The Midlife Ovary

Menopause

Every woman who lives past midlife will experience menopause. This process might occur spontaneously or occur through surgery or medications that affect ovarian production.

Menopause us considered 'early' if it occurs before the age of 45 years and 'premature' if it occurs before the age of 40 years. 

Globally, the mean age of natural menopause is 48.8 years, with little geographic variation. 

A woman's age at menopause influences health outcomes in later life. Early menopause is associated with a reduced risk of breast cancer, but increased risks of premature osteoporosis, cardiovascular disease and premature death.

We are in the early stages of truly investigating the impact that ovarian aging and its resulting estrogen fluctuations and ultimately depletion has on female physiology and cellular processes both at the macro level and cellular level.

In the past menopause was largely looked at as a time when women may have hot flashes or vaginal dryness, and hormone support was largely viewed through the lens of breast cancer risk.

As we look forward to listening to women and conducting properly designed studies at the pre clinical and clinical level, we can truly begin to understand the impact that fluctuating sex hormone levels derived from ovarian function have on all aspects of female physiology and move beyond the past narrow views of midlife women’s health and physiology. 

Women who transition into and through menopause may experience mood issues, sleep disruption, sexual health issues, skin changes, headaches, cognitive decline, weight gain, metabolic syndrome with elevated blood glucose and cholesterol, levels, elevated risk for cardiovascular disease and bone loss. Menopause can indeed be referred to as a state of accelerated aging. Beyond these known adverse impacts that ovarian aging has on female physiology we need to also explore areas such as estrogen’s impact on inflammation and the immune system. as well as the importance that estrogen has on biologic cellular aging. We need to understand the mechanism of how estrogen impacts so much of female physiology.

In order to understand the impact and mechanisms of fluctuating estrogen and sex hormone levels on women’s physiology we need to truly understand when these changes in ovarian function occur. For example, It has been demonstrated in animal models that some changes of fluctuating estrogen cannot be undone with hormone support or nutrition.. It has also been noted that changes in ovarian function occur before cycle irregularity ensues. Indeed we know that fertility is impeded well before cycle irregularity. We need to look to and better define this `pre-clinical' period of ovarian senescence.

Ovarian Senescence

The female reproductive axis is unique in that it reaches a senescent state when other organs in the body are generally healthy.

The process of oocyte depletion, which begins before birth and ends with menopause, cannot be predicted precisely by chronological age, as its age of onset varies greatly between women. However, a clinical staging system exists, which makes it possible to identify where a woman is in her process of reproductive aging.

There are now well described symptoms that are linked to specific time points along the menopausal transition.

There are numerous metabolic and physiologic changes the occur as women age, and many of these processes are directly impacted by fluctuating and absolute estrogen and sex hormone levels. These estrogen and sex hormone levels are impacted by ovarian function, which naturally declines as a woman ages.

A woman’s chronologic age does not necessarily correlate with her reproductive age. 

Physiology of the Menopausal Transition

Clinical Studies

SWAN Study

  • The Study of Women's Health Across the Nation (SWAN) is a prospective cohort study of the natural menopausal transition that began in 1995. Participants include a representative, community-based sample of African-American, non-Hispanic Caucasian, Chinese, Hispanic, and Japanese women from multiple sites across the country.

  • 3306 women participated.

  • Eligibility criteria included age 42–52 years, an intact uterus and at least one ovary, no current exogenous hormone use, at least one menstrual period in the previous 3 months, and self-identification with one of the designated race/ethnic groups.

  • Important findings of this study:

  • A strong association with progression from the early to late menopausal transition and increased hot flashes, depressive symptoms and major depression.

  • Serial study of bone mineral density reflects a similar trajectory to symptoms in that the late menopausal transition is the stage at which bone demineralization becomes detectable.

  • Transient short term memory deficits associated with the late transition and amenable to hormone treatment, but only if it is given prior to the FMP.

  • A general trend towards increased total cholesterol, LDL, and apolipoprotein B associated with progress through the transition and, a loss of the protective effect of HDL as women become postmenopausal.

POAS

  • The longitudinal Penn Ovarian Aging Study (POAS) that took place from 1995 to 2007 included a cohort of 436 women identified by random-digit dialing in Philadelphia County, Pennsylvania.

  • The group included equal numbers of African American and white women (n=218) ages 35 to 47, all of whom had regular menstrual cycles for the previous three cycles, intact uterus, and at least one ovary.

  • The data were collected during twelve assessment periods, the first 6 at approximately 8- to 9-month intervals, and the remaining conducted annually with a 2-year gap between periods 10 and 11.

  • Blood was drawn for hormone level assessment during days 1–6 of the cycle in two consecutive menstrual cycles or 1 month apart in noncycling women, therefore a maximum of 24 hormone samples per participant.

  • Additional information collected included anthropometric measures, an interview questionnaire about overall health, and a self-assessment concerning perception of overall health.

  • Important findings of this study:

    • The POAS was the first study to determine associations between depression and hormonal changes during the transition to menopause. Using the cohort described above with 6 assessment periods over a 4 year interval and adjusting for known predictors of depression, they found an increased likelihood of depressive symptoms during the transition to menopause that decreased after menopause. These symptoms were almost twice as likely in the early transition phase and decreased with age. This was consistent with earlier SWAN findings that early perimenopausal women had higher rates of psychologic distress.

    • They later had similar findings with a 9 year longitudinal assessment of the same cohort: depressed mood was again found to be increased in the early menopausal transition and then significantly associated with progression through stages of the transition after adjusting for other risk factors. Again, incidence of depressed mood significantly decreased postmenopause.  Subsequent to these findings, others have demonstrated the effectiveness of exogenous estradiol (50–100mcg transdermally) in treating menopausal transition-related depression and depressive symptoms.

SMWHS

  • The Seattle Women's Health Study (SMWHS) studied the natural menopausal transition from 1990 to 2006 in a population-based cohort. The focus of these studies was symptoms, hormones, stress, and stages of the menopausal transition. 

  • Participants provided annual data by questionnaires, menstrual calendars, and health diaries; in 1996 a subset began providing 3-day monthly diary data as well as first morning voided urine specimens 8–12 times per year for endocrine assays. This went through 2000 and then was quarterly from 2001 to 2005. In 2000, based on data from 184 midlife women in their study, they classified women into three stages of the transition: early (flow and/or cycle length changes by at least 7 days), middle (irregularity without skipping), and late (skipped periods, with the cycle length exceeding 60 days).

  • Important findings of this study:

    • Three cardinal features were described for the menopausal transition cycles studied: a foreshortened follicular phase, elevation of FSH, and decreased luteal progesterone production.

    • These authors concluded that a relative lack of inhibin was responsible for the FSH rise in the absence of follicle failure. Most of these observations, based upon a cohort of only 8 women, have held up over time.

    • Weekly urinary sampling on relatively small cohorts of perimenopausal women have also been undertaken. . In these studies, intermittent excretion of very variable amounts of estrogen with similarly variable gonadotropin output were first described. Although women no longer appeared to excrete progesterone after the FMP, intermittent production of estrogen was observed.

Ovarian Dynamics are Changing Prior to Menstrual  Irregularities

  • A few investigators have examined follicle and oocyte dynamics in reproductive aging, which provide further information. One study has evaluated ovarian follicle development and sampled oocytes in reproductively aged women 40–45, all of whom reported regular menstrual cycles. These studies showed an accelerated follicular phase, with normal indices of follicle growth and a monotropic rise of FSH. The early follicular phase was marked by early estradiol elevation. 

  • Another study looked at the follicle dynamics of older women, who had already evidenced menstrual cycle abnormalities, and observed accelerated folliculogenesis with ovulation at a smaller follicle size than midreproductive aged control women. The accelerated follicular phase of reproductive aging women that had been attributed to a decrease in inhibin B—even before it could be measured—has been confirmed by multiple investigators. There may be further detrimental consequences to this monotropic rise in FSH on oocytes themselves, as the oocytes of reproductively aged women appear to have a disorganized meiotic spindle assembly.  Moreover, this loss of inhibin restraint may lead to `overshoot' of subsequent estrogen production, as large excursions of have been observed in conjunction with decreased progesterone metabolites in some studies of perimenopausal women.

  • Anovulatory cycles become more common during the menopausal transition. Evidence for abnormalities of hypothalamic-pituitary function in perimenopausal women have been found. These investigators described their findings as `estrogen insensitivity' inasmuch as failure of an LH surge was observed in a proportion of these cycles in which a completely normal duration and amount of estrogen metabolites was observed. In the 3-year longitudinal follow-up study of the anovulatory cycles, it was observed that initially anovulatory cycles did not necessarily represent a progression through the transition. Women do not appear to go from ovulatory to anovulatory cycles on a consistent basis as they traverse the menopause. In summary, menstrual cycle studies of the transition have confirmed that the early menopausal transition, when cyclicity is for the most part preserved, is characterized by highly variable patterns of gonadotropin and sex steroid output. As women progress through the transition, follicle failure appears to occur, and sex steroid production wanes dramatically but intermittently. Eventually, menstrual cycles cease, but evidence of estrogen production occurs for a period of 6 months to 2 years, after which time women achieve a steady state of hypergonadotropic hypogonadism. These findings lend further strength to the inhibin hypothesis, and indicate that the initial loss of restraint on FSH secretion leads to the early transition patterns. Once follicle numbers become insufficient to sustain folliculogenesis, uncompensated ovarian failure ensues and eventually becomes permanent. Until that time, ovarian function can be highly erratic and may well account for the symptomatology that so often accompanies the menopausal transition.

  • Although much progress has been made in the past several years in terms of better understanding hormonal correlates of reproductive aging and the menopausal transition, a hormonal marker that predicts the timing of the FMP (final menstrual period) has not yet been clearly defined. It has been concluded that AMH is the best marker to predict timing to FMP. One group has found an 88% probability of predicting which women would not reach menopause within the next 6 years based on an AMH threshold of 0.39 ng/mL.

  • SWAN marshaled its longitudinal data to determine a set of variables for predicting timing of the FMP. They found several factors to be associated with a shorter time to FMP: more advanced baseline age, greater number of vasomotor symptoms, and more variable or less frequent menses.  Baseline age was the strongest predictor; the effect was greater for non-white than for white ethnic groups. Current smokers were 68% more likely to have an earlier FMP than nonsmokers, including never or past smokers. Regular exercise and having a higher educational level were both associated with a longer time to FMP. Estradiol levels proved to have a complex relationship to the measured outcome: both low E2 and high E2 (>100 pg/mL) were associated with a shorter time to FMP. Women with a higher follicular phase FSH levels at baseline had a shorter time to FMP, as expected. They concluded that “in the most extreme cases, i.e., age 54, high estradiol level, current smoking, and high follicle-stimulating hormone level, the FMP can be estimated to within 1 year”.

Pre Clinical Period of Ovarian Senescence

  • The menopausal transition is an `irregularly irregular' period of midlife. It involves the acquisition of irreversible ovarian infertility in a woman, along with permanent cessation of menses. Changes in key ovarian markers that predict fertility are found well before any menstrual cycle irregularity is observed. This `pre-clinical' period of ovarian senescence is poorly defined and remains to be better characterized in non-infertile women. In between the first onset of cycle irregularity and the final menstrual period, a series of hormonal changes occur. The weight of the evidence suggests that these changes are saccadic and thus regular menstrual cycles may disappear, only to resume again for a period of months to years. The clinically observable transition from the early to the late menopausal transition seems to be associated with the biggest increase in symptoms associated with menopause: hot flashes, adverse mood, poor sleep and vaginal symptoms.

  • Many health and lifestyle related factors are associated with progress through the transition and menstrual cyclicity. Of these, BMI is one of the most overweening covariates. Women with higher BMI, although they do not have an earlier age at FMP, are much more likely to report perimenopausal hot flashes, to have lower—not higher—reproductive hormone secretion/excretion, to have heavier bleeding and to have more menstrual irregularity preceding their FMP. Interestingly, the relationship between BMI and hot flashes changes after menopause. After the FMP, the larger the BMI the lless likely a woman is to have hot flashes. It is likely that adipose-derived estrogenic steroids protect the postmenopausal obese woman, while other mechanisms subserve hot flashes when the same woman is younger and still producing endogenous estrogen. Current research has been able to describe health processes up to the FMP for many women; however, the question of whether or not long-term health outcomes can be predicted by a woman's traversal of the menopause awaits further follow-up.

Butler L and Santoro. Steroids 2011 Jun:76(7):627-635 The Reproductive Endocrinology of the Menopausal Transition