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Chapter 24 Menopause


Natural menopause occurs between ages 45 and 55, with a median age of 51 for women in industrialized countries.1 Available evidence suggests that in less-developed countries with lower socioeconomic and nutritional level this event takes place earlier.2,3 These differences in onset of menopause support the hypothesis that menopause might not only be genetic, but may also be a biological marker echoing society’s longevity.

The significant medical and technologic gains of the past century in medicine and to some extent, the constant betterment of living standards, have yielded an improvement in life expectancy. In some countries increases of more than 40 years of life expectancy have been observed during the past 100 years alone.4 The life expectancy for women at birth in the United States is age 79.9.5

As a consequence of this demographic evolution, a large proportion of the female population will spend more than one third of their lives after the menopause. In 1950 there were 220 million women in the world older than age 50. More than half of these women lived in the so-called developed world (112 million). In 1990, there were 467 million women older than age 50 around the globe, and by 2030 this number is expected to approach 1.2 billion. Roughly three out of four of these menopausal women will be in the developing world (total of 912 million).6 At a national level, the U.S. Census Bureau calculated a total of 35.5 million women older than age 50 during the 1990 census, and by 1997 the menopausal population in the United States represented almost 30% of the total female population. By 2030, the menopausal population in the United States is expected to reach 66.5 million, representing 38% of the female population and 20 % of the entire population.7

These demographic changes will reflect an “inverted pyramid” phenomenon in certain countries. In this scenario, the elderly to nonelderly population ratio will significantly change, with obvious challenging consequences in the economic balance between productivity and expenditure. For these reasons understanding the menopausal state, associated diseases, and its full impact to society are fundamental for health providers and health policy makers. The present chapter aims at providing an overview of this challenge.


The supply of primordial follicles in the female gonad is predetermined before birth and diminishes with age until the gonad is unable to provide enough mature follicles to sustain menstrual cyclicity.8 The peak number of germ cell count is found at 20 weeks’ gestation, with decreased numbers at birth and puberty. Based on the number of follicles at three successive stages of development, which were obtained by counting follicles in histologic sections of ovaries from 52 normal women, a mathematical model was developed to describe the rates of growth and death of ovarian follicles in human ovaries between ages 19 and 50.9 While the number of oocytes dwindles throughout a woman’s life,10 there seems to be a transition at age 38 when the rate of follicle disappearance is augmented considerably with age. As a consequence, an estimated total of 1500 follicles remain at age 50 from the 300,000 present at age 19. This high death rate of small follicles appears to be responsible for advancing the timing of ovarian failure, and therefore of menopause, to midlife in our species.

Age of Menopause

The mean age of menopause in normal women in the United States ranges between age 50 and 52.11 This number was based on a cross-sectional study, which is associated with recall bias. However, these findings have been confirmed in a large prospective cohort study of middle-aged women: the Massachusetts Women’s Health Study. The cohort of 2570 women that was followed confirmed that the median age of natural menopause was 51.3 years with a mean difference of 1.8 years between current smokers and nonsmokers. This study also showed that smokers not only show an earlier menopause, but also a shorter perimenopause.12

In other parts of the world, population-based surveys have shown earlier onset of menopause. For example, the median age of onset of menopause was 48 in a survey of 742 United Arab Emirates women.13 In certain regions of India, such as the state of Himachal Pradesh, the mean age of onset of menopause can be as low as 43.5 years, according to data from 500 postmenopausal women.14

Factors Affecting the Onset of Menopause

Table 24-1 includes several factors that have been linked with an earlier onset of menopause. Among these factors, smoking has been the most often linked environmental agent to early age of onset of menopause. However, these studies have been inconclusive with regard to duration and intensity of smoking. Midgette and Baron concluded after a review of 14 studies that the risk of being menopausal was approximately doubled for current smokers compared with nonsmokers among women age 44 to 55.15 However, in 2004 van Asselt and colleagues, using data from a Dutch population-based cohort of 5544 women, assessed the effect of smoking duration and intensity on age at menopause, correcting for the chronologic age-dependency of the variables concerned. After their modeling they concluded like previous researchers that smoking lowers the menopausal age. However, the reduction in the menopausal age appears not to be dependent on smoking duration, and it appears that smoking cigarettes could have an effect only around the time of menopause itself.16 In other words, the number of cigarettes smoked during perimenopause is apparently more significant than smoking history as the culprit of earlier age of onset of menopause among smoking women.

Table 24-1 Factors Associated with Earlier Onset of Menopause

Women treated with total abdominal hysterectomy appear to be at risk of early menopause. Concurrent unilateral oophorectomy was associated with an even earlier onset. However, previous tubal ligation does not influence the age of menopause.

Time Course of Oocyte Pool Depletion

It is estimated that the entire process from initiation of follicle growth until complete maturation and finally ovulation takes months.17,18 The majority of follicles will experience atresia by apoptosis at some point in their developmental process.19 Fifty percent of apoptosis occurs at the small antral follicle stage of 2.1 to 5mm. On the other hand, atresia of the resting follicles in the human fetus seems to be set off by a process of necrosis rather than apoptosis.20 It seems clear now that the age-related decline in ovarian function in women is the result of the decline in both quantity and quality of the resting ovarian follicle pool. Recently a total of 182 resting follicles from a young cadre of women (age 25–32) were compared with 81 resting follicles from an older group (age 38–45) for signs of age-related changes by transmission-electron microscopy. De Bruin and colleagues concluded that, in resting follicles, the morphologic changes with age are different from the changes seen in quality decline by atresia.20 The morphologic changes with age specifically comprise the mitochondria, the dilated smooth endoplasmic reticulum, and the Golgi complex.

Genetic Contribution

The age of natural menopause is determined by the interplay of genetic and environmental factors.21 There are cross-sectional22 and case-control23 population studies suggesting the existence of genetic variability in the age of menopause to be as high as 70%. However, a study conducted in the Netherlands in 164 mother-daughter pairs with a natural menopausal age estimated a hereditability of 44% (95% confidence interval [CI] 36%–50%). The authors conclude that these estimates are more accurate than those of previous studies that were done in twins and siblings because siblings shared many environmental factors.24


Until recently there was an absence of a relevant organized nomenclature system for the different stages of female reproductive aging. With this in mind the Stages of Reproductive Aging Workshop (STRAW) was held in Park City, Utah on July 23 and 24, 2001 (Fig. 24-1).


Figure 24-1 The STRAW staging system.

(From Soules MR: Executive Summary of STRAW, 2001.2527)

As noted in Figure 24-1 the anchor for the staging system is the final menstrual period (FMP). Five stages occur before and two after this anchor point. Stages −5 to −3 cover the reproductive period; stages −2 and −1 are the menopausal transition; and stages +1 and +2 are the postmenopause.

Among the most concrete achievements of STRAW was the development of clear and specific nomenclature, which was previously vague and confusing in the literature. The authors of STRAW recognize that this is a draft and these concepts might evolve as knowledge advances.2527


The diagnosis of menopause can be established when the absolute level of serum FSH is elevated. The threshold for the diagnosis of menopause will vary according to the assay employed. In any event, the level will be two standard deviations above the normal value of a reproductive-age woman on cycle day 3. The luteinizing hormone (LH) level is of little value in the evaluation or diagnosis of menopause.

The clinical diagnosis of menopause is established retrospectively once a patient has had more than 12 months of amenorrhea in conjunction with vasomotor symptoms such as hot flashes and headaches. At this point the patient has made the transition in the STRAW classification from −1 to +1.The range of symptoms due to immediate estrogen deficiency in women during STRAW stages −1 to +1 includes hot flashes and urogenital changes (see Table 24-1).2527

Hot Flashes

The vasomotor flush is the most characteristic trait of estrogen deficiency. It is experienced at least once in 75% of women during menopause. It is also one of the most puzzling symptoms of menopause, because the etiology and physiology remain incompletely understood.28 It is thought to be the result of a hypothalamic dysregulation from estrogen withdrawal that culminates in peripheral vasodilation and increase in blood flow. This results in heat loss and a decrease in core body temperature. The hypothalamic dysfunction is also manifested by simultaneous pulse of LH and presumably gonadotropin-releasing hormone (GnRH) that is coincident with the hot flash. Hot flash, hot flush, night sweats, and vasomotor symptoms are words frequently used to express the same experience. Hot flashes are defined subjectively as the recurrent transient sensation of heat that can be accompanied by palpitations, perspiration, chills, shivering, and feeling of anxiety. It is then a heat dissipation response that habitually begins in the face, neck, and chest and often becomes generalized.29

Although menopause is the most common cause of hot flashes, other causes should be considered. Fever is by far the most common cause of hot flashes, especially when coupled with a night sweat; thus, if during an episode of hot flashes the oral temperature is elevated the cause of the fever should be sought.

In general we can divide the potential causes of hot flashes into seven categories: systemic diseases, neurologic, alcohol– medication interaction, drugs, food additives, eating, and miscellaneous30 (Fig. 24-2). However, is important to emphasize that these other causes are much less common than those associated with hypoestrogenemia.


Figure 24-2 Differential diagnosis of flushing.

(Adapted from Mohyi D: Differential diagnosis of hot flashes. Maturitas 27:203–214, 1997.)

Systemic Diseases

The most common systemic disorders associated with hot flashes are carcinoid syndrome, mastocytosis, pheochromocytoma, medullary thyroid carcinoma, pancreatic carcinoma, and renal cell carcinoma.

Carcinoid Syndrome

These are mainly neuroendocrine tumors of the bowel. They may also be found in the bronchus, pancreatic islets, retroperitoneum, liver,31 and even in the ovary.32 They probably arise from gastrointestinal or bronchopulmonary pluripotential stem cells.33 The carcinoid syndrome clinically has a classic triad of diarrhea, flushing, and valvular heart lesions. Skin flushing is the most common sign and is present in more than 90% of patients. The mechanism of flushing is at least partially due to serotonin release, but other substances, such as kinin, substance P, neurotensin, and prostaglandin, may play a role.33

Medullary Carcinoma of the Thyroid

Medullary carcinoma of the thyroid is a malignant tumor that originates from the parafollicular or thyroid C cells. These tumor cells typically produce an early biochemical signal (hypersecretion of calcitonin).36 This cancer can occur sporadically, but many times is inherited in an autosomal dominant way as a part of the syndrome multiple endocrine neoplasia type 2.37 Other bioactive substances that can be secreted by medullary carcinomas and may be responsible for the vasomotor symptoms include corticotropin, corticotropin-releasing hormone, and prostaglandins.30

Morbidity Associated with Hot Flashes

Sleep Disturbances

The relationship between hot flashes and interference with sleep is controversial. Multiple epidemiologic studies have shown an association between awakening and arousal from sleep and hot flashes in menopausal women.4042 This has led to the commonly held conception that hot flashes and night sweats cause awakening, which subsequently creates fatigue, and possibly decreases performance and quality of life.43 The flaw in these studies is that these hypotheses have not been properly tested in controlled laboratory investigations. Also, neither of these investigations screened out patients with apnea and other sleep disturbances that are also prevalent in menopause and may represent a confounder factor.

Recently, Freedman and Roehrs studied 31 patients between ages 46 and 51 who were classified into three groups: premenopausal asymptomatic (cycling), postmenopausal asymptomatic (asymptomatic), and postmenopausal symptomatic (symptomatic). They then assessed several outcome measures: sleep electroencephalogram recordings, sternal skin conductance to record hot flashes, multiple sleep latency tests to assess sleepiness, simple and divided attention performance tests, and sleep and fatigue questionnaires. There were no significant differences among the three groups on any sleep variable. Of the awakenings taking place within 2 minutes of a hot flash, 55.2% happened before the hot flash, 40% after the hot flash, and 5% simultaneously. Of arousals taking place within 2 minutes of a hot flash, 46.7% occurred before, 46.7% after, and 5.6% simultaneously. There were no significant group differences on any self-report measure or on any performance measure. They concluded that there is no evidence that hot flashes produce sleep disturbances in symptomatic postmenopausal women.44


There is sufficient observational data to suggest a link between hormones and migraines.45,46 However, the relationship between menopause and migraine is still being debated. Observational studies suggest that migraine worsens just before menopause and improves after cessation of menses in approximately two thirds of cases.

Neri, in a sample of 556 postmenopausal patients, studied the prevalence and characteristics of headaches in this cohort and found that many of them had migraine with aura. Interestingly, women with prior migraine generally improved with the onset of spontaneous menopause. In contrast, women with bilateral oophorectomy usually experienced worsening of their migraines.47 More recently, a cross-sectional, community-based study of 1436 women using the 1988 International Headache Society Criteria showed the highest prevalence of migraines in the perimenopausal group (31%) and the lowest (7%) in the postmenopausal group.48

Urogenital Changes

The lack of estrogen has been associated with a decrease in the moisture of the genital tissues. The persistent dryness of the vaginal mucosal surfaces may lead to symptoms of vaginitis, pruritus, dyspareunia, and even stenosis. Other symptoms that may be related to estrogen deprivation in the urogenital tissues are dysuria, urgency incontinence, and urinary frequency. It is unclear whether all these symptoms are related to the lack of estrogen or are part of the degenerative process of aging. It is postulated that changes in estrogen levels change the quality of the collagen content and the connective tissues in the urogenital area.49

More controversial are data suggesting that lack of estrogen increases the likelihood of menopausal women to experience recurrent urinary tract infections (UTIs). A randomized, placebo-controlled trial of vaginal estrogen in 93 postmenopausal women demonstrated that patients being treated could reduce their number of UTIs per year. This study observed 0.5 episodes of UTI in the treatment groups versus 5.9 episodes in the placebo group.50 On the other hand data from the Heart and Estrogen/Progestin Replacement Study (HERS) showed that urinary tract infection frequency was higher in the group randomized to hormone treatment, although the difference was not statistically significant (odds ratio, 1.16; 95% CI, 0.99–1.37).51

However conflicting these results are, from the clinician’s point of view it seems prudent to attempt a trial of vaginal estrogen therapy to address several of these postmenopausal urogenital symptoms. It should be considered in the presence of a vaginal pH greater than 4.5. Like FSH, elevated vaginal pH appears to be a good predictor of estrogen status.52,53


The two major long-term risks associated with menopause are osteoporosis and cardiovascular disease.


Chapter 25 reviews osteoporosis in detail. In this section we discuss its relationship as a long-term risk factor in menopausal women. The demographic changes and longevity increase described at the beginning of this chapter, coupled with the fact that osteoporosis rises dramatically with age, makes osteoporosis a serious economic burden for healthcare systems in our society.54 The estimated total direct expenditures (hospitals and nursing homes) for osteoporotic and associated fractures was $17 billion in 2001 ($47 million each day).55 The National Osteoporosis Foundation estimates that 50% of white women will suffer at least one osteoporosis-related fracture in their remaining lifetime. At least 90% of hip and spine fractures among elderly women can be attributed to osteoporosis.56 These statistics are the result of an accelerated decline in bone mass after menopause. However, this decline begins at approximately age 35 when a disparity between bone formation and bone resorption begins to occur. After menopause there are two periods of net bone loss: an accelerated stage that begins with the onset of menopause (1 to 3 years) and continues for 5 to 8 years57 (STRAW 0, 1, and 2) and a prolonged, slower stage of bone loss that remains throughout STRAW 2. The initial accelerated phase may account for bone loss of up to 30%.58

The three most common osteoporotic related fractures are hip, vertebral, and wrist. The most common are vertebral fractures, accounting for 700,000 cases a year in the United States.55 These should be suspected in postmenopausal women with back pain, loss of height, and kyphosis. In one observational study of 7223 postmenopausal women over age 65, patients with radiographically detected vertebral fractures were found to have significantly more limited-activity days, whether they were symptomatic or not.59 These data should raise awareness for the clinician of the decreased quality of life that menopausal patients may experience even with asymptomatic fractures.

The second most common fracture is hip fracture, accounting for 300,000 cases a year in the United States.55 These are without doubt the more serious consequence of osteoporosis in postmenopausal women. One in 5 women will die within 1 year after fracture, and 1 in 2 will have permanent loss of function.60 Lastly, distal forearm fractures occur in 250,000 patients a year in the United States.55 Only half of the patients who suffer these fractures recover full function of the arm in 6 months.61

Cardiovascular Disease

The American Heart Association has designated cardiovascular disease a “silent epidemic.” Despite the overall decline in the mortality rate due to cardiovascular disease in the United States, the absolute number of deaths due to cardiovascular disease is actually increasing.62 This is in part due to the demographic changes in our society described in the introduction of this chapter. Cardiovascular disease, which encompasses heart attacks and strokes, is responsible each year for more deaths than all other causes combined in postmenopausal women.62,63 The burden and threat of this disease during menopause is in part due to the discrepancy among the reality of the problem and the perception of its magnitude by both physicians and patients. Nothing exemplifies this better than a 1995 Gallup survey, which revealed that 4 out of 5 women ages 45 to 75 were unaware that cardiovascular disease was the first cause of death for their age group. Instead most of the women quoted cancer, specifically breast cancer, as their most probable cause of death. In reality this represents only 4% of the causes of death in this age group. The primary care physicians questioned did not do very well either; 32% of them did not know that heart disease was the main cause of death in this age group of women.64

The incidence of cardiovascular disease and particularly myocardial infarction dramatically increases after menopause and approximates the mortality of this entity in men.65,66 Furthermore, bilateral oophorectomy or premature ovarian failure increases the risk of cardiovascular disease beyond that of natural menopause.67 Despite this seemingly logical association between estrogen cardioprotection and other coherent data from observational studies, the Women’s Health Initiative (WHI) group of trials and the HERS have found no role for estrogen as a primary or secondary prevention for cardiovascular disease in postmenopausal women.

Very sound evidence from epidemiologic studies and clinical research make evident that the best tools are preventive measures and lifestyle habit modifications: smoking cessation, blood pressure control, lowering cholesterol, and promoting exercise.


The results of the Women’s Health Initiative study (WHI) have altered the principles of medical practice in menopausal women. We have changed from the concept of prevention of chronic diseases encompassed in the term hormone replacement therapy to the concept of hormone therapy. Thus, the U.S. Food and Drug Administration (FDA) and professional organizations such as the American College of Obstetricians and Gynecologists recommend the use of estrogen-containing medications to be restricted to the treatment of vasomotor and vaginal symptoms. They also affirm that the lowest effective dose be prescribed for the shortest duration of time.6870

Principles of Hormone Therapy

During the past three decades the clinical opinion on the use of estrogen during menopause has changed dramatically. Initially, estrogen was recommended as a short-term treatment for menopausal symptoms. Later, on the basis of observational studies, estrogen was given for long-term prevention of heart disease and an improved quality of life. The WHI hormone therapy trial, however, demonstrated that estrogen was not effective for the prevention of cardiovascular disease.

Key Findings from the Women’s Health Initiative

The WHI was a group of clinical trials designed to examine the impact of hormone therapy on cardiovascular disease and breast cancer, the effect of low-fat diet on breast and colon cancer, and the impact of vitamin D in calcium supplementation on fractures and colon cancer.71

These trials included:

In May 2002 the clinical trial that aimed to assess the cardiovascular effects of estrogen and progestin therapy in postmenopausal women with intact uterus was halted. The Data and Safety Monitoring Board reported that the estrogen/progestin treatment group had an increased risk of cardiovascular disease, thromboembolism, and breast cancer after 5.2 years of follow-up.72 In 2004, after 6.8 years of follow-up, the estrogen-only trial was halted.73 In this clinical trial, estrogen-only treatment demonstrated an increase risk of strokes similar to the one found in the estrogen/progestin clinical trial previously halted. They also reported a lack of benefit on cardiovascular disease incidents and a probable increase in dementia. The risks and benefits findings of the WHI are summarized in Table 24-2.74

The WHI findings should not be generalized to the whole menopausal population, but rather to the population studied and the specific treatment used in the trial. Some researchers argue that there might be a difference in the thromboembolic risk among the different estrogen compositions.

It should be emphasized that the WHI trial did not intend to evaluate the effects of estrogen or estrogen/progestin on vasomotor symptoms; therefore, these results must be translated into the specific needs of our patients when they request relief for hot flashes or other postmenopausal symptoms. It is also critical to point out that the rate of serious adverse events in patients treated with estrogen therapy is low, calculated to be 2 out of 1000 women treated per year.75 Healthcare providers and patients must balance the benefits of estrogen treatment versus the risk for adverse events. Today, more than ever, the concept of individualized menopausal care should be applied in the clinical setting.

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