Amenorrhea. A Case-Based, Clinical Guide

9. Natural and Surgical Menopause

Sara Morelli  and Gerson Weiss

(1)

Department of Obstetrics, Gynecology and Women’s Health, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA

Sara Morelli

Email: morellsa@umdnj.edu

Abstarct

Women outnumber men among older adults. In 2002, 33 million women in the US civilian population were aged 55 years and older, with a gender ratio of 81 men per 100 women [1]. By 2030, more than 1.2 billion women in the world will be at least 50 years old [2]. This increasing proportion of the female population will be experiencing the menopausal transition with its accompanying physiology and pathophysiology.

Women outnumber men among older adults. In 2002, 33 million women in the US civilian population were aged 55 years and older, with a gender ratio of 81 men per 100 women [1]. By 2030, more than 1.2 billion women in the world will be at least 50 years old [2]. This increasing proportion of the female population will be experiencing the menopausal transition with its accompanying physiology and pathophysiology.

Aging of the female reproductive axis occurs much earlier than aging of other organ systems, generally at a time when a woman is otherwise healthy. Females are born with a fixed number of oocytes (approximately 1–2 million) arrested in prophase I of meiosis. The basis of female reproductive aging is the gradual loss of these oocytes through atresia (beginning in utero and continuing throughout life) and ovulation (during the reproductive years), as well as a diminished sensitivity of the hypothalamic-pituitary axis to estrogen [3]. The median age at onset of irregular menstruation associated with the menopausal transition is 47.5 years, with a median age at final menstrual period (FMP) of 51.3 years [4]. Ethnic differences in the age at menopause have been reported. When compared with Caucasian women, Hispanic and African–American women experience menopause at an earlier age [56], whereas Chinese American and Japanese American women have a later completion of the transition [6]. Lifestyle and social factors play a role in the timing of menopause; cigarette smoking has been shown to advance menopause by as much as 2 years [46], and lower socioeconomic status (SES) has been associated with earlier menopause [6].

Defining the menopausal transition

Given the wide age range (41–57 years) over which reproductive senescence occurs in normal women [7], and that chronological age is a poor indicator of reproductive aging, defining the menopausal transition has presented a challenge to clinicians as well as the scientific community. The World Health Organization (WHO) presently defines the perimenopause as the “period immediately before the menopause (when the endocrinological, biological, and clinical features of approaching menopause commence) and the first year after menopause” [8]. According to the Massachusetts Women’s Health Study, one of the largest longitudinal studies that investigated a method for defining perimenopause based on self-reported data in 1,550 women over 5 years, the two findings that best define the perimenopause are increased menstrual irregularity and 3–11 months of amenorrhea [9].

These definitions still do not clearly define the commencement and natural history of the perimenopause. In 2001, participants of the Stages of Reproductive Aging Workshop (STRAW) convened in order “to address the absence of a relevant staging system for female reproductive aging and to discuss the confusing current nomenclature for the perimenopause” [7]. The workshop’s aim was to develop a general staging system for healthy women. The proposed criteria were deemed unsuitable for application in cigarette smokers, women at extremes of body weight (BMI <18 kg/m2 or >30 kg/m2), heavy aerobic exercisers (>10 h/week), women with chronic menstrual cycle irregularity, women with previous hysterectomy, or those with abnormal uterine or ovarian anatomy (e.g., fibroids, endometriomas).

As defined by STRAW, reproductive and postreproductive life are divided into seven stages (Fig. 9.1), with the menopausal transition accounting for two of those stages. The stages are anchored around the FMP, defined as the last period preceding 12 months of amenorrhea. They are primarily based on the characteristics of the menstrual cycle and secondarily on follicular phase follicle stimulating hormone (FSH) levels. Stages −5 to −3 span the reproductive years; stages −2 and −1 make up the menopausal transition; and stages +1 and +2 are early and late postmenopause. The age range and duration of each of these stages vary. In fact, not everyone transitions through the described sequence.

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Fig. 9.1

The STRAW staging system. Reprinted from Soules et al. [7], Fig. 1

There is no clear delineation between the early, peak, and late reproductive stages (stages −5 to −3). An elevated FSH level (defined as an early follicular phase level that exceeds 2 SDs of the mean level for a sample of normal women of peak reproductive age [25–30 years], often defined by clinicians as ≥10 mIU/mL) is the first measurable sign of reproductive aging and characterizes stage −3. According to STRAW, a single elevated FSH level is sufficient to categorize a woman as stage −3 and does not require repeating. However, there is significant intercycle variability in early follicular phase FSH levels, and a normal level in a 40- to 45-year-old woman may warrant a second measurement. The early follicular phase serum estradiol (E2) level in the late reproductive stage may be either normal or elevated. Elevated E2 levels may lower FSH levels due to negative feedback at the level of the pituitary; thus, FSH levels cannot be interpreted if E2 is over 80 pg/ml.

The early menopausal transition (stage −2) is characterized by more variable menstrual cycles, whereby the intermenstrual interval changes by seven days or more. The late menopausal transition (stage −1) is characterized by two or more skipped menstrual cycles and at least one intermenstrual interval of at least 60 days in length. Stage 0 is marked by the FMP, followed by 12 months of amenorrhea.

STRAW was the first to recognize that subtle changes in the menstrual cycle are important early markers of the menopausal transition. However, in 2005, Gracia et al. [10] proposed a stricter staging system to distinguish among women with even more subtle changes in cycle length. This system (PENN-5, Penn Ovarian Aging Study) incorporates an additional stage termed the “late premenopause,” and redefines the early and late menopausal transition (Table 9.1). The authors used a difference in mean serum reproductive hormone values obtained during the early follicular phase (cycle day 4) to validate their definitions of menopausal status. Significant differences in FSH (8.7 vs. 9.4 mIU/mL, p = 0.04) and inhibin B (44.9 vs. 39.0 pg/mL, p = 0.003) were detected between the premenopausal and late premenopausal stages, respectively, as well as between the late premenopausal and early transition stages. Thus, women with only one cycle length change of ≥7 days were distinguished from women with two or more cycle length changes, supporting the notion that early and subtle changes in cycle length reflect significant underlying hormonal changes among women in the earliest phases of the menopausal transition. Of note, differences in luteinizing hormone (LH) and E2 levels between the earliest stages did not reach statistical significance. A more in depth review of reproductive hormonal patterns characterizing the menopausal transition will follow later in the chapter.

Table 9.1

Menopausal status definitions

STRAW definition

PENN-5 definition

Premenopause (Stages –5 to –3)

Regular cycles, with no change in cycle length

Premenopause

Regular cycles, with no change in cycle length

Early Transition (Stage –2)

1 cycle length change (³7 days)

Late Premenopause

1 cycle length change (³7 days)

   

Early Transition

³2 cycle length changes (³7 days)

Late Transition (Stage –1)

2–11 months of amenorrhea

Late Transition

3–11 months of amenorrhea

Postmenopause Transition (Stage +1, +2)

³12 months of amenorrhea

Postmenopause

³12 months of amenorrhea

Adapted from Gracia et al. [10], Defining menopause status: creation of a new definition to identify the early changes of the menopausal trasition. Menopause 2005.

Ovarian follicular depletion is the primary driver of the menopausal transition

Follicle numbers as well as ovarian volume decrease over the course of reproductive aging. The declining number of primordial follicles over time may be reflected by a decreased size of the antral follicle cohort from which the monthly ovulatory follicle is selected. The number of antral follicles (between 2 and 10 mm on transvaginal ultrasound) has been reported to decrease progressively in women over an age range of 25–46 years [11]. In this study, the antral follicle count measured in the early follicular phase exhibited a mean yearly decline of 4.8% prior to age 37 years, and accelerated to a yearly decline rate of 11.7% thereafter. Additional studies utilizing transvaginal ultrasonography in the early follicular phase confirm the finding of reduced antral follicle counts in older reproductive-aged [12] and menopausal [13] women.

Histologic evidence for accelerated follicular depletion with reproductive aging was provided by a 1987 study by Richardson et al. [14] in which primordial follicle numbers were counted in one ovary obtained from each of 17 healthy women aged 45–55 years undergoing elective total abdominal hysterectomy with salpingo-oophorectomy. Women were divided into three groups: (1) premenopausal (regular menstrual cycles, n = 6), (2) women undergoing the menopausal transition (defined as the presence of irregular menses with intervals of less than 3 or more than 6 weeks for at least 1 year with or without hot flashes, n = 7), and (3) postmenopausal (>1 year since last menses, n = 4). The mean ages of the three groups were similar. The mean number of primordial follicles in premenopausal women was tenfold higher than that in women undergoing the menopausal transition (1,392 ± 355 vs. 142 ± 72, respectively). Follicles were virtually absent in the four postmenopausal ovaries examined; one primordial follicle was identified in one ovary. The data illustrated the dramatic acceleration of follicular depletion which occurs in the last decade of the reproductive years, and “support the view that declining follicular reserve is the immediate cause of both the perimenopausal and menopausal transitions” [14]. However, compelling evidence for independent effects of reproductive aging on the hypothalamic-pituitary-gonadal axis (beyond its release from the negative feedback of ovarian steroids and inhibin due to follicular depletion) exists and will be discussed later in the chapter.

Mullerian inhibiting substance (MIS), also known as anti-mullerian hormone (AMH), is a product of the granulosa cells of primary, secondary, and antral follicles, and is not involved in negative feedback regulation of gonadotropin secretion. It has gained recent attention as a marker of the primordial follicle pool and a predictor for the occurrence of the menopausal transition. The observation that serum MIS declines detectably over time in younger women still having regular menstrual cycles (prior to the detection of changes in FSH or antral follicle count) illustrates the potential advantage of MIS as an early predictor of declining ovarian reserve [15]. Limitations of its measurement, however, include the inadequate sensitivity of currently available assays to permit accurate assessment of MIS in the years immediately preceding menopause. As women progress to the later stages of the transition, levels of MIS become too low to be detectable [16], and MIS cannot be detected in postmenopausal women [15].

Endocrine changes in the menopausal transition

In 1975, Sherman and Korenman [17] were among the first to describe endocrine changes occurring with advanced reproductive age. The authors collected daily blood samples during several cycles from regularly cycling women (aged 40–41 years, 46–51 years, and a control group aged 18–30 years). The shortest cycle length was observed in the oldest group (mean cycle length 23.5 days in 46- to 51-year olds vs. 30 days in the control group), the shortening being due to a shorter interval between the onset of menses and the LH peak. The authors observed lower serum E2 levels and higher FSH levels throughout the menstrual cycle in the oldest group, “despite the attainment of levels of E2 that might be expected to suppress its secretion, while LH remained indistinguishable from normal” [17]. The finding of a monotropic rise in FSH (but not LH) secretion in the oldest age group led the authors to hypothesize that an ovarian hormone must exist which exerts negative feedback inhibition specifically on FSH secretion by the pituitary, and that this hormone decreases in the late reproductive years due to diminished ovarian follicle number. This hormone was later characterized as inhibin [18].

In the 1980s, Metcalf et al. [1922] carried out a longitudinal study of weekly hormone secretion in older (median age 42 years) and younger (median age 33 years) women which illustrated the unpredictable hormonal patterns of those undergoing the menopausal transition. In 31 women in the early transition according to STRAW criteria, median cycle length was 29 days (range 18–260 days) with only 52% of cycles being ovulatory. Notably, ovulatory cycles were noted at all stages of the menopausal transition. The authors noted both persistently low and persistently increased urinary estrogen excretion, as well as the sporadic appearance of persistently high FSH and LH levels sometimes associated with high estrogen levels. As stated by the authors, “menstrual cycles in perimenopausal women…are richly varied. Unpredictability is the norm, in marked contrast to the regular succession of ovulatory cycles observed in premenopausal women” [20]. Eight women (aged 44–55 years) were followed during the 6 months following the FMP and exhibited hormonal patterns which were indistinguishable from those observed in the long anovulatory cycles of the menopausal transition. In contrast, older postmenopausal women (aged 57–67 years) exhibited consistently high gonadotropin and low estrogen levels consistent with ovarian failure.

In a similar effort to characterize endocrine features of the perimenopause, Santoro et al. [23] collected daily urinary samples for 12 months on 6 cycling women aged 47 years or older as well as daily samples for a single cycle on 15 women aged 43–47 years. The authors compared menstrual and hormonal patterns in these perimenopausal women to those in midreproductive (aged 19–38 years) and postmenopausal women (aged 54–79 years). Similar to the findings of Sherman and Korenman [17], these authors also demonstrated shorter cycles in perimenopausal women when compared with midreproductive-aged women due to a shortened follicular phase. In contrast, however, overall estrone (E1) conjugate excretion was greater in perimenopausal than in midreproductive-aged women during both follicular and luteal phases. Although others have similarly demonstrated prolonged ­episodes of unopposed estrogen secretion in women approaching menopause [24], this study was the first to demonstrate significant hyperestrogenemia in ovulatory perimenopausal cycles, a finding that is consistent with the clinical findings of endometrial hyperplasia, enlarging leiomyomata, and dysfunctional bleeding that becomes more prevalent during the perimenopause. These authors also demonstrated elevated gonadotropins ­(particularly FSH), most pronounced in the early follicular phase, and diminished pregnanediol excretion in the luteal phase of perimenopausal women when ­compared with that in midreproductive-aged women. Postmenopausal women were found to have tonically elevated LH and FSH and persistently low E1 conjugate excretion. Periods of hypergonadotropic hypoestrogenism were similarly found in some ­perimenopausal women, becoming more common with proximity to the FMP. In addition to hypergonadotropic hypogonadism, however, perimenopausal cycles can manifest other types of patterns. Elevated gonadotropins with normal estrogen excretion, indicating a failure of negative feedback of estrogen on the hypothalamic-pituitary axis, and failure of estrogen’s biphasic, positive feedback on the ­hypothalamic-pituitary axis have been described [3].

Although the menopausal transition is characterized by menstrual irregularity with interspersed ovulatory and anovulatory cycles, elongated cycles become more frequent and longer in duration as menopause approaches [25]. Miro et al. [26] undertook a study of urinary hormonal profiles during 289 elongated cycles of 34 women undergoing the menopausal transition, STRAW stages −2 to −1. These authors described the concept of estrogen take-off (ETO), a measure of onset of ovarian response to FSH during the follicular phase, defined as time between cycle day 1 and the start of first sustained rise in urinary estrone 3-glucuronide (E1G). The authors demonstrated that elongation of the menstrual cycle is fundamentally the result of a delay in ovarian response (longer ETO), and that this was due to a temporary lack of responsiveness to FSH rather than inadequate FSH stimulus from the pituitary, as they reported an association between longer ETO and higher FSH levels. Similar to the findings of Santoro et al. [23], the authors demonstrated a decline in luteal progesterone synthesis, which correlated with increasing ETO. In the SWAN (Study of Women’s Health Across the Nation, a multiethnic observational cohort study of the menopausal transition in 3,302 women aged 42–52 years at seven US sites) study, examination of luteal progesterone excretion over time indicated a progressive decrease [27].

Several studies have investigated ethnic differences in serum FSH and E2 in women undergoing the menopausal transition. A cross-sectional analysis of early follicular serum E2 and FSH concentrations in early perimenopausal patients in the SWAN study reported higher serum FSH levels in African–American and Hispanic women compared with that in Caucasians, but no ethnic differences in E2 levels after adjustment for other factors such as BMI [28]. FSH differences with comparable E2 levels suggest ethnic differences in the pituitary-ovarian relationship during the menopausal transition. A subsequent longitudinal study on SWAN participants evaluated early follicular serum E2 and FSH during three consecutive annual visits [29]. Similar patterns in the decline of E2 and the increase in FSH were found across ethnic groups, but hormone levels differed by race/ethnicity. Consistent with the prior study, African–American women had higher FSH levels but similar E2 levels when compared with Caucasians, whereas Chinese and Japanese women had lower E2 levels but comparable FSH levels. These ethnic differences in E2 and FSH were independent of menopausal status and were indeed suggestive of ethnic differences in the pituitary-ovarian axis.

Markers of ovarian reserve also appear to vary with BMI. A cross-sectional study of 36 women aged 40–52 years found that mean AMH levels (but not FSH, E2, or antral follicle counts) were significantly lower in obese women (BMI ≥30 kg/m2) compared with those in normal weight women (BMI <25 kg/m2) [30]. However, Randolph et al. found in a larger longitudinal cohort study [29] that increasing BMI was associated with increasing E2 and decreasing FSH levels in late perimenopausal and postmenopausal women.

Inhibin and reproductive aging

Inhibin is a dimeric glycoprotein composed of an α (alpha)-subunit and a β (beta) A-subunit (inhibin A) or β (beta) B-subunit (inhibin B). During the normal menstrual cycle, inhibin B (a product of antral follicle granulosa cells) is highest in the early to midfollicular phase and decreases in the late follicular phase [31]. Inhibin A is a product of the preovulatory follicle and corpus luteum, and is thus highest in the late follicular and midluteal phases [31]. Production of ovarian inhibin B (and E2) is stimulated by the gonadotropins, and during the follicular phase, inhibin B appears to be the major negative regulator of FSH secretion. The fall in inhibin B in late reproductive age has been shown to trigger the monotropic rise in follicular phase FSH [32].

To evaluate the role of inhibin in reproductive aging, MacNaughton et al. [33] studied serum levels of immunoreactive inhibin in regularly cycling women aged 21–49 years during the early follicular (cycle days 4–7) and midluteal phases (3–12 days prior to menses). Mean follicular phase levels of immunoreactive inhibin were significantly lower in the oldest age group than those in the younger age groups (128 U/l in the 45–49 years age group vs. 239, 235, and 207 U/l in the 20–29, 30–39, and 40–44 years age groups, respectively (p < 0.05)), while mean FSH levels were significantly higher in the oldest age group. Conversely, the authors found no difference in E2 levels between the oldest and youngest age groups, and LH levels did not differ significantly with age. These results illustrated the concept of differential feedback. The authors postulated that decreasing inhibin levels with age reflected diminished folliculogenesis with approaching menopause.

The availability of assays specific for the inhibin dimers allowed subsequent investigations into the role of each in the endocrinology of the menopausal transition. Klein et al. [34] studied follicular phase secretion of inhibin A and B in older (aged 40–45 years) and younger (aged 20–25 years) ovulatory women and demonstrated that the monotropic rise in FSH seen in older ovulatory women was associated with a decrease in follicular phase levels of inhibin B but not inhibin A. Burger et al. [32] demonstrated similar findings in women undergoing the menopausal transition. These authors studied serum immunoreactive inhibin, inhibin A, inhibin B, FSH, and E2 levels from the follicular phase (or at random in those with >3 months of amenorrhea) of women aged 48–59 years. Women were divided into four menopausal stages (stage 1, premenopausal; stage 2, early perimenopausal [reported change in menstrual cycle frequency in the preceding year with a bleed in the preceding 3 months); stage 3, late perimenopausal [no menses in the preceding 3–11 months]; and stage 4, postmenopausal). FSH rose progressively and immunoreactive inhibin fell progressively with menopausal status, each demonstrating a significant change between early and late perimenopause. The authors demonstrated a significant decline in inhibin B (from 48 to 13.5 ng/l, p < 0.05) at early perimenopause, which preceded a decline in inhibin A and E2 at late perimenopause (52% and 71% decline from premenopausal levels, p < 0.05 for both) (Fig. 9.2). Thus, the authors demonstrated that falling inhibin B levels (reflecting a decrease in the size of the primary and early antral follicles) are the important factor in allowing the rise in FSH in older regularly cycling women, whereas inhibin A levels are preserved until late in the menopausal transition. It is important to keep in mind, however, that these hormone measurements have all been made in the early follicular phase of the menstrual cycle, and thus inhibin A levels do not truly reflect maximal secretion of this hormone, as it is primarily a product of the dominant follicle and corpus luteum.

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Fig. 9.2

Geometric mean levels (with lower 95% confidence intervals) of (a) FSH, (b) IR-INH, (c) INH-A, (d) INH-B, and (e) E2 as a function of menopausal status. Menopausal stages as given in text. Values with the same superscript (asterisk or dagger) are not statistically different; values with differing superscripts are different, p < 0.05. Reprinted from Burger et al. [32], Fig. 1

Muttukrishna et al. [35] compared daily serum hormone levels drawn throughout the menstrual cycle in young cycling women (aged 25–32 years) with those of older cycling women (aged 40–50 years) who were subdivided by early follicular phase FSH levels (FSH <8 vs. FSH >8). Young and older women with normal FSH levels exhibited similar patterns of inhibins A and B throughout the cycle. However, older women with elevated basal FSH levels had significantly lower concentrations of inhibin A prior to the LH surge and in the mid-luteal phase, and lower concen­trations of inhibin B in the early follicular phase than older women with normal basal FSH levels. The authors concluded that the rise in early follicular phase serum FSH in older women was associated with decreased early follicular phase inhibin B levels, but postulated that lower luteal phase inhibin A levels may also contribute to the rise in early follicular phase FSH levels in women of advanced reproduc­tive age.

Similarly, Santoro et al. [36] and Welt et al. [37] demonstrated lower luteal inhibin A levels in older (aged 43–47 years) vs. younger (aged 19–38 years) cycling women (668 ± 72 vs. 1152 ± 216 total pg, respectively, p = 0.03) and concluded that lack of negative feedback by both inhibin A and inhibin B may contribute to the FSH rise associated with reproductive aging. These authors and others [38] also demonstrated that activin A levels were significantly elevated throughout the cycle in older women when compared with younger women (21 ± 2 vs. 11 ± 1 total nanogram, p < 0.005), and postulated that activin A may also play an endocrine role in maintaining elevated FSH in older reproductive-aged women. Activin A, a homodimer of the inhibin A β (beta)-subunits, appears capable of direct stimulation of pituitary FSH secretion [39].

Collectively, these studies illustrate that it is primarily a decrease in inhibin B (a reflection of the diminishing ovarian follicular pool) that is the major peptide feedback factor causing a monotropic rise in FSH with advancing reproductive age. However, a decrease in inhibin A after ovulation, manifested later in the menopausal transition, may also be contributory.

Alterations in the hypothalamic-pituitary-ovarian (HPO) axis with reproductive aging

The onset of menopause in humans is related not only to oocyte depletion and ovarian failure, but also to alterations in hypothalamic-pituitary feedback. In 1978, Van Look et al. [40] reported that women of reproductive age with anovulatory dysfunctional uterine bleeding failed to exhibit a normal LH response to an exogenous E2 challenge, supporting the hypothesis that the pathophysiologic defect in these women may be a decrease of hypothalamic sensitivity to positive feedback. The subsequent findings of the Daily Hormone Study (DHS) [341], a substudy of SWAN, supported this notion in its examination of women experiencing anovulatory cycles during the menopausal transition. The authors measured daily urinary LH, FSH, E1 conjugates, and the progesterone urinary metabolite pregnanediol glucuronide (Pdg) over the course of one menstrual cycle ending in bleeding (or up to 50 days in the absence of a menstrual period). In some women, a rise in estrogen followed by an LH surge was observed; however, the absence of ovulation in these cycles (as documented by a lack of threefold increase in Pdg concentrations above a nadir for at least 3 days) indicated a defect at the ovarian level. However, the authors also reported frequent anovulatory cycles in perimenopausal women in which estrogen peaks were equivalent to those that result in LH surges in younger women, yet no LH surges occurred (Fig. 9.3). This finding suggests unresponsiveness of the hypothalamic-pituitary axis to an estrogen peak in older perimenopausal women (failure of “positive feedback”). In other anovulatory cycles, follicular phase estrogen levels similar to those in younger women did not lower LH secretion as occurs in cycles of younger women, indicating decreased negative feedback of estrogen on LH secretion. Collectively, the authors’ findings supported the hypothesis that “there is a relative hypothalamic-pituitary insensitivity to estrogen in aging women” [3] with failure of both positive and negative feedback mechanisms.

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Fig. 9.3

Daily urinary E1c levels in anovulatory older reproductive-age women with estrogen increases. Comparison of E1c levels (estrone conjugates) in women who had an LH surge (left panel) vs. those who did not (right panel). E1c levels (mean (SEM)) for women with both estrogen increases and LH surges are shown here, where day 0 is the day of maximum E1c. Reprinted from Weiss et al. [3], Fig. 2

Although gonadotropins are higher in perimenopausal women than in premenopausal women, levels decline with advancing age after menopause. In contrast, GnRH secretion appears to increase with age in postmenopausal women [42], which suggests that the pituitary is less responsive to GnRH in older compared with younger postmenopausal women. Gill et al. [42] studied 13 young (aged 45–55 years) and 11 old (70–80 years) postmenopausal women in an effort to investigate the effect of age (and gonadal steroid feedback with administration of exogenous estrogen or estrogen plus progesterone) on GnRH secretion by the hypothalamus in postmenopausal women. At baseline, mean LH and FSH levels were significantly lower in older compared with younger postmenopausal women. Percent inhibition of LH following administration of a fixed, submaximal dose of a GnRH antagonist decreased with age, implying an increase in endogenous GnRH secretion with age. With estrogen and progesterone treatment, mean FSH and LH levels decreased significantly and to a similar degree in both young and old postmenopausal women, implying that responsiveness to gonadal steroid negative feedback at the hypothalamus is maintained with aging. This differs from the previously described findings of the DHS [3] in which a lack of estrogen-negative feedback on LH secretion was seen in a subset of women. This may be explained by the shorter duration of estrogen exposure during the menstrual cycles of women in the DHS compared with that used in the protocol used by Gill et al. [42].

Symptoms of the menopausal transition

Whereas some women may experience few or no symptoms during the menopausal transition, many experience a variety of troublesome and sometimes disabling symptoms. These include hot flashes, night sweats, vaginal dryness and painful intercourse, sleep problems, mood and cognitive problems, somatic symptoms, urinary incontinence, bleeding problems, sexual dysfunction, and overall decreased quality of life [43]. Although commonly attributed to menopause, it is a challenge to discern whether these symptoms are truly associated with the hormonal changes of the menopausal transition rather than with aging in general. A 2005 report from the National Institutes of Health highlighted the paucity of scientific data on menopausal symptoms and concluded that although considerable evidence supports the association of vasomotor symptoms, vaginal dryness, and sleep disturbances with menopausal status, there is less information about whether other symptoms such as mood changes, cognitive dysfunction, urinary incontinence, sexual dysfunction, neuromuscular complaints, and overall quality of life are associated with menopausal stage [43].

The Penn Ovarian Aging Study studied 404 women of a mean age of 42.3 years spanning all stages of the menopausal transition over 9 years of follow-up [43]. After adjustment for various risk factors for menopausal symptoms such as age, race, BMI, smoking, and history of depression, the authors found that menopausal stage was significantly associated with hot flashes, aches, joint pain, stiffness, and depressed mood. The risk of hot flashes increased throughout the menopausal transition and was greatest in the postmenopausal group (OR 2.87, 95% CI 1.76–4.87, p < 0.001). The risk of depression was greatest in the late premenopausal stage (STRAW −3), and depressed mood decreased postmenopause. There was no significant association of menopausal stage with poor sleep, decreased libido, or vaginal dryness. Perceived stress was significantly associated with all menopausal symptoms. Others have found a similar association with perceived stress, as well as an overall increase in symptom reporting in women of low SES [45].

Increased FSH levels, decreased levels of inhibin B, and within-woman fluctuations of E2 (all measured during early follicular phase) were significantly and independently associated with menopausal symptoms.

A follow-up study of the same cohort of women [46] assessed headache, irritability, mood swings, anxiety, and concentration difficulties over the menopausal transition. Of these symptoms, only headache was associated with menopausal stage, and significantly decreased after menopause. Mean FSH levels were inversely associated with mood swings and mean testosterone levels were associated with irritability (p value for both <0.01), indicating a decrease in symptoms as hormone levels increased around menopause. Again, perceived stress independently correlated with all symptoms in the study.

A longitudinal Australian population-based study of 438 women aged 45–55 years followed over 7 years [47] found that the symptoms that were specifically related to hormonal changes during the menopausal transition were vasomotor symptoms, vaginal dryness, and breast tenderness. Hot flashes, night sweats, and vaginal dryness increased and breast tenderness decreased concurrent with the significant drop in E2 levels and rise in FSH levels found in the late menopausal transition. Difficulty in sleeping did not appear to be a direct effect of menopausal hormonal changes, but was predicted by hot flashes and psychosocial factors such as depression.

Hot flashes

Hot flashes and night sweats (collectively known as vasomotor symptoms) are reported with high frequency (up to 80%) in women during the menopausal transition [43]. They manifest as a transient sensation of heat with or without objective signs of skin vasodilation accompanied by variable degrees of flushing, sweating, palpitations, anxiety, irritability, and even panic [48]. The timing of their appearance in relation to the FMP varies by study; whereas one group reported an acceleration in prevalence of hot flashes during the menopausal transition to peak at about the time of the FMP [4], others have reported the greatest frequency 3 months or more after the FMP [49]. A prospective longitudinal study of 57 Norwegian women undergoing the menopausal transition reported a peak prevalence of hot flashes during the first year following the FMP [50]. Some report that these symptoms generally subside within 1 year [51], whereas others have reported a mean duration of approximately 5 years in both estrogen users and non-users [52].

A number of longitudinal cohort studies including both SWAN [4153] and the Penn Ovarian Aging Study [4454] have found that African–American women are more likely than white women to report hot flashes. A population-based study of women aged 45–54 years [54] also revealed that African–American women were more likely than Caucasian women to report any hot flashes (RR = 2.08), severe hot flashes (RR = 2.19), and hot flashes for more than 5 years (RR = 1.61). The reasons for this are unknown, but may be due to racial differences in a number of risk factors for hot flashes, including high BMI, current smoking, less than 12 drinks in the past year, and lower estrogen levels [55]. Indeed, obesity and smoking have been reported to increase the risk for hot flashes [5659].

The physiologic mechanism for the initiation of flashes is not entirely understood. A growing body of evidence supports the hypothesis that flashes result from a physiologic response to a marked narrowing of hypothalamic thermoregulatory set point or neutral zone, which increases the sensation of intense heat in response to internal and environmental triggers (Fig. 9.4). The exact trigger that induces this change in the hypothalamic thermoregulatory set point during menopause is not completely understood.

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Fig. 9.4

Small core body temperature (Tc) elevations that act within a reduced thermoneutral zone trigger hot flashes in symptomatic postmenopausal women. Reprinted from Freedman [69], Fig. 3

The withdrawal (or decrease in levels) of estrogen, rather than hypoestrogenism per se, appears to precipitate menopausal flashes [4749]. However, estrogen withdrawal alone does not explain the cause of vasomotor symptoms, as evidenced by the observation that there is no significant correlation between plasma hormone levels and the occurrence of vasomotor symptoms [60]. Furthermore, 73% of women experience vasomotor symptoms prior to menopause, which may occur during both ovulatory and anovulatory cycles [61]. Data from the SWAN study revealed that most of the premenopausal women experiencing vasomotor symptoms had estrogen secretion that was similar in quantity to or higher than the estrogen secretion of younger women, and revealed no relationship between hot flashes and ambient hormones [61].

A temporal relationship between pulsatile release of LH and initiation of menopausal flashes has been clearly demonstrated [62] (Fig. 9.5). However, it is not LH release by the pituitary itself which directly causes the flashes, as demonstrated by the presence of menopausal flashes in hypophysectomized women [63]. Furthermore, studies in which a GnRH agonist was administered to menopausal women with frequent hot flashes demonstrated the complete suppression of LH and FSH pulses, but no changes in frequency or severity of flash episodes [64]. Thus, a hypothalamic mechanism likely initiates both the pulsatile release of LH and flash episodes [62]. A study of serum levels of pituitary hormones during severe menopausal flashes demonstrated a significant rise in growth hormone, LH, and ACTH but not prolactin, TSH, or FSH [65]. Given that norepinephrine is the neurotransmitter believed to be the predominant hypothalamic stimulus of pituitary growth hormone [66], pulsatile LH release [67], and heat dissipation [68], the authors hypothesized that increased hypothalamic norepinephrine activity due to ovarian failure is the “neuroendocrine link between estrogen deficiency and cyclic activation of adjacent thermoregulatory neurons” [65].

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Fig. 9.5

Pattern of pulsatile LH release and associated menopausal flash episodes. Arrows indicate flash onset. Each part illustrates a separate 8- to 10-h study in which blood samples were obtained at 15-min intervals. Note that each flash is synchronized with an LH pulse. Reprinted from Casper et al. [61], Fig. 1

Estrogen withdrawal may also be correlated with a decline in circulating levels of serotonin, another neurotransmitter that appears to play a central role in the pathophysiology of hot flashes [69]. This decline may increase the sensitivity of hypothalamic serotonin (5-HT2A) receptors and may also contribute to a narrowing of the thermoregulatory neutral zone [70]. Similarly, animal studies report that increased CNS levels of norepinephrine are associated with a narrowing of the thermoregulatory neutral zone [71]. Thus, instability in both serotonin and norepinephrine levels during menopause (as a result of estrogen withdrawal) appears to contribute to increased risk of hot flashes.

Estrogen, by itself or with progestins, is the most consistently effective therapy for the treatment of vasomotor symptoms [43]. Concerns regarding the use of ­hormone therapy arose from the findings of the Women’s Health Initiative (WHI) [7273], a large prospective randomized study designed to evaluate the effect of hormone therapy on the incidence of cardiovascular disease and other adverse outcomes. Although this trial was not designed to evaluate the efficacy of hormone therapy in the treatment of menopausal symptoms, excluded perimenopausal women, and thus was not carried out on a study population representative of most who seek hormone therapy for menopausal symptoms, data from the WHI have been widely interpreted as demonstrating an unfavorable risk-to-benefit ratio for hormone therapy – regardless of its timing or indication. This is a most unfortunate outcome of the study, as the presence of menopausal symptoms tips the risk-to-benefit ratio for hormone therapy in a favorable direction for many, if not most women, favoring its short-term use.

Hormone therapy (combined conjugated equine estrogen (CEE) 0.625 mg/day plus medroxyprogesterone acetate (MPA) 2.5 mg/day) was not found to reduce the incidence of cardiovascular disease after 5.2 years of follow-up [73], at which time the estrogen–progestin trial was terminated. Whereas an increased risk of breast cancer was reported with estrogen–progestin therapy (HR 1.24, p < 0.001) [74], the use of 0.625 mg/day CEE alone in women with previous hysterectomy revealed no increased risk of breast cancer [75]. An increased risk of stroke (12 additional strokes per 10,000 person-years), however, was reported in the estrogen-only arm [75]. Other known risks of hormonal therapy include a twofold to threefold increased risk of venous thromboembolism and an increased risk of gall bladder disease [76].

Absolute contraindications for hormone therapy include undiagnosed vaginal bleeding, active thromboembolic disease, and active breast cancer [76]. The risks of hormone therapy in those without absolute contraindications must be balanced against the benefits, which include excellent control of vasomotor symptoms, treatment of genitourinary atrophy, and preservation of bone health. In assessing the patient for potential hormone therapy vs. nonhormonal options, one must consider factors such as personal history, family history, social history, and current medication use. Thromboembolic risk, cancer (including breast cancer) risk, cardiovascular health (including blood pressure, lipid profile, and tobacco use), bone density, vaginal health, urinary symptoms, and sexual function must all be taken into account.

In women with intact uteri, the use of estrogens with either cyclic or continuous progestins has been shown to relieve vasomotor symptoms and vaginal atrophy [7778]. The Postmenopausal Estrogen/Progestin Interventions Trial [77], a randomized, double-blind, placebo-controlled trial conducted in 875 postmenopausal women, evaluated the effect of 0.625 mg CEE alone or in combination with (1) 10 mg MPA given cyclically, (2) 2.5 mg MPA daily, or (3) 200 mg micronized progesterone given cyclically. At both 1 and 3 years of treatment, all treatment groups demonstrated a statistically significant protective effect against vasomotor symptoms compared with placebo. Women with more severe vasomotor symptoms at baseline experienced a greater treatment effect. Breast discomfort was significantly more common in those treated with progestins.

The Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) study, a randomized, double-blind, placebo-controlled trial conducted in 2,673 postmenopausal women, demonstrated that lower doses of CEE with daily MPA (lowest dose 0.3 mg CEE with 1.5 mg MPA) provide significant relief in vasomotor symptoms and vaginal atrophy above placebo and as effectively as commonly prescribed doses (0.625 mg CEE/2.5 mg MPA) [78]. These lower doses also confer endometrial protection comparable to that of standard dose regimens [79], with higher rates of amenorrhea [80] and more favorable changes in lipids, lipoproteins, and hemostatic factors, with minimal changes in carbohydrate metabolism [81] after 1–2 years of therapy.

A randomized, double-blind, placebo-controlled study of the lowest doses of transdermal estrogen available (0.023 mg/day 17β-estradiol and 0.0075 mg/day levonorgestrel or 0.014 mg/day 17β-estradiol alone) revealed a significant reduction in frequency of moderate and severe hot flashes after 12 weeks of treatment [82]. After 2 years of therapy, use of the 0.014 mg/day 17β-estradiol patch alone in women with intact uteri revealed similar rates of endometrial hyperplasia, endometrial proliferation, and vaginal bleeding when compared to placebo [83], with significant increase in bone mineral density (BMD) above placebo [84].

Although not generalizable to short-term treatment of a younger perimenopausal population, the results of the WHI dramatically increased the interest of patients and healthcare practitioners in nonhormonal therapies for menopausal symptoms. Centrally acting agents that have been studied include the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), clonidine, and gabapentin.

A double-blind, randomized, cross-over trial of the SSRI fluoxetine for the treatment of hot flashes evaluated 81 women with a history of, or increased risk of, breast cancer, experiencing at least 14 hot flashes per week [85]. The women were randomized to 20 mg/day of fluoxetine vs. placebo for 4 weeks, followed by a second 4-week period in which the patients were crossed over to the alternative treatment arm. The study demonstrated no significant difference in hot flash scores (frequency × severity) by the end of the first treatment period (50% decrease in score in the fluoxetine arm vs. 36% decrease in the placebo arm), although the cross-over analysis demonstrated a significantly greater improvement in score with fluoxetine (p = 0.02). However, the study did not adjust for confounding factors such as age or use of tamoxifen during the study period, a medication commonly associated with hot flashes as a side effect.

A randomized, double-blind, placebo-controlled trial evaluated the efficacy of controlled-release paroxetine (12.5 mg/day, 25.0 mg/day, or placebo) in the treatment of menopausal hot flashes in 165 women [86]. After 6 weeks of treatment, median hot flash composite scores (severity × frequency) were reduced by 62.2% in those taking 12.5 mg/day and 64.6% in those taking 25.0 mg/day, compared with 37.8% for those in the placebo group. This treatment difference remained after adjustment for age, breast cancer history, or antiestrogen use. A subsequent randomized, double-blind, placebo-controlled, cross-over trial demonstrated the efficacy of paroxetine (at doses of 10–20 mg) in the treatment of menopausal hot flashes [87] compared with placebo. The variability in results of studies evaluating different SSRIs may be related to the selectivity of different agents in this class for the serotonin vs. the norepinephrine transporter. Paroxetine is the SSRI with the highest activity at the norepinephrine transporter, whereas fluoxetine has a much lower affinity for the norepinephrine transporter [88].

Of the SNRIs, venlafaxine has been the most widely studied, and its efficacy in the management of menopausal hot flashes has been demonstrated in several randomized control trials [8990]. A recent randomized, double-blind, placebo-controlled trial [86] randomized 80 postmenopausal women with at least 14 hot flashes per week to receive extended release venlafaxine (37.5 mg/day for one week followed by 75 mg/day for 11 weeks) or placebo. Those receiving venlafaxine experienced a 51% reduction in patient-perceived hot flash scores, compared to a 15% reduction in the placebo group (p < 0.001). Commonly observed side effects in the treatment group included dry mouth, sleeplessness, and decreased appetite.

Among the centrally acting agents studied for the treatment of vasomotor symptoms, desvenlafaxine, the active metabolite of venlafaxine, has been assessed in the largest randomized controlled trials to date [91]. A recent double-blind, placebo-controlled trial randomized 567 postmenopausal women experiencing at least 50 hot flashes per week to receive desvenlafaxine (100 or 150 mg/day) or placebo [92]. Patients randomized to desvenlafaxine experienced a significantly greater decrease in number of moderate to severe hot flashes after 12 weeks of therapy, despite the large placebo effect observed (60 and 66% decrease in 100 mg and 150 mg groups, respectively, compared with 47% decrease in placebo group, p ≤ 0.002). This effect persisted at 26 weeks of therapy only in the 150 mg/day group. However, side effects were common (primarily nausea and dizziness), and the discontinuation rate due to side effects was 29%, most commonly during the first week of therapy.

Gabapentin is an anticonvulsant that has demonstrated superior efficacy to placebo in the treatment of vasomotor symptoms in all placebo-controlled trials [91]. Its mechanism of action in the treatment of hot flashes is unclear. A double-blind, placebo-controlled trial randomized 197 postmenopausal women with at least 14 hot flashes per week to receive gabapentin 900 mg/day or placebo for 4 weeks [93]. Hot flash scores decreased by 51% in the gabapentin group compared with 26% in the placebo group (p < 0.001). Reported side effects included dizziness, unsteadiness, and drowsiness which decreased to baseline levels by the fourth week. Another randomized placebo-controlled trial assessed gabapentin (titrated to 2,400 mg/day) in comparison with conjugated estrogens (0.625 mg/day) for 12 weeks [94]. Gabapentin and estrogen were similarly effective in reducing hot flash composite score at 12 weeks, and each had a significantly superior treatment effect when compared with placebo.

The α2-adrenergic receptor agonist clonidine has been used for treatment of hot flashes, but small trials of short duration have demonstrated modest efficacy at best [91]. Doses ranged from 0.5 to 1.5 mg/day, and common side effects such as dizziness and dry mouth make this drug difficult to tolerate and contribute to high discontinuation rates. This option should be reserved only for patients who cannot tolerate other nonhormonal options.

Urogenital symptoms

Vaginal dryness is reported by many perimenopausal women and becomes increasingly more common throughout the menopausal transition. Symptoms related to vaginal atrophy include itching, discomfort, and painful intercourse. Estimates of the prevalence of vaginal dryness range from 7 to 39% in perimenopause, and from 17 to 30% in postmenopause [43]. In addition, urinary symptoms are reported in as many as 36–39% of menopausal women [43]. If vaginal lubricants do not adequately alleviate mild dryness and dyspareunia, estrogen therapy may be needed. Oral estrogens with or without progestins as well as a variety of vaginal estrogen preparations are beneficial in the treatment of urogenital atrophy. A variety of options for local estrogen therapy are available and include creams, pessaries, tablets, and the E2-releasing ring. A recent meta-analysis of 19 randomized clinical trials comparing the safety and efficacy of different estrogenic preparations revealed significant improvement above placebo in vaginal symptoms in users of the cream (CEE), E2-releasing ring, and E2 tablets [95]. One trial found significant side effects (uterine bleeding, breast pain, and perineal pain) following cream administration when compared to tablets. There were no significant differences between treatment groups in endometrial hyperplasia or increasing endometrial thickness (>5 mm). As a treatment choice, women preferred the E2-releasing vaginal ring for ease of use, comfort of product, and overall satisfaction.

Bone

The rate of bone remodeling is increased in older adults. Osteoporosis occurs when the rate of resorption exceeds the rate of formation, and is defined by a Working Group of the World Health Organization as a BMD (T-score) that is 2.5 SD below the mean peak value in young adults [96]. Common risk factors for osteoporosis in postmenopausal women include thin habitus, physical inactivity, cigarette smoking, alcohol abuse, low calcium intake, little sunlight exposure, early menopause, and first-degree relative with low-trauma fracture [97]. Other risk factors include the use of certain medications (e.g., excessive thyroxine, heparin, phenytoin, and glucocorticoids) as well as endocrinopathies (primary hyperparathyroidism, thyrotoxicosis, and Cushing’s syndrome), hematologic diseases (multiple myeloma, lymphoma, and leukemia), and malabsorption syndromes (celiac disease and Crohn’s disease) [97].

Treatment of osteoporotic postmenopausal women with antiresorptive therapy increases BMD of the lumbar spine by 5–10% after 2–3 years, after which bone density changes very little. This change is associated with a decrease in the fracture rate of approximately 50% [97]. Although the response to medication is usually evaluated by serial measurements of BMD, the aim of treatment is to prevent fractures, which is the key end point of clinical trials of osteoporosis therapy. There are a number of therapeutic options that prevent further fractures in postmenopausal women with osteoporosis [97].

Trials evaluating calcium and vitamin D supplementation reveal variable efficacy in the prevention of fractures in postmenopausal women. A Dutch study of 1,278 men and women aged 70 years and older who were treated with vitamin D (400 IU/day) or placebo for 3.5 years revealed no difference in rates of hip fracture [98]. However, in a French study of 3,270 institutionalized elderly women (mean age 84 years) who were treated with calcium (1,200 mg/day) and vitamin D (800 IU/day) for 3 years, the risk of hip fractures was 30% lower than the risk in the placebo group [99]. Similarly, in a US study of 389 community-dwelling women and men aged over 65 years who were treated with calcium (500 mg/day) and vitamin D (700 IU/day) for 3 years, the rate of nonvertebral fractures was decreased (RR 0.4, p = 0.03), despite only a modest increase in BMD, evident primarily after the first year of therapy [100]. Possible explanations for the differences between these studies include differences in the population studied (the French women had lower dietary calcium intakes), dose of vitamin D, and coadministration of calcium.

A number of randomized, controlled trials report that estrogen or estrogen/progestin combinations prevent bone loss; on average, compared with placebo, increases in BMD of between 3 and 10% are observed, depending on the bone measured, the age of the participants, and the duration of therapy [101]. However, randomized, controlled trials of hormone replacement therapy with fracture reduction as the primary outcome are lacking, and information about the effect of estrogen-replacement therapy on risk of fracture in postmenopausal women is thus limited [97]. Due to the lack of antifracture efficacy data from randomized trials, the US Food and Drug Administration has withdrawn CEEs as an approved treatment for osteoporosis [102]. A meta-analysis of 22 randomized trials of HRT with fracture data, which included a number of unpublished studies, reported a 33% reduction in nonvertebral fractures (p = 0.03) when women started therapy before age 60 years [103]. This effect, however, was reduced to 12% (p = 0.22) in women starting therapy after 60 years of age. Considering that most women starting therapy for prevention/treatment of osteoporosis (and those at the highest risk of fracture) are older than 60 years, estrogen is no longer considered the first-line therapy for the prevention and treatment of postmenopausal osteoporosis.

Bisphosphonates are a useful treatment option for the treatment of postmenopausal osteoporosis and have been evaluated (both alone and in combination with HRT) for their efficacy in the prevention of bone loss in postmenopausal women with low BMD. Their exact mechanism of action is uncertain, but their net effect is increased osteoclast cell death, thereby decreasing bone resorption. Alendronate is given at a dose of 10 mg/day for the treatment of postmenopausal osteoporosis, or 5 mg/day for the prevention of osteoporosis. A recent meta-analysis of six randomized, placebo-controlled, double-blind trials evaluating the efficacy of alendronate (5–20 mg/day, range 1–4.5 years of therapy) in the prevention of hip fractures in postmenopausal women [104] revealed an overall risk reduction of hip fracture of 45% (p = 0.007) in patients with a T-score of less than or equal to −2.0 or with a vertebral fracture. In patients with osteoporosis (WHO criteria), the overall risk reduction was 55% (p = 0.0008).

A randomized, placebo-controlled trial to evaluate the effects of alendronate (10 mg/day) and CEE (0.625 mg/day), in combination and separately, on BMD in hysterectomized postmenopausal osteoporotic women [105] revealed a significantly greater increase in BMD after 2 years of therapy at both the lumbar spine and femoral neck in the combination group above that seen in either the CEE or alendronate group. The effects on BMD of alendronate alone did not differ significantly from those of CEE alone at any site, and a significant increase in BMD at all sites was seen for all treatment groups above that of placebo group. Fracture risk was not assessed in this study. In contrast, a 1 year randomized, placebo-controlled trial evaluating CEE (0.625 mg/day, ±cyclic or daily medroxyprogesterone acetate (up to 5 mg/day) depending on hysterectomy status) alone or in combination with risedronate (5 mg/day) in postmenopausal women [106] revealed significant increases in lumbar spine BMD in both treatment groups, but no difference between treatment groups was seen. Important differences between these two studies include the duration of therapy as well as the patient population studied (the population in the former study had substantially lower BMD and more years since menopause than the population in the latter). Thus, although bisphosphonates alone appear to be effective in increasing BMD and decreasing fracture rate [97], a clear and consistent benefit of combination therapy (bisphosphonates + HRT) above either treatment alone remains to be demonstrated. The optimal duration of bisphosphonate therapy is not known. It should be noted that alendronate has been associated with esophagitis, and should be taken with a glass of water while upright before breakfast in order to maximize absorption while minimizing the risk of esophagitis [93].

Raloxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that has estrogen-agonist effects on bone. It inhibits bone resorption in postmenopausal women without stimulating the breast or endometrium, leading to an increase in BMD and a reduction in markers of bone turnover [107]. The multiple outcomes of raloxifene (MORE) trial [108] studied the effects of raloxifene in 7,705 postmenopausal women with osteoporosis, in which the women were randomized to receive raloxifene 60 or 120 mg/day or placebo, as well as calcium and vitamin D supplementation. After 4 years, the cumulative relative risks for one or more new vertebral fractures were 0.64 (95% CI 0.53−0.76) with the 60 mg dose and 0.57 (95% CI 0.48−0.69) with the 120 mg dose. For both doses, BMD at the lumbar spine and femoral neck was significantly increased over that of placebo after 4 years (p < 0.001), and decreases in biochemical markers of bone turnover were significantly greater in both raloxifene groups when compared with that in the placebo group (p < 0.001). Notably, the nonvertebral fracture risk was not significantly reduced. A meta-analysis of seven clinical studies evaluating the anti-vertebral fracture efficacy of raloxifene in postmenopausal women (after 1–3 years of treatment) confirmed the findings of the MORE trial, reporting an overall 40% reduction in vertebral fracture in patients treated with 60 mg/day, and a 49% reduction in vertebral fracture in patients treated with 120 or 150 mg/day [109]. The more recently published raloxifene use for the heart (RUTH) trial [110] also reported a significantly reduced risk of clinical vertebral (but not nonvertebral) fractures in women randomized to 60 mg/day of raloxifene vs. placebo (HR 0.65, 95% CI 0.47−0.89), but these women were not selected on the basis of osteoporosis. Collectively, the data support the use of raloxifene in postmenopausal women with predominantly spinal osteoporosis, but the drug’s major limitations are the adverse effects associated with its estrogenic actions. In particular, the MORE trial [108] revealed a significantly increased risk of deep venous thrombosis in women receiving raloxifene compared with placebo (RR 2.76, 95% CI 1.30−5.86).

Surgical Menopause

Approximately 600,000 hysterectomies are performed each year in USA [111], and 50–60% of hysterectomy procedures involve oophorectomy [112]. The theoretical benefits of prophylactic oophorectomy at the time of hysterectomy include the prevention of ovarian cancer and fewer reoperations for ovarian pathology. Common indications for bilateral oophorectomy at the time of hysterectomy include familial breast–ovarian cancer syndromes, severe endometriosis, bilateral tubo-ovarian abscesses, and ovarian, endometrial, or fallopian tube cancers. If a woman has not yet experienced natural menopause, surgical menopause happens immediately upon removal of the ovaries. However, hysterectomy alone is associated with earlier menopause. The mean age of ovarian failure in women who have had hysterectomy is reported to be 45.4 ± 4.0 years, significantly lower than the mean age of 49.5 ± 4.0 years in women without hysterectomy in one series (p < 0.001) [113]. This may be explained by damage to the ovarian artery at the time of hysterectomy, or misclassification of oophorectomized women as women with intact ovaries.

With bilateral oophorectomy, the decline in circulating E2 is abrupt as opposed to gradual. Accordingly, the prevalence and severity of symptoms differ significantly in women who experience natural vs. surgical menopause [114]. The abrupt decline in E2 after surgical menopause is associated with more frequent and severe symptoms [43112]. These symptoms include hot flashes, sexual dysfunction, depression, and vaginal dryness [43115]. In one study, moderate to severe hot flashes (defined as episodes that affected a women’s capacity to function) were experienced by hysterectomized women 1.7 times more often than their naturally menopausal counterparts [115].

Conflicting data exist as to whether or not the postmenopausal ovary is a major androgen-producing gland. Several reports suggest that the postmenopausal ovaries are an important source of androgens, including studies which demonstrated higher androgen levels in the ovarian veins than peripheral veins of postmenopausal women [116117]. The primary estrogen produced after menopause is E1, derived principally from peripheral aromatization of adrenal and ovarian androstenedione, resulting in low circulating levels of estrogen in naturally menopausal women. The reported decline in androgens seen with surgical menopause is sustained throughout the menopausal period, as demonstrated in a study by Laughlin et al. [118] which demonstrated that plasma testosterone levels were 40% lower in oophorectomized women than that in intact postmenopausal women, independent of time since ­surgery. In contrast, an apparent return to premenopausal testosterone levels was demonstrated in intact women, some evaluated >20 years after natural menopause. In distinct contrast to these studies, Couzinet et al. reported that circulating ­androgens in postmenopausal women are of adrenal rather than ovarian origin by demonstrating very low plasma androgen levels in postmenopausal women with adrenal insufficiency, and similar levels between oophorectomized and nonoophorectomized postmenopausal women with normal adrenal function [119]. Several studies have also demonstrated absent to low expression of steroidogenic enzymes necessary for androgen biosynthesis (P450cc, 3β-hydroxysteroid dehydrogenase, P450c17) in the postmenopausal ovary [119120], supporting the hypothesis that the postmenopausal ovary is not a major androgen-producing gland.

In women who have undergone oophorectomy, some studies report that oral or transdermal testosterone improves sexual function and psychological well-being; however, these studies did not demonstrate any benefit of testosterone in the treatment of vaginal dryness, sleep disturbances, or mood [43121]. The consequences of the lower testosterone levels many years after oophorectomy for the health and well-being of aging women remain unknown. Furthermore, high doses (approximately 300 μg/day) are necessary to improve libido and sex drive. This dosage results in elevated circulating levels, which may produce unwanted androgenic side effects such as hirsutism, acne, and weight gain. The decision to institute androgen therapy must be weighed against these potential side effects; additionally, the long-term risks of taking testosterone have not been studied in this population [43]. Hormone therapy (estrogen with or without androgens) should be discussed preoperatively, as the menopausal symptoms associated with acute hypoestrogenism after surgical castration are generally much more severe than those associated with natural menopause.

A number of studies report an association of oophorectomy with an increased risk of cardiovascular disease (CVD) as well as mortality from all causes. In a recent cohort study including 1,274 women who had unilateral oophorectomy and 1,091 women who underwent bilateral oophorectomy with a median follow-up period of 25 years [122], women with bilateral oophorectomy before age 45 years experienced an increased mortality associated with CVD compared with age-matched women without oophorectomy (HR 1.44; 95% CI, 1.01–2.05). Within this age group, mortality was further increased in women who were not treated with estrogen through age 45 years or longer (HR 1.84; 95% CI, 1.27–2.68) but not in women treated with estrogen. Unilateral oophorectomy was not associated with increased cardiovascular mortality. Limitations of this study include its use of a predominantly white cohort as well as lack of data regarding risk factors for CVD (e.g., smoking status, adiposity, cholesterol and blood pressure measurements, and SES) in either the study cohort or control group. A recent meta-analysis [123] revealed that although natural menopause did not influence the rate of CVD (RR 1.14; 95% CI, 0.86–1.51), bilateral oophorectomy even around the age of 50 years increased CVD risk (RR 2.62; 95% CI, 2.05–3.35). Furthermore, bilateral oophorectomy prior to the age of 50 years increased the risk substantially (RR 4.55; 95% CI, 2.56–8.10). Data from the Nurses’ Health Study [124] revealed that over 24 years of follow-up, when compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy (after adjustment for CVD risk factors) was associated with an increased risk of death from CVD (HR 1.28; 95% CI, 1.00–1.64) as well as an increased risk of all-cause mortality (HR 1.12; 95% CI, 1.03–1.21). Those who had never used estrogen therapy and underwent oophorectomy before age 50 years had a higher risk of CVD (HR 1.98, 95% CI 1.18–3.32). Although further studies are necessary, cardiovascular protection linked to ovarian conservation in younger women should prompt reconsideration of routine prophylactic oophorectomy in women not at high risk of developing ovarian cancer.

Summary

Worldwide, an increasing proportion of women are experiencing the menopausal transition. It is thus imperative that providers of women’s health care achieve an adequate understanding of the diagnosis of the menopausal transition and proper management of menopause-related health issues. Although not all women will progress through a predicted sequence, use of the recently proposed STRAW criteria may be helpful in counseling the perimenopausal woman regarding her expected course. Measurement of serum FSH levels (with concomitant E2 measurement) is helpful in determining a woman’s menopausal status, although normal values may be encountered during advanced reproductive age. Measurements of serum inhibin and possibly AMH may prove clinically useful with further study.

The use of estrogen in the peri- and postmenopausal woman requires careful consideration of her personal history, family history, and comorbidities. This chapter has provided a review of nonhormonal options available for the treatment of vasomotor symptoms as well as postmenopausal osteoporosis. Finally, recent data indicating an association between surgical menopause and increased cardiovascular and all-cause mortality prompt the gynecologist to reconsider routine prophylactic oophorectomy at the time of hysterectomy for benign disease.

References

1.

Smith D (2003) The older population in the United States: March 2002. U.S. Census Bureau current population reports (Report No. P20-546). US Census Bureau, Washington, DC

2.

World Health Organization (1996) Research on the menopause in the 1990s: Report of a WHO scientific group. WHO Technical Report Series 866. WHO, Geneva

3.

Weiss G, Skurnick JH, Goldsmith LT et al (2004) Menopause and hypothalamic-pituitary sensitivity to estrogen. JAMA 292:2991–2996PubMed

4.

McKinlay SM, Brambilla D, Posner JG (2008) The normal menopause transition. Maturitas 61:4–16PubMed

5.

Bromberger JT, Matthews KA, Kuller LH et al (1997) Prospective study of the determinants of age at menopause. Am J Epidemiol 145:124–133PubMed

6.

Gold EB, Bromberger J, Crawford S et al (2001) Factors associated with age at natural menopause in a multiethnic sample of midlife women. Am J Epidemiol 153:865–874PubMed

7.

Soules MR, Sherman S, Parrott E et al (2001) Executive summary: stages of reproductive aging workshop (STRAW). Fertil Steril 76:874–878PubMed

8.

WHO Scientific Group (1996) Research on the menopause in the 1990’s: a report of the WHO Scientific Group, vol. 866. World Health Organization, Geneva. pp 1–79

9.

Brambilla DJ, McKinlay SM, Johannes CB (1994) Defining the perimenopause for application in epidemiologic investigations. Am J Epidemiol 140:1091–1095PubMed

10.

Gracia CR, Sammel MD, Freeman EW et al (2005) Defining menopause status: creation of a new definition to identify the early changes of the menopausal transition. Menopause 12:128–135PubMed

11.

Scheffer GJ, Broekmans FJ, Dorland M et al (1999) Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility. Fertil Steril 72:845–851PubMed

12.

Santoro N, Isaac B, Neal-Perry G et al (2003) Impaired folliculogenesis and ovulation in older reproductive aged women. J Clin Endocrinol Metab 88:5502–5509PubMed

13.

Giacobbe M, Mendes Pinto-Neto A et al (2004) The usefulness of ovarian volume, antral follicle count and age as predictors of menopausal status. Climacteric 7:255–260PubMed

14.

Richardson SJ, Senikas V, Nelson JF (1987) Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 65:1231–1237PubMed

15.

de Vet A, Laven JS, de Jong FH et al (2002) Antimüllerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril 77:357–362PubMed

16.

Santoro N (2004) Can a blood test predict the onset of menopause? Menopause 11:585–586PubMed

17.

Sherman BM, Korenman SG (1975) Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Investig 55:699–706PubMed

18.

McLachlan RI, Robertson DM, Healy DL (1987) Circulating immunoreactive inhibin levels during the normal human menstrual cycle. J Clin Endocrinol Metab 65:954–961PubMed

19.

Metcalf MG, Donald RA, Livesy JH (1981) Pituitary-ovarian function in normal women during the menopausal transition. Clin Endocrinol 14:245–255

20.

Metcalf MG, Donald RA, Livesey JH (1981) Classification of menstrual cycles in pre- and perimenopausal women. J Endocrinol 91:1–10PubMed

21.

Metcalf MG, Donald RA, Livesey JH (1982) Pituitary-ovarian function before, during and after the menopause: a longitudinal sudy. Clin Endocrinol 17:489–494

22.

Metcalf MG (1988) The approach of menopause: a New Zealand study. N Z Med J 101: 103–106PubMed

23.

Santoro N, Brown JR, Adel T et al (1996) Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab 81:1495–1501PubMed

24.

O’Connor KA, Ferrell RF, Brindle E et al (2009) Total and unopposed estrogen exposure across stages of the transition to menopause. Cancer Epidemiol Biomarkers Prev 18:828–836PubMed

25.

Taffe JR, Dennerstein L (2002) Menstrual patterns leading to the final menstrual period. Menopause 9:32–40PubMed

26.

Miro F, Parker SW, Aspinall LJ et al (2004) Origins and consequences of the elongation of the human menstrual cycle during the menopausal transition: the FREEDOM study. J Clin Endocrinol Metab 89:4910–4915PubMed

27.

Santoro N, Crawford SL, Lasley WL et al (2008) Factors related to declining luteal function in women during the menopausal transition. J Clin Endocrinol Metab 93:1711–1721PubMed

28.

Randolph JF Jr, Sowers MF, Gold EB et al (2003) Reproductive hormones in the early menopausal transition: relationship to ethnicity, body size, and menopausal status. J Clin Endocrinol Metab 88:1516–1522PubMed

29.

Randolph JF Jr, Sowers MF, Bondarenko IV et al (2004) Change in estradiol and follicle-stimulating hormone across the early menopausal transition: effects of ethnicity and age. J Clin Endocrinol Metab 89:1555–1561PubMed

30.

Su HI, Sammel MD, Freeman EW et al (2008) Body size affects measures of ovarian reserve in late reproductive age women. Menopause 15:857–861PubMed

31.

Groome NP, Illingworth PG, O’Brien M et al (1996) Measurement of dimeric inhibin B throughout the human menstrual cycle. J Clin Endocrinol Metab 81:1401–1405PubMed

32.

Burger HG, Cahir N, Robertson DM et al (1998) Serum inhibins A and B fall differentially as FSH rises in perimenopausal women. Clin Endocrinol 48:809–813

33.

MacNaughton J, Banah M, McCloud P et al (1992) Age related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age. Clin Endocrinol 36:339–345

34.

Klein NA, Illingworth PJ, Groome NP et al (1996) Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab 81:2742–2745PubMed

35.

Muttukrishna S, Child T, Lockwood GM et al (2000) Serum concentrations of dimeric inhibins, activin A, gonadotrophins and ovarian steroids during the menstrual cycle in older women. Hum Reprod 15:546–556

36.

Santoro N, Adel T, Skurnick JH (1999) Decreased inhibin tone and increased activin A secretion characterize reproductive aging in women. Fertil Steril 71:658–662PubMed

37.

Welt CK, McNicholl DJ, Taylor AE et al (1999) Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab 84:105–111PubMed

38.

Ream NE, Wyman TL, Phillips DJ et al (1998) Net increase in stimulatory input resulting from a decrease in inhibin B and an increase in activin A may contribute in part to the rise in follicular phase follicle-stimulating hormone of aging cycling women. J Clin Endocrinol Metab 83:3302–3307

39.

Ying SY (1988) Inhibins, activins and follistatins: gonadal proteins modulating the secretion of follicle-stimulating hormone. Endocr Rev 9:267–293PubMed

40.

Van Look PF, Hunter WM, Fraser IS et al (1995) Impaired estrogen-induced luteinizing hormone release in young women with anovulatory dysfunctional uterine bleeding. J Clin Endocrinol Metab 80:608–613

41.

Santoro N, Lasley B, McConnell D et al (2004) Body size and ethnicity are associated with menstrual cycle alterations in women in the early menopausal transition: the Study of Women’s Health Across the Nation (SWAN) Daily Hormone Study. J Clin Endocrinol Metab 89:2622–2631PubMed

42.

Gill S, Sharpless JL, Rado K et al (2002) Evidence that GnRH decreases with gonadal steroid feedback but increases with age in postmenopausal women. J Clin Endocrinol Metab 87:2290–2296PubMed

43.

National Institutes of Health (2005) National Institutes of Health State-of the Science Conference statement: management of menopause-related symptoms. Ann Intern Med 142:1003–1013

44.

Freeman EW, Sammel MD, Lin H et al (2007) Symptoms associated with menopausal transition and reproductive hormones in midlife women. Obstet Gynecol 110:230–240PubMed

45.

Miller SA, Santoro N, Lo Y et al (2005) Menopause symptoms in HIV-infected and drug-using women. Menopause 12:348–356PubMed

46.

Freeman EW, Sammel MD, Lin H et al (2008) Symptoms in the menopausal transition: hormone and behavioral correlates. Obstet Gynecol 111:127–136PubMed

47.

Dennerstein L, Dudley E, Hopper JL et al (2000) A prospective population-based study of menopausal symptoms. Obstet Gynecol 96:351–358PubMed

48.

Kronenberg F (1994) Hot flashes: phenomenology, quality of life, and search for treatment options. Exp Gerontol 29:319–336PubMed

49.

Guthrie JR, Dennerstein L, Hopper JL et al (1996) Hot flashes, menstrual status and hormone levels in a population-based sample of midlife women. Obstet Gynecol 88:437–442PubMed

50.

Overlie I, Moen MH, Holte A et al (2002) Androgens and estrogens in relation to hot flashes during the menopausal transition. Maturitas 41:69–77PubMed

51.

Rapkin AJ (2007) Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment. Am J Obstet Gynecol 196:97–106PubMed

52.

Col NF, Guthrie JR, Politi M et al (2009) Duration of vasomotor symptoms in middle-aged women: a longitudinal study. Menopause 16:453–457PubMed

53.

Gold EB, Colvin A, Avis N et al (2006) Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: Study of Women’s Health Across the Nation. Am J Public Health 96:1226–1235PubMed

54.

Freeman EW, Sammel MD, Grisso JA et al (2001) Hot flashes in the late reproductive years: risk factors for African American and Caucasian women. J Womens Health Gend Based Med 10:67–76PubMed

55.

Miller SR, Gallicchio LM, Lewis LM et al (2006) Association between race and hot flashes in midlife women. Maturitas 54:260–269PubMed

56.

Gold EB, Block G, Crawford S et al (2004) Lifestyle and demographic factors in relation to vasomotor symptoms: baseline results from the study of women’s health across the nation. Am J Epidemiol 159:1189–1199PubMed

57.

Gallicchio L, Miller SR, Visvanathan K et al (2006) Cigarette smoking, estrogen levels, and hot flashes in midlife women. Maturitas 53:133–143PubMed

58.

Gallicchio L, Visvanathan K, Miller SM et al (2005) Body mass index, estrogen levels, and hot flashes in midlife women. Am J Obstet Gynecol 193:1353–1360PubMed

59.

Whiteman MK, Staropoli CA, Langenberg PW et al (2003) Smoking, body mass, and hot flashes in midlife women. Obstet Gynecol 101:264–272PubMed

60.

Hutton JD, Jacobs HS, Murray MS et al (1978) Relation between plasma oestrone and oestradiol and climacteric symptoms. Lancet 1:678–681PubMed

61.

Skurnick JH, Weiss G, Goldsmith LT et al (2009) Longitudinal changes in hypothalamic and ovarian function in perimenopausal women with anovulatory cycles: relationship with vasomotor symptoms. Fertil Steril 91:1127–1134PubMed

62.

Casper RF, Yen SSC, Wilkes MM (1979) Menopausal flashes: a neuroendocrine link with pulsatile luetinizing hormone secretion. Science 205:823–825PubMed

63.

Mulley G, Mitchell JRA, Tattarsall RB (1977) Hot flashes after hypophysectomy. Br Med J 2(6094):1062PubMed

64.

Casper RF, Yen SSC (1981) Menopausal flashes: effect of pituitary gonadotropin desensitization by a potent luteinizing hormone-releasing factor agonist. J Clin Endocrinol Metab 53:1056–1058PubMed

65.

Meldrum DR, Defazio JD, Erlik Y et al (1984) Pituitary hormones during the menopausal hot flash. Obstet Gynecol 64:752–756PubMed

66.

Weiner RJ, Ganong WF (1978) Role of brain monoamines and histamine in regulation of anterior pituitary secretion. Physiol Rev 58:905–976PubMed

67.

Bhattacharya AN, Dierschke DJ, Yamaji T et al (1972) The pharmacological blockade of the circhoral mode of LH secretion in the ovariectomized rhesus monkey. Endocrinol 90:778–786

68.

Cox B, Lomax P (1977) Pharmacologic control of temperature regulation. Ann Rev Pharmacol Toxicol 17:341–353

69.

Stearns V, Ullmer L, Lopez JF et al (2002) Hot flashes. Lancet 360:1851–1861PubMed

70.

Berendsen HH (2000) The role of serotonin in hot flashes. Maturitas 36:155–164PubMed

71.

Freedman RR (2005) Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med 23:117–125PubMed

72.

Rossouw JE, Anderson GL, Prentice RL et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333PubMed

73.

Manson JE, Hsia J, Johnson KC et al (2003) Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 349:523–534PubMed

74.

Chlebowski RT, Hendrix SL, Langer RD et al (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 289:3243–3253PubMed

75.

Anderson GL, Limacher M, Assaf AR et al (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative randomized control trial. JAMA 291:1701–1712PubMed

76.

Sikon A, Thacker HL (2004) Treatment options for menopausal hot flashes. Clev Clin J Med 71:578–582

77.

Greendale GA, Reboussin BA, Hogan P et al (1998) Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions trial. Obstet Gynecol 92:982–988PubMed

78.

Utian WH, Shoupe D, Bachmann G et al (2001) Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 75:1065–1079PubMed

79.

Pickar JH, Yeh IT, Wheeler JE et al (2003) Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Fertil Steril 80:1234–1240PubMed

80.

Archer DF, Dorin M, Lewis V et al (2001) Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 75:1080–1087PubMed

81.

Lobo RA, Bush T, Carr BR et al (2001) Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril 76:13–24PubMed

82.

Bachmann GA, Schaefers M, Uddin A et al (2007) Lowest effective transdermal 17β (beta)-estradiol dose for relief of hot flashes in postmenopausal women. Obstet Gynecol 110:771–779PubMed

83.

Johnson SR, Ettinger B, Macer JL et al (2005) Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol. Obstet Gynecol 105:779–787PubMed

84.

Ettinger B, Ensrud KE, Wallace R et al (2004) Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet Gynecol 104:443–451PubMed

85.

Loprinzi CL, Sloan JA, Perez EA et al (2002) Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 6:1578–1583

86.

Stearns V, Beebe KL, Iyengar M et al (2003) Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized control trial. JAMA 289:2827–2834PubMed

87.

Stearns V, Slack R, Greep N et al (2005) Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 28:6919–6930

88.

Nemeroff CB, Owens MJ (2004) Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis. CNS Spectr 9(6 suppl 4):23–31PubMed

89.

Loprinzi CL, Kugler JW, Sloan JA et al (2000) Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized control trial. Lancet 356:2059–2063PubMed

90.

Evans ML, Pritts E, Vittinghoff E et al (2005) Management of postmenopausal hot flashes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol 105:161–166PubMed

91.

Jenkins MR, Sikon AL (2008) Update on nonhormonal approaches to menopausal management. Clev Clin J Med 75(suppl 4):S17–S24

92.

Archer DF, Dupont CM, Constantine GD et al (2009) Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-­controlled trial of efficacy and safety. Am J Obstet Gynecol 200:238e1–238e10

93.

Butt DA, Lock M, Lewis JE et al (2008) Gabapentin for the treatment of menopausal hot flashes: a randomized controlled trial. Menopause 15:310–318PubMed

94.

Reddy SY, Warner H, Guttuso T et al (2006) Gabapentin, estrogen and placebo for treating hot flashes: a randomized controlled trial. Obstet Gynecol 108:41–48PubMed

95.

Suckling J, Lethaby A, Kennedy R (2006) Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev (4):CD001500

96.

Kanis JA, Melton LJ III, Christiansen C et al (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141PubMed

97.

Eastell R (1998) Treatment of postmenopausal osteoporosis. N Engl J Med 338:736–746PubMed

98.

Lips P, Graafmans WC, Ooms ME et al (1996) Vitamin D supplementation and fracture incidence in elderly persons: a randomized, placebo-controlled clinical trial. Ann Intern Med 124:400–406PubMed

99.

Chapuy MC, Arlot ME, Delmas PD et al (1994) Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. Br Med J 308:1081–1082

100.

Dawson-Hughes B, Harris SS, Krall EA et al (1997) Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 337:670–676PubMed

101.

Greendale GA, Wells B, Marcus R et al (2000) How many women lose bone mineral density while taking hormone replacement therapy? Results from the Postmenopausal Estrogen/Progestin Interventions Trial. Arch Intern Med 160:3065–3071PubMed

102.

Fitzpatrick LA, Litin SC, Bell MR (2000) The Women’s Health Initiative: a heart to HRT conversation. Mayo Clin Proc 75:559–561PubMed

103.

Torgerson DJ, Bell-Syer SE (2001) Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA 285:2891–2897PubMed

104.

Papapoulos SE, Quandt SA, Liberman UA et al (2005) Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women. Osteoporos Int 16:468–474PubMed

105.

Bone HG, Greenspan SL, McKeever C et al (2000) Alendronate and estrogen effects in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab 85:720–726PubMed

106.

Harris ST, Eriksen EF, Davidson M et al (2000) Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women. J Clin Endocrinol Metab 86:1890–1897

107.

Riggs BL, Hartmann LC (2003) Selective estrogen-receptor modulators-mechanism of action and application to clinical practice. N Engl J Med 348:618–629PubMed

108.

Delmas PD, Ensrud KE, Adachi JD et al (2002) Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 87:3609–3617PubMed

109.

Seeman E, Crans GG, Diez-Perez A et al (2006) Anti-vertebral fracture efficacy of raloxifene: a meta-analysis. Osteoporos Int 17:313–316PubMed

110.

Ensrud KE, Stock JL, Barrett-Connor E et al (2008) Effects of Raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial. J Bone Miner Res 23:112–120PubMed

111.

Keshavarz H, Hillis SD, Kieke BA et al (2002) Hysterectomy surveillance: United States, 1994–1999. MMWR CDC Surveill Summ 51(SS-5):1–8

112.

Hendrix SL (2005) Bilateral oophorectomy and premature menopause. Am J Med 118:131S–135S

113.

Siddle N, Sarrel P, Whitehead M (1987) The effect of hysterectomy on the age at ovarian failure: identification of a subgroup of women with premature loss of ovarian function and literature review. Fertil Steril 47:94–100PubMed

114.

Bachmann G (2001) Physiologic aspects of natural and surgical menopause. J Reprod Med 46:307–315PubMed

115.

Oldenhave A, Jaszmann LJ, Everaerd WT et al (1993) Hysterectomized women with ovarian conservation report more severe climacteric complaints than do normal climacteric women of similar age. Am J Obstet Gynecol 168:765–771PubMed

116.

Judd HL, Judd GE, Lucas WE et al (1974) Endocrine function of the postmenopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab 39:1020–1024PubMed

117.

Fogle RH, Stanczyk FZ, Zhang X et al (2007) Ovarian androgen production in postmenopausal women. J Clin Endocrinol Metab 92:3040–3043PubMed

118.

Laughlin GA, Barrett-Connor E, Kritz-Silverstein DK et al (2000) Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernado Study. J Clin Endocrinol Metab 85:645–651PubMed

119.

Couzinet B, Meduri G, Lecce MG et al (2001) The postmenopausal ovary is not a major androgen-producing gland. J Clin Endocrinol Metab 86:5060–5066PubMed

120.

Jabara S, Christenson LK, Wang CY et al (2003) Stromal cells of the human postmenopausal ovary display a distinctive biochemical and molecular phenotype. J Clin Endocrinol Metab 88:484–492PubMed

121.

Sherwin BB (2002) Randomized clinical trials of combined estrogen-androgen preparations: effects on sexual functioning. Fertil Steril 77(suppl 4):S49–S54PubMed

122.

Rivera CM, Grossardt BR, Rhodes DJ et al (2009) Increased cardiovascular mortality after early bilateral oophorectomy. Menopause 16:15–23PubMed

123.

Atsma F, Bartelink ML, Grobbee DE et al (2006) Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 13:265–279PubMed

124.

Parker WH, Broder MS, Chang E et al (2009) Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses’ Health Study. Obstet Gynecol 113:1027–1037PubMed