Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging

Seven Stages of the 2001 STRAW Staging System

STRAW divided the adult female life into three broad phases: reproductive, the menopausal transition, and postmenopause. These three phases included a total of seven stages centered on the FMP (Stage 0).^1-4 The reproductive phase was divided into Stages −5, −4, and −3 corresponding to early, peak, and late, respectively. The menopausal transition phase consisted of Stage −2 (early) and Stage −1 (late), and the postmenopause phase contained Stages +1 (early) and +2 (late). Stage −3 was characterized by regular menstrual cycles and increasing levels of FSH. Stage −2 was characterized by variability in menstrual cycle length and increased levels of FSH. Stage −1 was characterized by onset of skipped cycles or amenorrhea of at least 60 days and continued elevation of FSH.

The ReSTAGE Collaboration

The ReSTAGE Collaboration subsequently conducted empirical analyses to assess the validity and reliability of the 2001 STRAW’s original menstrual cycle criteria in four cohort studies—the TREMIN study, the Melbourne Women’s Midlife Health Project, the Seattle Midlife Women’s Health Study, and the Study of Women’s Health Across the Nation (SWAN). Findings supported STRAW’s recommendations, provided more precise specification of menstrual criteria for early and late transition, and recommended a quantitative cutpoint for FSH levels characteristic of the late transition.^19-22

Generalizability

A limitation of the original STRAW was its recommendation, based on the available evidence, that the staging system only be applied to healthy women. STRAW explicitly recommended against applying the criteria to seven subgroups of women,^1-4 including smokers (19% of US women aged 45-64 y²³), women with a body mass index (BMI) greater than 30 kg/m² (38% of US women²⁴), and women who had undergone hysterectomy (35% of US women²⁵). Women engaged in heavy aerobic exercise and women with chronic menstrual cycle irregularities, uterine abnormalities or ovarian abnormalities, or significant illness such as cancer were also excluded. Another limitation of the 2001 STRAW was the lack of insight regarding the applicability of the staging system in diverse populations. In 2001, few data were available from studies of multiethnic or diverse socioeconomic populations. Recent data from multiethnic cohorts now permit the assessment of generalizability,^17,22,26-33 although data from low-resource countries remain quite limited.^34,35

STRAW had a sustained influence on research in the field, prompting the assessment of trajectories of change in endocrine levels and biomarkers of ovarian senescence as well as the evaluation of how these trajectories vary by body size, smoking, ethnicity, and other factors.^26-33,36-55 Ten years later, the understanding of ovarian aging and its endocrine and clinical correlates has advanced considerably, providing a more nuanced and comprehensive understanding of the critical junctures that occur during reproductive aging before and after the FMP. For example, Fig. 1 illustrates changes in mean FSH and estradiol concentrations in relation to time before and after the FMP in the SWAN cohort.²² The role of AMH and inhibin-B as markers of declining fertility and ovarian aging is more clearly understood, as are the relationships among patterns of decline in AMH, inhibin-B, AFC, and primordial follicle counts.26,37,38,42,43,45-48,51,53,56-58 The goal of the STRAW + 10 was to review significant advances in the field and develop recommendations for updating the original STRAW criteria.

Late reproductive stage (Stage −3)

The late reproductive stage marks the time when fecundability begins to decline and during which a woman may begin to notice changes in her menstrual cycles. Given that critical endocrine parameters begin to change before overt changes in menstrual cyclicity and that these endocrine changes are important to fertility assessments, STRAW + 10 recommended that the late reproductive stage be subdivided into two substages (−3b and −3a). In Stage −3b, menstrual cycles remain regular without change in length or early follicular phase FSH levels; however, AMH and antral follicle counts are low. Most^53,62 but not all⁶³ studies suggest that inhibin-B is also low. In Stage −3a, subtle changes in menstrual cycle characteristics, specifically shorter cycles,^64-66 begin. Early follicular phase (cycle days 2-5) FSH increases and becomes more variable, with the other three markers of ovarian aging being low. The lack of standardized AMH assays prevented the development of quantitative recommendations for this biomarker.

Early menopausal transition (Stage −2)

Early menopausal transition is marked by increased variability in menstrual cycle length, defined as a persistent difference of 7 days or more in the length of consecutive cycles. Persistence is defined as recurrence within 10 cycles of the first variable length cycle. Cycles in the early menopausal transition are also characterized by elevated but variable early follicular phase FSH levels and low AMH levels and AFC.

Late menopausal transition (Stage −1)

The late menopausal transition is marked by the occurrence of amenorrhea of 60 days or longer. Menstrual cycles in the late menopausal transition are characterized by increased variability in cycle length, extreme fluctuations in hormonal levels, and increased prevalence of anovulation. In this stage, FSH levels are sometimes elevated into the menopausal range and sometimes within the range characteristic of the earlier reproductive years, particularly in association with high estradiol levels. The development of international standards and the availability of substantive population-based data now permit the definition of quantitative FSH criteria, with levels greater than 25 IU/L in a random blood draw characteristic of being in late transition, based on current international pituitary standards that approximate more than 40 IU/L in the previously used urine-based gonadotropin standards.^67-69 Empirical analyses should be undertaken to confirm this recommendation, and researchers and clinicians should carefully evaluate the appropriate FSH value, depending on the assay they use. Based on studies of menstrual calendars and on changes in FSH and estradiol, this stage is estimated to last, on average, 1 to 3 years. Symptoms, most notably vasomotor symptoms, are likely to occur during this stage.

Early postmenopause (Stage +1a, +1b, +1c)

New data on the trajectories of change in mean levels of FSH and estradiol22,30,32,40,41,52,54,55 indicate that FSH continues to increase and that estradiol continues to decrease until approximately 2 years after the FMP, after which the levels of each of these hormones stabilize. Therefore, STRAW + 10 recommended that early postmenopause be subdivided into three substages (+1a, +1b, and +1c).

Stages +1a and +1b each last 1 year and end at the time point at which FSH and estradiol levels stabilize. Stage +1a marks the end of the 12-month period of amenorrhea required to define that the FMP has occurred. It corresponds to the end of “perimenopause,” a term still in common usage that means the time around menopause and begins at Stage −2 and ends 12 months after the FMP. Stage +1b includes the remainder of the period of rapid changes in mean FSH and estradiol levels. Based on studies of hormonal changes, Stages +1a and +1b together are estimated to last, on average, 2 years. Symptoms, most notably vasomotor symptoms, are most likely to occur during this stage.

Stage +1c represents the period of stabilization of high FSH levels and low estradiol values that is estimated to last 3 to 6 years; therefore, the entire early postmenopause lasts approximately 5 to 8 years. Further specification of this stage will require additional studies of trajectories of change in FSH and estradiol from the FMP through the late postmenopause.

Late postmenopause (Stage +2)

Stage +2 represents the period in which further changes in reproductive endocrine function are more limited and processes of somatic aging become of paramount concern. Symptoms of vaginal dryness and urogenital atrophy become increasingly prevalent at this time.^7,70-72 However, many years after menopause, it has been observed that there may be a further decline in levels of FSH in very old persons^73,74; future studies will be needed to determine whether an additional stage is warranted near the end of life.

Inclusiveness of the STRAW + 10 criteria

Evidence now supports the applicability of the STRAW + 10 recommendations for most women. Epidemiologic and clinical studies have documented that the process of reproductive aging, although influenced by demographic factors, lifestyle, and BMI, follows a robust and predictable pattern.^{22,26,27,32,33,41,75} Although smoking and BMI influence hormonal levels and the timing of transition, these factors do not alter the trajectory of change in bleeding patterns or hormonal levels with reproductive aging. Therefore, the STRAW + 10 staging system is applicable to women regardless of age, demographic, BMI, or lifestyle characteristics.

The STRAW + 10 model does not use age as a criterion for determining reproductive staging. However, women meeting the criteria for POI/premature ovarian failure (age <40 y with 4 mo of amenorrhea and two serum FSH levels [at least a month apart] in the menopausal range) do not easily fit into this model. The course of reproductive aging in women with POI/premature ovarian failure seems to be considerably more variable than that of women with normal reproductive aging. Not only are there several potential etiologies but also a substantial proportion of women have spontaneous resumption of menstrual function once the diagnosis has been confirmed, including ovulation and successful spontaneous pregnancy.⁷⁶ Additional research is needed to better document the process of ovarian aging in these women and whether the course of ovarian aging differs by etiology of POI. Studies of reproductive aging in POI are considered to be a research priority.

Hysterectomy and endometrial ablation

Women who have undergone hysterectomy or endometrial ablation cannot be staged by menstrual bleeding criteria.⁷⁷ Reproductive stage in these women can only be assessed using the supportive criteria, that is, the endocrine markers of ovarian aging. It is recommended that clinicians and researchers wait at least 3 months after surgery to assess endocrine status, given emerging evidence that pelvic surgeries may transiently raise FSH levels.^78-81 Further research on the nature and duration of alterations in biomarkers of ovarian aging secondary to pelvic surgery is warranted. In most cases, staging will be limited to the classification of whether such women are premenopausal or postmenopausal. A single sample for measurement of FSH and estradiol may be ambiguous or misleading, and at least one repeated measurement is often required.

Polycystic ovarian syndrome

Women with PCOS frequently experience oligomenorrhea that is not attributable to ovarian aging. Therefore, the current menstrual cycle criteria used to stage reproductive aging are not applicable to this population. Understanding of the changes occurring before menopause in this group of women is limited. Some data suggest that women with PCOS may experience a later age at menopause,^{48, 82} as well as more regular cycles with reproductive aging^83,84; however, the experience of reproductive aging in PCOS is not well understood. Similarly, menstrual cycle criteria are not applicable in women with hypothalamic amenorrhea. Studies of reproductive aging in these subgroups of women are considered to be a research priority.

Women with chronic illness undergoing chemotherapy

Many medications and loss of body fat can cause amenorrhea, which can make the staging of the menopausal transition difficult. Several important subgroups remain difficult to stage yet deserve attention in any staging system.^38,56,85-88 Depending on the age at treatment and cancer treatment type, a significant proportion of women who undergo cancer treatment, particularly with alkylating agents, may experience transient increases in FSH and decreases in AMH and AFC with return of bleeding even after 12 months or more of amenorrhea.^38,56,87-89 In these women, resumption of menstrual cycles may not indicate a return of normal menstrual function. Women undergoing treatment with tamoxifen pose an additional problem because FSH and estradiol levels may be altered by this treatment and may therefore be misleading and cause abnormal bleeding.⁹⁰ Women with chronic illnesses such as HIV–AIDS also pose a problem in the staging of reproductive aging because of the lack of reliability of bleeding patterns and hormonal markers.^85,86 Staging in these women will require assessment with menstrual cycle criteria, the supportive criteria using relevant biomarkers, and age to better characterize their ovarian function. Large prospective cohort studies are needed to better characterize the trajectories of ovarian aging in these populations.