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Department of Medicine, Division of Endocrinology, University of British Columbia, and Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia, Canada V5Z 1C6
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Abstract |
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 Top Abstract I. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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I. Introduction |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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Another difficulty in the study of the perimenopause is that it has been virtually ignored. The only mention of perimenopause in a recent two-volume gynecological reference text is its definition as "the time preceding the normal menopause during which declining ovarian function causes oligomenorrhea or dysfunctional uterine bleeding, symptoms of estrogen deficiency and elevated gonadotrophins" (11). That definition is in a chapter on premature menopause (11). This same reference publication devotes 160 pages to menopause (11). Likewise, two national consensus documents relating to midlife women do not mention the perimenopause (12) or, only in passing, indicate that perimenopausal women may find oral contraceptive therapy to be useful (13).
The purpose of this review is to integrate the best available data on hormonal levels, menstrual cycles, bone changes, and experiences of perimenopause as a midlife hormonal and sociocultural transition. The primary focus is to review hormonal and spinal bone change data from prospective studies in population-based samples of perimenopausal women. A second purpose is to integrate the available hormonal data into a hypothesis explaining the (patho)physiology of erratic and often high estrogen levels, high [but inconsistent (14)] FSH levels, and prevalent nonovulation in perimenopausal cycles (15, 16). Finally, this review will synthesize the available data to arrive at an understanding of perimenopause-related symptoms, bone density changes, and to point toward research that is still needed.
Cultural (17, 18) and social status (19) differences in the reporting of midlife symptoms and the meaning of menopause in different societies (20), although very important, have been reviewed elsewhere (9, 21, 22). In addition, because Sowers and La Pietra (2) and Khaw (23) have recently reviewed the epidemiology of menopause, and there are few ways to relate the endocrinological events to the age at menopause, this review will not examine the epidemiology of menopause nor factors contributing to age at onset of menopause (23, 24, 25, 26, 27). Finally, this review will not attempt to evaluate the sparse prospective evidence that risk factors for cardiovascular disease increase during the menopausal transition (2, 28, 29).
This review used a systematic search of Medline and Premedline references from 1990 to the present under the following search titles: human, perimenopause, prospective, hormone, vasomotor symptoms (VMS), bone. In addition, earlier epidemiological, histological, and endocrinological sources were used to obtain data on studies on women 45–55 yr of age published before 1990. These sources were supplemented with additional references cited in the papers that were reviewed. All data were assessed for their prospective design and appropriate prospective statistical analysis (e.g., each woman’s perimenopausal data compared with her own premenopausal data). Cross-sectional data were excluded unless no comparable prospective data were available.
For the purposes of this review, all sources were critically evaluated for inclusion of sampling methods, physical and sociocultural description of the participants, and methods of assessment of women’s experiences, hormone levels, and bone measures. (Because few hormonal studies contained adequate descriptive data on subject selection/exclusion and sociodemographic characteristics, no study was excluded on these grounds).
Primary data on serum hormone levels were all converted into SI units (estradiol was converted from picograms/ml to picomoles/liter through multiplication by 3.671; progesterone was converted from nanograms/ml to nanomoles/liter through multiplication by 3.18). A weighted mean was generated (in which a larger study influenced the mean data proportionately more than a small one). Many data were acquired from graphs or figures; some were in primary tabular form. The variances in SI units were derived from the primary data where possible; ranges are included where no variance could be obtained. A final option was to assume similar variances as those reported in other data sets for the studies lacking them. These data were then combined and analyzed using the Fisher’s method of combining P values (30). Because hormone assay standards vary, when perimenopausal data were reported, control data from pre- and menopausal women from the same study or, lacking that, from the same laboratory were included for comparison. [For example, the largest population from Melbourne Midlife Women’s Health Study (31) did not include any premenopausal control data. Therefore, comparison data were obtained from two studies of premenopausal women from the same laboratory (32, 33).]
Estradiol levels were generally reported for cycle days 4–7 after start of menstrual flow, which is in the early or midfollicular phase (depending on the follicular phase length). This sampling point will be designated simply as the follicular phase (FP) in this review, and the specific cycle days noted if they are different than days 4–7. These days were chosen for hormonal sampling by the Melbourne investigators (31) and those in several other centers and are also in common clinical use. Estradiol and progesterone levels obtained during the week before flow were designated as premenstrual (because ovulation was inconsistent and therefore use of the term "luteal" would often have been inappropriate). For urine hormone levels, it was difficult to compare and combine data from different studies. This is true, in part, because some used overnight data corrected for creatinine (34) and others used 24 h urine collections (35, 36, 37) without creatinine correction. Following the suggestion of Metcalf and MacKenzie (38), this review has analyzed the number of days in a cycle in which the total urinary estrogen excretion exceeded the normal midcycle peak (MCP) level in that assay system. The maximum number of days of MCP estrogen levels that should occur is 4 (median, 2; range, 0–4) (38). Using criteria for diagnosis of ovulation in each assay, pregnanediol glucuronide (PDG) levels were interpreted to show whether or not a luteal phase was present; a luteal phase duration of less than 10 days was considered to be a short luteal phase (16).
In the development of an integrating hypothesis for the hormonal changes of the perimenopause, this review sought explanations in the gynecological literature including studies of ovarian hyperstimulation for the purposes of in vitro fertilization (IVF) in women over 40 yr of age. The new hypothesis that excessive endogenous ovarian follicular stimulation occurs during the perimenopausal transition (39) is based on the physiology of intra- and extra-ovarian hormonal and paracrine controls of folliculogenesis as described in clinical studies of IVF and investigations in primates, and on cross-sectional anatomical studies of ovarian follicle numbers from ovaries of women of different ages who died or had ovariectomy.
A final aspect of this review is an effort to provide a hormonal or physiological explanation for the changes, symptoms, and signs reported by perimenopausal women. The data support the premise that the perimenopause includes a time of erratic estrogen production (both high and low) and that the times of high estrogen levels (especially coupled with anovulation) are causally associated with significant clinical manifestations such as short or long intermenstrual intervals, heavy flow, increased dysmenorrhea, breast tenderness and nodularity, emotional stress-type experiences, weight gain, and cyclic VMS. It is hoped that a more accurate understanding of the dynamic ovarian hormonal changes of the menopausal transition will lead to needed observational and therapy research and to rational, effective approaches to the education and clinical care of perimenopausal women.
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II. Defining the Perimenopause |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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There has been a general consensus for some years that the perimenopause ends when 1 yr has elapsed without menstrual flow (2, 40, 41, 42, 43). That is part of the perimenopause definition proposed by the WHO (10). However, menopause is defined by WHO as the "final menstrual period" (retrospectively defined as 1 yr without flow) (10). Therefore, during the last year of the perimenopause, women are also in the "postmenopause" as defined by WHO (10) or are in their first year after menopause (although they cannot know either classification except in retrospect). Because of the 12-month overlap in these definitions, it is difficult to understand whether the year beyond the final menstrual period is or is not included in the perimenopause, even when comparing papers from the same investigators using the same dataset, that focus, respectively, on defining the perimenopause (44), and on describing the normal menopause transition (45). Some reports in the literature even refer to menopause as beginning when 3 or 6 months have elapsed without flow (46), although, in statistical terms, the permanent end of flow requires 12 months without a menstrual period (47). Therefore, although the WHO definition of the perimenopause clearly includes the year after the final menstrual period, the end of the perimenopause and the beginning of menopause are problematic both in definition and in their use in the literature.
The definition of the onset of the perimenopause, like its end, also poses problems for epidemiologists, clinical investigators, physicians, and women. The WHO definition says that it is the period "immediately" (which implies a short span of time) before menopause when the "endocrinological, biological and clinical features of approaching menopause commence" (10). That definition implies that there are a typical set of features that will make onset of the perimenopause obvious. However, variability is the hallmark of the menopausal transition, and no operational definition was given of those features by the WHO (10). A definition of "the inception of perimenopause" for use in epidemiological studies was recently constructed from prospective data of the Massachusetts Women’s Health Study (based on a population-based sample of 1,550 women followed for 5 yr) (44). Perimenopause was defined as beginning when the woman reported "at least three but less than 12 months of amenorrhea" or "a self report of increased menstrual irregularity" (44). Those definitions had a positive predictive value of 0.70 for final menstrual period within the next 3 yr (44). For epidemiological purposes, that report and the earlier one (45) found the perimenopause duration to be an average of "about four" years. That is consistent with the 4.8-yr transition documented by Treloar (48) in a prospective study of cycle intervals and symptoms. Women’s self-reports of VMS or lighter flow were not very strongly predictive of the onset of perimenopause (44); however, clusters of experiences were not tested as a new factor in the prediction equation. In addition, women who reported a change in cycle regularity "at only isolated interviews" were classified as premenopausal rather than perimenopausal by at least one of the New England Research Institute studies (45), although all participants were over age 45 and 13% of the "premenopausal women" reported VMS (which would be consistent with the "clinical features" of menopause). Finally, about 10% of women apparently changed from pre- to menopausal status between two interviews separated by 9 months (45). [That, of course, is an impossibility if the 12 months of amenorrhea beyond the final menstrual period are considered in the perimenopause as defined by WHO (10).]
It is useful to have an epidemiological definition for the onset of the perimenopause (44). That is especially true because FSH levels increase gradually (49), are often intermittently high and normal, and are not diagnostic (14). If this review’s hypothesis about perimenopause physiology is confirmed, it is possible that inhibin levels or inhibin to estradiol relationships might provide a biochemical indicator of the onset of perimenopause. At present, however, a better definition of the onset of the perimenopause is needed for appropriate clinical care as well as for research. It is important for the WHO definition of perimenopause onset to be made into something that can assist a woman to understand what lies ahead for her and that can guide physicians in their care of women in their late thirties through their fifties.
Given the current absence of a biochemical, hormonal, or symptom-cluster marker for the onset of perimenopause, it is possible that women may be able to accurately determine when they begin to be perimenopausal. Dennerstein and colleagues (50) asked women in the Melbourne Women’s Midlife Health Study’s cross-sectional baseline survey of cycle regularity and flow changes to classify themselves related to whether they believed they had or had not started into the transition, were mid or late in the perimenopause, or had completed it. In ANOVA factor scores, premenstrual complaints were significantly related to dysphoria, vasomotor, skeletal, digestive, respiratory, and general somatic symptoms. These investigators speculate that "self reported menopausal status is a more sensitive measure of endocrine status" (50). However, the subsequent study of hormones in a subset of that Melbourne population did not attempt to use women’s self-classification (31), although it found follicular phase estradiol levels that were significantly higher than in premenopausal women reported from the same laboratory (32, 33). Based on the results of this review, an increase in or new onset of high estrogen-related symptoms may signal the onset of perimenopause. If such a symptom cluster were adopted, it is likely that the perimenopause would begin sooner and the transition last longer than an average of 4 yr, as is currently asserted (44, 45).
As outlined above, although extensive work as been done to achieve a consensus about the definition of the perimenopause (9, 10, 44, 45, 50), two difficulties may persist with the current definition: 1) the perimenopause ends at the end of the year after the final menstrual period, which means it can only be defined in retrospect, and it overlaps with the definition of menopause, and 2) the onset of oligomenorrhea or "irregular flow" may occur after several years of observable changes (that can be hormonally characterized as different from those of premenopausal women). The definition of menopause in retrospect is of little use to the clinician or to the perimenopausal woman prospectively experiencing the transition. A more appropriate definition of the start of menopause is to define it as beginning when a year has passed without flow. The likelihood of a subsequent normal period (e.g., not caused by endometrial hyperplasia, a polyp, or some other pathology) is less than 5% (47). This review includes the last year of no flow in the perimenopause as defined by WHO (10) (and also because hormonal data from many studies to be subsequently reviewed show variable and not consistently low estrogen levels during that time). For the purposes of clarity, this review will term menopause as beginning when a year has elapsed without flow and not as the "final menstrual period" (10).
The WHO definition of the perimenopause does not indicate particular hormonal characteristics. It is commonly understood, however, that this period of time is characterized by declining estrogen levels (6, 11). This review, in contrast, will demonstrate from published data that estrogen levels are highly variable and, in the early part of the perimenopause, estrogen levels average higher than during a woman’s reproductive life. Given the lack of clarity about the onset of the perimenopause, all studies were included in this review that characterized women between the ages of 45–55, that used the term "perimenopause," or that indicated that a woman’s periods had changed, or that the last menstrual flow occurred within the subsequent 4 yr. In the latter part of this review, an attempt will be made to integrate the clinical and hormonal features of the perimenopause studies into a proposed series of five phases based on clinical and hormonal characteristics.
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III. Classic Studies of the Perimenopause |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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B. Early reports of women’s experiences in the perimenopause
Between the time of Tilt’s study in the mid-1800s until the
1930s, menorrhagia disappeared from the perimenopause. [Wilbush, an
anthropological historian, believes this change occurred because
hysterectomy had become prevalent (51).] A new concept that the
"complaints" and experiences of midlife women were largely
psychological was prevalent in Britain and increased in the early years
of this century. The first therapy for menopause in the "modern
era" (e.g., when medicine had evolved beyond blood letting
and leeches) was apparently the early antiepileptic sedative,
phenobarbital. Subsequently, and apparently about the time estrogens
were isolated and synthesized in the late 1930s, the idea of menopause
changed again. Menopause began to be understood as a time of estrogen
deficiency. It was low estrogen levels that explained the psychological
symptoms of menopausal women.
By 1953, some "objective" way of characterizing the response of "patients exhibiting endocrine insufficiencies" was needed to monitor responses to estrogenic preparations (53). Blatt, Kupperman, and colleagues developed a systematic description of the timing and quantity of the flow response of a menopausal woman to a given dose and estrogen preparation. The estrogen preparation (and by 1953 there were 17 choices!) was given for 3 weeks followed by a single 100-mg injection of progesterone. The onset, duration, and amount of flow were used to derive an "Amenorrhea index," which predicted the potency of the estrogen (53). A "Menopausal Index" was also created from women’s "11 most common menopausal complaints," which has become the standard assessment tool for climacteric experiences (53, 54). The Kupperman and Blatt Index, which divides symptoms into psychological and physical, has been used in most subsequent studies. It included VMS, paresthesia, insomnia, nervousness, melancholia, vertigo, weakness (fatigue), arthralgia and myalgia, headaches, palpitations, and formications. It specifically did not include questions about menstrual flow, breast, weight gain, and fluid symptoms, perhaps because symptoms were a priori defined as occurring after menstrual flow had ceased, and because they were understood to be the consequence of estrogen deficiency.
Neugarten and Kraines (55), behavioral scientists with the Committee on Human Development in Chicago, used the previously developed Kupperman and Blatt Menopausal Index (53, 54), combined with symptoms reported by patients and their physicians to occur in midlife, to derive a 22-item menopausal symptom instrument which they published in 1964. Their new instrument included weight gain, flooding, irregular cycles, cold hands, trouble concentrating, and breast pain as well as feelings of suffocation. This new instrument was reproducible to retest within women (r = 0.8) and correlated well with the Kupperman and Blatt Menopause Index (r = 0.7).
The Neugarten Menopause Symptoms instrument was validated through its completion by women of different ages. The responses of a large sample of adolescent girls, midreproductive life women, women over 40 reporting some change in cycles (who were perimenopausal but whom the authors called "menopausal"), and women more than a year after their last menstrual flow were all compared (55). Perimenopausal women shared with adolescents (and not with normally menstruating women or those after menopause) the experiences of weight gain, cold hands and feet, feeling excitable and blue, and having headaches. Significantly more than any other group of women, the perimenopausal women experienced "weight gain, cold hands and feet, skin crawls, headaches, feeling blue, cold sweats, tired feelings, excitable, can’t concentrate, crying spells." The group of women who were more than 1 yr beyond their last flow were the least symptomatic of any of the groups (55). Neugarten and Kraines’ interpretion of their data stated: "the increased production of sex hormones in adolescence (signaled by the first menses) and the decreased production of estrogen (signaled by menopause) ... are primary in producing heightened sensitivity to and the increased frequency of reported symptoms" (55). That the menopausal women 1 yr after their last period were the least symptomatic was ascribed to an improved ability to cope (55).
C. Early prospective menstrual cycle interval and basal temperature
documentation
The first physiological, longitudinal study of the perimenopausal
transition was an anecdotal study of two women, reported in 1949 by a
physiologist, Mary Collett (56). This study documented the transition
into the menopause by yearly cycle interval averages and ranges in one
woman (recorded from 34–48 yr of age), and primary cycle interval data
from a second subject (from 41–57 yr of age). Basal metabolic rate
(BMR) was periodically documented in subject 1. The BMR showed a marked
decrease of 14.5–18%, which occurred at the age of 45, coincident
with the onset of her cycle interval irregularity. The rate continued
to be suppressed until age 48, when she had her last menstrual flow.
During her mid-forties she experienced an initial weight gain of 14 kg
(56). This was followed by "Evidences of endocrine imbalance ...
weight loss along with falling BMR, softening of the teeth at 46 to 48,
low hemoglobin... , hot flushes, great fatigue and extreme
nervousness." The other subject’s prospective data showed marked
menstrual cycle variability (from 19–89 days in length) beginning 4 yr
before the last flow (56). This initial study is still one of the few
that has followed women prospectively from the premenopause through to
the menopause.
Several large descriptive, prospective studies were begun in the late 1940s, at a time before hormonal measurements from urine or blood were widely available. Women were asked to record the day on which flow began on calendar cards, or calendars were coupled with basal temperature records (as a bioassay for progesterone action). These studies have documented menstrual cycle characteristics in women of different ages both cross-sectionally and prospectively (16, 47, 48, 57, 58). Collett performed one of the earliest published studies in which an unknown number of women recorded 302 cycles (57). The longest continuous sample was 176 cycles in a woman in her forties. Collett noted that with increasing age, cycle intervals shortened (from a mean of 30 days in the youngest to a mean of 25 in the oldest), that the follicular phase also shortened, and that anovulation increased to 15% of the cycles in the oldest women (57).
Two large prospective cycle interval studies, by Chiazze et al. (59) and Treloar et al. (47), showed shortening cycle intervals from a mean of 29 days for women in their twenties to a mean of 26 days for women in their forties. Treloar and colleagues prospectively followed more than 2,700 women over an average of 5 yr. A number of women recorded from their twenties until they were menopausal (47, 48). Although initially the sample only included women who were undergraduates at the University of Minnesota, it later included some of their daughters and friends. Annual questionnaires documented surgeries, pregnancies, and hormone use, which, along with age and postsecondary education, have been used in data analysis (47, 48).
The volunteers for Treloar et al. recorded the onset of flow on a menstrual card. No data about ovulation were available. The 120 women providing data through menopause (47) showed "heterogeneity," with an increase in both short and long cycle intervals (which was noted to be similar to that after puberty) (47). In a subsequent questionnaire, 14% of women reported hot flushes in the years preceding the cessation of flow (48). The cycle interval changes noted for women in their late forties and early fifties are similar to those documented by Doring [n = 67 (58)], by Collett et al. [n = 43 (57)], and by Vollman [n = 41 (16)], who sampled women from infertility clinics, from general advertising, or from a general medical practice, respectively.
The largest prospective basal temperature study was by a Swiss
physician named Vollman (16). More than 1 yr of prospective,
quantitatively analyzed rectal basal temperature data were documented
in 332 women, and the perimenopausal transition was prospectively
recorded in 41 women (16). [It is of interest that Vollman developed
the first quantitative method for evaluation of luteal phase onset from
basal temperature data—the day the temperature curve crosses the mean
temperature line correlates with the day of the midcycle LH peak day
(r = 0.891, P < 0.001)(60).] As shown
in Fig. 1
, which depicts the last 100
cycles of one woman (16), 9% of the cycles were less than 21 days in
length, and 10% were greater than 36 days long. In contrast to
Vollman’s documented 4% mean rate of nonovulation for women in their
mid-twenties to early forties, 16% of this woman’s perimenopausal
cycles were nonovulatory (16). Stratifying the data by gynecological
age (years from menarche), Vollman noted that 34% of cycles were
anovulatory in women of gynecological age 40–45. In addition, Vollman
(16) observed that, even within cycles that were ovulatory, an
increasing percentage of cycles of older women had short luteal phase
lengths of less than 10 days.
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IV. Prospective Epidemiological Studies of the Perimenopause |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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A. Manitoba Project on Women and Their Health in the Middle Years
The Manitoba Project, which began in the early 1980s, has provided
a wealth of information about the perimenopausal period of women’s
lives (7, 21, 40, 41, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77). Although the original sample was not
strictly population based, the design and subsequent conduct of the
study met the best of epidemiological principles. The design included
interview of women over the telephone at 6-monthly intervals for 3 yr.
The initial cohort of 477 women, ages 45–55, represented 87% of the
sample of an earlier cross-sectional study (40). An analysis of the
longitudinal reports of menstrual periods documented that more than 100
different patterns of menstrual flow (e.g., regular followed
by a skipped period, or no flow for 3 months followed by every other
month) occurred in just over 300 women (40). Menstrual flooding, in
addition to "menstrual problems, lack of energy, and nervous
tension," were the best predictors of a change from regular to
irregular cycles (40). In a subsequent analysis, depression scores over
16 on the Centre for Epidemiological Studies Depression Scale occurred
in 26% of all of the women at one time or another in the 3 yr of the
study. In a cross-sectional analysis of the prospective data, neither
change in menstrual cycle status nor children leaving home were
associated with depression, but having a hysterectomy was (76).
However, the potential for a causal relationship between the endocrine
changes that led to flooding and the mood symptoms appears not to have
been adequately considered in the Manitoba (76) study (or in the
Massachusetts study described below) (42).
B. Massachusetts Women’s Health Study
This important study, which was initiated in 1981, observed 2,570
women, aged 45–55, who were identified using census lists. This study
achieved a 77% initial response rate, and 93% of those participated
during the entire 4.5-yr prospective study (61), which has provided key
information about midlife women (21, 26, 42, 44, 45, 78, 79, 80, 81, 82). Women
were contacted by telephone every 9 months and were asked standardized
questions concerning their menstrual cycle status as well as other
experiences (similar to the questions and instruments used in the
Manitoba Project). Those who had menstruated in the preceding 3 months
and reported no change, or only intermittent changes in cycle
regularity, on one of two consecutive interviews were called
premenopausal; those with irregularity or 3–11 months of no flow were
called perimenopausal; and those who were more than 12 months beyond
their last flow were classified as menopausal. By these criteria, 1,178
of the sample were premenopausal at the initial telephone interview
(45). Excluding women with surgical menopause, the average age of onset
of the perimenopause was 47.5 yr, and menopause occurred at an average
age of 51.3 yr (26, 45). The average duration from onset of irregular
periods until 12 months past the last flow was approximately 4 yr.
Nulliparous women and smokers started the perimenopause at a slightly
younger age (45). Smokers and those starting perimeopause at a later
age experienced a shorter perimenopausal transition. Smokers were
approximately 2 yr younger at menopause (45).
Perimenopausal women tended to be more symptomatic (VMS, musculoskeletal symptoms, anxiety, fatigue, sleep disturbances, gastrointestinal concerns) than women menstruating regularly and those a year beyond their last flow. Approximately 20% of perimenopausal women visited their physician early in the transition with concerns about their menstrual cycles, while 12% sought help late in the transition because of symptoms they defined as menopausal (45, 61). It appeared that women with a longer perimenopausal transition were more likely to report VMS. Very few of the perimenopausal women were treated with ovarian hormone therapy or oral contraceptive agents (45, 82).
C. Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study
Tuppurainen and colleagues (46) reported on the design of the
OSTPRE study in which all 14,220 women ages 47–56 in Kuopio Province
were surveyed by a postal enquiry sent in 1989. This is the largest
population-based study of the menopausal transition to date but
includes no published hormonal nor menstrual cycle data. There was a
92.8% response rate to the questionnaire, which included
anthropomorphic and gynecological topics, use of medication, disease
diagnosis, and fractures. In addition to the lack of hormonal data, the
study has several drawbacks: menopause is defined as beginning after 6
months without flow; no category is provided for the perimenopause
(although the mean age of all women was 52); and 21.7% of women
aged 56 were still menstruating, probably because of hormone therapy.
As evidence of its careful epidemiological design, however, the Kuopio
study undertook a reproducibility analysis (repeat questionnaire
completion by a sample) that showed moderate correlations for milk and
cheese consumption (r = 0.548 and 0.469), high
correlations for weight, height, and oral contraceptive use
(r = 0.81 to 0.93), and low correlations for physical
activity in hours per day (r = 0.212, P
= 0.03) (46). In addition, they proved the validity of their
questionnaire for fractures against computerized medical records and
showed only three false-positive and three false-negative reports out
of a total of 2,935 fractures.
The epidemiological data from Kupio include age at hysterectomy. A total of 7,826 gynecological operations were performed on the 13,100 women who were followed longitudinally; 0.9% of these operations were because of cancer. Hysterectomy was performed in 15.8% of the population [which is lower than is reported from studies in the United States and Canada (67) but greater than in Japan]. The peak incidence of hysterectomy is 13.5/1,000 person years between the ages of 46–48 yr. The incidence was at or above 10/1000 person years from ages 40 to 52, which effectively spans the ages in which the perimenopause occurs in a North American population. These data are of importance because high estradiol levels and disturbed ovulation, which this review documents to occur during the perimenopause, are likely to be causal in abnormal menstrual bleeding problems (83), which are a common reason for hysterectomy.
The average age for the 13,100 women at the start of prospective observation in the Kuopio study was 52.4 yr; they had a body mass index (BMI) of 26.3 and consumed 817.2 mg/day of calcium from dairy products. Twelve percent of the population smoked regularly, and 8.7% had never been pregnant. At baseline, menopausal symptoms were reported by 55% of the "premenopausal" women (i.e., women who had experienced flow in the last 6 months) and by 69% of the postmenopausal women (who were 6 months or more beyond their last menstrual period). The bone and fracture data from this study will be reported in Section IX.C. (46).
The above three prospective studies of the epidemiology of the perimenopause have provided important information about women’s symptoms, the timing of events, and the process of the perimenopause. However, none of these studies has included detailed (more frequent than every 6- to 9-month telephone questionnaire) self-reports of experiences, primary menstrual cycle information, or hormone levels. To provide the needed direct hormonal information about the perimenopause, detailed physiological studies (the majority of which lack population-based validity) must be reviewed.
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V. Systematic Studies of the Endocrinology of the Perimenopause |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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. The designs of the hormonal studies in
perimenopausal women performed to date, except for the population-based
Melbourne Women’s Midlife Health Study (31) and the Malmo, Sweden,
study (84), have reported data from selected groups of women (often
gynecology patients or hospital staff paid for their participation) and
have not described the subjects adequately for comparison with other
studies. The Melbourne population-based study appropriately reported
the response rate (56%) and women’s descriptive characteristics (31)
but separated the hormonal data (31) and symptom information (50)
except for one paper cross-sectionally comparing follicular phase
hormone levels in women with and without VMS (85). Also, no primary
menstrual cycle data are available, although the hormonal analysis is
in five different groups based on reported menstrual cycle
characteristics (i.e., Group I includes women who reported
no change in cycle interval or flow in the last year, and Group V
designates women reporting no period for 3 months but who had
experienced flow within the last 12 months). Despite this
menstrual cycle classification (whose validity has been questioned)
(86), the Melbourne Women’s Midlife Health Study, as now reported,
does not allow integration of data on hormonal levels with
perimenopausal flow characteristics, vasomotor, and other experiences
of perimenopausal women.
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, and the three with urine measurements are
listed subsequently. All are in chronological order by date of
publication. FSH and LH changes through the perimenopause, although
documented in many of the cited studies, will not be reviewed here.
These data confirm what has been known for many years, that with
increasing gynecological age, FSH levels increase first followed by LH
levels (32, 91, 93, 94), and that an elevated FSH level is not
diagnostic of perimenopause (14). These data also confirm that the
early follicular phase is the time in the cycle during which FSH is
most likely to first be elevated (91).
In contrast to the expectation that perimenopausal estradiol levels are
on the decline or are low, many studies have shown at least one cycle
or group of subjects in whom follicular phase estrogen levels were high
(31, 87, 88, 89, 90, 91, 95). This anecdotal observation of erratic high estradiol
levels, however, has been confirmed by mean data and by this
meta-analysis. Mean FP estradiol levels taken from 415 perimenopausal
women were compared with mean FP levels in 292 premenopausal controls
reported in 12 different papers (32, 33, 65, 89, 90, 91, 92, 93, 96, 97, 98, 99, 100). As shown
in Table 1, the mean FP estradiol level in perimenopausal women was
higher than in controls (224.9 ± 98 vs. 174.7 ±
57 pmol/liter). A Fisher’s combined P test of the four
studies that provided serum samples of both pre- and perimenopausal
women (65, 89, 91, 99) showed significantly higher estradiol levels in
the FP in perimenopausal women (Fisher’s F = 16.13, df =
2 k = 2 x 4 = 8; P = 0.041).
The most convincing evidence that FP estradiol levels are
inappropriately high during the perimenopause comes from the Melbourne
Women’s Midlife Health Study, which provides the largest number of
women cross-sectionally sampled in a well designed population-based
study. FP estradiol data, by cycle and flow-based categories, are
illustrated in (Fig. 2) (31). Average
estradiol levels did significantly decrease across the five
menstrual cycle groups with a lower level in the group who reported
skipping three or more cycles. Group I, who reported no change in cycle
interval or flow in the preceding year and were considered
premenopausal, had a FP estradiol geometric mean of 273 pmol/liter,
while that mean was 113 pmol/liter in Group V (31). However, excluding
data from Group I (who may have been either pre- or perimenopausal)
still leaves a weighted mean estradiol level of 226
pmol/liter, which is high compared with mean EF phase estradiol of 173
pmol/liter in normal young women controls in two studies published by
the same laboratory (184 ± 30 and 162 ± 73 pmol/liter,
respectively) (32, 33). The average estradiol levels are higher than
normal premenopausal FP phase levels for all except the last group
(86). In addition to the higher mean estradiol levels, more than 10%
of the individual values in every group exceeded the mean laboratory
normal midcycle estradiol peak level of 750 pmol/liter (32, 33) (Fig. 2).
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is more striking because in
young women FP estradiol levels are low and range from 50–200
pmol/liter, with a mean of 175 ± 57 pmol/liter in the combined
premenopausal controls (Table 1). The high perimenopausal FP levels
published by Burger and colleagues (31) are, in fact, not different
from cycle mean estradiol levels (obtained by quantitative combined FP
and midluteal phase samples) from two cycles in each of 66 ovulatory
women studied in this laboratory (86, 101).
Estradiol levels during the premenstrual (or luteal phase) portion of
the cycle are also significantly elevated in perimenopausal women
(Table 1). The mean premenstrual estradiol level exceeded the mean in
premenopausal controls (371 ± 97 vs. 304 ± 84
pmol/liter). Although only a subset of studies provided systematically
studied data from both pre- and perimenopausal women (65, 89, 99),
Fisher’s combined P test shows perimenopausal levels to be
significantly elevated (F = 15.55, df = 2 k = 2 x
3 = 6; P = 0.0164) compared with normal
premenopausal values.
The three cross-sectional studies in which urinary hormonal data were used also showed elevated estrogen levels, this time as estrogen excretions. Before lending too much weight to these data, it is worth remembering that all of these studies sampled women with abnormal flow and ovulatory disturbances (63, 87, 88). Seven of the 12 cycles showed individual cycle estrogen excretions to be high (greater than MCP levels) for durations of 8, 12, 14, 6, 15, 5, and 5 days, respectively (63, 87, 88). In addition, dysfunctional uterine bleeding was observed to be associated with high estrogen excretions that occurred during flow (87). Thus, whether by urine or serum testing, one of the characteristics of the perimenopause is high mean estrogen excretions or estradiol levels, both in the FP and premenstrually. These data, however, do not indicate that every perimenopausal woman experiences high estradiol levels consistently, nor can we yet understand what percentage of women and for what periods of time will be exposed to high estrogen levels.
Studies of ovulatory characteristics or progesterone levels are few in
perimenopausal women in contrast to the many studies that have
documented estradiol levels or estrogen excretions. Of the 12 studies
of perimenopausal endocrinology shown in Table 1, all of those
measuring urine excretions but only two of those measuring serum
hormones tabulated the percentage of the cycles that were ovulatory. In
paid midwifery students studied by Abe et al. (90), five of
eight cycles were nonovulatory. Two studies excluded otherwise eligible
women because they were nonovulatory (89, 100). Despite excluding 24%
of the sample, the midluteal progesterone levels averaged 15.75
nmol/liter in women ages 45–50 compared with 39.65 nmol/liter in women
ages 20–29 (P < 0.05) (89). That suggests ovulatory
but insufficient luteal phase cycles were occurring. Although Ballinger
et al. (65) do not categorize cycles as nonovulatory or
ovulatory, they showed significantly lower mean progesterone values
(16.3 vs. 25.3 nmol/liter) in women in the later
perimenopause compared with controls. Furthermore, Ballinger et
al. showed that mean progesterone levels over 16 nmol/liter
(e.g., indicating ovulation) occurred on only one rather
than two of the weekly samples in women 
45 yr old compared with those
less than 45 (65). These data suggest ovulatory but short luteal phase
cycles, as previously shown by Vollman (16), occur more
frequently in the menopausal transition. Studies by Lee et
al. (91) and Fitzgerald and co-workers (98) did not document any
age-related differences in progesterone levels. Unfortunately, The
Melbourne Midlife Women’s Health Study provides no information about
ovulation (31).
The three cross-sectional studies in which 24-h urinary PDG levels were
reported (Table 1), as previously mentioned, all sampled women with
abnormal bleeding or from gynecological patient populations (63, 87, 88). In these three studies, anovulation occurred 77% of the time.
This appears to exceed the frequency of anovulation from other studies
of the perimenopause (15, 16). This lends support to a probable causal
relationship between dysfunctional uterine bleeding and lower levels of
progesterone (83). Therefore, these cross-sectional data confirm the
earlier basal temperature studies (16, 57, 58) showing a significantly
increased frequency of cycles having ovulation disturbances
(anovulation, short or insufficient luteal phases) during the
menopausal transition.
In summary, these cross-sectional data describing the serum hormonal
characteristics of one cycle each from 415 perimenopausal women show
that mean estradiol levels, both in the follicular and premenstrual
phases, are significantly higher than in younger women. Although this
observation may be caused by sampling relatively later in a shortened
FP, or in some cycles in which midcycle bleeding rather than normal
menstruation was occurring (86), approximately 10% of levels are
extremely high and exceed the normal MCP estradiol level (Fig. 2) (31).
Also, when cycles are aligned by their MCPs as is done by Santoro and
colleagues (34), FP values remain higher in perimenopausal than in
premenopausal women. In addition to higher FP estradiol values,
premenstrual estradiol levels are also higher than in premenopausal
controls. In general, these papers do not comment on the high estrogen
levels they document. This omission may occur because high estrogen
levels were contrary to their anticipated results (86). Finally,
perimenopausal women have a higher (by almost 50%) frequency of
anovulation compared with women in their twenties and thirties (16).
Despite the many studies and data from large numbers of women that
strengthen these conclusions, prospective data are needed to confirm
them and to understand the physiological changes leading to higher
estrogen productions and disturbed ovulation that appear to
characterize the perimenopause.
B. Prospective ovarian hormonal levels in the perimenopause
Eight studies, spanning the years from 1976 to 1996, have recorded
hormone levels over several menstrual cycles in each of a total of 248
women. These data are reported in detail in Table 2. Although some studies report only
summary data, 193 cycles are shown in detail in the respective
publications (34, 38, 61, 84, 93, 102, 103, 104). These data differ from the
single-cycle cross-sectional data in that they allow some appreciation
of the cycle-by-cycle hormonal variability of the perimenopause. All
except three of the prospective hormonal data sets have been obtained
from 24-h or overnight urine samples rather than serum measurements
because it is less invasive. As shown in Table 2, high and prolonged or
inappropriately timed (such as the start of flow) and high estrogen
levels (as high as the MCP) are documented in several studies (34, 38, 87, 102). Although it is counterintuitive, both Longcope et
al. (103) and Metcalf and MacKenzie (38) documented high estrogen
levels during long cycles, or, in one instance, in a perimenopausal
woman who subsequently did not have further vaginal bleeding.
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Based on urinary PDG excretion in the prospective perimenopausal data from two women, only 56% of the 38 cycles were ovulatory. The patterns of urinary estrogen, mucus, and bleeding show anovulatory cycles with high premenstrual estrogen levels followed by cycles with short FP that are normally ovulatory. Typically, that ovulatory cycle might be followed by a very long FP cycle with a short luteal phase length. In a few instances, the well-trained subjects did not record stretchy mucus despite high estrogen and low PDG excretions. That observation suggests some decrease in cervical gland responsiveness to estrogen may develop during the perimenopause (102).
Three prospective studies reported in Table 2 used serum sampling (84, 93, 103). Only the Sherman study (93) sampled daily across several
cycles in three women while the others measured serum levels at 3- to
6-month intervals in 39 and 152 women, respectively (84, 103). Sherman
and colleagues summarized their data to say that FSH levels were rising
and estradiol levels were declining in women ages 46–56 with regular
cycles. However, when the hormonal data are examined more closely, they
include several characteristics suggesting intermittent high estrogen
levels. For example, in 4 of 13 cycles shown in detail, estradiol
levels over 260 pmol/liter occurred at the time of flow, a time when
levels have normally dropped. In addition, 3 of 13 cycles showed
clearly short FP lengths (93). Normative data for menstrual cycle
hormone levels show a significant inverse relationship between the FP
length and the mean FP estradiol level (r = -0.551)
(96). Therefore, the data of Sherman et al. (93), although
not documenting high mean estradiol levels, show intermittent high
values. Also, two of the three women whose cycles were shown in detail
had at least one anovulatory cycle. Longcope’s study, which sampled 39
peri-menopausal women at 3- or 4-month intervals for 2.5 yr, found
that the weighted mean estradiol level was 294 ± 327 pmol/liter,
which is clearly not low (103) compared with a mean cycle estradiol
level of 275 ± 112 pmol/liter in 66 ovulatory premenopausal women
(101).
The Malmo Perimenopause Project, which includes 152 women who
contributed serum hormone samples every 6 months during the interval
from 80 months before up to more than 48 months after the last flow
(84), has recently published the largest and best designed set of
prospective data. Unfortunately, as in the Longcope study (103),
serum samples were not timed within cycles. Data are presented
according to how many months the women were before or beyond their
final menstrual period. This presentation indicates that the mean
estradiol level was 379 pmol/liter during the peri-menopause (as
defined by the 48 months before and the 12 months after the last flow).
The mean serum estradiol level, however, was 459 pmol/liter if only the
4 yr before the last flow were included (84). Even in the
year after the last flow, during which the mean estradiol levels were
182 ± 163 and 171 ± 151 pmol/liter (for the first and the
final 6 months, respectively), these estradiol levels were normal for
the premenopausal FP (Table 1).
The Malmo study also shows a high estradiol variance (as SD of 427 for a mean of 513 pmol/liter) when women were 4 yr before the last flow (84). This variance may be due to the collection of serum with no relationship to flow or may be a vivid expression of the variability as well as the elevation of estradiol levels during the perimenopausal transition. In both the Malmo and the Massachusetts study by Longcope, the estradiol variance did not become less than 50% of the mean until approximately 24–48 months had passed since the last flow (84, 103). Thus, the three prospective studies of the perimenopause in which serum hormonal sampling was used, like the cross-sectional data, show high estradiol levels.
The first of several prospective studies in which urinary hormone measurements were used focused on the incidence of ovulation disturbances during three consecutive cycles in women 40 to 55 yr old (61). Metcalf documented that anovulation occurred in more than 50% of women reporting a recent history of oligomenorrhea (who were classified as perimenopausal). Anovulation, however, was present in only 5% of cycles in those who reported regular cycles, even if they were more than 50 yr old (61). Ovulation was inconsistent in 66% of women who noted recent changes in cycle length. In two other reports from New Zealand with similar design, 17 of 31 perimenopausal women ovulated within 16 weeks of their final menstrual period (15) or 52% of peri-menopausal women were ovulatory (66). Midcycle spotting occurred for 12 of 139 women; 5 of these had regular and consistently ovulatory cycles, and 4 of the 7 with irregular cycles also had inconsistent ovulation (61).
The prospective urinary hormone studies from New Zealand described
above included no estrogen data (15, 61, 66). However, some years later
the urinary estrogen excretion data from the same set of subjects were
reported indirectly as a ratio of estrogen excretion divided by PDG
excretion (107). In 22% of the cycles, the ratio of estrogen to PDG
excretion at or above 100 (which is typical of the midcycle estrogen
peak) lasted for a prolonged time of 14 or more days. In their 16
normal premenopausal women, the urinary midcycle ratio of hormones over
100 averaged 2 days and had a range of 0–5 days (107). Extremely high
ratios (>100) occurred on only 18% of cycle days in younger women
while ratios over 100 were present on 40% of the measurement days in
the perimenopausal women (P < 0.01) (107).
Furthermore, as mentioned above, the longer the cycle the more likely
it was that a prolonged high ratio would occur. Ratios over 100
for 14 days occurred in 6.9% of cycles that were 18–35 days
in length, and in 46.9% of cycles that were 50–260 days long (107).
Although low PDG levels, as expected in long anovulatory cycles might
be postulated to explain this, a ratio over 100 required high estrogen
excretion (which was not anticipated in oligomenorrhea).
The two further prospective studies using urinary steroid excretion
levels corrected for creatinine were authored by Shideler and
colleagues (104) and by Santoro and colleagues (34). These two studies
show from three to six cycles of daily urinary data in detail for each
of several women (Table 2). Furthermore, Santoro’s group
systematically compared urinary hormonal data from 11 regularly cycling
women over 47 yr old (whom she called perimenopausal) with data from
younger women also studied across one cycle. These data, which are
illustrated in Fig. 3, show significantly
increased estrogen excretions in both the follicular and premenstrual
phases of the cycle in the older women (34). The mean estrone level of
76.9 ng/mg Cr is clearly greater than the mean level of 40.7 ng/mg Cr
in controls (34). The final important observation from these data is
that PDG excretion was significantly less in regularly cycling women
over 47 yr old compared with younger women (P < 0.015)
(34) (Fig. 3). These data confirm lower progesterone excretion levels
during the early perimenopause and suggest, in contrast to the Metcalf
data, that short or insufficient luteal phases may begin before
anovulation develops and that these subtle ovulation disturbances are
present before menstrual cycles become irregular or oligomenorrhea
develops. Data from the groups of Shidelar and Santoro show that high
estrone conjugate excretion (at greater than midcycle levels) exists
for prolonged periods that last from 3–13 days (34, 104) as
illustrated in Fig. 4. Unfortunately,
Santoro et al. do not record times of vaginal bleeding on
this graph or allow a calculation of the FP lengths which Shideler
et al. noted to be short during several cycles (104).
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Both the cross-sectional (Table 1) and prospective (Table 2) published
studies on the endocrinology of the perimenopause just reviewed show
consistent evidence of significantly higher estrogen levels than are
normal in younger women. This observation contrasts sharply with our
current understanding. Is it possible that, until recently, estrogen
levels did gradually decrease during the perimenopausal transition?
That is highly unlikely given that the time of acquisition of these
data spans more than 20 yr, and that evidence of high estrogen levels
such as menorrhagia and breast tenderness have been reported to occur
during the perimenopausal transition since Tilt’s time, and short FPs
since the 1950s (57). The endocrinology of the perimenopause has not
recently changed. Rather, the construct that menopause is a time of low
estrogen production likely led to an inability of scientists and
clinicians to see the (intermittently) high estrogen levels that were
present (86).
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VI. Histological Studies of Ovarian Changes Across the Lifespan |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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It is well established that, from birth onward, primordial follicles
are continuously being activated, maturing partially, and then
regressing. This follicle activation continues in a constant pattern
that is independent of pituitary stimulation. Evidence suggests that
this regular follicular activation changes during late reproductive
life. Richardson and colleagues (111) performed a careful quantitative
histological study of the ovaries and endometrium coupled with a single
hormonal measurement and a reproductive history on a randomly selected
ovary from each of 17 women ages 44 to 55 who underwent ovariectomy and
hysterectomy for uterine fibroids or menorrhagia. (Although these are
important data, the women were a selected and abnormal sample because
they apparently required hysterectomy.) The six women reporting regular
cycles had an average of 1700 follicles in the ovary compared with an
average of 180 follicles in the ovaries of those who reported irregular
cycles (111). The endometria from the perimenopausal women showed no
evidence of ovulation although three of seven, by timing, should have
been in the luteal phase. Furthermore, in contrast with this review’s
reported endocrinology of the perimenopause (Tables 1 and 2), estrogen
levels were equal in the premenopausal and perimenopausal women and
ranged from 146 to over 450 pmol/liter, which is well within normal
ranges for the menstrual cycle (96).
The steady number of follicles undergoing partial stimulation and atresia without any hormonal intervention does not appear to increase at puberty (112), although few peripubertal ovaries have been examined thus far. The marked increase in pituitary stimulation of the ovary at puberty does not appear to alter that follicular "depletion rate" (112, 113). A number of pathologists have performed quantitative analysis of the remaining ovarian follicles in ovaries of women from random autopsy series or women having ovarian surgery (111, 112, 113, 114). Only recently, however, has the remaining number of follicles been related to the age of the woman to construct an age-specific rate of apparent follicle disappearance (113). When the cross-sectional ovarian follicle count data are ordered by the age of the woman examined, observations show a marked increase in the slope of follicle loss that appears to indicate an accelerated rate of follicle depletion beginning in the late thirties or early forties (111, 112, 113, 114).
What are the implications of an accelerated rate of follicle depletion? It seems obvious that more follicles would disappear if more were being stimulated consequent to gonadotrophin levels that begin to rise in women in their thirties (49). Another possibility is that the cohort of follicles, although normal in number, develops more rapidly. That would explain the shortened FPs but does not account for the accelerated rate of follicle depletion that has been observed. Is it likely that these morphological observations are associated with changes in hormonal production in the perimenopause? To date, this question cannot be answered. Clearly, a larger number of ovaries from a nonselected series of women is needed to systematically study follicle numbers and hormonal levels in women dying suddenly during both the peripubertal years and during the late thirties through to the sixties.
The ovary in perimenopausal and menopausal women is an active endocrine organ that has not yet been adequately studied. The time of increasing depletion of follicle numbers appears to correspond with a time when the ovaries are under increasing stimulation from rising FSH levels. Could the estrogen production of a larger cohort of partially stimulated follicles (few of which ovulate) explain the preserved or high estrogen productions documented during the perimenopause? Could the increased rate of dizygotic twinning that increases with increased maternal age also provide evidence for the stimulation of multiple follicles in the perimenopause?
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VII. Physiological Studies of Changing Ovarian Hormones in Women in Their Forties and Fifties |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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The last two decades have seen a rapid increase in studies of exogenous ovarian hyperstimulation for ovulation induction in infertility treatment and the investigation of the control of folliculogenesis and fertility. This is especially true as increasing numbers of women who have delayed their first pregnancy until their late thirties and early forties are found to be relatively infertile. In parallel with studies of IVF and embryo transfer in women over 40, is an increasing appreciation of the roles of inhibin, not only in feedback inhibition of FSH secretion in women, but also as a possible indicator of ovarian reserve (115, 116, 117), and as a paracrine factor in ovarian physiology (118). The following sections will review this physiological literature with an eye to illuminating the hormonal changes during the perimenopausal period.
A. Folliculogenesis and ovarian hyperstimulation for in vitro
fertilization (IVF)
Just as it has been known for many years that FSH levels increase
with increasing gynecological age in normal women (32, 91, 93, 94), so
has it been evident that an elevated early FP FSH level carries a
negative prognosis for pregnancy during IVF (119, 120). In a systematic
study of pregnancy rates during IVF in 29 women above age 40 compared
with women in younger age groups, the older women had as many oocytes
recovered at laparoscopy, equal estrogen and progesterone levels, but
more oocytes with fractured zonae. The pregnancy rate was also equal
(
30% with multiple preembryos transferred) to that in younger
women, but 60% of the older women (compared with 30%) subsequently
spontaneously aborted (119). Inhibin responses to exogenous
hyperstimulation were significantly lower in women older than 35,
although estradiol responses were not related to age (117). Luteal
phase inhibin levels correlated significantly with progesterone levels
(r = 0.87). Finally, it is possible that the inhibin
response to maximal ovarian stimulation might predict the onset of
perimenopause (117), although this needs to be systematically tested in
well matched, regularly cycling women whose ages range from 30–50.
The variability of the early FP FSH in women of greater gynecological age is probably important to the perimenopause. Not only is FSH known to increase during the early FP in women in their late thirties and early forties, the elevated FSH is variable from cycle to cycle (14, 120). The reproductive medicine unit in London, Ontario, Canada, investigated whether a single raised FSH (>20 IU/liter) on day 3, followed by a normal one in the cycle in which IVF was undertaken, carried an adverse pregnancy prognosis. In a cohort examination of 1,868 IVF cycles, women who currently had a normal day 3 FSH level, but for whom it had been elevated once in the past, had a pregnancy rate reduced to 5.6% compared with 16.5% in those with consistently normal FSH levels. No pregnancies occurred if two previous FSH levels had been raised, even though the FSH level was normal in the cycle in which IVF was used. Thus, when the FP FSH is ever raised, some aspect of ovarian folliculogenesis appears to have changed.
To investigate hormonal changes occurring in women over 45 who
continued to report regular menstrual cycles, MacNaughton and
colleagues (32) studied nine such women compared with nine women from
each of the age groups: twenties, thirties, and early forties.
Volunteers were selected among regularly cycling clinic employees who
were not receiving exogenous hormones. A FP serum sample (days 4–7)
and a midluteal phase serum sample were analyzed for FSH, LH,
estradiol, progesterone, and inhibin (32). Using ANOVA, women 45 yr old
or over had lower FP inhibin levels as well as higher FSH levels but no
consistent difference in estradiol levels. Again, inhibin was lower in
the luteal phase in the older women (as will be discussed below), but
FSH, LH, progesterone, and estradiol were not different (32). FSH
levels during the early FP were negatively correlated with estradiol
(r = -0.35, P < 0.05) suggesting some
element of normal feedback inhibition; no correlations existed during
the luteal phase (32). In a study of similar design, 11 women ages 37
to 45 reporting regular cycles were recruited from hospital staff and
contrasted with similar women ages 21–25 (n = 14), 26–31 (n
= 13), and 32–36 (n = 15) who met the same criteria (98). In
addition to measurements of estradiol and progesterone, serial pelvic
ultrasound scanning was performed for both follicular cyst number and
size and for endometrial thickness monitoring (98). In this study, the
FP was longer (16 days) in women over 37 (which contrasts with the
short FPs shown in older women in large longitudinal basal temperature
studies (16, 57) and in the perimenopausal endocrinology reviewed
above). The maximum follicle diameter was 17 mm and significantly
smaller than in younger women (P < 0.01). MCP
estradiol levels were equal in all age groups as were maximal luteal
phase progesterone levels, but there was a tendency for the day 8
estradiol to be elevated in the older age group (range 115–352
compared with 111–268 pmol/liter) and a mean of 234 vs. 171
pmol/liter (P = 0.17). It is of interest and probable
clinical importance that the endometrial thickness at its maximal
during the luteal phase was significantly greater in women over 37
compared with both groups of younger women (Fig. 5) (98).
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).
B. Inhibin physiology in women over 40
Thus far, many puzzling hormonal characteristics of menstrual
cycles in midlife women remain to be explained. These puzzling aspects
include observations that: 1) elevated early FP FSH levels occur
despite normal or high estradiol levels (which should be suppressing
FSH); 2) an increased risk for ovarian hyperstimulation and multiple
stimulated follicles exists during IVF in cycles having elevated early
FP FSH or estradiol levels; 3) an increased endometrial thickness
occurs in older women despite similar estradiol and progesterone levels
as younger women; and 4) an apparently depleted pool of potential
follicles and low fertility rates after age 40 coexist with maintained
estradiol levels (which must be produced by ovarian follicles). All of
these different characteristics of cycles in women in their forties
point toward some change in the regulation of folliculogenesis in older
regularly menstruating women. Is it possible that ovarian inhibin
production plays a role in this process and can explain some of these
observations?
As reviewed above, mean estradiol levels are normal or high in perimenopausal women, and FSH levels are often not suppressed despite these high estradiol levels. These aspects of pituitary-ovarian relationships are contrary to expected physiology. It is proposed that decreasing ovarian production of inhibin plays a role in the high average estrogen levels documented during the perimenopause. More specifically, the B subtype of inhibin, a small peptide made in ovarian granulosa cells, which is known to be stimulated by FSH and, in turn, to suppress FSH, may play a role in the altered physiology of the perimenopause (100, 123). Increasing evidence suggests that ovarian inhibin plays a role in ovarian folliculogenesis (115, 117); therefore, new information about inhibin levels and their functional relationships in women in their forties and fifties becomes important.
Inhibin is a small pleomorphic peptide made within the ovarian granulosa and luteinized granulosa cells, which, although assay specificity and sensitivity are still problematic, has been shown to be important in ovarian physiology (123). Inhibin may be an intraovarian regulator [although other peptides such as activin and follistatin are more likely paracrine factors (118)] but one of its more important functions appears to be feedback suppression of FSH production (116). Inhibin is produced by the granulosa cells of the corpus luteum and, in a lesser amount, by granulosa cells of the growing follicle during the FP. FSH stimulates inhibin (124), which in turn suppresses FSH.
Women with what is called "incipient ovarian failure," based on higher early FP FSH levels, have been shown to have lower FP inhibin levels than controls (125). These women, who experienced an ovulatory cycle after therapy with estrogen and cyclic progesterone, had normal estradiol levels. Their vaginal ultrasounds indicated multiple small follicular cysts and inappropriate follicular maturation (125). In both the follicular and luteal phases, inhibin and FSH levels within the same cycles were inversely related. In response to follicular stimulation with clomiphene and hMG, women over 35 had lower levels of inhibin, although estradiol levels were equivalent to those in women in their twenties and early thirties (117). In addition, luteinized granulosa cells harvested from women with low and high day 3 FSH levels showed, respectively, high and low inhibin secretions in vitro (116). Women with high FSH levels, although producing normal amounts of estradiol and progesterone, have lower levels of total inhibin and dimeric inhibin (116).
The most recent and important evidence suggesting that inhibin is
instrumental in the menstrual cycle changes of women in their
forties (and probably in the perimenopause) was obtained from a
cross-sectional study of the FP in ovulatory women of ages 40–45
(n = 10) compared with women of ages 20–25 (n = 13) (100).
The protocol involved observation until a 16-mm cyst was visible on
ultrasound or until estradiol levels exceeded 550 pmol/liter, at which
time 10,000 IU of hCG was administered. This study, which sampled serum
daily from onset of menstruation and obtained vaginal ultrasounds daily
in the early FP, documented that inhibin B levels were lower while both
FSH and estradiol levels were higher in the older women (Fig. 6) (100). The authors speculated that
inhibin B is a product of primary and early antral follicles while
inhibin A is produced by the dominant follicle. Although the
biochemistry and measurement of inhibin and its forms remain to be
fully clarified, the dynamic association of low inhibin B levels with
high FSH and high estradiol in the early FP is the best evidence of the
role of inhibin in the physiological changes occurring in the menstrual
cycles of women in their forties. Do these observations relate to the
endocrinology of the perimenopause?
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VIII. Hypotheses to Explain Perimenopausal Endocrinology |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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, in contrast to the ovaries during
the premenopausal early FP, the decreased inhibin production during the
perimenopause allows a small but important rise in FSH. This increased
FSH causes more follicles to be recruited [thus leading to the
observed increased rate of follicular depletion (111, 113)] as these
follicles, usually without progressing to ovulation, eventually
involute. As would be expected, each of these recruited follicles makes
a finite amount of estradiol. Together, these multiple recruited
follicles produce the elevated FP estradiol levels previously
documented in the perimenopause (Tables 1 and 2) and in IVF studies
(121, 122). That more follicles are recruited is also suggested by the
multiple small follicular cysts noted in older women during IVF (119)
and observed after suppression with ovarian hormone therapy (125). That
more follicles are stimulated is also supported by the increased
tendency for dizygotic twinning in older mothers (127).
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Strong cross-sectional evidence suggests that FP inhibin levels decrease during the perimenopause, based on the population-based study by Burger and colleagues (31). This is especially true in comparison to published normal ranges from the same laboratory (32, 33), as has recently been noted (86). It would be useful to reanalyze sera from the Melbourne Women’s Midlife Health Study in the more specific N. Groome assay system used to detect dimeric inhibin B (100). Despite many questions about the cellular origins of inhibins A and B, and the characteristics and normal ranges of different inhibin assays, it is clear that perimenopausal inhibin levels are lower than premenopausal levels. They probably also decrease over time beginning before periods become irregular in the perimenopause; however, prospective data are necessary to confirm that hypothesis.
Why do inhibin levels appear to decrease in the perimenopause? There is no current explanation for this suggestion. Perhaps it is a biological characteristic of the more centrally located follicles that move outward as the outer follicles are stimulated and regress. There may be changes in as yet unknown paracrine factors. And, as in most other aspects of physiology, it is likely that there are hereditary differences that impact on ovarian inhibin production. Whatever the reason, lower levels of inhibin appear to indicate a decrease in the reserve of follicles that can be stimulated (117, 125). The best hypothesis for explaining the endocrinology of the perimenopause is that luteal phase inhibin levels (or reserves, perhaps specifically of inhibin B) become low before the absolute number of potentially responsive follicles has decreased. This allows FSH levels to rise and in turn results in what is descriptively termed "endogenous perimenopausal ovarian hyperstimulation." The resulting perimenopausal "syndrome" may include breast tenderness and enlargement, fluid retention, heavy, prolonged, or unpredictable menstrual bleeding, new onset of migraine headaches, and new or unpredictable mood swings. These symptoms, however, are far less dramatic, and the estradiol levels are lower (117) than during the extremely serious iatrogenic "ovarian hyperstimulation syndrome" that occasionally complicates IVF.
B. Five hypothesized phases of the perimenopausal transition
This review has documented an extreme variability of ovarian
hormone levels in women in the transition into menopause. In addition,
the early anecdotal reports and several epidemiological studies suggest
an amazing array of symptoms that some perimenopausal women may
experience. Some integration of this collected data into a postulated
temporal series of changes would provide a framework for future
research and some guidance (until prospective population-based studies
are completed) for the clinician and the perimenopausal woman. This
section includes an effort to produce a hypothetical timeline for all
of these observations and documented hormone levels based on
prospective studies by Brown (102), Collett and associates (56, 57),
Treloar (48), and Vollman (16), and cross-sectional data by Burger
et al. (31), Santoro et al. (34), and Lenton and
colleagues (49, 129) integrated with prospective population-based
studies by Kaufert and associates (40, 71) and McKinlay et
al. (45). The first necessity is to understand that any
physiological transition that spans an average of 4 yr is likely to
have differing characteristics during various parts of that period of
time. Because menstrual cycle intervals and women’s experience of
symptoms are fundamental aspects of the clinical entity of
perimenopause, they were used to divide the perimenopause into five
postulated phases as shown in Table 3.
Although estimated durations have been included, these may be
sufficiently variable between women that no clear predictions are
possible.
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), changes that are hormonally distinct
compared with premenopausal women occur before cycles become irregular.
Many women will notice shorter cycles as noted by Treloar, Vollman, and
others. Often the FP is short. During this phase of the perimenopause,
early morning night sweats (VMS) commonly are first experienced.
Estradiol levels are at least intermittently high during this phase.
Weight gain, migraine headaches, and abnormally heavy or flooding
menstruation may occur. FSH levels are intermittently in the early FP
but are usually normal. It is likely that inhibin levels would already
be low. During Phase B, perimenopausal women are likely to continue to have basically regular cycles but disturbances of ovulation (such as short luteal phase, luteal phase insufficient, and anovulatory cycles) become more common. Again, episodes of heavy flow may occur, premenstrual symptoms and dysmenorrhea are increased, and VMS may predictably return or increase in the days just preceding flow. FSH is now intermittently elevated but still only during the early FP. LH continues to be normal and estradiol is often high. Inhibin levels are probably inappropriately low.
Phase C is the beginning of what is now considered the onset of the perimenopause with unpredictable flow and alternating short and long or skipped cycles. Estradiol levels are intermittently quite high but may also be normal and sometimes low. VMS are postulated to begin to occur more commonly during the waking hours during this phase of the transition, although most women will have minor symptoms. For some women, night VMS become more persistent but continue to be cyclic before flow and may still predict flow in some cycles. By this phase, FSH levels are usually at least slightly elevated. LH levels may occasionally be increased during this phase. Inhibin levels are low.
Phase D is postulated to include the onset of oligomenorrhea, and more VMS, but may yet have times of high estrogen signs and symptoms after longer periods without flow. Ovulation occurs less than 50% of the time and often is abnormal in progesterone levels, if it does occur. By this phase, flow is usually light but unpredictable. Heavy flow during one menstruation may predict the onset of oligomenorrhea. FSH is now persistently elevated and LH also becomes consistently increased. Inhibin levels are postulated to be clearly low.
Phase E begins with the final menstrual period and includes the year after what is retrospectively defined as menopause by the WHO (10). This is a time of increased intensity and frequency of VMS, although a few women who experienced them earlier may also find they disappear. However, premenstrual type symptoms and cramps are usually less but sometimes occur without any subsequent flow. Breast, fluid, and mood symptoms decrease. FSH and LH are high and estrogen levels low or normal. Inhibin levels are consistently low.
This theoretical time course, as can be seen (Table 3) includes
remarkably variable hormonal patterns. The actual time, menstrual cycle
patterns, hormone levels, and women’s experiences for each of the
phases of this proposed timeline will need to be documented in
appropriate prospective studies in population-based samples of women.
Some women may also appear to be perimenopausal and then apparently
recover ovarian/pituitary function for a time. The percentage of women
experiencing this pattern has not yet been documented.
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IX. Hormonal Physiology of Clinical Changes in the Perimenopause |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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Although reports of the perimenopause before the "estrogen deficiency era" report flooding menstruation, increased cervical mucus, breast tenderness, and emotional symptoms (52), and some of the anecdotal (130) and early epidemiological literature (40, 55, 71) can be interpreted to show high estrogen levels, nothing yet written has integrated women’s experiences with the endocrinology of this transition. What follows will be a brief discussion of some of the symptoms reported by perimenopausal women in parallel with their hypothesized hormonal etiologies.
A. Endocrinology of menstrual flow and cycle-related symptoms
Menstrual flooding was one of the most distressing symptoms
reported by midlife women in the Manitoba study (67). It was the reason
for a physician visit in 25% of those seeing their doctor during the
perimenopause. McKinlay et al. (45) likewise noted that 20%
of doctor visits related to concerns about abnormal flow. Kaufert and
colleagues (40), using factor analysis, identified flooding
menstruation to be highly correlated (r = 0.68,
P < 0.01) with a change from regular to irregular
cycles. Likewise, heavy flow was a reported symptom in 51% of women
studied by Neugarten and Kraines (55). Oldenhave and co-workers (43, 131) speculated that menorrhagia occurred "more often" than 20% in
"premenopausal anovulatory cycles." Likewise, Shideler et
al. (104) noted that a high estrogen level at the start of flow
was associated with heavy flow. This observation was confirmed by
Ballinger et al. (65) who found heavy flow was significantly
associated with high estradiol levels in the fourth week of the cycle.
The prevalence of menorrhagia was 45% in women in the early
perimenopausal period and 48% in the late perimenopause as defined by
Ballinger and associates (65).
The Melbourne Women’s Midlife Health Study paper on perimenopausal symptoms does not mention menstruation (50) although reported flow characteristics were used as a method of classification of women into five groups (31). This is a strange omission given the prominence of abnormally increased vaginal bleeding just noted in many reports concerning perimenopausal women. Likewise, the papers reporting on the Massachusetts Women’s Health study rarely mention flow. This tendency to downplay vaginal bleeding in the perimenopause is more directly expressed by Santoro and colleagues (34): "We consider menses a less reliable marker of ovarian activity than hormones." Based on the evidence in this review, however, and the endocrinology of the perimenopause that is characterized by high mean estrogen levels and anovulatory cycles, it seems inappropriate to divorce vaginal bleeding from the menopausal transition.
Short cycles, short FPs, heavy flow (including clotting and flooding
menstruation), midcycle spotting, and possibly an increased incidence
of dysmenorrhea are all probably caused by high levels of estrogen
(Table 1). These high estrogen levels are likely caused by endogenous
perimenopausal ovarian hyperstimulation as previously proposed. It is
also probable that the thickened endometrium shown in older women (Fig. 5), with or without local lesions such as polyps or submucous fibroids,
predisposes to heavy flow (98). Anovulation coupled with high estrogen
levels would further increase the risk for dysfunctional uterine
bleeding as occurs with adolescent anovulatory cycles (83).
As has previously been discussed (in Section IV.C), the Kuopio study reported that the peak incidence of hysterectomy was between ages 46 and 48 (46), the age at onset of irregular periods, and thus the perimenopause in a population-based prospective study (45). It is not yet known whether the higher mean estradiol levels shown in the FP and premenstrually relate to the coincidence of hysterectomy and perimenopause onset. In addition, anovulation is prevalent in the perimenopause and often associated with persistent and abnormally high estrogen excretions (132, 133, 134). For this reason, appropriate therapy for menorrhagia, or menometrorrhagia in a woman in or approaching perimenopause, may be cyclic progesterone (oral micronized progesterone or medroxyprogesterone) on days 14–27 of the cycle in doses sufficient to effectively counterbalance high endogenous estrogen levels (135). (Note that, for women with cycles of 24 days or less, cyclic progesterone should be begun on day 10 and continued for 14 days.) Should abnormal bleeding persist despite increasing the doses of progesterone or medroxyprogesterone, androgen-derived progestins such as norethistrone or norgestrol will usually provide effective therapy. These progestins, however, cause significant reductions in high-density lipoprotein cholesterol (136) and, therefore, would not be ideal first-line therapy for midlife women in whom cardiovascular risks are already increasing (29). The reliance on gynecological surgeries (D & C, endometrial ablation, hysterectomy) to treat these perimenopausal bleeding patterns may be inappropriate given new understandings of the roles that ovulation disturbances and high estrogen productions related to endogenous perimenopausal ovarian hyperstimulation may play in their pathogenesis.
B. Vasomotor symptoms (VMS) in the perimenopause
Most Western physicians and women define menopause as beginning
when VMS occur for the first time. Perhaps this classification is
because these sudden episodes of subjective hot feelings and
diaphoresis are commonly considered to be "classic symptoms of
estrogen deficiency" (137). "Of the various sequelae resulting from
the cessation of ovarian function, the occurrence of hot flashes is by
far the most frequent... " (138). [It is worth noting that women
in other countries and from different cultures report far fewer or less
intense hot flashes and often do not even have a name for the
experience (72). It is beyond the scope of this review to speculate on
this observation and the reasons for it, which may include differences
in genetics, diet, and even the status of women in the culture.]
VMS (meaning both day and night time episodic flushing and sweating) epidemiology and physiology have recently been extensively reviewed by Kronenberg (139). She tabulated published epidemiology studies showing that VMS occur in 11–60% of menstruating perimenopausal women (139). Although Kronenberg clearly states that hot flushes are "a phenomenon of women who are in the transition to, or have become menopausal" (139), most physicians believe VMS imply low estrogen levels and are therefore synonymous with established menopause. However, the current equation of VMS with low estrogen had already been shown (admittedly with crude data) to be incorrect by 1935! That year Fuller Albright (140) wrote: "Hypoestrinism has been shown not be a direct cause of the vasomotor phenomena." Likewise, in a prospective study documenting both hormone levels and a score for VMS intensity recorded over 12 yr across the perimenopause, Rannevik and associates (84) said, "There was no correlation between the severity of vasomotor symptoms and the levels of E2... " However, this study did find (without showing the primary data) that VMS "inversely correlated to the decrease in E2 around the menopause" (141). These observations do not negate the efficacy of estrogen therapy for VMS (142, 143). However, they do indicate that the relationships between estrogen levels and VMS are more complex than directly inverse with low estrogen levels.
Perimenopausal endocrine changes (reviewed in Section V)
include intermittent times of high estrogen, elevated mean estradiol
levels (Table 1), and ovulation disturbances. How does this information
fit with the knowledge that VMS often begin in regularly menstruating
women during the early years of the perimenopausal transition? Phrased
another way: Can hot flushes occur when estrogen levels are high? The
answer is yes, based on the data in two very different physiological
studies (137, 144) that will be described in detail.
Bider and colleagues (144) were treating six normally menstruating infertile women with GnRH agonist (GnRHa) to assess pituitary function before planned IVF. They began treatment with injected estradiol benzoate immediately after first performing GnRH testing followed by a GnRHa test. Estrogen was injected weekly thereafter in a dose that changed the serum estradiol from 110 pmol/liter at baseline to the high level of 1011 pmol/liter. Hot flushes began about a week after the first estrogen injection at a time when, without therapy, estrogen levels would have fallen (144). However, the VMS began and continued during a time when estrogen was consistently high and equivalent to MCP levels (144).
A second study also documents that VMS may occur despite persistently high estrogen levels. Gangar and colleagues studied symptomatic menopausal women attending a menopause clinic (137). Women were scheduled to receive 50 mg estradiol implants every 6 months. However, because women began to complain of VMS before 6 months had elapsed, the 12 tested women had received their last previous implants of 50–200 mg estradiol at an average interval of 4 months (range 2–7). At the point at which women next experienced a recurrence of symptoms of "flushes, sweats, mood swings, and irritability," levels of estradiol were 1450 to >3500 pmol/liter. These estradiol levels were clearly supraphysiological (137). Although these authors concluded that "tachyphylaxis" (e.g., a kind of tolerance requiring higher and higher doses to achieve a given effect) to estrogen accounted for their observation, Ginsburg and Hardiman (145) wrote a letter to the editor clarifying that VMS are triggered by "oestrogen withdrawal" rather than simply being caused by low estrogen levels.
Estrogen withdrawal, or rapidly decreasing estrogen levels, as a cause for VMS appears highly plausible and likely explains some or all of perimenopausal women’s experiences. This postulate would fit all of the current data if three corollary conditions are added: 1) the higher the immediately preceding estrogen level, the greater the likelihood of provoking VMS; 2) the shorter the time period of, or the greater the withdrawal slope of estrogen levels, the more intense the VMS; and 3) previous exposure of the hypothalamus to high estrogen levels (for an unknown duration) is necessary before decreasing estrogen levels would cause VMS. These conditions would all be met during the postpartum period. Some women clearly do experience VMS immediately after childbirth. It is not known why all women do not develop postpartum VMS, except that progesterone as well as estrogen levels are high during pregnancy. That differs from the perimenopause in which estradiol levels are often high, but progesterone levels are normal or low.
There are important emerging relationships between undesirable
premenstrual symptoms and hot flushes or night sweats. As an example of
swinging and high but not low estrogen levels causing VMS, Casper and
colleagues (146) reported in passing that 72% of 120 premenopausal
women with severe premenstrual syndrome experienced VMS. VMS were
documented (by skin temperature and conductance measures) in two cycles
from one young women with premenstrual symptoms. Her VMS occurred
during times within the menstrual cycle when estradiol levels should
normally be dropping: after the midcycle estrogen peak in one cycle and
just before menstrual flow in both cycles (146) (Fig. 8). Dennerstein and colleagues (50) noted
that women who reported past premenstrual syndrome experiences were
more likely to develop VMS during the final perimenopausal year. In a
later analysis of 453 women participating in the Melbourne Midlife
Women’s Health longitudinal trial, a significant relationship (with
odds ratio of 1.42; confidence interval of 1.04–1.93) between earlier
reports of premenstrual symptoms and current experience of VMS was
documented (85). Forty-seven percent of women with a history of
premenstrual complaints reported VMS compared with 32% of women
without that history (85). Estradiol and inhibin levels were not
different but FSH levels were higher in the women with VMS compared
with those without (85). The association of distressing premenstrual
symptoms with VMS may explain why regularly menstruating women over 45
yr of age with VMS who were participating in the population-based study
from a Rotterdam suburb had a high likelihood of reporting a disturbed
sense of well-being compared with those without VMS (odds ratio, 4.8;
confidence interval, 2.3–9.7) (147).
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To date, no study in perimenopausal women has prospectively documented
all of the variables that are necessary to understand these complex
relationships: VMS occurrence, frequency, severity, and timing in
relationship to physical and emotional experiences, hormone levels, and
to menstrual flow. Kronenberg mentioned that 7 of the 500 women she
surveyed wrote a comment in the margins of the questionnaire stating
that they experienced flushes they felt were cyclic or related to flow
(139). Women in phases A and B of the perimenopause (Table 3) commonly
report VMS occurring before, and often as a reliable predictor of,
menstrual flow (39)(Fig. 8). The cyclic VMS, which typically begin very
early in the menopausal transition, also seem to differ from those
experienced later in the perimenopause. These early VMS typically occur
during sleep, often in the early hours of the morning, are associated
with few or no daytime VMS, are often preceded by an aura (which may
include anxiety, anger, or panic feelings), and are commonly associated
with nausea, palpitations, dizziness, or faint feelings. Midcycle VMS
(as shown by Fig. 8) appear to occur less commonly than do premenstrual
ones (146) and might be postulated to be more likely in anovulatory
cycles in which progesterone secretion does not immediately
follow the high estrogen levels. [This hypothesis is based on the
evidence that progesterone is effective in VMS prevention and
therapy (150, 151)].
VMS appear to be central to women’s experience of the perimenopausal transition, yet they are very poorly documented. For example, typical studies investigate whether or not hot flushes or night sweats occur or the number experienced in a day. In contrast, what is important about VMS is both when they occur (especially if they waken a woman from sleep) and how intense they are. VMS, as mentioned earlier, are negatively related to women’s sense of well-being, especially in the early perimenopausal and later menopausal years (147). As a graphic illustration of the importance of VMS, the only study of the risk for falling in perimenopausal women noted that women with flushes were more likely to fall (and therefore were at greater risk for fractures) (152). VMS are also associated with sleep disturbances (142), which may play a causal or even central role in perimenopausal women’s decreased sense of well-being. On the other hand, women may report experiencing VMS and state that they are not bothered by them. In either case, VMS need to be described in better detail: when they occur in the perimenopausal transition, their relationship (if any) to vaginal bleeding, and their number and intensity during a waking or sleeping 24-h day (153). To understand the physiology of VMS and determine their relationship to women’s experiences and well-being, they need to be meticulously documented prospectively in a population-based study.
In summary, VMS commonly start when estrogen levels are high and erratic in the early perimenopause [and occur during premenopausal years in women with PMS and frequent high estrogen levels (149)]. They are highly associated with a decreased quality of life (147), especially when they disturb sleep (40, 41). VMS have also been associated with an increased risk for falling (152) and with osteoporosis (131). Understanding the physiology of VMS and developing a range of nonhormonal and hormonal strategies for their control are important priorities in perimenopause research.
C. Perimenopause and the risk for osteoporosis
The risk for osteoporosis is one of the major reasons for
recommending ovarian hormonal therapy to menopausal women (12, 154).
For women, the terms "bone loss" and "menopause" have come to
be said in the same breath as though they were synonymous. Numerous
cross-sectional studies in selected populations appear to show an onset
of bone loss at the average age of menopause (155, 156, 157). But, when does
bone loss actually begin? Like studies of bone change in premenopausal
women, that depends on the method of measurement [using, for example,
quantitative computed tomography, dual energy absorptiometry (DXA),
single energy absorptiometry (SPA) of radius or calcaneus, or
radiogrammetry of the metacarpals], the site and architecture of the
bone being measured, and the design of the study (158). Leaving aside
those considerations, the determination of when bone loss begins can
most accurately be ascertained by observational prospective studies.
Although full publications on the prospective data are not available
for the study currently ongoing in Hull, United Kingdom (141), or for
the Melbourne Women’s Midlife Study (159), preliminary prospective
bone density data have been obtained from the authors. These data have
been collated with other prospective information below.
1. Bone information from cross-sectional studies in the perimenopause. Several recent cross-sectional studies, including the population-based studies in Allegheny County, Pennsylvania (160, 161), and the Kuopio OSTPRE study from Finland (46, 162, 163, 164), are important to review. The Pennsylvania study, called Women’s Healthy Lifestyle Project, enrolled 470 healthy premenopausal women who had menstruated within the preceding 3 months and measured vitamin D receptor status (a genetic characteristic recently associated with risk for osteoporosis), assessed life-style, and measured bone mineral density (160). In 334 women lean and fat mass measurements were made using the whole body DXA (160). That study showed lean body mass (muscle) was important in the prevention of bone loss (160), as were exercise, obesity, and dietary calcium intake, while the presence of the vitamin D receptor restriction site specified as "bb" was negatively associated with spinal bone density in this cross-sectional study in perimenopausal women (161).
The design and plan of the Kuopio study were described earlier in Section IV.C. Briefly, this 100% sample of women ages 45–56 in an entire province obtained a 93% response rate and 13,100 women completing questionnaires concerning whether or not and in what part of their body they had sustained fractures in the preceding 10 yr. This population averaged a BMI of 26 and consumed an average of 820 mg/day of calcium from dairy foods; 12% smoked and less than half reported regular physical activity. Eight percent of women with menstrual flow (within 6 months) and 12.5% of the menopausal women had experienced a fracture in the preceding 10 yr (P = 0.0000) (46).
Bone mineral density (BMD) by DXA of the spine and hip was measured in 1600 women in the Kuopio study sampled in a stratified random manner from the original cohort. Before this sampling, women with diseases or medications known to affect bone were excluded. (Oral contraceptives surprisingly were not a reason for exclusion, but hormonal replacement therapies were.) This sample of the population averaged 53.2 yr in age with an average BMI of 26.3; 529 of these women, whose average age was 51.2 yr, were still menstruating. The mean spinal DXA in the group was 1.130 ± 0.157 g/cm2 while the femoral neck BMD was 0.932 ± 0.123 g/cm2 (163). In both regions, the BMDs of menopausal women were lower than those of perimenopausal women even when corrected for age. Despite extensive life-style and morphometric investigations (excluding other DXA sites) only 18.7% of the spine and 25.4% of the hip BMD variance could be explained by measured variables including menopausal status. Menopausal status was a significant contributor to multiple regression equations for both spine and proximal femur (163). Life-style variables such as smoking, coffee consumption, calcium intake, and physical activity level did not statistically predict the spine BMD, but grip strength and alcohol intake both made significant positive contributions (163). Physical activity, weight, and age as well as menopausal status were related to the femoral neck BMD (163).
The question that is most crucial to answer is whether or not a given woman is at risk for fractures. In the Kuopio perimenopausal (OSTPRE) study, a 2-yr prospective report documented that women in the lowest quartile for spine BMD had an incidence of fracture of 31.6 per 1000 person years compared with an incidence of 12 per 1000 person years for women in the highest two BMD quartiles (162). Furthermore, a spine BMD predicted the typical wrist fracture associated with menopause with an odds ratio of 1.8 (CL 1.29–2.46) and predicted rib fracture with an OR of 2.4 (CL 1.6–3.6) (162).
A final recent cross-sectional investigation studied women from three outpatient clinics near Sao Paulo, Brazil (165). This study measured bone density by DXA in the hip and spine in 417 healthy women (as documented by a medical history and physical examination) who ranged in age from 20–79 yr (165). Perimenopausal women were defined as those with oligomenorrhea of less than 1 yr duration. The average BMI for women in the decades of 40–59 yr was 25.0, mean lumbar spine BMD was 1.08, and femoral neck BMD was 0.86 g/cm2 (165). Regression of spine BMD against age in perimenopausal women required a separate line with a slope of -0.66%/yr compared with a slope of -0.39% for the menopausal women. The women who were regularly cycling were described by a regression with no slope (165).
2. Prospective studies of bone density change in the perimenopause. Although large cross-sectional population-based studies provide some information about decade-related differences in bone density, the only informative data about bone change during a long and variable hormonal transition such as the perimenopause require prospective monitoring. Three prospective studies of radial bone density, as measured by single photon absorptiometry (SPA), include 2, 5, and 12 yr of follow-up, respectively (84, 166, 167). The first study measured radius SPA in 103 women in placebo groups for a therapy trial and the second in a convenience sample of 217 Caucasian women from a rural community in the United States of whom 89% participated (166, 167). The third study was a population-based sample from Malmo, Sweden, including 152 women of an original cohort of 192 who maintained participation for 12 yr (84). The Danish study showed that placebo-treated women experienced approximately 4% loss of bone mineral content at the radius over the 2 yr of study (2646). The US study showed that the women who were perimenopausal during the study lost an average of 5.6 ± 7.0% of their radial bone density during 5 yr vs. a loss of 8.4 ± 5.7% for women already menopausal at the study onset. Wide variations among individuals make these rates of bone loss not different (167). In the Swedish study the radius data are presented only sketchily with a frequency graph indicating losses of less than 5% to more than 40% with the average being 20%, not differentiated by menopausal status. Perhaps because of the variability of estradiol levels in perimenopausal women, only after menopause did estradiol relate to the rate of change in radius BMD (84).
In contrast to the scant prospective BMD data for the radius, more studies using measurements of the spine by dual energy methods (DPA and DXA) have been performed. Before describing these studies, it is important to note the omission of an important 2-yr prospective study by Recker and colleagues of 75 menstruating women over age 46 (average 49) who were enrolled with premenopausal levels of estradiol and FSH at the outset (168). This study was excluded because it was impossible to determine which of the women were pre- or perimenopausal (except for five who became menopausal during the study) (168). That study showed no significant overall change in spinal BMD by DPA measured every 6 months (168). In addition, two large dose-ranging studies of the new bisphosphonate, alendronate, have been excluded because, although they included some perimenopausal women who were 6 months from their last menstrual flow, the BMD change in the placebo groups were not broken down by rates in the late perimenopausal vs. early menopausal women (169, 170). These two studies include 90 placebo-treated women whose mean age was 51.4 (169) and 502 whose mean age was 53 in Stratum I of the "EPIC" study for prevention of bone loss with alendronate in postmenopausal women under 60 yr of age (170). However, thanks to S. A. Steel and D. W. Purdie of the North Humberside Osteoporosis Screening Project (141), and J. R. Guthrie and P. R. Ebeling of the Melbourne Women’s Midlife Health Study, who are each performing prospective studies that are still acquiring data or have not yet been published, important prospective BMD data are available as unpublished communications.
Including the data from the two population-based, but as yet
unpublished, studies from England and Australia, a total of 10 studies
of spinal bone change by DPA or DXA are summarized in Table 4 (141, 171, 172, 173, 174, 175, 176, 177). Together, these
combined data provide rates of spinal BMD change across 1–8 yr of
observation on 335 perimenopausal women whose data can often be
contrasted with simultaneously studied premenopausal (n = 319) or
menopausal (n = 758) women. As can be seen, however, only a few
studies used population-based samples. In several cases demographic
data were unavailable—where it has been reported, BMI has been listed
and ranges from 21.7 [in the Pouilles study in which women with a
BMI > 24 were excluded (173)] to 24.7 in the Melbourne study.
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document that, in the 7 of 10 studies for
which control premenopausal and menopausal control data are available,
the perimenopausal rate of spinal BMD loss exceeded that of women in
the early menopause. To appropriately compare rates of change among
different groups, a Fisher’s combined P test (30) was used.
The rate of spinal BMD change in 267 perimenopausal women (from the
studies in which variance was available) was numerically greater than
in 695 menopausal controls (-1.83% per yr vs. -1.29% per
year; Fisher’s F = 34.16, df = 16, P =
0.0052). Similar evidence of increased perimenopausal bone loss in the femoral neck and the Ward’s area were also present in the prospective data (171, 172, 173, 174, 175, 176, 177). In the shortest study, which examined a 1-yr rate of change (175), the only bone site whose rate of change was significantly different in perimenopausal women compared with premenopausal controls was the Ward’s area of the proximal femur. Cross-sectional, age-stratified data published only as an abstract (178) also suggested that the Ward’s area (which contains a preponderance of trabecular bone) was most sensitive to change in menstruating women in their forties. Therefore, in summary of these various studies, the rate of spinal (and sometimes femoral) bone loss in the perimenopause exceeds the rate in early menopause as well as in the premenopausal years (which would be expected).
These data are surprising because bone loss has long been equated with
low estradiol levels and with a lack of menstrual flow. As has been
documented (Tables 1 and 2), the perimenopausal period includes
times of erratic and normal or high, but not consistently low,
estradiol levels and of unpredictable, but not absent, menstruation
until what is eventually the final flow. Ovulation disturbances and
therefore low progesterone levels are also typical of the
perimenopause (15, 16, 84). It is postulated that in
perimenopausal, as in premenopausal, women (101, 158), lack of
consistent, normal ovulation is associated with accelerated bone loss.
Finally, the increased rate of bone loss in the perimenopause may
relate to elevated levels of cortisol secondary to major sleep
disruption, emotional stress, and the socio-cultural transition that is
the perimenopause in this culture (179).
3. Bone marker changes and the perimenopause. The physiology
of the perimenopausal increased rate of spinal bone loss (as depicted
in Table 4) should be revealed by the several cross-sectional or
prospective studies of changes in bone markers in the menopausal
transition (159, 167, 171, 172, 180, 181, 182, 183). These studies are
characterized by the use of a wide variety of bone resorption markers
beginning with hydroxyproline and calcium (Ca) excretions
corrected for creatinine to more specific excretions of Type I collagen
products such as pyridinolines, and N- and C-terminal cross-linked
telopeptides (NTx, CTx) both bound and free.
The largest population-based study to date, the Melbourne Women’s Midlife Health Study, although still only reporting cross-sectional data, showed that NTx, as a sensitive marker of bone resorption (184), increased by 24% during the perimenopause without the expected coupling-related increases in bone formation markers such as bone-specific alkaline phosphatase and human osteocalcin (159). These authors asserted that "bone loss occurs before a decrease in (FP) serum sex hormone concentrations" and that NTx positively correlated with gonadotropin levels (159).
4. Quantitative bone ultrasound studies in the perimenopause. Two studies of quantitative ultrasound transmission through bone in perimenopausal women have been published. The first, from Hyogo, Japan, used transmission ultrasound through the patella in a convenience sample of 160 women ages 20 to 80 (185). In 19 perimenopausal women, the apparent velocity of ultrasound through bone was significantly faster than in the 28 menopausal women (P < 0.02) although the two groups did not differ in age nor in BMD by DXA (185). The second perimenopausal ultrasound study used the calcaneal broadband ultrasound attenuation (BUA) as measured by the Walker-Sonix instrument in 1000 consecutive consenting women ages 45–49 in the Aberdeen Osteoporosis Screening Study (186). Because DXA measurements of the spine and femur were available for correlation, as were assessments of height, weight, and menopausal status, ultrasound could be tested for its sensitivity and specificity as a screening tool. It was judged that BUA was a poor predictor of either spine or hip BMD with only 44% of women with spine BMD in the lowest quartile having the lowest quartile for BUA (186). Subsequently, both fracture and falling prediction publications have come from the Aberdeen Osteoporosis Screening Study (152, 187). It would be of great importance to determine from prospective data the sensitivity and specificity of ultrasound in predicting fractures in perimenopausal women.
Some evidence suggests that ultrasound reflects the architectural and
structural characteristics of bone. That would be preferable to the
purely mineral determinations obtained with DXA or other bone density
measures. If rates of bone loss are accelerated during the last
perimenopausal years, as a consequence of high bone resorption without
increased formation, trabecular integrity may be breached (188). If
ultrasound is able to detect these microarchitectural changes, it may
provide a sensitive predictor of fracture risk in the perimenopause.
The Japanese data suggest that this may be the case (185). Calcaneal
ultrasound using a portable "dry" system (Concordant, International
Medical Research, Ottawa, Ottawa, Ontario, Canada) is currently
being obtained in a large population-based prospective study of men and
women 25 to 80 yr of age in the Canadian Multicentre Osteoporosis Study
(CaMOS) (189, 190). Women and men ages 40 to 60 at baseline are
scheduled for a 3.0-yr prospective study in which ultrasound as well as
BMD will be repeated. The yearly surveillance for fractures and the
large number of likely perimenopausal women studied (1500) should
allow an assessment of the role of ultrasound in identifying those
women at highest risk for fracture.
5. Falling and fractures in the perimenopause. Two prospective studies of fracture and falling in perimenopausal women ages 45–49 have been published in women from the Aberdeen, Scotland Osteoporosis Screening Study (152, 187). In addition, several papers reporting cross-sectional and retrospective fracture data from the ongoing Kuopio Osteoporosis Screening and Prevention Study have recently been published (46, 162, 163, 164). The rate of fracture in perimenopausal women (designated as "premenopausal" by the authors) with a mean age of 50 was 7.65 per 1000 person years, while in the menopausal women it was 17.4 per 1000 person years. In recalling any fractures since age 15, 17.7% of women reported experiencing at least one with the most frequent sites being wrist and ankle. The vast majority of fractures occurred during falls. In a bivariate analysis, menopause was associated with an increased number of fractures, and in a multivariate analysis parity decreased, and menopause increased, the risk for fractures (46).
Both studies show that perimenopausal fractures are more prevalent, a result that had been expected. The 2-yr incidence of fractures in 1857 women was 44 in the Scotland study (187). The odds ratio for a fracture was 4.55 (confidence interval, 1.5–13.50) if the spine DXA was in the lowest quartile (P < 0.01) (187). Also, perimenopausal women were more likely to fall than were pre- or postmenopausal women (152). Past fractures were also predicted by low spinal or femoral BMD in perimenopausal women (46, 164). The fracture incidence (retrospectively determined over the preceding 10 yr and verified by medical reports) was significantly less in premenopausal women than in menopausal women (7.65 vs. 17.4 per 1000 person years) (46). One difficulty with both of these studies, however, is that they have not carefully separated the menstrual cycle characteristics of the participants so it is difficult to know which are truly pre-, peri-, or menopausal (46, 152, 162, 163, 164, 187). It is also important, although these are well designed epidemiological studies, that the major emphasis be placed on the prospective data and an even and unbiased assessment of fractures across the populations (191).
In summary, increasing numbers of women have been enrolled in population-based prospective studies of bone change, risk factors, and fracture incidence during the perimenopause. The present data indicate that the most rapid rate of spinal bone loss occurs before menopause during the years of the late perimenopause. This bone loss appears to be associated with increased bone turnover without the expected increase in bone formation markers and to be accompanied by both an increased risk for fractures and perhaps an increased risk for falling. Many variables including hereditary ones (maternal hip fracture and hip axis length), life-style (exercise, calcium intake, and cigarette, caffeine, or alcohol abuse) menstrual cycle (estradiol levels, changing estradiol levels, ovulation prevalence and luteal phase length, and cycle intervals) and morphometric variables (muscularity, body fat, and body weight) may be cofactors in the bone loss in the perimenopausal period. Prospective studies will be needed to document the subtle relationships about which only speculation is currently possible.
D. The endocrinology of perimenopausal psychosocial and emotional
experiences
The perimenopausal period is known to be a complex sociocultural
as well as a hormonal event (41, 72, 179). Part of the stress reported
by Western women is clearly culture specific (17). However, the end of
predictable menstruation, as occurs during the perimenopause, may be
important to a woman simply because it is a change, no
matter how aging and the end of reproductive life are viewed by that
woman and by her culture (192). Whether or not the adjustment to this
change causes emotional symptoms and help-seeking or illness behaviors
will depend on that woman’s own characteristics and the meanings
attached to menopause in her culture.
As a review of endocrinology, it is appropriate to ask whether there
are any hormonal links between the reported emotional experiences of
perimenopausal women and the erratic and often high estrogen levels of
the menopausal transition. Rather than equating affective symptoms with
psychopathology, recent evidence suggests that increases in stress
hormones (and probably symptoms that are stress related) are
physiologically linked with high estrogen levels. A double-blind
placebo-controlled study of 100 µg transdermal estradiol in young men
documented that the estradiol-treated men experienced enhanced
pituitary, adrenal, and sympathetic responses before, during, and after
a standardized psychosocial stress test (193). All of the young men
(who were asked to speak and do arithmetic in front of a group) had
increases in ACTH, cortisol, and norepinephrine levels as well as heart
rates. However, as shown in Fig. 9, men
who had been exposed to transdermal estradiol for 24–48 h before the
test had significantly greater stress-related increases in ACTH and
cortisol levels and showed a greater area under the norepinephrine
curve. They also had an increased but nonsignificantly greater heart
rate compared with those in the placebo group (193).
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In support of a causal relationship between high estradiol levels and women’s perimenopausal concerns are the similarity to those experienced by teenagers (55) and by women with the premenstrual syndrome (148). Ballinger et al. (65) reported that women who had abnormal scores on psychometric tests early after menopause had higher estradiol levels than those with lower scores (65). In prospective, physiological studies of women reporting severe PMS, estrogen levels are correlated with the intensity of symptoms (148). A randomized, placebo-controlled menopause treatment study administering standard doses of conjugated equine estrogen (0.625 mg/day), which significantly improved sleep, also showed an estrogen-related increase in "inward directed hostility" (142). The irritability and mood swings reported by Gangar et al. (137) in women with VMS and implant-related high estradiol levels can also be attributed to the high estradiol exposure, rather than to menopause, per se.
Finally, given the associations of emotional symptoms with high estradiol levels, it is not surprising that cycling perimenopausal women whose estrogen levels are at least intermittently extremely high (31, 34, 104) would experience unwanted emotional symptoms. The term "mood swings" used commonly by women may be literally true and linked to wide fluctuations in estrogen levels. Thus the perimenopause and its resulting loss of fertility and social status (179) are coupled with erratic and high estrogen levels which, in addition to causing breast tenderness, fluid retention, and troublesome menstrual cycle bleeding, also increase the physiological responses to stress (193).
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X. Summary and Necessary Research |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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A hypothesis to explain the high estradiol levels, elevated FSH, and inconsistent ovulation postulates that lower inhibin levels (especially in the premenstrual portion of an anovulatory cycle) allow an increase in the early FP FSH level. This high FSH, in turn, stimulates a larger than normal number of ovarian follicles, and each stimulated follicle produces more estradiol. The resulting prolonged high or erratic estradiol levels, coupled with ovulation disturbances including anovulation, probably explain many of the morbidities associated with this phase in a woman’s life: menorrhagia, breast tenderness, breast enlargement and fibrocystic breast problems, increased PMS, migraine headaches, increasing fibroid size, and risks for hysterectomy (± ovariectomy). This review proposes a new name for the signs and symptoms of high estrogen levels that some perimenopausal women experience: "Perimenopausal Endogenous Ovarian Hyperstimulation Syndrome." This name was chosen because, in hormone levels and pathogenesis, the perimenopausal state is similar to exogenous ovarian hyperstimulation therapy used for infertility treatment.
Paradoxically, despite elevated estradiol levels, the perimenopause is associated with a significant rate of spinal BMD loss. Early studies suggest that this loss exceeds that during the early menopausal period. Although this relationship had previously been documented (173), combined data from 10 studies provide increasing statistical evidence that significant, almost 2% per year, spinal bone loss occurs in the year before and after the last flow. These data require a reevaluation of the concept equating low estrogen levels with bone loss. Detailed prospective studies are needed that include measurements of bone changes in parallel with assessments of estradiol, progesterone, ovulation, menstrual cycles, weight (fat and muscle) changes, diet (calcium and Vitamin D), bone resorption and formation markers, and both the hormonal and the experiential aspects of stress.
The difficulty in defining the onset of the perimenopause will likely not be resolved until a longitudinal study of the perimenopausal transition is performed that includes women’s prospectively recorded experiences in parallel with their hormonal, cycle interval, and ovulation characteristics. Although studies of menstrual cycle intervals, hormone levels, ovulation frequency, and women’s symptoms and experiences have each been performed, no study combines all assessments. Such a study would need to extend over a long period of time to encompass a woman’s last premenopausal years and to continue until 12 months have elapsed without flow. From data currently published, it is not evident that this lack of information is being rectified by the several important ongoing prospective studies [Melbourne Women’s Midlife Health Study, the new National Institutes of Health-funded Study of Women Across the Nation (SWAN) (194)], or the osteoporosis studies in Kuopio, Finland, Hull, United Kingdom, or Malmo, Sweden).
The currently conducted Canadian Multicentre Osteoporosis Study (CaMOS) (189, 190), which has completed its recruitment of approximately 7,000 women ages 25 to over 80, in nine centres across Canada, has the potential to document the perimenopausal transition in a population-based sample of women. Serum samples have, so far, been obtained in only one center. However, CaMOS is now ready to begin a 3-yr interim data collection for women (and men) who were ages 40–60 at baseline. A 5.0-yr prospective assessment is planned for the entire cohort including about 3000 men. In addition to a detailed questionnaire (demographics, dietary, heredity, diet, reproductive history, quality of life) a Daily Perimenopause Diary has been developed and pilot tested (39). This instrument is similar to both the Menstrual Cycle Diary (195) (including flow characteristics, dysmenorrhea, and vaginal mucus) and to the Daily Menopause Diary (153) in documenting VMS by number and intensity occurring in both the night and day. Using data gathered with the Daily Perimenopause Diary, the CaMOS questionnaire, and bone assessments by DXA and ultrasound that are being documented, an improved understanding of the pathophysiology of perimenopausal bone loss is possible.
The perimenopause, in summary, is a unique hormonal transition. It is demonstrably more complex than it was previously understood to be; it is clearly not a time of "declining ovarian function" (11). Instead, dynamic perimenopausal ovaries produce erratic and high estradiol levels and rarely ovulate normally. These changes in hormonal levels manifest themselves in most aspects of a woman’s health and may present as conditions involving almost every system of her body. Because the perimenopause is a time of high social and medical morbidity and is associated with significant costs for the health care system, it is important that research be conducted in impeccably designed prospective observational studies.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractI. IntroductionII. Defining the PerimenopauseIII. Classic Studies of...IV. Prospective Epidemiological...V. Systematic Studies of...VI. Histological Studies of...VII. Physiological Studies of...VIII. Hypotheses to Explain...IX. Hormonal Physiology of...X. Summary and Necessary...References |
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