Key points
- •
The average age of menopause in the United States is 51.3 years; it is younger in certain ethnic groups, and is genetically predetermined and is not related to the number of ovulations, race, socioeconomic conditions, education, height, weight, age at menarche, or age at last pregnancy.
- •
Because most diseases in women occur after menopause, the onset of menopause heralds an important opportunity to institute prevention strategies for prolonging and improving the quality of life for women.
- •
Vasomotor symptoms or hot flushes may persist for 10 or more years, with bothersome flushes occurring for about 7 years. Estrogen is the best therapy for the hot flush; other effective therapies are progestogens, selective serotonin reuptake inhibitors (SSRIs), gabapentin, clonidine, some phytoestrogens, acupuncture, and stellate ganglion blockade.
- •
Dual-energy x-ray absorptiometry (DEXA) is the most accurate method to measure bone density. A country-specific algorithm (FRAX) using DEXA has been developed to calculate the 10-year risk of fracture. In addition to estrogen (with and without progestogen), alendronate, risedronate, ibandronate, zoledronic acid, raloxifene, calcitonin, denosumab, romosozumab and teriparatide will reduce postmenopausal bone loss, and some agents will stimulate bone formation as well.
- •
The primary indication for estrogen therapy is symptoms of menopause (hot flushes as well as quality-of-life issues); bone health may also be an indication in some women. In younger postmenopausal women who are receiving hormonal therapy for symptoms, the benefits outweigh risks. There are consistent data for a reduction in all-cause mortality of 20% to 30% in younger women who initiate estrogen therapy at the onset of menopause. These findings suggest a potential role of estrogen as a prevention therapy after menopause
Menopause is defined by the last menstrual period. Because cessation of menses is variable and many of the symptoms thought to be related to menopause may occur before cessation of menses, there is seldom a precise timing of this event. Other terms used are perimenopause , which refers to a variable time beginning a few years before and continuing after the event of menopause, and climacteric , which merely refers to the time after the cessation of reproductive function. Although the terms menopausal and postmenopausal are used interchangeably, the former term is less correct because menopausal should only relate to the time around the cessation of menses.
As life expectancy increases beyond the eighth decade worldwide, particularly in developed countries, an increasing proportion of the female population is postmenopausal. With the average age of menopause being 51 years, more than a third of a woman’s life is now spent after menopause . Here, symptoms and signs of estrogen deficiency merge with issues encountered with natural aging. As the world population increases and a larger proportion of this population is made up of individuals older than 50, medical care specifically directed at postmenopausal women becomes an important aspect of modem medicine. Indeed an opportunity exists at the onset of menopause for providers to address the long-term needs of women after menopause and to have an impact on longevity and quality of life ( ). In the United States, the number of women entering menopause is projected to have doubled in the 30 years between 1990 and 2020, and the total number of postmenopausal women is expected to be in range of 60 million ( Table 14.1 ).
| Year | Population (in Millions) |
|---|---|
| 1990 | 10.8 |
| 2000 | 12.1 |
| 2010 | 17.1 |
| 2020 | 19.3 |
Age of menopause, which is a genetically programmed event, is subject to some variability. The age of menopause in Western countries (between 51 and 52 years) is thought to correlate with general health status; socioeconomic status is associated with an earlier age of menopause. Higher parity, on the other hand, has been found to be associated with a later menopause. Smoking has consistently been found to be associated with menopause onset taking place 1 to 2 years earlier. Hysterectomy has also been cited as resulting in an earlier menopause, presumably because of a diminution in the blood supply to the ovary; however, the data have not been consistent. Although body mass has been thought to be related to age of menopause (with greater body mass index [BMI] associated with later menopause), the data have not been consistent. However, physical or athletic activity has not been found to influence the age of menopause. There also appear to be ethnic differences in the onset of menopause. In the United States black and Hispanic women have been found to have menopause approximately 2 years earlier than white women. Although parity is generally greater around the world than in the United States, the age of menopause appears to be somewhat earlier outside the United States. Malay women have menopause at approximately age 45, Thai women at age 49.5, and Filipina women between ages 47 and 48. Menopause has also been reported to occur at an average age of 46.2 years in women from India (Ajuja, 2016). Women in countries at higher altitude (Himalayas or Andes) have been shown to have menopause 1 to 1.5 years earlier. Because the average age of menopause in the United States is 51 to 53 years, menopause before age 40 is considered premature and before age 45 is considered early. Conversely, by age 58, 97% of women will have gone through menopause. The primary determinate of age of menopause is genetic. Based on family studies, de Bruin and colleagues ( ) showed that heritability for age of menopause averaged 0.87, suggesting that genetics explains up to 87% of the variance in menopausal age. The maternal contribution is around 50%.
Other than specific gene mutations that have been shown to cause premature ovarian failure or insufficiency (explained later in this chapter), no specific genes have been implicated to account for this genetic influence. However, several genes are likely to be involved in determining the age of menopause; they include genes regulating immune function and DNA repair ( ) and may also include genes coding telomerase activity, which affects aging in general.
Premature ovarian insufficiency
Premature ovarian failure (POF) or premature ovarian insufficiency (POI), which is a newer term, is defined as hypergonadotropic ovarian failure occurring before age 40 . POI occurs in 5% to 10% of women who are evaluated for amenorrhea ; thus the incidence varies according to the prevalence of amenorrhea in various populations. Estimates of the overall prevalence of POI in the general population range between 0.3% and 0.9% of women. Throughout life, there is an ongoing rate of atresia of oocytes. Because this process is accelerated with various forms of gonadal dysgenesis because of defective X chromosomes, one possible cause of POI is an increased rate of atresia that has yet to be explained. A decreased germ cell endowment or an increased rate of germ cell destruction can also explain POI. Nevertheless, about 1000 (of the original 2 million) primarily follicles may remain. Although most of these oocytes are likely to be functionally deficient, spontaneous pregnancies occur occasionally in young women in the first few years after the diagnosis of POI. There are several possible causes of POI ( Box 14.1 ).
Genetic
Enzymatic
Immune
Gonadotropin defects
Ovarian insults
Idiopathic
Defects in the X chromosome may result in various types of gonadal dysgenesis with varied times of expression of ovarian failure. Even patients with classical gonadal dysgenesis (e.g., 45,XO) may undergo a normal puberty, and occasionally a pregnancy may ensue as a result of genetic mosaicism. Very small defects in the X chromosome may be sufficient to cause POI . Familial forms of POI may be related to either autosomal dominant or sex-linked modes of inheritance. Mutations in the gene encoding the follicle-stimulating hormone (FSH) receptor (e.g., mutation in exon 7 in the gene on chromosome 2p) have been described, but these are extremely rare outside of the Finnish population, in whom these mutations were originally described. An expansion of a trinucleotide repeat sequence in the first exon on the FMR1 gene (Xq 27.3) leads to fragile X syndrome, a major cause of developmental disabilities in men.
The permutation in fragile X syndrome has been shown to be associated with POI. Type 1 blepharophimosis/ptosis/epicanthus inversus (BPES) syndrome, an autosomal dominant disorder caused by mutations in the forkhead transcription factor FOXL2, includes POI. Triple X syndrome has also been associated with POI. It has been suggested that functional mutations of antimüllerian hormone (AMH) may also be associated with POI.
Dystrophic myotonia has also been linked to POI, although the mechanism underlying this relationship is unclear. Under the category of enzymatic defects, galactosemia is a major cause of POI that is related to the toxic buildup of galactose in women who are unable to metabolize the sugar. Even in women with fairly well-controlled galactose-free diets, POI tends to occur. Another enzymatic defect linked to POI is 17α-hydroxylase deficiency. This rare condition manifests differently from the other causes discussed here because the defect in the production of sex steroids leads to sexual infantilism and hypertension.
The degree to which autoimmunity may be responsible for POI is unclear, but it has been suggested to be associated in 17.5% of cases. Virtually all autoimmune disorders have been found to be associated with POI, including autoimmune polyendocrinopathies such as autoimmune polyendocrinopathy/candidiasis/ectodermal dystrophy (APECED), which is caused by mutations in the autoimmune (AIRE) gene on band 21 q22. The presence of the thymus gland appears to be required for normal ovarian function because POI has been associated with hypoplasia of the thymus. In patients who have undergone ovarian biopsy as part of their evaluation, lymphocytic infiltration surrounding follicles has been described, as well as resumption of menses after immunosuppression. Immunoassays using antibodies directed at ovarian antigens have been developed and have demonstrated positive findings in some patients with POI, although the relevance of these findings remains unsettled. Ovarian autoantibodies could also conceivably be a secondary phenomenon to a primary cell-mediated form of immunity. Specific enzymes such as 3β-hydroxysteroid dehydrogenase (3βHSD) may also be the target of ovarian autoimmunity. Approximately 2% to 4% of women with autoimmunity for POI will have antiadrenal antibodies as well ( ). This can be screened for by an assay for 21-hydroxlase antibodies. Adrenal function, more practically, can be assessed by measuring dehydroepiandrosterone sulfate (DHEA-S) levels, which are higher in younger women than in menopausal women, unless the adrenal gland is affected. It may also be helpful to assess ovarian volume and follicular presence by vaginal ultrasound in these women as well. The ovaries in younger women with POI are more normal in size and have follicles present compared with the smaller atrophic ovary in menopause.
From a practical standpoint, screening for the common autoimmune disorders is appropriate in women found to have POI. Not practical to measure, however, are abnormalities in the structure of gonadotropins, in their receptors, or in receptor binding, which could be associated with POI; these measurements are difficult. Although abnormal urinary forms of gonadotropins have been reported in women with POI, these data have not been replicated. Abnormalities of FSH receptor binding, as mediated by a serum inhibitor, have been described. A genetic defect that may lead to alterations in FSH receptor structure was mentioned previously.
Under the category of ovarian insults, POI may be induced by ionizing radiation, chemotherapy, or overly aggressive ovarian surgery. Although not well documented, viral infections have been suggested to play a role, particularly mumps. A dose of 400 to 500 rads is known to cause ovarian failure 50% of the time , and older women are more vulnerable to experiencing permanent failure. A dose of approximately 800 rads is associated with failure in all women. Ovarian failure (transient or permanent) may be induced by chemotherapeutic agents, although younger women receiving this insult have a better prognosis. Alkalizing agents , particularly cyclophosphamide, appear to be most toxic. By exclusion, the majority of women are considered to have idiopathic POI because no demonstrable cause can be pinpointed. Among these women, small mutations in genes lying on the X chromosome or yet to be identified autosomal genes may be the cause.
Management of premature ovarian insufficiency
Evaluation of POI in women younger than 30 should include screening for autoimmune disorders and a karyotype; detailed recommendations for screening of such women are available ( ). In addition, vaginal ultrasound may be useful for assessing the size of the ovaries and the degree of follicular development, which, if present, may signify an immunologic defect. Women with POI caused by immunologic defects should be screened carefully for thyroid, adrenal, and other autoimmune disorders.
Treatment of all cases usually consists of estrogen replacement . Although in menopausal therapy clinicians have steered away from the term replacement therapy, in this specific instance of POI, estrogen treatment is truly replacement therapy. If fertility is a concern, the most efficacious treatment is oocyte donation. Various attempts at ovarian stimulation are usually unsuccessful; sporadic pregnancies that may occur (~5%) are just as likely to occur spontaneously as with any intervention, and often while on physiologic estradiol (E 2 ) replacement. In this setting it has been our preference not to use oral contraceptive pills for replacement in women wishing to conceive. In a long-term follow-up of a large number of women diagnosed with POI, within a year spontaneous ovarian function was observed in 24% of the women and over time the rate of spontaneous pregnancies was 4.4% ( ).
Estrogen replacement in these young women with POI is extremely important and is not analogous to hormone therapy (HT) after menopause because these young women are at substantial long-term risk for osteoporosis and cardiovascular disease (CVD). Coronary heart disease and death are specifically increased in approximately 70% of women with POI, but not stroke. Another review emphasized the increased risks in several organ systems, including brain, cardiovascular, and bone, and early mortality with untreated premature or early menopause (Faubion, 2015). A more extreme example of this phenomenon is with premature oophorectomy, with which the risk of CVD is many-fold increased ( Fig. 14.1 ) ( ). Women with POI should be offered estrogen replacement, with some form of progestogen in women with a uterus, at least up to the natural age of menopause.
Menopausal transition (perimenopause)
A workshop was convened in 2001 to build consensus on describing various stages of the menopausal transition. A follow-up conference, the Study of Reproductive Aging Workshop (STRAW+10) , had more streamlined bleeding criteria for the various stages and expanded the stages including the use of biochemical markers such as inhibin B and AMH, in addition to FSH ( ) ( Fig. 14.2 ). This scheme is important from a descriptive standpoint for the physiology behind the normal menopausal transition and is useful for characterization of women in various stages in research studies. The earliest sign of impending menopause during the menopause transition is a change in menstrual length.
The ovary changes markedly from birth to the onset of menopause ( Fig. 14.3 ). The greatest number of primordial follicles is present in utero at 20 weeks’ gestation, and the follicles undergo a regular rate of atresia until around the age of 37. After this time, the decline in primordial follicles appears to become more rapid between age 38 and menopause ( Fig. 14.4 ), when no more than 1000 follicles remain. These remaining follicles are primarily atretic in nature.
These changes are reflected in circulating levels of AMH, which decline rapidly with ovarian aging. When levels of serum AMH become undetectable, menopause is likely to occur in 4 to 5 years.
Ovarian changes during perimenopause
Although perimenopausal changes are generally thought to be endocrine in nature and result in menstrual changes, a marked diminution of reproductive capacity precedes this period by several years. This decline may be referred to as gametogenic ovarian failure and is reflected by decreased AMH, inhibin B levels, and antral follicle counts and a rising FSH. The concept of dissociation in ovarian function is appropriate. These changes may occur with normal menstrual function and no obvious endocrine deficiency; however, they may occur in some women as early as age 35 (10 or more years before endocrine deficiency ensues). Although subtle changes in endocrine and menstrual function can occur for up to 3 years before menopause, it has been shown that the major reduction in ovarian estrogen production does not occur until approximately a year before menopause ( Fig. 14.5 ) ( ). There is also a slow decline in androgen status (i.e., androstenedione and testosterone), which cannot be adequately detected at the time of perimenopause. The decline in androgen is largely a phenomenon of aging . Products of the granulosa cell are most important for the feedback control of FSH. As the functional capacity of the follicular units decreases, the secretion of substances that suppress FSH also decreases. A marker of this is inhibin B, in which levels are lower in the early follicular phase in women in their late 30s ( Fig. 14.6 ). Inhibin B is seldom measured clinically; rather AMH (which also reflects granulosa cell function) is most often assessed, as noted previously. Indeed, FSH levels are higher throughout the cycle in older ovulatory women than in younger women ( Fig. 14.7 ). The functional capacity of the ovary is also diminished as women enter into perimenopause. With gonadotropin stimulation, although E 2 levels are not very different between younger and older women, total inhibin production by granulosa cells is decreased in women older than 35. From a clinical perspective, subtle increases in FSH on day 3 of the cycle, or increases in the clomiphene challenge test, correlate with decreased ovarian responses to stimulation and decreased fecundability. AMH serves as the most practical marker of reproductive aging. Levels decrease throughout life, being undetectable at menopause, and show less variability during the menstrual cycle compared with other markers such as FSH. However, values are lower by up to 20% in women on oral contraceptives, and this should be taken into account when assessing levels in younger women. When values reach an undetectable range (<0.05 ng/mL), menopause has been found to occur within 5 years, as stated previously ( Fig. 14.8 ).
Although there is a general decline in oocyte number with age, an accelerated atresia occurs around age 37 or 38 (see Fig. 14.4 ). The reason for this acceleration is not clear, but one possible theory relates to activin secretion. Because granulosa cell–derived activin is important for stimulating FSH receptor expression, the rise in FSH levels could result in more activin production, which in turn enhances FSH action. A profile of elevated activin with lower inhibin B has been found in older women ( Fig. 14.9 ). This autocrine action of activin, involving enhanced FSH action, might be expected to lead to accelerated growth and differentiation of granulosa cells. Furthermore, activin has been shown to increase the size of the pool of preantral follicles in the rat. At the same time, these follicles become more atretic. Clinical treatment of perimenopausal women should address three general areas of concern: (1) irregular bleeding; (2) symptoms of early menopause, such as hot flushes ; and (3) the inability to conceive. Treatment of irregular bleeding is complicated by the fluctuating hormonal status. Estrogen levels may be higher than normal in the early follicular phase and progesterone secretion may be normal or slightly decreased, although not all cycles are ovulatory. For these reasons, short-term use of an oral contraceptive (usually 20 μg ethinyl estradiol) may be an option for otherwise healthy women who do not smoke to help them cope with irregular bleeding. Early symptoms of menopause, particularly vasomotor changes, may occur as the result of fluctuating hormonal levels. In this setting an oral contraceptive may be an option if symptoms warrant therapy. Alternatively, lower doses of estrogen used alone may be another option.
Hormonal changes with established menopause
Fig. 14.10 depicts the typical hormonal levels of postmenopausal women compared with those of ovulatory women in the early follicular phase. The most significant findings are the marked reductions in E 2 and estrone (E 1 ). Serum E2 is reduced to a greater extent than E1. Serum E 1 , on the other hand, is produced primarily by peripheral aromatization from androgens, which decline principally as a function of age. Levels of E 2 average 15 pg/mL and range from 10 to 25 pg/mL but are closer to 10 pg/mL or less in women who have undergone oophorectomy. More sensitive assays for E 2 using mass spectroscopy give lower levels of E 2 with average levels around 3 to 5 pg/mL. Serum E 1 values average 30 pg/mL but may be higher in women with obesity because aromatization increases as a function of the mass of adipose tissue. Estrone sulfate (E 1 S) is an estrogen conjugate that serves as a stable circulating reservoir of estrogen, and levels of E 1 S are the highest among estrogens in postmenopausal women. In premenopausal women, values are usually more than 1000 pg/mL; in postmenopausal women, levels average 350 pg/mL. Apart from elevations in FSH and luteinizing hormone (LH), other pituitary hormones are not affected. The rise in FSH, beginning in stage −2 as early as age 38 (see Fig. 14.2 ), fluctuates considerably until approximately 4 years after menopause (stage +1c), when values are consistently greater than 20 mIU/mL. Specifically, growth hormone (GH), thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH) levels are normal. Serum prolactin levels may be slightly decreased because prolactin levels are influenced by estrogen status. Both the postmenopausal ovary and the adrenal gland continue to produce androgen. The ovary continues to produce androstenedione and testosterone but not E 2 , and this production has been shown to be at least partially dependent on LH. Androstenedione and testosterone levels are lower in women who have experienced bilateral oophorectomy, with values averaging 0.8 ng/mL and 0.1 ng/mL, respectively. The adrenal gland also continues to produce androstenedione, DHEA, and DHEA-S; primarily as a function of aging, these values decrease somewhat (adrenopause), although cortisol secretion remains unaffected. Most “ovarian” testosterone production may actually arise from the adrenal gland by way of precursors ( ). Most likely, the adrenal gland supplies precursor substrates (DHEA and androstenedione) for ovarian testosterone production. More recent measurements of 11-oxygenated androgens, which are mainly adrenal derived, will be important to investigate, but there are few data on this at present. Although DHEA-S levels decrease with age (approximately 2% per year), data have suggested that levels transiently rise in perimenopause before the continuous decline thereafter ( Fig. 14.11 ). This interesting finding from the Study of Women Across the Nation (SWAN) also suggested that DHEA-S levels are highest in Chinese women and lowest in African American women.
Testosterone levels also decline as a function of age, which is best demonstrated by the reduction in 24-hour means levels ( Fig. 14.12 ). Because of the role of the adrenal gland in determining levels of testosterone after menopause, adrenalectomy or dexamethasone treatment results in undetectable levels of serum testosterone. Compared with total testosterone, the measurement of bioavailable, or “free,” testosterone is more useful in postmenopausal women. After menopause, sex hormone–binding globulin (SHBG) levels decrease, resulting in relatively higher levels of bioavailable testosterone or a higher free androgen index ( Fig. 14.13 ). In women receiving oral estrogen, bioavailable testosterone levels are extremely low because SHBG levels are increased. How this relates to the decision to consider androgen therapy in postmenopausal women is discussed later in this chapter.
Elevated gonadotropin (FSH/LH) levels arise from reduced secretion of E 2 and inhibin, as described earlier. Although some aging effects of the brain are likely to exist, there is abundant human evidence that menopause in women is an ovarian-induced event.
Effects of menopause on various organ systems
Central nervous system
The brain is an active site for estrogen action and estrogen formation. Estrogen activity in the brain is mediated via estrogen receptor (ER) α and ER β . Whether or not a novel membrane receptor (non-ER α /ER β ) exists is still being debated. However, both genomic and nongenomic mechanisms of estrogen action clearly exist in the brain. Fig. 14.14 illustrates the predominance of ER β in the cortex (frontal and parietal) and the cerebellum, based on work in rats. Although 17 β E 2 is a specific ligand for both receptors, certain synthetic estrogens (e.g., diethylstilbestrol) have greater affinity for ER α , whereas phytoestrogens have a greater affinity for ER β .
Estrogen has multiple actions on the brain, as reviewed by Henderson ( Box 14.2 ); thus some important functions linked to estrogen contribute to well-being in general and, more specifically, to cognition and mood. The hallmark feature of declining estrogen status in the brain is the hot flush, which is more generically referred to as a vasomotor episode. Hot flash usually refers to the acute sensation of heat, and the flush or vasomotor episode includes changes in the early perception of this event and other skin changes (including diaphoresis).
Organizational actions
Effects on neuronal number, morphology, and connections occurring during critical stages of development
Neurotrophic actions
Neuronal differentiation
Neurite extension
Synapse formation
Interactions with neurotrophins
Neuroprotective actions
Protection against apoptosis
Antioxidant properties
Antiinflammatory properties
Augmentation of cerebral blood flow
Enhancement of glucose transport into the brain
Blunting of corticosteroid response to behavioral stress
Interactions with neurotrophins
Neurotransmitters affected
Acetylcholine
Noradrenaline
Serotonin
Dopamine
Glutamate
Gamma-aminobutyric acid
Neuropeptides
Effects on glial cells
Proteins involved in Alzheimer disease effected
Amyloid precursor protein
Tau protein
Apolipoprotein E
Hot flushes usually occur for 2 years after the onset of estrogen deficiency but can persist for 10 or more years. Prospective data suggest that the average time for persistence of bothersome hot flushes is 7.4 years ( ), and up to 42% of women aged 60 to 65 years have bothersome symptoms. In 10% to 15% of women, these symptoms are severe and disabling. In the United States the incidence of these episodes varies in different ethnic groups. Symptoms are greatest in Hispanic and black women, intermediate in white women, and lowest among Asian women ( Fig. 14.15 ). The severity and persistence of hot flushes for 10 or more years may cause a series of “irregular” symptoms, such as irritability, which may affect quality of life ( ) ( Fig. 14.16 ). The fall in estrogen levels precipitate the vasomotor symptoms. It has been found that some women who experience hot flushes have a thermoregulatory disruption with a much narrower temperature range between sweating and shivering. Freedman has shown that the difference in temperature at which shivering occurs and when sweating occurs, termed the thermoneutral zone, is wide in asymptomatic women ( ). This zone is substantially more narrowed in symptomatic women, explaining their vulnerability to vasomotor symptoms ( Fig. 14.17 ). Although these data have validity, our current understanding of hot flush generation relates to the thermoregulatory region of the brain ( Fig. 14.18 ), which is innervated by afferent neurokinin-kisspeptin -dynorphin neurons. With menopause these neurons swell and activate the thermoregulatory centers, triggering flush activity. This can be attenuated by estrogen, and more specifically by the use of NK3 receptor antagonists, which provide a therapeutic opportunity for nonhormonal treatment of hot flushes ( ).
The flush has been well characterized physiologically. It results in heat dissipation, as witnessed by an increase in peripheral temperature (fingers, toes); a decrease in skin resistance, associated with diaphoresis; and a reduction in core body temperature ( Fig. 14.19 ). There are hormonal correlates of flush activity, such as an increase in serum LH and in plasma levels of pro-opiomelanocortin peptides (ACTH, β -endorphin) at the time of the flush, but these occurrences are thought to be epiphenomena that result as a consequence of the flush and are not related to its cause. One of the primary complaints of women with hot flushes is sleep disruption. They may awaken several times during the night and require a change of bedding and clothes because of diaphoresis. Nocturnal sleep disruption in postmenopausal women with hot flushes has been well documented by electroencephalographic (EEG) recordings. Sleep efficiency is lower, and the latency to rapid eye movement (REM) sleep is longer in women with hot flushes compared with asymptomatic women. This disturbed sleep often leads to fatigue and irritability during the day, and sleep may be disrupted even if the woman is not conscious of being awakened from sleep. In this setting, EEG monitoring has indicated sleep disruption occurs in concert with physiologic measures of vasomotor episodes. The frequency of awakenings and hot flushes is reduced appreciably with estrogen treatment ( Fig. 14.20 ).
In postmenopausal women, estrogen has been found to improve depressed mood regardless of whether or not this is a specific complaint (critics of some of this work point out that mood is affected by the symptomology and by sleep deprivation). Blinded studies carried out in asymptomatic women have also shown benefit. In an estrogen-deficient state such as occurs after menopause, a higher incidence of depression (clinical or subclinical) is often manifest. However, menopause per se does not cause depression, and although estrogen does generally improve depressive moods, it should not be used for psychiatric disorders. Nevertheless, very high pharmacologic doses of estrogen have been used to treat certain types of psychiatric depression. Progestogens as a class generally attenuate the beneficial effects of estrogen on mood, although this effect is highly variable.
Cognitive decline in postmenopausal women is related to aging and to estrogen deficiency. The literature is somewhat mixed about whether there are benefits of estrogen in terms of cognition. Studies have suggested that in natural menopause, there is an early decline in cognitive function at the onset of menopause, but this spontaneously improves over time, ( ). Verbal memory appears to be enhanced with estrogen and has been found to correlate with acute changes in brain imaging, signifying brain activation. Dementia increases as women age, and the most common form of dementia is Alzheimer disease (AD). Box 14.2 lists several neurotropic and neuroprotective factors related to how estrogen deficiency may be expected to result in the loss of protection against the development of AD. In addition, estrogen has a positive role in enhancing neurotransmitter function, which is deficient in women with AD. This function of estrogen has particular importance and relevance for the cholinergic system, which is affected in AD. Estrogen use after menopause appears to decrease the likelihood of developing or delaying the onset of AD according to several observational studies and meta-analyses. However, once a woman is affected by AD, estrogen is unlikely to provide any benefit. Data from the Women’s Health Initiative (WHI), however, suggested a lack of benefit of estrogen or estrogen/progestogen, or even a worsening of cognition, in women initiating hormonal therapy after age 65. This suggests that timing of initiation of HT is critical , and this has also been supported by basic science studies, which have found that early exposure to estrogen decreased the possibility of brain damage from free radicals and also promoted maintenance of neuronal and synaptic activity. However, prospective trials in younger women still have not been able to confirm the older observational data, suggesting a cognitive benefit of estrogen. Therefore this area remains somewhat inconclusive. In summary, although early treatment with estrogen in younger women at the onset of menopause may be beneficial for cognition as it is with certain types of mood (although not proved yet), later treatment (e.g., after age 65) has no benefit and may even be detrimental, depending on the regimen of hormones used.
Collagen and other tissues
Estrogen has a positive effect on collagen , which is an important component of bone and skin and serves as a major support tissue for the structures of the pelvis and urinary system. Both estrogen and androgen receptors have been identified in skin fibroblasts. Nearly 30% of skin collagen is lost within the first 5 years after menopause , and collagen decreases approximately 2% per year for the first 10 years after menopause. This statistic, which is similar to that of bone loss after menopause, strongly suggests a link between skin thickness, bone loss, and the risk of osteoporosis . Although the literature is not entirely consistent, estrogen therapy generally improves collagen content after menopause and improves skin thickness substantially after about 2 years of treatment ( ). There is a possible bimodal effect with high doses of estrogen causing a reduction in skin thickness. The supportive effect of estrogen on collagen has important implications for bone homeostasis and for the pelvis after menopause. Here, reductions in collagen support and atrophy of the vaginal and urethral mucosa have been implicated in a variety of symptoms, including prolapse and urinary symptoms ( ). Vaginal estrogen has also been shown to reduce recurrent urinary tract infections. Symptoms of urinary incontinence and irritative bladder symptoms occur in 20% to 40% of perimenopausal and postmenopausal women. Uterine prolapse and other gynecologic symptoms related to poor collagen support, as well as urinary complaints, may improve with estrogen therapy. Although estrogen generally improves symptoms, urodynamic changes have not been shown to be altered. Estrogen has also been shown to decrease the incidence of recurrence of urinary tract infections. Restoration of bladder control in older women with estrogen has been shown to decrease the need for admission to nursing homes in Sweden. Estrogen may also have an important role in normal wound healing. In this setting, estrogen enhances the effects of growth factors such as transforming growth factor- β (TGF- β ) ( ).
Although still not completely settled, it appears that oral estrogen does not improve stress urinary incontinence in postmenopausal women and may even cause such symptoms in previously asymptomatic older women. Estrogen may, however, improve urge and other irritative urinary symptoms.
Genitourinary syndrome of menopause
Genitourinary syndrome of menopause (GSM) is now the accepted terminology and replaces terms such as atrophic vaginitis or vulvovaginal atrophy. The definition encompasses subjective and objective findings of the vulva, vagina, and lower urinary tract. The constellation of established symptoms and signs may be found in Table 14.2 ( ).
| Symptoms | Signs |
|---|---|
| Genital dryness | Decreased moisture |
| Decreased lubrication with sexual activity | Decreased elasticity |
| Discomfort or pain with sexual activity | Labia minora resorption |
| Postcoital bleeding | Pallor/erythema |
| Decreased arousal, orgasm, desire | Loss of vaginal rugae |
| Irritation/burning/itching of vulva or vagina Dysuria | Tissue fragility/fissures/petechiae |
| Urinary frequency/urgency | Urethral eversion or prolapse Loss of hymenal remnants Prominence of urethral meatus Introital retraction Recurrent urinary tract infections |
| Supportive findings: pH > 5, increased parabasal cells on maturation index, and decreased superficial cells on wet mount or maturation index. | |
Vulvovaginal complaints are often associated with estrogen deficiency. During perimenopause, symptoms of dryness and atrophic changes occur in 21% and 15% of women, respectively. However, these findings increase with time, and by 4 years these incidences are 47% and 55%, respectively. With this change, an increase in sexual complaints also occurs, with an incidence of dyspareunia of 41% in sexually active 60-year-old women. Estrogen deficiency results in a thin, paler vaginal mucosa. The moisture content is low, the pH increases (usually >5), and the mucosa may exhibit inflammation and small petechiae.
With estrogen treatment, particularly when used locally, vaginal cytologic changes have been documented, transforming from a cellular pattern of predominantly parabasal cells to one with an increased number of superficial cells. Along with these changes, the vaginal pH decreases, the vaginal blood flow increases, and the electropotential difference across the vaginal mucosa increases to that found in premenopausal women. Vaginal DHEA (0.25% to 1.0%) has been used with some suggested efficacy; the mechanism is presumed to be the local conversion of DHEA into estrogen, with possibly some other modulating effects as well ( ).
Ospemifene 60 mg, a selective estrogen receptor agonist (SERM), has been approved as an oral treatment for vulvovaginal atrophy. This SERM has particular properties of acting as an agonist in the vagina and as an antagonist in other tissues such as the breast.
The approach to urinary symptoms will be addressed in different chapters.
Bone health
Estrogen deficiency has been well established as a cause of bone loss . This loss can be noted for the first time when menstrual cycles become irregular in perimenopause from 1.5 years before menopause to 1.5 years after menopause, and spine bone mineral density (BMD) has been shown to decrease by 2.5% per year, compared with a premenopausal loss rate of 0.13% per year. Loss of trabecular bone (spine) is greater with estrogen deficiency than is loss of cortical bone .
Postmenopausal bone loss leading to osteoporosis is a substantial health care problem. In Caucasian women, 35% of all postmenopausal women have been estimated to have osteoporosis based on BMD. Furthermore, the lifetime fracture risk for these women is 40%. The morbidity and economic burden of osteoporosis is well documented. Interestingly, some data suggest that up to 19% of Caucasian men also have osteoporosis. Bone mass is substantially affected by sex steroids through classic mechanisms to be described later in this chapter. Attainment of peak bone mass in the late second decade ( Fig. 14.21 ) is key to ensuring that the subsequent loss of bone mass with aging and estrogen deficiency does not lead to early osteoporosis. E 2 together with GH and insulin-like growth factor-1 act to double bone mass at the time of puberty, beginning the process of attaining peak bone mass. Postpubertal estrogen deficiency (amenorrhea from various causes) substantially jeopardizes peak bone mass. Adequate nutrition and calcium intake are also key determinants. Although estrogen is of predominant importance for bone mass in both women and men, testosterone is important in stimulating periosteal apposition; as a result, cortical bone in men is larger and thicker.
However, even in men estrogen appears to be important for bone health in that in male individuals with aromatase deficiency (inability to convert androgen to estrogen) osteoporosis ensues ( ).
Estrogen receptors are present in osteoblasts, osteoclasts, and osteocytes. Both ER α and ER β are present in cortical bone, whereas ER β predominates in cancellous or trabecular bone ( ). However, the more important actions of E 2 are believed to be mediated via ERα. Estrogens suppress bone turnover and maintain a certain rate of bone formation. Bone is remodeled in functional units, called bone multicenter units (BMUs), where resorption and formation should be in balance. Multiple sites of bone go through this turnover process over time. Estrogen decreases osteoclasts by increasing apoptosis, thus reducing their life span. The effect on the osteoblast is less consistent, but E 2 antagonizes glucocorticoid-induced osteoblast apoptosis. Estrogen deficiency increases the activities of remodeling units, prolongs resorption, and shortens the phase of bone formation. It also increases osteoclast recruitment in BMUs, and thus resorption outstrips formation. The molecular mechanisms of estrogen action on bone involve the inhibition of production of proinflammatory cytokines, which increase with a decrease in estrogen at menopause, leading to increased bone resorption ( ). These cytokines include interleukin-1, interleukin-6, tumor necrosis factor- α , colony-stimulating factor-1, macrophage colony-stimulating factor, and prostaglandin E 2 , all of which may contribute to increased resorption. E 2 also upregulates TGF- β in bone, which inhibits bone resorption. Receptor activation of nuclear factor kappa B (NF κ B) ligand (RANKL) is responsible for osteoclast differentiation and action. A scheme for how all these factors interact has been proposed ( Fig. 14.22 ) ( ). In women, Riggs has suggested that bone loss occurs in two phases. With estrogen levels declining at the onset of menopause, an accelerated phase of bone loss, which is predominantly of cancellous bone, occurs. Approximately 20% to 30% of cancellous bone and 5% to 10% of cortical bone can be lost in a span of 4 to 8 years. Thereafter, a slower phase of loss (1% to 2% per year) ensues, during which more cortical bone is lost. This phase is thought to be induced primarily by secondary hyperparathyroidism. The first phase is also accentuated by the decreased influence of stretching or mechanical factors, which generally promotes bone homeostasis, as a result of estrogen deficiency. Genetic influences on bone mass are more important for the attainment of peak bone mass (heritable component, 50% to 70%) than for bone loss. Polymorphisms of the vitamin D receptor gene, TGF- β gene, and the Spl binding site in the collagen type 1 Al gene have all been implicated as being important for bone mass ( ).
Bone mass can be detected by a variety of radiographic methods ( Table 14.3 ). Dual-energy x-ray absorptiometry (DEXA) scans have become the standard of care for detection of osteopenia and osteoporosis. By convention, the T score is used to reflect the number of standard deviations of bone loss from the peak bone mass of a young adult. Osteopenia is defined by a T score of –1 to –2.5 standard deviations; osteoporosis is defined as greater than 2.5 standard deviations.
| Precision in | Examination and Analysis | Estimated | ||
|---|---|---|---|---|
| Effective | ||||
| Technique | Anatomic Site of Interest | Vivo (%) | Time (min) | Dose |
| Equivalent (uSv) | ||||
| Conventional radiographs | Spine, hip 2000 | NA | <5 | 2000 |
| Radiogrammetry | Hand | 1-3 | 5-10 | <1 |
| Radiographic absorptiometry | Hand | 1-2 | 5-10 | <1 |
| Single x-ray absorptiometry | Forearm, heel | 1-2 | 5-10 | <1 |
| Dual x-ray absorptiometry | Spine, hip, forearm, total body | 1-3 | 5-20 | 1-10 |
| Quantitative computed tomography | Spine, forearm, hip | 2-4 | 10-15 | 50-100 |
| Quantitative ultrasound | Heel, hand, lower leg | 1-3 | 5-10 | None |
Various biochemical assays are also available to assess bone resorption and formation in both blood and urine ( Table 14.4 ). At present, serum markers appear to be most useful for assessing changes, with antiresorptive therapy having less variability compared with the urinary assessments. Although these biochemical measurements cannot reliably predict bone mass, they may be useful as markers of the effectiveness of treatment. For example, an increased resorption marker may decrease within months into the normal range with an antiresorptive therapy, whereas it takes 1 to 2 years to see a change in BMD with DEXA.
| Marker | Specimen |
|---|---|
| B one R esorption M arkers | |
| Cross-linked N-telopeptide of type I collagen (NTX) | Urine, serum |
| Cross-linked C-telopeptide of type I collagen (CTX) | Urine ( αα and ββ forms), serum (ββ form) |
| MMP-generated telopeptide of type I collagen (ICTP or CTX-MMP) | Serum |
| Deoxypyridinoline, free and peptide bound (fDPD, DPD) | Urine, serum |
| Pyridinoline, free and peptide bound (fPYD, PYD) | Urine serum |
| Hydroxyproline (OHP) | Urine |
| Glycosyl hydroxylysine (GylHyl) | Urine, serum |
| Helical peptide (HelP) | Urine |
| Tartrate resistant acid phosphatase | Serum, plasma |
| 5b Isoform specific for osteoclasts (TRACP 5b) | |
| Cathepsin K (Cath K) | Urine, serum |
| Osteocalcin fragments (uOC) | Urine |
| Bone Formation Markers | |
| Osteocalcin (OC) | Serum |
| Procollagen type I C-terminal propeptide (PICP) | Serum |
| Procollagen type I N-terminal propeptide (PINP) | Serum |
| Bone-specific alkaline phosphatase (bone ALP) | Serum |
Fracture risk is determined not only by bone mass but by many factors, the most important of which is bone strength. This in turn is determined by bone mass and by bone turnover, for which biochemical assessments may be helpful. A research method employs a high-resolution quantitative computed tomography of bone, which is intended to provide a “virtual” bone biopsy. This may be available in the future. The World Health Organization (WHO) has made available an algorithm to predict the 10-year fracture risk of men and women living around the world. This model, called FRAX , can be assessed at www.shef .ac.uk/FRAX and is calculated based on individual patient history data and the results from DEXA. Although there are other assessment tools as well, FRAX is perhaps the most used, but it requires a DEXA measurement. The FRAX tool is used as a rationale for pharmacologic therapy. For example, with osteopenia, if the FRAX score shows a 10-year risk of hip fracture of more than 3% or a 10-year risk of any other osteoporotic fracture of more than 20%, treatment should be initiated .
In terms of the use of DEXA, U.S. Preventative Task Force guidelines suggest screening with DEXA at age 65 or older in all women and in younger women with traditional risk factors for fracture ( ). These traditional risk factors include advanced age, previous fracture, glucocorticoid therapy, parental history of hip fracture, low body mass, cigarette smoking, excessive alcohol use, rheumatoid arthritis and secondary osteoporosis as a result of factors such as hypogonadism/POI, malabsorption, and liver disease.
Many agents are now available for preventing osteoporosis. Guidelines for initiating treatment are history of a fracture, osteoporosis as determined on DEXA, or osteopenia with FRAX scores, as noted earlier. It is important to make a distinction about using various agents for the prevention of osteoporosis (e.g., in a woman who has risk factors and is osteopenic: T score greater than −2.5) as opposed to using drugs to treat established osteoporosis (T scores greater than −2.5).
The use of estrogen depends on whether there are other indications for estrogen treatment and whether there are any possible contraindications. Estrogen has been shown to reduce the risk of osteoporosis and to reduce osteoporotic fractures. A dose equivalent of 0.625 mg of conjugated equine estrogens (CEEs) was once thought to be necessary for the prevention of osteoporosis, but we now know that lower doses (0.3 mg of CEE or its equivalent) in combination with progestogens, or even with adequate calcium alone, can prevent bone loss, although there are no long-term fracture data with lower-dose therapy. Whether the addition of progestogens by stimulating bone formation increases bone mass beyond that produced by estrogen alone is unclear. The androgenic activity of certain progestogens such as norethindrone acetate (NET) also has been suggested to play a role by stimulating bone formation. Fig. 14.23 provides data on changes in BMD at the hip using various agents (Cranney, 2002). Companion figures from the same review (not shown) provide data on vertebral and other nonvertebral fractures. Although these data from an earlier meta-analysis have been updated, the graphic comparisons are basically unchanged. A more recent network meta-analysis suggests that for prevention of hip fracture, compared with placebo, only the following agents have efficacy: romosozumab, an anabolic agent (relative risk [RR], 0.44); alendronate (RR, 0.61); zoledronate (RR, 0.60); risedronate (RR, 0.73); denosumab (RR, 0.56), estrogen/progestogen (RR, 0.72); and calcium with vitamin D (RR, 0.81) ( ).
SERMs such as raloxifene , droloxifene, and tamoxifen all have been shown to decrease bone resorption. Raloxifene has been shown to decrease vertebral fractures in a large prospective trial ( ). All of these agents are used for prevention. In younger women, one complicating factor is that agents such as raloxifene may induce hot flushes; however, they do afford some protection for breast cancer risk because they act as estrogen antagonists at the level of the breast. SERMs such as raloxifene act as a low-dose estrogen and can prevent vertebral fractures but not hip fractures. Tibolone (structurally related to 19-nor progestins) has also been shown to be an effective treatment for the prevention of osteoporosis. Tibolone (not marketed in the United States) has SERM-like properties, but it is not specifically a SERM because it has mixed estrogenic, antiestrogenic, androgenic, and progestogenic properties as a result of its metabolites. The drug does not seem to cause uterine or breast cell proliferation and also is beneficial for vasomotor symptoms. It prevents osteoporosis and has been shown to be beneficial in treatment of osteoporosis as well at a dose of 2.5 mg daily.
Bisphosphonates have been shown to have a significant effect on the prevention and treatment of osteoporosis, using similar doses for both indications. With this class of agents (etidronate, alendronate, risedronate, ibandronate, and zoledronic acid), incorporation of the bisphosphonate with hydroxyapatite in bone increases bone mass. The skeletal half-life of bisphosphonates in bone can be as long as 10 years, and their effects on the skeleton are sustained for a few years after discontinuation, which does not occur with other agents. These agents reduce both spine and hip fractures (see Fig. 14.23 ). Most data have been derived with alendronate , which, at a dosage of 5 mg daily (35 mg weekly), prevents bone loss; at 10 mg daily (70 mg weekly), alendronate is an effective treatment for osteoporosis, with evidence available that this treatment reduces vertebral and hip fractures ( ). Similar data are available for risedronate (35 mg weekly). Ibandronate has been approved as a once-a-month treatment (150 mg), and some data to date support the reduction in vertebral fractures. It can also be injected (3 mg) every 3 months. Zoledronic acid 5 mg is available as an intravenous infusion (over 15 minutes) once a year for the treatment of osteoporosis and every 2 years for prevention. This class of medications has the property of causing esophageal irritation, and care must be taken in administering the oral doses in an upright position with a full glass of water.
Some concern has been raised about bisphosphonates and osteonecrosis of the jaw, fractures of long bones such as the femur with long-term use, and atrial fibrillation. Jaw problems only occur with high doses when poor dentition is present. Femur fractures with long-term use are extremely rare, and atrial fibrillation, although statistically increased with bisphosphonate use, is also rare. Nevertheless, we do not have long-term data (>10 years), and these drugs should not be used for more than 10 years and not with another antiresorptive agent. Their use in younger postmenopausal women (<60 years) should be limited unless there is significant osteoporosis present.
RANKL secreted by osteoblasts causes bone resorption (see Fig. 14.22 ). Denosumab is a monoclonal antibody that binds up RANKL, thus preventing bone resorption. It is an effective treatment for osteoporosis, and although it can also be used for prevention, it is largely viewed as a secondary agent, particularly for women intolerant to other treatments. Denosumab 60 mg is administered subcutaneously every 6 months, and it is effective both at the vertebrae and at the hip, with an efficacy that is similar to or greater than that of the bisphosphonates. Unlike the bisphosphonates, however, the effects wear off immediately after discontinuation of treatment. Although denosumab does not carry the small risks of jaw osteonecrosis and long bone fractures, as an immune therapy, long-term effects of immune modulation are not known.
Calcitonin (50 IU subcutaneous injections daily or 200 IU intranasally) has been shown to inhibit bone resorption, and vertebral fractures have been shown to decrease with calcitonin therapy. Long-term effects, however, have not been established, and this is not a first-line therapy today.
Fluoride has been used for women with osteoporosis because it increases bone density. A lower dose (50 μ g daily) of slow-release sodium fluoride does not seem to cause adverse effects (gastritis) and has efficacy in preventing vertebral fractures.
Intermittent parathyroid hormone (PTH) (teriparatide, abaloparatide ) is effective at increasing bone mass in women with significant osteoporosis. In a randomized trial lasting 3 years, average bone density increased in the hip and spine, with fewer fractures observed. This is a second-tier therapy reserved for severe cases of osteoporosis. Teriparatide at 20 μg needs to be injected subcutaneously on a daily basis for no longer than 18 months ( ).
Romosozumab, mentioned earlier, an anabolic agent that is a monoclonal antibody against sclerostin, is now approved for the treatment of severe osteoporosis. Sclerostin is a product of osteocytes and inhibits bone formation; thus romosozumab, as an antibody, increases bone formation and reduces fractures. Like teriparatide, it is a second-line therapy in patients with an intolerance to other drugs and for severe osteoporosis. Romosozumab 210 mg injected subcutaneously once monthly performed as well as or better than teriparatide in head to head clinical trials.
Adjunctive measures for prevention of osteoporosis are calcium, vitamin D, and exercise.
It should be noted that with all the drug therapies noted here, women should not be deficient in calcium or vitamin D, and supplements are usually required.
Calcium with vitamin D, used together, has been shown to increase bone only in older individuals and was found to be better than placebo for preventing hip fractures in the meta-analysis reviewed earlier. However, this will not be sufficient to prevent bone loss in younger women at the onset of menopause, and these modalities alone are not thought to be effective for the treatment of osteoporosis. A woman’s total intake of elemental calcium should be 1500 mg daily if no agents are being used to inhibit resorption, and 400 to 800 IU of vitamin D should also be ingested. Caution should be exercised in prescribing excessive calcium, particularly in older individuals, because this has been linked to coronary events. Exercise has been shown to be beneficial for building muscle and bone mass and for reducing falls.
There has been a realization that many women in the United States are vitamin D deficient , particularly those in the northern parts of the country because of less sunlight exposure. Vitamin D may also be important as an antimitotic agent that may prevent certain types of cancer. Although there is some controversy about what a normal vitamin D level should be, a blood level of 25-hydroxyvitamin D (25[OH]D) less than 30 ng/mL usually warrants supplemental treatment with 25(OH)D.
Although it is clear that women with established osteoporosis (fractures or a T score of −2.5 or greater) should receive an antiresorptive agent (usually a bisphosphonate), there is more controversy regarding initiating preventive strategies in patients with T scores in the osteopenia range (–1.0 to −2.5) unless there are significant risk factors, as noted earlier. Many women, however, may sustain fractures when in this range of T scores. Age and risk factors largely help determine the need to treat those with osteopenia. In this setting, depending on the age of the woman, her family history, and whether she has vasomotor symptoms, she may be offered HT, a SERM, or a bisphosphonate. The FRAX algorithm should be used as a guide to therapy.
Degenerative arthritis
Degeneration of intervertebral discs is a process that occurs rapidly after menopause. This is consistent with changes in collagen, as noted previously. There is evidence that this is benefited by estrogen after menopause.
Osteoarthritis is a source of significant distress. Estrogen is powerful inhibitor of damage to chondrocytes . The WHI study found that estrogen alone (but not combination hormone therapy) significantly decreased osteoarthritis. A 2018 Korean health assessment study showed that knee osteoarthritis was reduced by 30% in users of HT ( ). However, much more work is needed in this area.
Cardiovascular effects
Women have a very low incidence of CVD before menopause, but after menopause the risk increases significantly. Data from the Framingham study have shown that the incidence is three times lower in women before menopause than in men (3.1 per 1000 per year in women ages 45 to 49). The incidence is approximately equal in men and women aged 75 to 79 (53 and 50.4 per 1000 per year, respectively). This trend also pertains to gender differences in mortality resulting from CVD. Coronary artery disease is the leading cause of death in women, and the lifetime risk of death is 31% in postmenopausal women versus a 3% risk of dying of breast cancer.
Although CVD becomes more prevalent only in the later years after a natural menopause, premature cessation of ovarian function (before the average age of menopause) constitutes a significant risk. Premature menopause, occurring before age 35, has been shown to increase the risk of myocardial infarction two- to threefold, and oophorectomy before age 35 increases the risk sevenfold ( ).
When the possible reasons for the increase in CVD are examined, the most prevalent finding is an accelerated rise in total cholesterol in postmenopausal women. The changes of weight, blood pressure, and blood glucose with aging, although important, are not thought to be as important as the rate of rise in total cholesterol, which is substantially different in women after menopause versus men. This increase in total cholesterol is explained by increases in levels of low-density lipoprotein cholesterol (LDL-C). The oxidation of LDL-C is also enhanced, as are levels of very-low-density lipoproteins and lipoprotein (a). High-density lipoprotein cholesterol (HDL-C) levels trend downward with time, but these changes are small and inconsistent relative to the increases in LDL-C.
Coagulation balance is not substantially altered as a counterbalance of changes occurs. Some procoagulation factors increase (factor VII, fibrinogen), but so do counterbalancing factors such as antithrombin III, plasminogen, protein C, and protein S. Blood flow in all vascular beds decreases after menopause; prostacyclin production decreases, endothelin levels increase, and vasomotor responses to acetylcholine are constrictive, reflecting reduced nitric oxide synthetase activity. Most of these latter changes primarily are due to the fairly rapid reduction in estrogen levels, in that with estrogen all these parameters (generally) improve, and coronary arterial responses to acetylcholine are dilatory, with a commensurate increase in blood flow.
Circulating plasma nitrites and nitrates have also been shown to increase with estrogen, and angiotensin-converting enzyme levels tend to decrease. Estrogen and progesterone receptors have been found in vascular tissues, including coronary arteries (predominantly ERβ). In addition, some membrane effects are mediated by estrogen.
Overall, the direct vascular effects of estrogen are considered to be as important, or more important, than the changes in lipid and lipoproteins after menopause. Although replacing estrogen has been thought to be beneficial for the mechanisms previously cited, these beneficial arterial effects may only be seen in younger (stage +1[a-c]) postmenopausal women ( Fig. 14.24 ) ( ). Women with significant atherosclerosis or risk factors such as those studied in secondary prevention trials, who have established atherosclerosis and prior coronary disease, do not respond well to this treatment because of coronary plaque burden (see Fig. 14.24 ), which prevents estrogen action. Some of this lack of effect may be accounted for by increased methylation of the promoter region of ERα, which occurs with atherosclerosis and aging. Another mechanism is the significant conversion of cholesterol to 27-OH cholesterol, which also impedes estrogen’s production of nitric oxide ( Fig. 14.25 ).
In normal, nonobese postmenopausal women, carbohydrate tolerance also decreases as a result of an increase in insulin resistance. This, too, may be partially reversed by estrogen, although the data are mixed, and high doses of estrogen with or without progestogen cause a deterioration in insulin sensitivity. Biophysical and neurohormonal responses to stress (stress reactivity) are exaggerated in postmenopausal women compared with premenopausal women, and this heightened reactivity is blunted by estrogen. Whether these changes influence cardiovascular risk with estrogen deficiency is not known, but clearly estrogen treatment returns many parameters into the range of premenopausal women in early postmenopausal women. Several trials including data from both hormonal trials of the WHI have shown a reduction in the development of diabetes with HT ( ; ).
These consistently strong basic science and clinical data for the protective effects of estrogen on the cardiovascular system together with strong epidemiologic evidence for a protective effect of estrogen ( Fig. 14.26 ) led to the belief that estrogen should be prescribed to prevent CVD in women. Clinical trial data, however, have refuted this notion in women with established disease, as noted previously. Results from several randomized trials in women have failed to show a protective effect in women with established coronary disease . Furthermore , a trend toward increased cardiovascular events (early harm) has been observed in this setting in some women within the first 1 to 2 years. The WHI trial, which compared CEE/medroxyprogesterone acetate (MPA) with placebo, came to similar conclusions. Though considered to be a primary prevention trial, it studied participants in a large range of ages (mean age 63). These women did not have vasomotor symptoms and had more risk factors than the healthy women studied in observational cohorts, as shown in Fig. 14.26 .
The protective effect of estrogen demonstrated in the observational trials such as the Nurse’s Health Study (NHS) (see Fig. 14.26 ) occurred predominantly in young, healthy, symptomatic women. Table 14.5 compares the demographics of the participants of the WHI and the NHS. Trials carried out in a monkey model have shown a 50% to 70% protective effect against coronary atherosclerosis when estrogen is begun at the time of oophorectomy, with or without an atherogenic diet; delaying the initiation of hormonal therapy for even 2 years (in the monkey) prevents this protective effect ( Fig. 14.27 ). This has been called the timing hypothesis, in which early intervention shows benefit and late intervention with hormonal therapy is possibly harmful for the cardiovascular (CV) system. This has been shown in clinical trial data (see later) and also pertains to the beneficial effects of estrogen on glucose tolerance and insulin sensitivity.
| WHI | NHS | |
|---|---|---|
| Mean age or age range at enrollment (years) | 63 | 30-55 |
| Smokers (past and current) | 49.9% | 55% |
| Body mass index (BMI: mean) | 28.5 kg/m 2 | 25.1 kg/m 2 |
| Aspirin users | 19.1% | 43.9% |
| Menopausal symptoms | Rare | Common |
The perception of coronary harm and other risks in older women receiving combined CEE/MPA in WHI led to widespread confusion and concern about HT in general and led to most women stopping HT and not starting it even when there were significant symptoms. As will be discussed later, more recent data now have confirmed that HT is safe for young, healthy women, and it is particularly indicated in women with symptoms . It appears we have come full circle as many of the original concepts of cardioprotection and reduction in all-cause mortality with estrogen have been once again confirmed from the randomized trials, when one examines the effects in younger women close to menopause ( ) ( Fig. 14.28 ). However, what we have learned from the WHI is that although younger women benefit, older women do not (the timing hypothesis) and may endure harm, as several secondary prevention trials (in women with established coronary disease) have shown. No clear explanation exists for what may cause the observed “early harm,” but these effects were not observed in those women receiving statins concurrently. This finding suggests that HT (in the doses used) may lead to plaque destabilization and thrombosis in some women with established (although possibly silent) coronary disease. The molecular mechanisms for this effect may be due to estrogen upregulating matrix metalloproteinase-9 and inhibiting its natural inhibitor within the mural area of the plaque; the resultant disruption of the gelatinous covering then leads to thrombosis. The antiinflammatory effects of statins inhibit this process. Additional lessons learned from WHI and more recent data are findings that estrogen is what is protective, and progestogens , depending on the type and dose, are likely to attenuate or eliminate any protective effect and also may be implicated in the risk of breast cancer.
