassure patients who experience a treatment failure that other options are available.
MISCELLANEOUS
Medical/Legal Pitfalls:
Every patient presenting with uterine bleeding should first undergo pregnancy testing. Threatened or incomplete abortion, ectopic pregnancy, or retained products of conception must be considered before any imaging studies may be ordered.
Every high-risk or postmenopausal patient with uterine bleeding first must be evaluated for endometrial or other gynecological malignancy.
When treating patients with progestin therapy of any form, they must be informed that this is not a form of birth control. Pregnancy is possible, especially if ovulation is induced by the cycling of the progesterone.
All medications and procedures must be administered only after informed consent of all benefits and risks.
Menorrhagia 1
Menorrhagia
INTRODUCTION
Background: Menorrhagia is menstruation at regular cycle intervals but with excessive flow and duration. It is defined clinically as total blood loss exceeding 80 mL per cycle or menses lasting longer than 7 days. Menorrhagia is one of the most common gynecologic complaints in contemporary gynecology. Current gynecological surveys report that 30% of all premenopausal women perceive their menses to be excessive. The World Health Organization recently reported that 18 million women aged 30-55 years perceive their menstrual bleeding to be exorbitant. Reports show that only 10% of these women experience blood loss severe enough to be defined clinically as menorrhagia.
A normal menstrual cycle is 21-35 days in duration, bleeding lasting an average of 7 days, and flow between 25 and 80 mL.
Menorrhagia must be distinguished clinically from other common gynecologic diagnoses. These include metrorrhagia (flow at irregular intervals), menometrorrhagia (frequent, excessive flow), polymenorrhea (bleeding at intervals <21 d), and dysfunctional uterine bleeding (abnormal uterine bleeding without any obvious structural or systemic abnormality).
Nearly 30% of all hysterectomies performed in the United States are performed to alleviate heavy menstrual bleeding. Definitive surgical correction has been the mainstay of treatment for menorrhagia. Modern gynecology dictates the trend toward conservative therapy for cost containment and because many women desire to preserve their uteruses. Alternatives to hysterectomy also are the result of statistics revealing that nearly 50% of uterine pathology findings from hysterectomies for menorrhagia are free of disease and histopathologic abnormalities.
Heavy menstrual bleeding is a subjective finding, making the exact problem definition difficult. Treatment regimens must address the specific facet of the menstrual cycle the patient perceives to be abnormal, (ie, cycle length, quantity of bleeding). Finally, treatment success usually is evaluated subjectively by each patient, making positive outcome measurement difficult.
Pathophysiology: Knowledge of normal menstrual function is imperative in understanding the etiologies of menorrhagia. Four phases constitute the menstrual cycle, follicular, luteal, implantation, and menstrual.
In response to gonadotropin-releasing hormone (GnRH) from the hypothalamus, the pituitary gland synthesizes follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which induce the ovaries to produce estrogen and progesterone.
During the follicular phase, estrogen stimulation results in an increase in endometrial thickness. This also is known as the proliferative phase.
The luteal phase is intricately involved in the process of ovulation. During this phase, also known as the secretory phase, progesterone causes endometrial maturation.
If fertilization occurs, the implantation phase is maintained. Without fertilization, estrogen and progesterone withdrawal results in menstruation.
Etiologic causes are numerous and often unknown. Factors contributing to menorrhagia can be sorted into several categories, including organic, endocrinologic, anatomic, and iatrogenic.
If the bleeding workup does not provide any clues to the etiology of the menorrhagia, a patient often is given the diagnosis of dysfunctional uterine bleeding (DUB). Most cases of DUB are secondary to anovulation. Without ovulation, the corpus luteum fails to form, resulting in no progesterone secretion. Unopposed estrogen allows the endometrium to proliferate and thicken. The endometrium finally outgrows its blood supply and degenerates. The end result is asynchronous breakdown of the endometrial lining at different levels. This also is why anovulatory bleeding is heavier than normal menstrual flow.
Hemostasis of the endometrium is directly related to the functions of platelets and fibrin. Deficiencies in either of these components results in menorrhagia for patients with von Willebrand disease or thrombocytopenia. Thrombi are seen in the functional layers but are limited to the shedding surface of the tissue. These thrombi are known as "plugs" because blood can only partially flow past them. Fibrinolysis limits the fibrin deposits in the unshed layer. Following thrombin plug formation, vasoconstriction occurs and contributes to hemostasis.
Anatomic defects or growths within the uterus can alter either of the aforementioned pathways (endocrinologic/hemostatic), causing significant uterine bleeding. The clinical presentation is dependent on the location and size of the gynecologic lesion.
Organic diseases also contribute to menorrhagia in the female patient. For example, in patients with renal failure, gonadal resistance to hormones and hypothalamic-pituitary axis disturbances result in menstrual irregularities. Most women in this renal state are amenorrheic, but others also develop menorrhagia. If uremic coagulopathy ensues, it usually is due to platelet dysfunction and abnormal factor VIII function. The resulting prolonged bleeding time causes menorrhagia that can be very tenuous to treat.
Due to the overwhelming factors that can contribute to the dysfunction of either the endocrine or hematological pathways, in-depth knowledge of an existing organic disease is just as imperative as understanding the menstrual cycle itself.
Frequency:
In the US: While menorrhagia remains a leading reason for gynecologic office visits, only 10-20% of all menstruating women experience blood loss severe enough to be defined clinically as menorrhagia.
Mortality/Morbidity: Infrequent episodes of menorrhagia usually do not carry severe risks to women’s general health.
Patients who lose more than 80 mL of blood, especially repetitively, are at risk for serious medical sequelae. These women are likely to develop iron-deficiency anemia as a result of their blood loss. Menorrhagia is the most common cause of anemia in premenopausal women. This usually can be remedied by simple ingestion of ferrous sulfate to replace iron stores. If the bleeding is severe enough to cause volume depletion, patients may experience shortness of breath, fatigue, palpitations, and other related symptoms. This level of anemia necessitates hospitalization for intravenous fluids and possible transfusion and/or intravenous estrogen therapy. Patients who do not respond to medical therapy may require surgical intervention to control the menorrhagia.
Other sequelae associated with menorrhagia usually are related to the etiology. For example, with hypothyroidism, patients may experience symptoms associated with a low-functioning thyroid (eg, cold intolerance, hair loss, dry skin, weight gain) in addition to the effects of significant blood loss.
Sex: Only females are affected by menorrhagia.
Age: Any woman of reproductive age who is menstruating may develop menorrhagia. Most patients with menorrhagia are older than 30 years. This is because the most common cause of heavy menses in the younger population is anovulatory cycles, in which bleeding does not occur at regular intervals.
CLINICAL
History: Symptoms related by a patient with menorrhagia often can be more revealing than laboratory tests. Considering the lengthy list of possible etiologies that contribute to menorrhagia, taking a detailed patient history is imperative. Inquiries should include the following:
Exclusion of pregnancy
This is the most common cause of irregular bleeding in women of reproductive age.
Pregnancy should be the first diagnosis to be excluded before further testing or medications are instituted.
Quantity and quality of bleeding
Quantity is a very subjective issue when considering vaginal bleeding. Best estimates usually are the only source clinicians have available to consider. Helpful references for totaling blood loss may include that the average tampon holds 5 mL and the average pad holds 5-15 mL of blood. Asking the patient what type of pad (liner vs overnight) was used and if it was soaked may add some insight into what the patient believes to be heavy bleeding.
Quality of bleeding involves the presence of clots and their size.
Age
Young patients, from menarche to the late-teen years, most commonly have anovulatory bleeding due to the immaturity of their hypothalamic-pituitary axis. If bleeding does not respond to usual therapy in this age group, a bleeding disorder must be considered.
Women aged 30-50 years may have organic or structural abnormalities. Fibroids or polyps are frequent anatomical findings. Organic causes can be anything from thyroid dysfunction to renal failure.
Postmenopausal women with any uterine bleeding should receive an immediate workup for endometrial cancer.
Endometrial hyperplasia must be considered in women who are obese, aged 70 or older, nulliparous, or have diabetes.
Pelvic pain and pathology
Knowing if a patient has any long-standing diagnosis or known pathology (eg, fibroids) is helpful.
Records from other physicians or hospitalizations may prevent redundancy in ordering lab work or diagnostic imaging.
Menses pattern from menarche
If a young patient has had irregular menses since menarche, the most common etiology of her bleeding is anovulation.
Anovulatory bleeding is most common in young girls (aged 12-18 y) and common in obese females of any reproductive age.
If a patient's bleeding normally occurs at regular intervals and the irregularity is new in onset, pathology must be ruled out, regardless of age.
Sexual activity
Simple vaginitis (eg, candidal, bacterial vaginosis) may cause intermenstrual bleeding, while gonorrhea and chlamydia may present with heavier bleeding attributed primarily to the copious discharge mixed with the blood.
Chlamydia is a common cause of postpartum endometritis, leading to vaginal bleeding in the weeks following a delivery.
A postpartum infection (eg, endometritis) also may be due to organisms unrelated to sexual activity.
Contraceptive use (intrauterine device or hormones)
Commonly, an intrauterine device (IUD) causes increased uterine cramping and menstrual flow.
If a patient has recently discontinued birth control pills, she may return to her "natural" menses and report an increase in flow. This actually is normal because most oral birth control pills decrease the flow and duration of a woman's menses.
Presence of hirsutism (polycystic ovarian syndrome)
These patients commonly are obese and in an anovulatory state. When they do have a period, it may be very heavy and cause concern for the patient.
The etiology of this is explained in the Introduction to this article.
Galactorrhea (pituitary tumor): Any patient complaining of a milky discharge from either breast (while not pregnant, postpartum, or breastfeeding) needs a prolactin level to rule out a pituitary tumor.
Systemic illnesses (hepatic/renal failure or diabetes)
As explained in the Introduction, organic diseases may affect either the hormonal or hematologic pathways that are involved in the manifestation of menorrhagia.
If either the hypothalamic-pituitary axis or the coagulation paths are disrupted, heavy bleeding may result.
Symptoms of thyroid dysfunction: The alteration of the hypothalamic-pituitary axis may create either amenorrhea (hyperthyroidism) or menorrhagia (hypothyroidism).
Excessive bruising or known bleeding disorders
This is especially important in a young patient who does not stop bleeding during her first menses.
This is a very common presentation for an undiagnosed bleeding disorder (von Willebrand disease) in a young girl.
Current medications (hormones or anticoagulants)
Any medication that prolongs bleeding time may cause menorrhagia.
A patient treated with any progestin therapy may have a withdrawal bleed after cessation of the medication. This bleeding often is heavy and worrisome to patients if they are not forewarned.
Previous medical or surgical procedures/diagnoses: This also is helpful in preventing duplication of testing.
Physical: The physical examination should be tailored to the differential diagnoses formulated by the results of the patient's history.
Initial inspection should include evaluation for the following:
Signs of severe volume depletion (eg, anemia): This may help confirm the patient's history of very heavy bleeding and/or prompt immediate inpatient care.
Obesity: This is an independent risk factor for endometrial cancer. Adipose tissue is a locale for estrogen conversion. Therefore, the larger the patient, the more increased the risk (and the higher the unopposed estrogen level on the endometrium).
Signs of androgen excess (eg, hirsutism): This usually points to polycystic ovarian syndrome (PCOS), leading to anovulatory bleeding (see Presence of hirsutism).
Ecchymosis: This usually is a sign of trauma or a bleeding disorder.
Purpura: This also is a sign of trauma or a possible bleeding disorder.
Pronounced acne: This is a sign of PCOS.
General examination should include evaluation of the following:
Visual fields
Bleeding gums
Thyroid evaluation
Galactorrhea
Enlarged liver or spleen
Pelvic examination should evaluate for the presence of external genital lesions.
Vaginal/cervical discharge: Look for a copious discharge indicating infection, and confirm the actual site of the bleeding (if present). Assess as follows:
Uterine size, shape, and contour: An enlarged irregularly shaped uterus suggests fibroids if the patient is aged 30-50 years. An enlarged uniformly shaped uterus in a postmenopausal patient with bleeding suggests endometrial cancer until proven otherwise.
Cervical motion tenderness: This is a common symptom of pelvic inflammatory disease (PID) that usually is caused by gonorrhea or chlamydia. This is an important diagnosis to exclude, especially in young nulliparous women, because it can lead to pelvic adhesions and infertility.
Adnexal tenderness or masses: This is especially concerning in patients older than 40 years. Ovarian cancer may present with intermenstrual bleeding as its only symptom. Rare but deadly ovarian tumors also can present in teenage girls. Any suspicion of an adnexal mass should prompt an immediate pelvic ultrasound.
Causes: Etiologies of menorrhagia are divided into 4 categories, organic, endocrinologic, anatomic, and iatrogenic.
Organic causes of menorrhagia include infection, bleeding disorders, and organ dysfunction.
Infections can be of any genitourinary origin. The aforementioned sexually transmitted diseases are of greater concern in the teenage and early adult population. Bleeding from the urethra or rectum always must be considered in the workup, especially in the postmenopausal woman who has negative findings after a workup for vaginal bleeding.
Coagulation disorders can evade diagnosis until menarche, when heavy menstrual bleeding presents as an unrelenting disorder. These include von Willebrand disease; factor II, V, VII, and IX deficiencies; prothrombin deficiency; idiopathic thrombocytopenia purpura (ITP); and thromboasthenia.
Organ dysfunction causing menorrhagia includes hepatic or renal failure. Chronic liver disease impairs production of clotting factors and reduces hormone metabolism (eg, estrogen). Either of these problems may lead to heavy uterine bleeding.
Endocrine causes of menorrhagia include thyroid and adrenal gland dysfunction, pituitary tumors, anovulatory cycles, PCOS, obesity, and vasculature imbalance.
Both hypothyroidism and hyperthyroidism result in menorrhagia. Even subclinical cases of hypothyroidism produce heavy uterine bleeding in 20% of patients. Menorrhagia usually resolves with correction of the thyroid disorder.
Prolactin-producing pituitary tumors cause menorrhagia by disrupting (GnRH) secretion. This leads to decreased LH and FSH levels, which ultimately cause hypogonadism. Interim stages of menorrhagia result until hypogonadism manifests.
The most common etiology of heavy uterine bleeding is anovulatory cycles. The finding of menorrhagia at irregular intervals without any known organic etiology confirms the clinical diagnosis. This is most common in adolescent and perimenopausal populations.
The hallmarks of PCOS are anovulation, irregular menses, obesity, and hirsutism. Insulin resistance is common and increases androgen production by the ovaries.
Hyperinsulinemia is a direct consequence of obesity. This overproduction of insulin leads to ovarian production of androgens, as occurs in PCOS.
Vasculature imbalance is theorized to be the result of a discrepancy between the vasoconstricting and aggregating actions of prostaglandin F2 (alpha) and thromboxane A2 and the vasodilating actions of prostaglandin E2 and prostacyclin on the myometrial and endometrial vasculature.
Anatomic etiologies for menorrhagia include uterine fibroids, endometrial polyps, endometrial hyperplasia, and pregnancy.
Fibroids and polyps are benign structures that distort the uterine wall and/or endometrium. Either may be located within the uterine lining, but fibroids may occur almost anywhere on the uterus.
The mechanism by which endometrial polyps or fibroids cause menorrhagia is not well understood. The blood supply to the fibroid or polyp is different compared to the surrounding endometrium and is thought to function independently. This blood supply is greater than the endometrial supply and may have impeded venous return, causing pooling in the areas of the fibroid. Heavy pooling is thought to weaken the endometrium in that area, and break-through bleeding ensues.
Fibroids located within the uterine wall may inhibit muscle contracture, thereby preventing normal uterine attempts at hemostasis. This also is why intramural fibroids may cause a significant amount of pain and cramping. Fibroids may enlarge to the point that they outgrow their blood supply and undergo necrosis. This also causes a great deal of pain for patients.
Endometrial hyperplasia usually results from unopposed estrogen production, regardless of the etiology. Endometrial hyperplasia can lead to endometrial cancer in 1-2% of patients with anovulatory bleeding, but it is a diagnosis of exclusion in postmenopausal bleeding (average age at menopause is 51 y). If a woman takes unopposed estrogen (without progesterone), her relative risk of endometrial cancer is 2.3 compared to nonusers and 9.5 if taken for 10 years or longer.
Iatrogenic causes of menorrhagia include IUDs, steroid hormones, chemotherapy agents, and medications (eg, anticoagulants).
IUDs can cause increased menstrual bleeding and cramping due to local irritation effects.
Steroid hormones and chemotherapy agents disrupt the normal menstrual cycle, which is restored easily upon cessation of the products.
Anticoagulants decrease clotting factors needed to cease any normal blood flow, including menses. This type of menorrhagia also is easily reversible. DIFFERENTIALS
Abortion Adnexal Tumors Adrenal Adenoma Adrenal Carcinoma Anovulation Cervicitis Endometrial Carcinoma Endometritis Gestational Trophoblastic Neoplasia Hyperprolactinemia Hyperthyroidism Hypothyroidism Obesity Pelvic Inflammatory Disease Pituitary Microadenomas Pregnancy Diagnosis Uterine Cancer Vaginitis
Other Problems to be Considered:
Coagulation disordersEndometrial polypsGenitourinary infectionIntrauterine deviceLiver disease/failureMedicationsRenal disease/failureSteroid hormonesUterine fibroidsVascular imbalance
INTRODUCTION
Background: Menorrhagia is menstruation at regular cycle intervals but with excessive flow and duration. It is defined clinically as total blood loss exceeding 80 mL per cycle or menses lasting longer than 7 days. Menorrhagia is one of the most common gynecologic complaints in contemporary gynecology. Current gynecological surveys report that 30% of all premenopausal women perceive their menses to be excessive. The World Health Organization recently reported that 18 million women aged 30-55 years perceive their menstrual bleeding to be exorbitant. Reports show that only 10% of these women experience blood loss severe enough to be defined clinically as menorrhagia.
A normal menstrual cycle is 21-35 days in duration, bleeding lasting an average of 7 days, and flow between 25 and 80 mL.
Menorrhagia must be distinguished clinically from other common gynecologic diagnoses. These include metrorrhagia (flow at irregular intervals), menometrorrhagia (frequent, excessive flow), polymenorrhea (bleeding at intervals <21 d), and dysfunctional uterine bleeding (abnormal uterine bleeding without any obvious structural or systemic abnormality).
Nearly 30% of all hysterectomies performed in the United States are performed to alleviate heavy menstrual bleeding. Definitive surgical correction has been the mainstay of treatment for menorrhagia. Modern gynecology dictates the trend toward conservative therapy for cost containment and because many women desire to preserve their uteruses. Alternatives to hysterectomy also are the result of statistics revealing that nearly 50% of uterine pathology findings from hysterectomies for menorrhagia are free of disease and histopathologic abnormalities.
Heavy menstrual bleeding is a subjective finding, making the exact problem definition difficult. Treatment regimens must address the specific facet of the menstrual cycle the patient perceives to be abnormal, (ie, cycle length, quantity of bleeding). Finally, treatment success usually is evaluated subjectively by each patient, making positive outcome measurement difficult.
Pathophysiology: Knowledge of normal menstrual function is imperative in understanding the etiologies of menorrhagia. Four phases constitute the menstrual cycle, follicular, luteal, implantation, and menstrual.
In response to gonadotropin-releasing hormone (GnRH) from the hypothalamus, the pituitary gland synthesizes follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which induce the ovaries to produce estrogen and progesterone.
During the follicular phase, estrogen stimulation results in an increase in endometrial thickness. This also is known as the proliferative phase.
The luteal phase is intricately involved in the process of ovulation. During this phase, also known as the secretory phase, progesterone causes endometrial maturation.
If fertilization occurs, the implantation phase is maintained. Without fertilization, estrogen and progesterone withdrawal results in menstruation.
Etiologic causes are numerous and often unknown. Factors contributing to menorrhagia can be sorted into several categories, including organic, endocrinologic, anatomic, and iatrogenic.
If the bleeding workup does not provide any clues to the etiology of the menorrhagia, a patient often is given the diagnosis of dysfunctional uterine bleeding (DUB). Most cases of DUB are secondary to anovulation. Without ovulation, the corpus luteum fails to form, resulting in no progesterone secretion. Unopposed estrogen allows the endometrium to proliferate and thicken. The endometrium finally outgrows its blood supply and degenerates. The end result is asynchronous breakdown of the endometrial lining at different levels. This also is why anovulatory bleeding is heavier than normal menstrual flow.
Hemostasis of the endometrium is directly related to the functions of platelets and fibrin. Deficiencies in either of these components results in menorrhagia for patients with von Willebrand disease or thrombocytopenia. Thrombi are seen in the functional layers but are limited to the shedding surface of the tissue. These thrombi are known as "plugs" because blood can only partially flow past them. Fibrinolysis limits the fibrin deposits in the unshed layer. Following thrombin plug formation, vasoconstriction occurs and contributes to hemostasis.
Anatomic defects or growths within the uterus can alter either of the aforementioned pathways (endocrinologic/hemostatic), causing significant uterine bleeding. The clinical presentation is dependent on the location and size of the gynecologic lesion.
Organic diseases also contribute to menorrhagia in the female patient. For example, in patients with renal failure, gonadal resistance to hormones and hypothalamic-pituitary axis disturbances result in menstrual irregularities. Most women in this renal state are amenorrheic, but others also develop menorrhagia. If uremic coagulopathy ensues, it usually is due to platelet dysfunction and abnormal factor VIII function. The resulting prolonged bleeding time causes menorrhagia that can be very tenuous to treat.
Due to the overwhelming factors that can contribute to the dysfunction of either the endocrine or hematological pathways, in-depth knowledge of an existing organic disease is just as imperative as understanding the menstrual cycle itself.
Frequency:
In the US: While menorrhagia remains a leading reason for gynecologic office visits, only 10-20% of all menstruating women experience blood loss severe enough to be defined clinically as menorrhagia.
Mortality/Morbidity: Infrequent episodes of menorrhagia usually do not carry severe risks to women’s general health.
Patients who lose more than 80 mL of blood, especially repetitively, are at risk for serious medical sequelae. These women are likely to develop iron-deficiency anemia as a result of their blood loss. Menorrhagia is the most common cause of anemia in premenopausal women. This usually can be remedied by simple ingestion of ferrous sulfate to replace iron stores. If the bleeding is severe enough to cause volume depletion, patients may experience shortness of breath, fatigue, palpitations, and other related symptoms. This level of anemia necessitates hospitalization for intravenous fluids and possible transfusion and/or intravenous estrogen therapy. Patients who do not respond to medical therapy may require surgical intervention to control the menorrhagia.
Other sequelae associated with menorrhagia usually are related to the etiology. For example, with hypothyroidism, patients may experience symptoms associated with a low-functioning thyroid (eg, cold intolerance, hair loss, dry skin, weight gain) in addition to the effects of significant blood loss.
Sex: Only females are affected by menorrhagia.
Age: Any woman of reproductive age who is menstruating may develop menorrhagia. Most patients with menorrhagia are older than 30 years. This is because the most common cause of heavy menses in the younger population is anovulatory cycles, in which bleeding does not occur at regular intervals.
CLINICAL
History: Symptoms related by a patient with menorrhagia often can be more revealing than laboratory tests. Considering the lengthy list of possible etiologies that contribute to menorrhagia, taking a detailed patient history is imperative. Inquiries should include the following:
Exclusion of pregnancy
This is the most common cause of irregular bleeding in women of reproductive age.
Pregnancy should be the first diagnosis to be excluded before further testing or medications are instituted.
Quantity and quality of bleeding
Quantity is a very subjective issue when considering vaginal bleeding. Best estimates usually are the only source clinicians have available to consider. Helpful references for totaling blood loss may include that the average tampon holds 5 mL and the average pad holds 5-15 mL of blood. Asking the patient what type of pad (liner vs overnight) was used and if it was soaked may add some insight into what the patient believes to be heavy bleeding.
Quality of bleeding involves the presence of clots and their size.
Age
Young patients, from menarche to the late-teen years, most commonly have anovulatory bleeding due to the immaturity of their hypothalamic-pituitary axis. If bleeding does not respond to usual therapy in this age group, a bleeding disorder must be considered.
Women aged 30-50 years may have organic or structural abnormalities. Fibroids or polyps are frequent anatomical findings. Organic causes can be anything from thyroid dysfunction to renal failure.
Postmenopausal women with any uterine bleeding should receive an immediate workup for endometrial cancer.
Endometrial hyperplasia must be considered in women who are obese, aged 70 or older, nulliparous, or have diabetes.
Pelvic pain and pathology
Knowing if a patient has any long-standing diagnosis or known pathology (eg, fibroids) is helpful.
Records from other physicians or hospitalizations may prevent redundancy in ordering lab work or diagnostic imaging.
Menses pattern from menarche
If a young patient has had irregular menses since menarche, the most common etiology of her bleeding is anovulation.
Anovulatory bleeding is most common in young girls (aged 12-18 y) and common in obese females of any reproductive age.
If a patient's bleeding normally occurs at regular intervals and the irregularity is new in onset, pathology must be ruled out, regardless of age.
Sexual activity
Simple vaginitis (eg, candidal, bacterial vaginosis) may cause intermenstrual bleeding, while gonorrhea and chlamydia may present with heavier bleeding attributed primarily to the copious discharge mixed with the blood.
Chlamydia is a common cause of postpartum endometritis, leading to vaginal bleeding in the weeks following a delivery.
A postpartum infection (eg, endometritis) also may be due to organisms unrelated to sexual activity.
Contraceptive use (intrauterine device or hormones)
Commonly, an intrauterine device (IUD) causes increased uterine cramping and menstrual flow.
If a patient has recently discontinued birth control pills, she may return to her "natural" menses and report an increase in flow. This actually is normal because most oral birth control pills decrease the flow and duration of a woman's menses.
Presence of hirsutism (polycystic ovarian syndrome)
These patients commonly are obese and in an anovulatory state. When they do have a period, it may be very heavy and cause concern for the patient.
The etiology of this is explained in the Introduction to this article.
Galactorrhea (pituitary tumor): Any patient complaining of a milky discharge from either breast (while not pregnant, postpartum, or breastfeeding) needs a prolactin level to rule out a pituitary tumor.
Systemic illnesses (hepatic/renal failure or diabetes)
As explained in the Introduction, organic diseases may affect either the hormonal or hematologic pathways that are involved in the manifestation of menorrhagia.
If either the hypothalamic-pituitary axis or the coagulation paths are disrupted, heavy bleeding may result.
Symptoms of thyroid dysfunction: The alteration of the hypothalamic-pituitary axis may create either amenorrhea (hyperthyroidism) or menorrhagia (hypothyroidism).
Excessive bruising or known bleeding disorders
This is especially important in a young patient who does not stop bleeding during her first menses.
This is a very common presentation for an undiagnosed bleeding disorder (von Willebrand disease) in a young girl.
Current medications (hormones or anticoagulants)
Any medication that prolongs bleeding time may cause menorrhagia.
A patient treated with any progestin therapy may have a withdrawal bleed after cessation of the medication. This bleeding often is heavy and worrisome to patients if they are not forewarned.
Previous medical or surgical procedures/diagnoses: This also is helpful in preventing duplication of testing.
Physical: The physical examination should be tailored to the differential diagnoses formulated by the results of the patient's history.
Initial inspection should include evaluation for the following:
Signs of severe volume depletion (eg, anemia): This may help confirm the patient's history of very heavy bleeding and/or prompt immediate inpatient care.
Obesity: This is an independent risk factor for endometrial cancer. Adipose tissue is a locale for estrogen conversion. Therefore, the larger the patient, the more increased the risk (and the higher the unopposed estrogen level on the endometrium).
Signs of androgen excess (eg, hirsutism): This usually points to polycystic ovarian syndrome (PCOS), leading to anovulatory bleeding (see Presence of hirsutism).
Ecchymosis: This usually is a sign of trauma or a bleeding disorder.
Purpura: This also is a sign of trauma or a possible bleeding disorder.
Pronounced acne: This is a sign of PCOS.
General examination should include evaluation of the following:
Visual fields
Bleeding gums
Thyroid evaluation
Galactorrhea
Enlarged liver or spleen
Pelvic examination should evaluate for the presence of external genital lesions.
Vaginal/cervical discharge: Look for a copious discharge indicating infection, and confirm the actual site of the bleeding (if present). Assess as follows:
Uterine size, shape, and contour: An enlarged irregularly shaped uterus suggests fibroids if the patient is aged 30-50 years. An enlarged uniformly shaped uterus in a postmenopausal patient with bleeding suggests endometrial cancer until proven otherwise.
Cervical motion tenderness: This is a common symptom of pelvic inflammatory disease (PID) that usually is caused by gonorrhea or chlamydia. This is an important diagnosis to exclude, especially in young nulliparous women, because it can lead to pelvic adhesions and infertility.
Adnexal tenderness or masses: This is especially concerning in patients older than 40 years. Ovarian cancer may present with intermenstrual bleeding as its only symptom. Rare but deadly ovarian tumors also can present in teenage girls. Any suspicion of an adnexal mass should prompt an immediate pelvic ultrasound.
Causes: Etiologies of menorrhagia are divided into 4 categories, organic, endocrinologic, anatomic, and iatrogenic.
Organic causes of menorrhagia include infection, bleeding disorders, and organ dysfunction.
Infections can be of any genitourinary origin. The aforementioned sexually transmitted diseases are of greater concern in the teenage and early adult population. Bleeding from the urethra or rectum always must be considered in the workup, especially in the postmenopausal woman who has negative findings after a workup for vaginal bleeding.
Coagulation disorders can evade diagnosis until menarche, when heavy menstrual bleeding presents as an unrelenting disorder. These include von Willebrand disease; factor II, V, VII, and IX deficiencies; prothrombin deficiency; idiopathic thrombocytopenia purpura (ITP); and thromboasthenia.
Organ dysfunction causing menorrhagia includes hepatic or renal failure. Chronic liver disease impairs production of clotting factors and reduces hormone metabolism (eg, estrogen). Either of these problems may lead to heavy uterine bleeding.
Endocrine causes of menorrhagia include thyroid and adrenal gland dysfunction, pituitary tumors, anovulatory cycles, PCOS, obesity, and vasculature imbalance.
Both hypothyroidism and hyperthyroidism result in menorrhagia. Even subclinical cases of hypothyroidism produce heavy uterine bleeding in 20% of patients. Menorrhagia usually resolves with correction of the thyroid disorder.
Prolactin-producing pituitary tumors cause menorrhagia by disrupting (GnRH) secretion. This leads to decreased LH and FSH levels, which ultimately cause hypogonadism. Interim stages of menorrhagia result until hypogonadism manifests.
The most common etiology of heavy uterine bleeding is anovulatory cycles. The finding of menorrhagia at irregular intervals without any known organic etiology confirms the clinical diagnosis. This is most common in adolescent and perimenopausal populations.
The hallmarks of PCOS are anovulation, irregular menses, obesity, and hirsutism. Insulin resistance is common and increases androgen production by the ovaries.
Hyperinsulinemia is a direct consequence of obesity. This overproduction of insulin leads to ovarian production of androgens, as occurs in PCOS.
Vasculature imbalance is theorized to be the result of a discrepancy between the vasoconstricting and aggregating actions of prostaglandin F2 (alpha) and thromboxane A2 and the vasodilating actions of prostaglandin E2 and prostacyclin on the myometrial and endometrial vasculature.
Anatomic etiologies for menorrhagia include uterine fibroids, endometrial polyps, endometrial hyperplasia, and pregnancy.
Fibroids and polyps are benign structures that distort the uterine wall and/or endometrium. Either may be located within the uterine lining, but fibroids may occur almost anywhere on the uterus.
The mechanism by which endometrial polyps or fibroids cause menorrhagia is not well understood. The blood supply to the fibroid or polyp is different compared to the surrounding endometrium and is thought to function independently. This blood supply is greater than the endometrial supply and may have impeded venous return, causing pooling in the areas of the fibroid. Heavy pooling is thought to weaken the endometrium in that area, and break-through bleeding ensues.
Fibroids located within the uterine wall may inhibit muscle contracture, thereby preventing normal uterine attempts at hemostasis. This also is why intramural fibroids may cause a significant amount of pain and cramping. Fibroids may enlarge to the point that they outgrow their blood supply and undergo necrosis. This also causes a great deal of pain for patients.
Endometrial hyperplasia usually results from unopposed estrogen production, regardless of the etiology. Endometrial hyperplasia can lead to endometrial cancer in 1-2% of patients with anovulatory bleeding, but it is a diagnosis of exclusion in postmenopausal bleeding (average age at menopause is 51 y). If a woman takes unopposed estrogen (without progesterone), her relative risk of endometrial cancer is 2.3 compared to nonusers and 9.5 if taken for 10 years or longer.
Iatrogenic causes of menorrhagia include IUDs, steroid hormones, chemotherapy agents, and medications (eg, anticoagulants).
IUDs can cause increased menstrual bleeding and cramping due to local irritation effects.
Steroid hormones and chemotherapy agents disrupt the normal menstrual cycle, which is restored easily upon cessation of the products.
Anticoagulants decrease clotting factors needed to cease any normal blood flow, including menses. This type of menorrhagia also is easily reversible. DIFFERENTIALS
Abortion Adnexal Tumors Adrenal Adenoma Adrenal Carcinoma Anovulation Cervicitis Endometrial Carcinoma Endometritis Gestational Trophoblastic Neoplasia Hyperprolactinemia Hyperthyroidism Hypothyroidism Obesity Pelvic Inflammatory Disease Pituitary Microadenomas Pregnancy Diagnosis Uterine Cancer Vaginitis
Other Problems to be Considered:
Coagulation disordersEndometrial polypsGenitourinary infectionIntrauterine deviceLiver disease/failureMedicationsRenal disease/failureSteroid hormonesUterine fibroidsVascular imbalance
Menopause 2
CARDIOVASCULAR
Coronary artery disease (CAD) is known to be increasingly prevalent with older age in both men and women. Menopause increases the risk for women still further, independent of age. Prior to menopause, the risk of CAD for women lags behind the risk for men by approximately 10 years. After menopause, women come to have similar risks of CAD as men of the same age. As a result, the rate of death in women from CAD is increasing. The Framingham study was pivotal in showing the relationship between menopause and increased cardiovascular mortality rate (Kannel, 1976).
The benefit of estrogen on cardiovascular mortality rates is due to many factors. One mechanism appears to be estrogen’s effects on lipid metabolism, which includes reducing low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL). Studies have suggested that the best predictors of CAD in men and women are different (Assman, 1998) and that triglycerides, HDL, and lipoprotein(a) may be more significant in women (Erikkson, 1999). Women with elevated lipoprotein(a) levels should be treated more aggressively, and the treatment considered should include ERT as well as a statin. A positive relationship between ERT and reduction of primary cardiovascular risk has been demonstrated in several studies, and the reduction in risk in women who are taking ERT may be similar to the risk reduction of those receiving specific lipid-lowering therapy (Darling, 1997).
The Heart and Estrogen/Progestin Replacement (HERS) Study (Hulley, 1998; Wells, 1999; Grady, 1998), a study of 2763 postmenopausal women with known CAD, compared the effect of continuous combined HRT versus that of placebo over an average of 4.2 years. No beneficial reduction of CAD event rates was initially observed in the HRT groups. In fact, the initial adverse event rate was higher in the treatment arm than in the placebo arm, which offset a later reduction in risk in the HRT group. An 11% reduction in LDL level and a 10% increase in HDL level were apparent in the treatment group. These observations together suggest that the protective effects of estrogen on cardiovascular morbidity result from many mechanisms and not solely from lowering of lipids, and that estrogen alone is not adequate therapy for secondary prevention of CAD.
The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, which included 875 healthy postmenopausal women, compared various CAD risk factors as predictors of outcomes in women who received various HRT regimens by randomizing the participants to receive placebo or 1 of 5 regimes of estrogen/progestin therapy (Writing Group for the PEPI Trial, 1995). All treatment groups showed an overall improvement in HDL and LDL levels compared to the placebo group. The improvement in HDL level was better in the group that received unopposed estrogen than in the other treatment groups; however, individuals using unopposed estrogen also had the highest rate of endometrial hyperplasia.
The Nurses’ Health Study demonstrated an approximately 11% risk reduction for primary cardiovascular disease in postmenopausal women using HRT compared with women who had never used HRT, irrespective of duration of use (Grodstein, 2000). The risk reduction did not appear to be dose dependent. ERT has a role in primary prevention of CAD.
The greatest beneficial effect of estrogen appears to be on endothelial function. Women undergoing angioplasty appear to be protected against restenosis by ERT (Abu-Halawa, 1998). Progression of early atherosclerosis in postmenopausal women who smoked, as measured by carotid intimal thickness, was greater over time than in women who smoked and were on ERT (Teeds, 1999).
BREAST CANCER ISSUES
ERT is known to benefit postmenopausal women in a multitude of ways, although some data indicate that ERT increases the risk of breast cancer. Estrogen's possible link to cancer is also suggested by the fact that the risk of breast cancer is increased in women with an earlier age at menarche and later age at menopause. With early age at pregnancy, however, and the interruption of menstrual hormonal changes, a reduction in risk is observed.
Data suggest a slightly increased RR with estrogen use at approximately 1.1-1.3 (Schairer, 2000; Collaborative Group on Hormonal Factors in Breast Cancer, 1997), but not all the evidence supports this finding (Gapstur, 1999). The risk appears to be related to duration of use, with longer-term users being more affected (Lando, 1999).
Data suggest that the addition of sequential progestin to the regime increases the RR of subsequently developing breast cancer beyond the risk of estrogen alone, although the suggestion has been made that continuous combined HRT using much smaller doses of progestin attenuates this risk (Ross, 2000). Most earlier studies evaluating breast cancer risk and ERT were conducted at a time when the progestin in HRT was administered on a cyclical basis.
Notably, women with a history of using HRT have more localized tumors as well as better survival rates. That is, women receiving HRT who are diagnosed with breast cancer are found to have more favorable staging at the time of diagnosis (Collaborative Group on Hormonal Factors in Breast Cancer, 1997), including smaller tumor size, negative lymph node involvement, and more well-differentiated tumor histology (Colditz, 1990; Holli, 1990; Strickland, 1992; Squiteri, 1994; Bonnier, 1995; Salmon, 1995; Harding, 1996; Magnusson, 1996; Fowble, 1999).
A beneficial effect on breast cancer mortality rates has been shown in postmenopausal women who have received HRT compared with controls who have no prior history of HRT use (Schairer, 2000). Study findings do not agree on whether this is due to earlier detection or to effects of the therapy itself on breast tissue. The general belief is that any increase in risk is small and that each patient should be evaluated as a candidate for ERT on an individual basis, with consideration of the overall balance of risks and benefits. An essential precept in the management of menopause is that each individual is unique and that therapy should be tailored accordingly.
CENTRAL NERVOUS SYSTEM EFFECTS
The association of estrogen and memory function is an intriguing area of research. Normal aging itself induces a decline in certain cognitive capabilities, and a lack of estrogen may contribute to this process. If this is the case, postmenopausal ERT may be able to preserve this function and slow or even prevent decline in certain cognitive functions. An inherent difficulty in this area of study is the limitations of objective cognitive testing for functions such as memory. In general, ERT is associated with better performance on memory testing in postmenopausal women than in postmenopausal controls who are not receiving ERT (Sherwin, 1997; Resnick, 1997). The estrogen effect is one of slowing the decline of preserved memory function. Further clinical research must be conducted in this area to differentiate the benefits of estrogen in cognitive function in women who develop clinical dementia and those who do not.
Currently, data suggest that women have a higher incidence of Alzheimer disease than men, even after allowing for the longer life span of women, because Alzheimer disease is primarily an age-related condition (Anderson, 1999). ERT appears to reduce the RR of developing this condition and/or to delay its onset (Tang, 1996; Kawas, 1997). Estrogen has not been demonstrated to show an improvement in cognitive function in patients with Alzheimer disease, that is, it cannot reverse previous cognitive decline and therefore has no role as a sole treatment modality in Alzheimer disease. However, estrogen may be beneficial as adjuvant therapy in conjunction with cholinesterase inhibitors.
Perimenopause is frequently a time of depressive symptoms associated with direct hormonal effects through variation in levels and changes in life circumstances and secondary to effects such as estrogen-related sleep disturbance and vasomotor symptoms. However, major depression is associated with the female sex at all ages, and objective demonstration of a cluster of cases around menopause has been difficult, although this appears to be anecdotally true.
Regardless of whether the criteria for a definitive diagnosis of major depression are met, depressive symptoms should always be considered in the context of level of functioning; any impairment warrants consideration of intervention.
In all but a very few cases, distinguishing the etiology of the symptoms as menopausal versus primary depression is usually not possible. Treatment of depressive symptoms with estrogen in perimenopause, the postpartum period (Gregoire, 1996), and premenstrual syndrome is common, with observed resultant improvement in functioning and mood, both subjective and objective, in many clinical instances. Clinical depression, however, warrants treatment with antidepressants, with estrogen showing benefit as adjuvant therapy in this scenario.
The microcellular effects of estrogen in the CNS have yet to be clearly outlined but may reveal intricate processes by which estrogen has a direct effect in CNS functioning. One of these processes may turn out to be a reduction in free radical damage by ERT.
MENOPAUSE MARKERS
Gonadotropin secretion increases dramatically after menopause. FSH levels are higher than LH levels, and both rise to even higher levels than in the surge during the menstrual cycle. The FSH rise precedes that of LH. The large cyclical variation of estradiol and estrone observed during the menstrual years ceases, and fluctuation in levels is small and inconsequential, with the mean being very much lower. The levels of circulating estradiol have very different ranges before and after menopause, and these levels are obviously much lower in menopause. Smears of the vaginal epithelium provide a composite picture of endogenous and exogenous estrogen stimulation over time; the more estrogen, the greater the number of superficial cells. No specific changes related to menopause have been found in thyroid function.
Endometrial biopsy can show a range of endometrial appearances, from mildly proliferate to atrophic. No secretory changes are observed after menopause because no ovulation occurs, and therefore no corpus luteum forms to produce progesterone. Endometrial hyperplasia is a sign of hyperstimulation by estrogen from either endogenous sources or replacement therapy and may be a precursor of endometrial cancer. Endometrial hyperplasia can also be suggested by ultrasonography (an endometrial thickness of >5 mm), which is useful in trying to exclude hyperplasia and cancer of the endometrium in postmenopausal women.
REPLACEMENT THERAPY
Among the many reasons to treat symptoms of estrogen level fluctuation prior to actual menopause are to provide relief of vasomotor symptoms, reduce the risk of unwanted pregnancy, avoid the irregularity of menstrual cycles, and mitigate the long-term effects of menopause (eg, osteoporosis, cardiovascular disease, decline in cognitive function).
The time to begin therapy depends on the patient’s current illness(es), if any, and medical history. Whether a woman is perimenopausal or postmenopausal helps in choosing the most suitable type of therapy. Each patient should make a choice after receiving counseling on all the facts and an explanation of the options. For example, the perimenopausal woman may be started on HRT if either she or her spouse has undergone a sterilization procedure, whereas the same woman may need an OCP if she still needs birth control. Many factors, including personal history, family history, smoking, peer and commercial influences, culture, ethnicity, and economics, also play roles in the final decision, and all must be carefully weighed by the doctor and patient together.
Adverse effects of replacement therapy may include bloating, mastodynia, vaginal bleeding, and headaches. Unexplained adverse effects are often the reason for discontinuation of therapy, and reassuring counseling as well as options and dose combinations should be tried before therapy is stopped.
HRT can be administered systemically through the oral, transdermal, or topical routes or locally via the vaginal route using cream, ring, or tablet. Topical preparations are used solely to treat vaginal symptoms.
Contraindications to estrogen therapy are undiagnosed vaginal bleeding, severe liver disease, pregnancy, and venous thrombosis. Well-differentiated and early endometrial cancer, once treatment for the malignancy is completed, is no longer an absolute contraindication. Estrogen receptor–positive breast carcinoma has traditionally been a contraindication, but this has also been challenged recently. Progestins alone may relieve symptoms if the patient is unable to tolerate estrogens, but the other concomitant protective effects of estrogen are lost. Alternative products—ranging from herbal preparations to dietary supplements containing various phytoestrogens—are reputed to ease the transition from perimenopause to postmenopause and are widely available. However, these agents require rigorous and objective evaluation, which has yet to be conducted.
Coronary artery disease (CAD) is known to be increasingly prevalent with older age in both men and women. Menopause increases the risk for women still further, independent of age. Prior to menopause, the risk of CAD for women lags behind the risk for men by approximately 10 years. After menopause, women come to have similar risks of CAD as men of the same age. As a result, the rate of death in women from CAD is increasing. The Framingham study was pivotal in showing the relationship between menopause and increased cardiovascular mortality rate (Kannel, 1976).
The benefit of estrogen on cardiovascular mortality rates is due to many factors. One mechanism appears to be estrogen’s effects on lipid metabolism, which includes reducing low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL). Studies have suggested that the best predictors of CAD in men and women are different (Assman, 1998) and that triglycerides, HDL, and lipoprotein(a) may be more significant in women (Erikkson, 1999). Women with elevated lipoprotein(a) levels should be treated more aggressively, and the treatment considered should include ERT as well as a statin. A positive relationship between ERT and reduction of primary cardiovascular risk has been demonstrated in several studies, and the reduction in risk in women who are taking ERT may be similar to the risk reduction of those receiving specific lipid-lowering therapy (Darling, 1997).
The Heart and Estrogen/Progestin Replacement (HERS) Study (Hulley, 1998; Wells, 1999; Grady, 1998), a study of 2763 postmenopausal women with known CAD, compared the effect of continuous combined HRT versus that of placebo over an average of 4.2 years. No beneficial reduction of CAD event rates was initially observed in the HRT groups. In fact, the initial adverse event rate was higher in the treatment arm than in the placebo arm, which offset a later reduction in risk in the HRT group. An 11% reduction in LDL level and a 10% increase in HDL level were apparent in the treatment group. These observations together suggest that the protective effects of estrogen on cardiovascular morbidity result from many mechanisms and not solely from lowering of lipids, and that estrogen alone is not adequate therapy for secondary prevention of CAD.
The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, which included 875 healthy postmenopausal women, compared various CAD risk factors as predictors of outcomes in women who received various HRT regimens by randomizing the participants to receive placebo or 1 of 5 regimes of estrogen/progestin therapy (Writing Group for the PEPI Trial, 1995). All treatment groups showed an overall improvement in HDL and LDL levels compared to the placebo group. The improvement in HDL level was better in the group that received unopposed estrogen than in the other treatment groups; however, individuals using unopposed estrogen also had the highest rate of endometrial hyperplasia.
The Nurses’ Health Study demonstrated an approximately 11% risk reduction for primary cardiovascular disease in postmenopausal women using HRT compared with women who had never used HRT, irrespective of duration of use (Grodstein, 2000). The risk reduction did not appear to be dose dependent. ERT has a role in primary prevention of CAD.
The greatest beneficial effect of estrogen appears to be on endothelial function. Women undergoing angioplasty appear to be protected against restenosis by ERT (Abu-Halawa, 1998). Progression of early atherosclerosis in postmenopausal women who smoked, as measured by carotid intimal thickness, was greater over time than in women who smoked and were on ERT (Teeds, 1999).
BREAST CANCER ISSUES
ERT is known to benefit postmenopausal women in a multitude of ways, although some data indicate that ERT increases the risk of breast cancer. Estrogen's possible link to cancer is also suggested by the fact that the risk of breast cancer is increased in women with an earlier age at menarche and later age at menopause. With early age at pregnancy, however, and the interruption of menstrual hormonal changes, a reduction in risk is observed.
Data suggest a slightly increased RR with estrogen use at approximately 1.1-1.3 (Schairer, 2000; Collaborative Group on Hormonal Factors in Breast Cancer, 1997), but not all the evidence supports this finding (Gapstur, 1999). The risk appears to be related to duration of use, with longer-term users being more affected (Lando, 1999).
Data suggest that the addition of sequential progestin to the regime increases the RR of subsequently developing breast cancer beyond the risk of estrogen alone, although the suggestion has been made that continuous combined HRT using much smaller doses of progestin attenuates this risk (Ross, 2000). Most earlier studies evaluating breast cancer risk and ERT were conducted at a time when the progestin in HRT was administered on a cyclical basis.
Notably, women with a history of using HRT have more localized tumors as well as better survival rates. That is, women receiving HRT who are diagnosed with breast cancer are found to have more favorable staging at the time of diagnosis (Collaborative Group on Hormonal Factors in Breast Cancer, 1997), including smaller tumor size, negative lymph node involvement, and more well-differentiated tumor histology (Colditz, 1990; Holli, 1990; Strickland, 1992; Squiteri, 1994; Bonnier, 1995; Salmon, 1995; Harding, 1996; Magnusson, 1996; Fowble, 1999).
A beneficial effect on breast cancer mortality rates has been shown in postmenopausal women who have received HRT compared with controls who have no prior history of HRT use (Schairer, 2000). Study findings do not agree on whether this is due to earlier detection or to effects of the therapy itself on breast tissue. The general belief is that any increase in risk is small and that each patient should be evaluated as a candidate for ERT on an individual basis, with consideration of the overall balance of risks and benefits. An essential precept in the management of menopause is that each individual is unique and that therapy should be tailored accordingly.
CENTRAL NERVOUS SYSTEM EFFECTS
The association of estrogen and memory function is an intriguing area of research. Normal aging itself induces a decline in certain cognitive capabilities, and a lack of estrogen may contribute to this process. If this is the case, postmenopausal ERT may be able to preserve this function and slow or even prevent decline in certain cognitive functions. An inherent difficulty in this area of study is the limitations of objective cognitive testing for functions such as memory. In general, ERT is associated with better performance on memory testing in postmenopausal women than in postmenopausal controls who are not receiving ERT (Sherwin, 1997; Resnick, 1997). The estrogen effect is one of slowing the decline of preserved memory function. Further clinical research must be conducted in this area to differentiate the benefits of estrogen in cognitive function in women who develop clinical dementia and those who do not.
Currently, data suggest that women have a higher incidence of Alzheimer disease than men, even after allowing for the longer life span of women, because Alzheimer disease is primarily an age-related condition (Anderson, 1999). ERT appears to reduce the RR of developing this condition and/or to delay its onset (Tang, 1996; Kawas, 1997). Estrogen has not been demonstrated to show an improvement in cognitive function in patients with Alzheimer disease, that is, it cannot reverse previous cognitive decline and therefore has no role as a sole treatment modality in Alzheimer disease. However, estrogen may be beneficial as adjuvant therapy in conjunction with cholinesterase inhibitors.
Perimenopause is frequently a time of depressive symptoms associated with direct hormonal effects through variation in levels and changes in life circumstances and secondary to effects such as estrogen-related sleep disturbance and vasomotor symptoms. However, major depression is associated with the female sex at all ages, and objective demonstration of a cluster of cases around menopause has been difficult, although this appears to be anecdotally true.
Regardless of whether the criteria for a definitive diagnosis of major depression are met, depressive symptoms should always be considered in the context of level of functioning; any impairment warrants consideration of intervention.
In all but a very few cases, distinguishing the etiology of the symptoms as menopausal versus primary depression is usually not possible. Treatment of depressive symptoms with estrogen in perimenopause, the postpartum period (Gregoire, 1996), and premenstrual syndrome is common, with observed resultant improvement in functioning and mood, both subjective and objective, in many clinical instances. Clinical depression, however, warrants treatment with antidepressants, with estrogen showing benefit as adjuvant therapy in this scenario.
The microcellular effects of estrogen in the CNS have yet to be clearly outlined but may reveal intricate processes by which estrogen has a direct effect in CNS functioning. One of these processes may turn out to be a reduction in free radical damage by ERT.
MENOPAUSE MARKERS
Gonadotropin secretion increases dramatically after menopause. FSH levels are higher than LH levels, and both rise to even higher levels than in the surge during the menstrual cycle. The FSH rise precedes that of LH. The large cyclical variation of estradiol and estrone observed during the menstrual years ceases, and fluctuation in levels is small and inconsequential, with the mean being very much lower. The levels of circulating estradiol have very different ranges before and after menopause, and these levels are obviously much lower in menopause. Smears of the vaginal epithelium provide a composite picture of endogenous and exogenous estrogen stimulation over time; the more estrogen, the greater the number of superficial cells. No specific changes related to menopause have been found in thyroid function.
Endometrial biopsy can show a range of endometrial appearances, from mildly proliferate to atrophic. No secretory changes are observed after menopause because no ovulation occurs, and therefore no corpus luteum forms to produce progesterone. Endometrial hyperplasia is a sign of hyperstimulation by estrogen from either endogenous sources or replacement therapy and may be a precursor of endometrial cancer. Endometrial hyperplasia can also be suggested by ultrasonography (an endometrial thickness of >5 mm), which is useful in trying to exclude hyperplasia and cancer of the endometrium in postmenopausal women.
REPLACEMENT THERAPY
Among the many reasons to treat symptoms of estrogen level fluctuation prior to actual menopause are to provide relief of vasomotor symptoms, reduce the risk of unwanted pregnancy, avoid the irregularity of menstrual cycles, and mitigate the long-term effects of menopause (eg, osteoporosis, cardiovascular disease, decline in cognitive function).
The time to begin therapy depends on the patient’s current illness(es), if any, and medical history. Whether a woman is perimenopausal or postmenopausal helps in choosing the most suitable type of therapy. Each patient should make a choice after receiving counseling on all the facts and an explanation of the options. For example, the perimenopausal woman may be started on HRT if either she or her spouse has undergone a sterilization procedure, whereas the same woman may need an OCP if she still needs birth control. Many factors, including personal history, family history, smoking, peer and commercial influences, culture, ethnicity, and economics, also play roles in the final decision, and all must be carefully weighed by the doctor and patient together.
Adverse effects of replacement therapy may include bloating, mastodynia, vaginal bleeding, and headaches. Unexplained adverse effects are often the reason for discontinuation of therapy, and reassuring counseling as well as options and dose combinations should be tried before therapy is stopped.
HRT can be administered systemically through the oral, transdermal, or topical routes or locally via the vaginal route using cream, ring, or tablet. Topical preparations are used solely to treat vaginal symptoms.
Contraindications to estrogen therapy are undiagnosed vaginal bleeding, severe liver disease, pregnancy, and venous thrombosis. Well-differentiated and early endometrial cancer, once treatment for the malignancy is completed, is no longer an absolute contraindication. Estrogen receptor–positive breast carcinoma has traditionally been a contraindication, but this has also been challenged recently. Progestins alone may relieve symptoms if the patient is unable to tolerate estrogens, but the other concomitant protective effects of estrogen are lost. Alternative products—ranging from herbal preparations to dietary supplements containing various phytoestrogens—are reputed to ease the transition from perimenopause to postmenopause and are widely available. However, these agents require rigorous and objective evaluation, which has yet to be conducted.
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