Menopause 1

Menopause

INTRODUCTION
Menopause is a universal and irreversible part of the overall aging process involving a woman’s reproductive system, after which she no longer menstruates. Climacteric is the general term for the time from the period of this transition to the early postmenopausal phase of a woman’s reproductive life cycle.
Perimenopause refers to the time before menopause when vasomotor symptoms and irregular menses often commence. Menopause, by definition, begins 12 months after the final menses and is characterized by a continuation of vasomotor symptoms and by urogenital symptoms such as vaginal dryness and dyspareunia.
Epidemiology
The increasing number of middle-aged and older individuals includes a concomitant and continuing rise in the number of women who live most of their lives in a hypoestrogenic state. More and more women can expect to live approximately 79 years and to experience the consequences of gonadal hormone loss.
Although the time spent in menopause (now up to one third of the life cycle) has increased with the phenomenon of increasing longevity, the actual age of menopause, approximately 50-51 years, has not changed since antiquity. Women from ancient Greece experienced menopause at the same age as modern women, with the symptomatic transition to menopause usually commencing at approximately age 45.5-47.5 years (McKinlay, 1981; Cramer, 1995). Factors that lower the age of physiologic menopause are few and include smoking (Cramer, 1995), hysterectomy, and living at high altitudes.
Physiology
Menopause results from loss of ovarian sensitivity to gonadotropin stimulation, which is directly related to follicular decline and dysfunction. The oocytes in the ovaries undergo atresia throughout a woman’s life cycle, and both the quantity and quality of follicles undergo a critical decline approximately 20-25 years after menarche. Thus, the variable menstrual cycle length during perimenopause can be due to anovulation or to irregular maturation of follicles. Hormonal fluctuation may not be responsible for all irregular bleeding during this period; therefore, pelvic pathology (eg, uterine fibroids, uterine polyps, endometrial hyperplasia, endometrial cancer), which becomes more prevalent during this time, must be excluded.
During the fifth decade of life, many women are lulled into a false sense of security, thinking that they are no longer fertile because they are so close to menopause. Although fertility declines, pregnancy can still occur, as demonstrated by a relatively high rate of unintended pregnancies in women aged 40-44 years. In fact, the number of unintended pregnancies in this age group has increased over the past decade (Henshaw, 1998), which underscores the need for continued contraceptive practice in heterosexual couples.
A shorter menstrual cycle length is the most common change in menstrual cyclicity that occurs during the perimenopausal period in women who have no pelvic pathology and who continue to be ovulatory (Santoro, 1996). The follicular phase of the menstrual cycle shortens because of the decreased number of functional follicles. Because these follicles, which are stimulated by follicle-stimulating hormone (FSH) during the first part of the menstrual cycle, have declined in number, less recruitment of oocytes occurs and the follicular phase shortens accordingly. However, once ovulation occurs, the luteal phase remains fairly constant, at 14 days.
Over time, as aging follicles become more resistant to gonadotropin stimulation, circulating FSH and luteinizing hormone (LH) levels increase. Elevated FSH and LH levels lead to stromal stimulation of the ovary, with a resultant increase in estrone levels and a decrease in estradiol levels. Inhibin levels also drop during this time because of the negative feedback of elevated FSH levels (Lenton, 1991). With the commencement of menopause and a loss of functioning follicles, the most significant change in the hormonal profile is the dramatic decrease in circulating estrogen levels. Without a follicular source, the larger proportion of postmenopausal estrogen is derived from ovarian stromal and adrenal secretion of androstenedione, which is aromatized to estrone in the peripheral circulation. Testosterone levels also decrease with menopause (Smith, 1994), but this decrease is not as marked as the decline in 17-estradiol (Wells, 1999).
With cessation of ovulation, estrogen production by the aromatization of androgens in the ovarian stroma and production in extragonadal sites continue, unopposed by progesterone production by a corpus luteum. Perimenopausal and menopausal women are thus often exposed to unopposed estrogen for long periods, which can lead to endometrial hyperplasia, a precursor of endometrial cancer. Estradiol levels decrease significantly because of loss of follicular production with menopause and postmenopause, but estrone, which is aromatized from androstenedione from nonfollicular sources, is still produced and is the major source of circulating estrogen in the postmenopausal female.
Androgen-to-estrogen aromatization can occur in adipose tissue, muscle, liver, bone, bone marrow, fibroblasts, and hair roots (Smith, 1994). Because most conversion of androgens to estrogens occurs in adipose tissue, it is frequently assumed that obese women, who have more circulating estrogen, should have fewer complaints of vasomotor symptoms. However, this is not always the case, and vasomotor symptoms of menopause can be as frequent and severe in heavier women as they are in thinner women.
The clinical indication that menopause has occurred is the measure of an elevated FSH level. Because the FSH level rises more than the LH level, owing to the reduced renal clearance of FSH compared with LH, obtaining an FSH level alone is not helpful. On the other hand, the FSH level may not be a reliable indicator because of the wide variation of FSH and LH levels in response to increased release of gonadotropin-releasing hormone (GnRH) by the hypothalamus and increased pituitary sensitivity to GnRH.
CLINICAL EFFECTS OF MENOPAUSE
Throughout the time when the physiologic changes in responsiveness to gonadotropins and their secretions occur, with resultant wide variation in hormonal levels, women often experience several symptoms that are collectively termed the climacteric syndrome. Typical climacteric symptoms include hot flashes or flushes, insomnia, weight gain and bloating, mood changes, irregular menses, mastodynia, and headache. As already noted, the length of time over which the climacteric occurs is widely variable; symptoms may begin during perimenopause and continue for 5-10 years after menopause.
Irregular ovarian function and considerable estrogen level fluctuation—not a deficiency of estrogen—cause climacteric symptoms during menopause; thus, stopping hormone fluctuation with oral contraceptive pills (OCPs) and hormone replacement therapy (HRT) alleviates climacteric symptoms. Ovarian function and menstruation therefore usually does not resume if the woman has experienced one year of amenorrhea. Cessation of menstruation in women of the appropriate age continues to be the best confirmation of loss of follicular function. As the postmenopause years progress, with an accompanying loss of ovarian response to gonadotropins, associated symptoms of the climacteric also decline.
The effects of gonadal hormone depletion can be obvious on pelvic examination, with changes noted as early as perimenopause in some women. The reproductive organs of a woman of reproductive age greatly differ in appearance from those of a woman who is menopausal. With loss of estrogen, the vaginal epithelium becomes redder because of thinning of the epithelial layer and increased visibility of the small capillaries below the surface. Later, as the vaginal epithelium further atrophies, the surface becomes pale because of a reduced number of capillaries. A decrease in urine pH leading to a change in bacterial flora may result in pruritus and a malodorous discharge. Rugation also diminishes, and the vaginal wall becomes smooth. Such changes often result in insertional dyspareunia and, for many women, eventually lead to sexual abstinence if left untreated.
Inside the pelvis, the uterus becomes smaller. Fibroids, if present, become less symptomatic, sometimes shrinking to the point that they can no longer be palpated on pelvic examination. Endometriosis and adenomyosis are also alleviated with the onset of menopause, and many patients with pelvic pain finally achieve permanent pain relief.
The menopausal ovary diminishes in size and is no longer palpable during gynecologic examination. A palpable ovary on pelvic examination warrants a full evaluation in all women who are menopausal or postmenopausal.
For most older women, a general loss of pelvic tone also occurs, and this may manifest as prolapse of reproductive or urinary tract organs. Vaginal pressure, lower back pressure, or bulging at the vaginal introitus is common in women with prolapse. On examination, cystocele, rectocele, and uterine prolapse are obvious as causes of these symptoms.
Atrophic cystitis, when present, can mimic a urinary tract infection. Women report symptoms of urinary frequency, urgency, and incontinence. However, women are more prone to urinary tract infection during this time because of atrophic cystitis, and a urine culture should be obtained in all symptomatic women.
In addition to alterations in the pelvic organs, marked changes occur throughout the body. Skin loses elasticity, bone mineral density (BMD) declines, and dense breast tissue is replaced by adipose tissue, making mammographic evaluation easier.
The most common reason a woman presents at menopause is because of symptomatic hot flashes. Flashes, or flushes, which are unpredictable in onset and sometimes occur over many years, are reported in about 75% of women who are perimenopausal or postmenopausal. Hot flashes often cause embarrassment and discomfort, as well as sleep disturbances and emotional lability, especially if they are intense and occur frequently. Vasomotor episodes usually last a few minutes. Episodes vary in frequency from every hour to every few days.
A woman who flushes to the extent that she has major sleep disturbances may also complain of cognitive or affective disorders resulting from sleep deprivation. The vasomotor flush is described as a feeling of warmth or heat that begins from the umbilical area and moves upward toward the head, followed by sweating of the head and upper body. Other cardiovascular or neurologic symptoms (eg, palpitations, dizziness, light-headedness, vertigo) can also occur, with or without flushing, making the episode more difficult to classify as simply a climacteric symptom. Because of the wide range of symptoms, symptomatic women who have risk factors for a condition other than menopause should undergo thorough evaluation.
OSTEOPOROSIS
Although osteoporosis is one of the most pervasive conditions in older women, the condition is often not taken seriously enough by menopausal women. With proper intervention, osteopenia is a largely preventable sequela of menopause. A recently published article by Grady and Cummings (2001), a meta-analysis of 22 trials with data on a total of 8800 women, found a 27% reduction in risk of nonvertebral fractures in older women who received HRT. For hip and wrist fractures, the risk reduction was 40%, increasing to 55% in women younger than 60 years.
With the onset of menopause, BMD is rapidly lost because bone resorption, uncoupled from bone formation, is accelerated, whereas formation continues at the premenopausal rate. Trabecular bone is affected more than cortical bone, and bone loss is therefore more commonly observed at vertebral, coxal, and radial sites. Normal bone loss associated with senescence is different from the accelerated bone loss observed after menopause. Bone loss in just the few years after onset of menopause may be as high as 20% of lifetime bone loss (Grady, 2001).
The overall effect of menopausal bone loss is reduction of bone strength, leading to an increased risk of fracture. The younger the woman at cessation of ovarian function, the more severe bone loss is likely to be. Similarly, the lower the woman’s bone mass when entering menopause, the more severe the osteoporosis will be. Severity of osteoporosis is also related to race, being worse in whites than in Asians, and least severe in women with dark complexions. Other risk factors are smoking and slender build. Osteoclasts have been shown to have estrogen receptors, and these are hypothesized to be the mechanism by which estrogen replacement protects against osteoporosis.
Bone densitometry is the most accurate clinical predictor of osteoporosis. If bone mass is less than 1 standard deviation below the average for the specific bone measured, then the individual is at a much higher risk of fracture. Other risk factors, such as low serum estrogen level, female sex, and low serum androgen level, have been shown to increase fracture risk but have not been found to have as strong an association as bone densitometry. Bone densitometry testing is recommended for all postmenopausal women. Neither the age of initial BMD screening nor the optimal frequency of screening has been determined.
As noted, estrogen therapy is considered the optimal therapy for osteoporosis. Oral and transdermal routes have been approved for osteoporosis prevention in postmenopausal women who are considered at risk. Postmenopausal women and elderly women should be treated early and on a long-term basis unless estrogen replacement therapy (ERT) is contraindicated.
Because loss of ovarian function is a universal occurrence and not all women can or will use HRT, other therapies have been developed. These include raloxifene, calcitonin, and bisphosphonates. Raloxifene acts directly on estrogen receptors and modulates them to decrease bone resorption, resulting in reduced vertebral fracture risk (Ettinger, 1999) and increased BMD. No effect on hip fracture risk has been documented (Ettinger, 1999).
Calcitonin is a peptide hormone that acts by inhibiting osteoclasts, which are involved in bone resorption activity. A decreased vertebral fracture rate has been demonstrated with this therapy, as has a small increase in BMD in older women. Serum calcium levels must be monitored in patients taking this drug.
Bisphosphonates are the most useful pharmacological intervention and work as antiresorptives. They have been shown to have a beneficial effect on vertebral and hip fracture rates and to cause a more significant increase in BMD than raloxifene and calcitonin (Harris, 1999; Black, 1996). Two widely used and effective bisphosphonates are alendronate and risedronate. The Vertebral Efficacy With Risedronate Therapy (VERT) study was conducted at 110 centers and included 2458 postmenopausal women who had vertebral fractures. Risedronate was administered at a dose of 5 mg for 36 months and showed a statistically significant reduction in relative risk (RR) of new vertebral fractures (RR = 0.59, 95% confidence interval [CI], 18-58%). Cumulative incidence of nonvertebral fractures was also reduced (Harris, 1999).
Alendronate was first introduced with 10 mg daily dosing for treatment of osteoporosis. Patients can now be prescribed a weekly 70-mg dose. Supplementation to 1000-1500 mg of calcium per day remains a mainstay of prevention therapy, as does vitamin D supplementation and regular weight-bearing exercise. Excessive salt, animal protein, alcohol, and caffeine offset these benefits. Unlike estrogens, which are commonly administered for many years, often decades, the long-term use of bisphosphonates has not been fully studied and is currently under investigation.