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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0066
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3060-3067
Copyright © 2007 by The Endocrine Society

Endocrine Features of Menstrual Cycles in Middle and Late Reproductive Age and the Menopausal Transition Classified According to the Staging of Reproductive Aging Workshop (STRAW) Staging System

Georgina E. Hale, Xue Zhao, Claude L. Hughes, Henry G. Burger, David M. Robertson and Ian S. Fraser

Department of Obstetrics and Gynaecology (G.E.H., X.Z., I.S.F.), University of Sydney, New South Wales, Australia, 2006; RTI International (C.L.H.), Research Triangle Park, North Carolina 27709; and Prince Henry’s Institute (H.G.B., D.M.R.), Monash Medical Centre, Clayton, Victoria, Australia, 3168

Address all correspondence and requests for reprints to: Georgina E. Hale, M.D., Ph.D., QE II Building (DO2), University of Sydney, New South Wales, Australia, 2006. E-mail: ghale{at}med.usyd.edu.au.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Female reproductive aging based on changes in menstrual cycle length and frequency progresses through a number of stages as defined by the Stages of Reproductive Aging Workshop (STRAW) staging criteria.

Objective: This paper provides a comprehensive description of the endocrine features associated with the STRAW stages.

Design: Healthy women aged 21–35 and 45–55 yr submitted three blood samples a week over a single menstrual cycle. They were classified as mid-reproductive age (n = 21), late-reproductive age (n = 16), early menopause transition (n = 16), and late menopause transition (n = 23).

Results: There were nine, one, zero, and two anovulatory cycles identified in the late menopause transition, early menopause transition, late-reproductive age, and mid-reproductive age groups, respectively. Ovulatory cycle FSH, LH, and estradiol levels increased with progression of STRAW stage (P = 0.001, P < 0.01, and P < 0.05, respectively), and mean luteal phase serum progesterone decreased (P < 0.01). Early cycle (ovulatory and anovulatory) inhibin B decreased steadily across the STRAW stages (P < 0.01) and was largely undetectable during elongated ovulatory and anovulatory cycles in the menopause transition. Anti-Mullerian hormone decreased markedly (10- to 15-fold) and progressively across the STRAW stages (P < 0.01 and P < 0.001, respectively).

Conclusions: Progression through the STRAW stages is associated with elevations in serum FSH, LH, and estradiol and decreases in luteal phase progesterone. The marked fall in inhibin B and particularly anti-Mullerian hormone indicate that they may be useful in predicting STRAW stage but future analyses of early cycle measurements on larger cohorts are needed to draw predictive conclusions.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE HIGHLY VARIABLE and unpredictable nature of the endocrine changes during female reproductive aging, particularly during the menopause transition when women’s experiences become troublesome (1, 2), has attracted increasing interest among clinicians. Although traditionally it has been thought that both estradiol (E2) and progesterone (P) levels decline with progression through the menopause transition, detailed analyses of many of the early small endocrine studies suggest that E2 levels can increase rather than decrease toward the final menstrual period (3). Recent studies suggest that although P levels fall toward the final menstrual period (4), serum E2 levels do not (5, 6, 7) and that elevated E2 levels can occur throughout the menopause transition, particularly associated with elongated ovulatory cycles (7). A more thorough investigation of the steroid hormone changes before and during the menopause transition is warranted given the clinical relevance and potential cumulative risk of hormone-dependent cancers (8) and the complexity of symptoms. This investigation should include the measurement of gonadotropins (FSH and LH), inhibin A (INHA) inhibin B (INHB), and anti-Mullerian hormone (AMH) to generate hypotheses concerning the underlying mechanics of these changes and the use of consistent and standardized nomenclature, subject classification criteria, and sampling methods.

The first standardized classification guidelines for female reproductive aging were proposed at the Stages of Reproductive Aging Workshop (STRAW) in July 2001 (Fig. 1Go) (9). The stages were nominated using the final menstrual period as the reference point and were based on changes in menstrual cycle patterns and FSH levels. When the STRAW guidelines were proposed, FSH was considered to be the most suitable and readily available biomarker to indicate onset of late reproductive age, despite the limitations in its ability to predict stage of menopause transition or the final menstrual period (10). Although an early cycle FSH level of greater than 40 IU/liter is an independent marker of the late menopause transition, it is less predictive of the late transition than menstrual bleeding markers, such as amenorrhea for 60 or more days (11, 12). Other biomarkers such as INHB (13) and AMH (14) appear to change earlier in reproductive aging than FSH and may be more suitable in predicting reproductive stage. AMH in particular remains relatively unchanged throughout the menstrual cycle (15), is more predictive of the number of early antral follicles than either FSH or INHB (16), and declines from about the age of 30 (17).


Figure 1
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  		FIG. 1. The seven STRAW staging criteria adapted from Soules et al. (9 ). Amen., Amenorrhea.

 
The aims of this present study were to provide a detailed description of menstrual cycle endocrinology in women classified according to the STRAW staging criteria by measuring a series of endocrine biomarkers (FSH, LH, E2, P, INHA, INHB, and AMH) at regular intervals across a single cycle. To achieve this objective, serum hormone levels were measured three times a week in a cohort of healthy women classified as mid-reproductive age, late-reproductive age, and the menopause transition according to the STRAW criteria (9). Serum samples were collected throughout an entire menstrual cycle regardless of cycle length (up to a maximum of 90 d).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Methods and study subjects

This study was approved by the Ethics Committees (Institutional Review Boards) at the University of Sydney and Family Planning, New South Wales, and all women provided informed consent before participation in the study. Healthy women between the ages of 21 and 35 (n = 21) and 45 and 55 (n = 56) were recruited from community advertisements distributed by the Queen Elizabeth II Research Institute for Mothers and Infants at the University of Sydney. Exclusion criteria for all participants were abnormal prolactin levels or thyroid function, amenorrhea for 3 months or more, smoking within the previous 12 months, chronic illness, hormone therapy or oral contraceptive use within the previous 6 months, hysterectomy, previous uterine pathology, body mass index greater than 35, high level or competitive physical training, or recent (≥10%) weight loss. The younger women comprised a group of healthy mid-reproductive aged (MRA) controls with regular menstrual cycles. Menstrual cycles were defined as regular if they remained in the range of 23 and 35 d with variability of fewer than 7 d between the shortest and longest observed cycle and if there was no subjective change in regularity. The older women were categorized into STRAW stage 3, late-reproductive age (LRA) with regular menstrual cycles; STRAW stage 2, early menopause transition (EMT) with variable length cycles where consecutive cycle length differed by more than 7 d; and STRAW stage 1, late menopause transition (LMT) with at least one intermenstrual interval of 60 d or more regardless of the early cycle FSH levels.

Study design

Each volunteer provided a detailed menstrual diary for 3–6 months that included a daily first morning oral basal body temperature (BBT) measurement. After at least 1 month of diary recording, blood samples were taken three times a week (Mondays, Wednesdays, and Fridays) commencing from the start of one menses and continuing throughout the cycle (cycle 1) until 7–10 d into the subsequent cycle (cycle 2; Fig. 2Go). The frequency of blood testing was decreased to weekly after 4 wk if a luteal phase had not commenced (according to P levels). In these cases, the weekly blood sampling continued until subjective signs of ovulation or luteal activity (such as a BBT rise), after which time, the blood sampling was increased to three times a week until 7–10 d into cycle 2. Quantitative menstrual blood loss measurements were performed at the start and finish of the blood testing interval, and an endometrial biopsy was performed on the last day of blood testing in cycle 2. The results of these data along with the cycle 2 hormone data will be published elsewhere.


Figure 2
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  		FIG. 2. Categorization of blood samples using serum E2 from a MRA subject as a reference. Each point represents a single blood level taken throughout cycle 1 (ovulatory cycle) and part of cycle 2. In the four elongated LMT ovulatory cycles (>36 d), the days between the menstrual and beginning of the follicular phase in cycle 1 were nominated as the lag phase.

 
Blood samples were collected using a 10-ml syringe and 23-gauge needle (to avoid excessive bruising after repeated venipunctures) into a plain 10-ml red-top tube. The tubes were left to stand for at least 15 min at room temperature before being centrifuged at 3000 rpm for 10 min. Serum was removed and separated into several 1-ml aliquots. All of the aliquots were stored at –20 C to be assayed at a later date as a batch except when a P assay was required to ascertain the onset or otherwise of a luteal phase.

Assays

E2 was measured using a highly sensitive competitive RIA (Diasorin s.r.l. 13040; Saluggia, Italy) at the Westmead Children’s Hospital Endocrinology Laboratory. At 80 pmol/liter, the intraassay coefficient of variation (CV) was 3.5%, and at 40 pmol/liter, the interassay CV was 5.0%. The reference range for E2 during the early follicular, preovulatory, and luteal phases was quoted as 110–183, 550-1650, and 550–845 pmol/liter, respectively. P was measured using a standard competitive immunoassay kit by ADVIA Centaur (Bayer, Tarrytown, NY) at the Laboratories of Sydney Diagnostic Services. At 23 nmol/liter, the intraassay CV was 3.9% and the interassay CV was 3.7%. The reference range for luteal phase P was quoted as 13.0–75 nmol/liter.

FSH assays were performed using microparticle enzyme fluoroimmunoassay (Beckman Coulter Inc., Fullerton, CA). At FSH concentrations ranging from 8.6–55 IU/liter, the interassay CV was 4.3%, and at concentrations from 10–44 IU/liter, the intraassay CV was 3.5–4.3%. The analytical range was from 0.2–200 IU/liter. The reference ranges for the follicular, midcycle, and luteal phases were 3.9–10.3, 4.5–23, and 1.8–5.1 IU/liter, respectively, and for post menopause was 16.8–114 IU/liter. LH assays were performed using a time-Resolved fluoroimmunoassay (Delphia, Turku, Finland). At concentrations ranging from 3.6–50.8 IU/liter, the interassay CV was 3.1–4.2% and the intraassay CV was 2.1–2.4%. The analytical range was from 0.2–200 IU/liter. The reference ranges for the follicular, midcycle, and luteal phases were 1.6–9.3, 13.8–71.8, and 0.5–12.8 IU/liter, respectively, and for post menopause, it was 15–64 IU/liter.

INHA and INHB were assayed according to the methods of Groome et al. (18, 19), using a pretreatment boiling step in the presence of SDS and OBI kit reagents (Oxford Bio-Innovation Ltd., Oxford, UK). The samples were assayed using the kit INHA and INHB standards. The between-assay variation based on the repeated assay of a serum pool for INHA was 15.6% (n = 25) and for INHB 11.4% (n = 27). The levels of detection or sensitivity of the respective assays were 7.8 pg/ml for INHA and 12.5 pg/ml for INHB.

AMH ELISA kits were obtained from DSL-Beckman Coulter (Webster, TX). The between-assay variations based on the repeated assay of two serum pools were 6.6 and 8.3 ng/ml (n = 36), and the sensitivity was 0.017 ng/ml.

Categorization of ovulatory status, cycle phase, and illustrating group data

Cycle 1 was defined as ovulatory if two of the three following criteria were fulfilled: 1) a rise in P levels to at least 16 nmol/liter during the last 10 d of the cycle, 2) evidence of a typical luteal phase rise and fall in P levels in the second half of the cycle, with the fall in levels being followed or accompanied by the onset of a menstrual period, and 3) BBT data least-mean-squares analysis (20) was indicative of an ovulatory cycle. Because the blood sampling interval could lead to an LH peak being missed, the day of ovulation and onset of the luteal phase were estimated using the LH peak and P levels and, where necessary, graphical representations of individual cycle data. The day of ovulation was nominated as the day before the onset of the increase in P, which itself was nominated as the onset of the luteal phase. The menstrual phase was nominated as those days upon which the study subjects had recorded menstrual flow on their daily records (up to a maximum of 8 d). The follicular phase was nominated as those days between the menstrual and luteal phases, including the estimated day of ovulation (Fig. 2Go). In four LMT subjects in which the ovulatory cycle length was 36 d or more, the period of days after the menstrual phase and the start of the 15-d interval before ovulation (follicular phase) was referred to as the lag phase. A cycle was defined as anovulatory if there was no evidence of a rise in P and the BBT data could not detect a luteal phase.

Statistical analysis

All data were entered into and analyzed by SPSS (version for Windows, release 11.5; SPSS Australia Pty. Ltd., North Sydney, Australia). Residuals calculation indicated a nonnormal distribution for all data, including means from each of the three phases (menstrual, follicular, and luteal) of ovulatory cycles. Data were log10 transformed, and general linear model univariate analyses applied for all subject-group and pair-wise comparisons. The Pearson coefficient was used for all correlations between all log10-transformed data except when calculating correlations according to subject group (categorical data), when the Spearman coefficient was used. Predictability of early cycle hormone/biomarker levels, regression analyses were performed on four groups using the MRA (STRAW stage 4) as the reference group and on the three older age groups (STRAW stages 1–3) using the LRA subjects as the reference group.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Participants

Seventy-seven of the 98 subjects interviewed were enrolled (MRA, n = 21; LRA, n = 16; EMT, n = 17; LMT, n = 23) and commenced the blood testing interval, and only one subject (in the MRA group) dropped out (due to time constraints). The baseline characteristics of the 77 study subjects are presented in Table 1Go.


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  		TABLE 1. Age, body mass index, and demographic data in the four subject groups

 
There were two, one, and nine anovulatory cycles (cycle 1) captured in the MRA (9%), EMT (6%), and LMT (39%) groups, respectively, and in one of the LMT subjects, there were no further menstrual period after the blood testing interval (cycle was classified as indeterminate). The two MRA anovulatory cycles were 24 and 60 d long, and mean length ± SD in the nine LMT anovulatory cycles was 80.1 ± 55 d.

Ovulatory cycle length and characteristics of the lag phase

Ovulatory cycle length was shorter in the LRA group than the MRA and EMT groups (Fig. 3Go) and was longer than 36 d in four LMT subjects (41, 49, 55, and 68 d long). Mean follicular phase length in cycle 1 was shorter in the LRA subjects (12.9 ± 2.8 d) than the MRA subjects (15.8 ± 3.5 d; P = 0.05), but luteal phase length was similar in all four groups. There were, however, six ovulatory cycles (37%) with a luteal phase length of less than 11 d in the LRA group.


Figure 3
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  		FIG. 3. Box plots of cycle length (cycle 1) in the ovulatory (gray boxes) and anovulatory (hatched boxes) cycles demonstrating median, 25th and 75th percentiles, 10th and 90th percentiles (error bars), and outliers ({circ}). The number of subjects in each group is shown on the top of the boxes. There were no anovulatory cycles in the LRA subject group, and the 216-d LMT anovulatory cycle is not shown. *, Ovulatory cycle length was shorter in the LRA group compared with the MRA group (P < 0.001) and the LMT group (P < 0.04).

 
Mean E2 and INHA were lower and mean FSH and LH higher during the lag phase (Fig. 2Go) in the four LMT ovulatory cycles with a length of more than 26 d, compared with the menstrual phase of normal-length LMT ovulatory cycles (E2, 230 ± 250 vs. 344 ± 241 pmol/liter, P = 0.002; INHA, 12.8 ± 10 vs. 40.6 ± 35 pg/ml, P = 0.05; LH, 24.5 ± 18 vs. 9.3 ± 7.2 IU/liter, P < 0.001; FSH, 46.8 ± 32 vs. 11.7 ± 7.5 IU/liter, P = 0.03, respectively). INHB was largely undetectable (<12.5 pg/ml) during the lag phase of the four elongated LMT ovulatory cycles.

Ovulatory cycles: early cycle (menstrual phase) hormone levels

Early cycle E2 in the ovulatory cycles increased across the four groups (P = 0.001) and was significantly higher in the LMT subjects than the EMT subjects (P = 0.05; left column in Fig. 4Go). FSH was significantly higher in the LRA, EMT, and LMT groups (P = 0.003, P < 0.001, and P 0.01, respectively) than in the MRA group. INHA was higher in the LMT subjects than the MRA (P = 0.007) and LRA subjects (P = 0.005). INHB and AMH decreased progressively across the four subject groups, and there were significant differences between all groups except the LRA and EMT groups for INHB and between the EMT and LMT groups for AMH. Early cycle FSH, INHB, and AMH levels (data from both ovulatory and anovulatory cycles included) are illustrated in Fig. 5Go. None were predictive of STRAW stage.


Figure 4
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  		FIG. 4. Box plots of mean hormone levels in the three phases of the ovulatory cycles in each of the four STRAW groups demonstrating median, 25th and 75th percentiles, 10th and 90th percentiles (error bars), and outliers (°). Separate box plots of the AMH levels in the LRA, EMT, and LMT groups are shown in the bottom three graphs.

 

Figure 5
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  		FIG. 5. Scatter plots of mean early cycle (menstrual phase) FSH, INHB, and AMH in all cycles (ovulatory and anovulatory); the dotted line indicates the 10.3 IU/liter upper limit of the reference range for early cycle FSH.

 
Ovulatory cycles: follicular phase hormone levels

Follicular phase E2 was similar across the four STRAW groups, but FSH increased significantly with differences between all the groups (P < 0.001) except the EMT and LMT groups (Fig. 4Go). Follicular phase LH was higher in the LMT subjects than the MRA (P = 0.001) and LRA (P = 0.001) subjects (middle column in Fig. 4Go). Follicular phase INHB and AMH decreased progressively across the four subject groups (Fig. 4Go) with significant differences between all groups except between the MRA and LRA groups and the EMT and LMT groups for INHB and between the EMT and LMT groups for AMH.

Ovulatory cycles: luteal phase hormone levels

Luteal phase serum P decreased progressively across the four subject groups (P = 0.01) and in the pair-wise comparison was lower in the LMT subjects than the MRA subjects (P = 0.02; Table 2Go and right column in Fig. 4Go). Luteal phase E2 was significantly lower in the LRA subjects than in the EMT (P = 0.02) and LMT subjects (P = 0.002). Luteal phase LH was higher in the LMT and EMT groups than the LRA group (P = 0.03 and 0.001, respectively; Fig. 4Go), and FSH was significantly lower in the MRA than in the LRA (P = 0.01), EMT (P < 0.001), and LMT (P < 0.001) groups and higher in the EMT than LRA groups (P = 0.04). Luteal phase AMH decreased progressively across the four subject groups (Fig. 4Go) with significant differences between all groups.


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  		TABLE 2. Mean ovulatory cycle hormone levels in the four subject groups

 
Anovulatory cycles

In the LMT anovulatory cycles, the E2, INHA, INHB, and AMH levels was lower (E2, 166 ± 168 vs. 320 ± 289 pmol/liter; INHA, 12.1 ± 8.8 vs. 35.2 ± 34 pg/ml; INHB, 14.1 ± 11.7 vs. 26.7 ± 21.6 pg/ml; AMH, 0.018 ± 0.006 vs. 0.056 ± 0.07 ng/ml) and FSH and LH levels higher (FSH, 43.8 ± 22 vs. 14.6 ± 13.7 IU/liter; LH, 24.5 ± 18.1 vs. 10.6 ± 9.8 IU/liter) than in the LMT ovulatory cycles.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study is the first of its kind to attempt to prospectively correlate changes in a range of hormonal markers with the STRAW stages of reproductive aging. The results demonstrates that STRAW stages 2 (EMT) and 1 (LMT) are associated with elevated gonadotropin levels, erratic and often elevated levels of E2, and decreased levels of luteal phase P. STRAW stage 3 (LRA) was associated with a significantly elevated early cycle FSH but no detectable change in E2 or luteal phase P compared with STRAW stages 4 and 5 (MRA). Although several earlier endocrine studies demonstrated elevated E2 levels during reproductive aging (3, 21, 22), this study suggests that elevations in E2 are largely confined to the menstrual and luteal phases of ovulatory cycles during STRAW stages 2 and 1. Accelerated follicular growth (23) and earlier initiation of follicle development (24) have been postulated as causing early elevations in E2, both of which may result from elevations in early cycle FSH, which in turn may be a result of decreased INHB (25). Although serum data from the large multicenter Study of Women’s Health Across the Nation (SWAN) suggest that there is a steep decline in early cycle E2 levels toward the end of reproductive life, this finding may have been largely a reflection of the steep increase in incidence of anovulatory cycles and long lag phases during this period (26).

Several studies have observed decreased luteal phase P levels or pregnanediol 3-glucuronide (PdG) excretion in association with the onset of irregular cycles (6, 7, 27, 28, 29, 30, 31) and in the British Fertility Recognition and Enabling Early Detection of Menopause (FREEDOM) study, a decrease in PdG excretion was found in association with elevated early cycle FSH excretion, increased luteal phase estrone excretion, and increased lag phase length (6). Although these data suggest that elevated follicular phase FSH may adversely affect the ability of the granulosa cells to luteinize or the corpus luteum to secrete P (32), there was no clear inverse relationship between FSH and PdG excretion found in this study (7). The FREEDOM study, however, did find an inverse relationship between LH and PdG excretion, which may indicate an age-related fall in LH responsiveness at the granulosa cell level. A defect in the luteinization process with increasing reproductive age has also not been excluded.

INHB levels decreased progressively across the four STRAW stages, a finding that is consistent with previous study observations (13, 21, 33). INHB, which is produced by antral follicles, has been shown to decline with increasing reproductive age (13, 34) and to be a reasonably consistent marker of ovarian reserve (13). Early cycle INHB has been suggested as a promising biomarker because it falls consistently across all reproductive stages and appears less dependent on the ovulatory status of the cycle being sampled (35). Its application in stages 2 and 1 may be limited, however, by the assay’s lower limit of detection (12.8 pg/ml).

AMH levels decreased markedly and progressively across the four STRAW stages. This finding is consistent with those from a study of early cycle serum AMH levels in 238 women aged 18–46 yr, where AMH levels remained relatively stable until age 30 and declined steeply thereafter (14). AMH is secreted by the granulosa cells of secondary and preantral follicles and of antral follicles up to the size of about 5 mm (36) and appears to be more highly predictive of early antral follicle count than INHB (16). Early cycle AMH has also been shown to have superior cycle-to-cycle reproducibility compared with E2, INHB, and FSH (37). A thorough evaluation of the ability of AMH measurements to predict STRAW stage in a large cohort would be warranted given it may be superior to both FSH and INHB in this regard, especially if AMH assays remain equally sensitive at low serum concentrations.

Despite the significant changes in FSH, INHB, and particularly AMH across the STRAW groups in this study, there was a large amount of overlap in levels between STRAW stages (Fig. 5Go). As a consequence of this and the relatively small subject numbers, none of the markers were found to be predictive of STRAW stage. Larger cohorts, such as those in the SWAN and FREEDOM studies may be required to fully assess the ability of early cycle INHB, AMH, or a combination of the two hormones to predict STRAW stage. Analyses of early follicular phase serum samples from the SWAN study suggest that although a single FSH measure is an independent marker of the late menopause transition, it is less predictive than menstrual bleeding criteria such as a 60-d intermenstrual interval (11). Additional analyses on early cycle INHB or AMH measurements from this study are awaited.

The menstrual criteria in the STRAW system have been more fully evaluated with respect to their ability to predict reproductive stage. Using data from the TREMIN, Melbourne Women’s Midlife Health Project, Seattle Midlife Women’s Health Study, and the SWAN (12) found that a skipped segment, a 10-segment running range greater than 42 d, a 60-d intermenstrual interval, and a 90-d intermenstrual interval were all equally predictive of the final menstrual period but that the first three criteria were more common and occurred 1–2 yr earlier than the 90-d interval. On the basis of their findings, the investigators concluded that the 60-d interval was a suitable criterion for the onset of the later menopause transition as in the STRAW proposals. In another analysis of the TREMIN data, Lisbeth et al. found that a 60-d interval was a desirable marker for entry into the late transition stage because of its reliability, proximity to the final menstrual period, and ease of calculation (38). They, however, found no menstrual criteria suitable for reliably predicting the early menopause transition.

This study has provided a novel snapshot of the changes in hormone levels, including INHB and AMH, across a single menstrual cycle in women classified according to the STRAW criteria; however, there was insufficient power to adequately assess the ability of FSH, INHB, or AMH to predict STRAW stage. In addition, the fact that serum samples were taken throughout a single cycle, the within-subject variability in subsequent menstrual cycles could not be taken into account when assessing the differences between the STRAW stages. A thorough presentation of the individual within-cycle secretion patterns (including cycle 2 data) associated with the observed changes in steroid hormone levels and menstrual cycle irregularity, particularly during STRAW stages 2 and 1, will be presented elsewhere, in addition to the associated changes in menstrual blood loss and endometrial proliferative markers.

To summarize, between STRAW stages 5/4 and 3, there is a marked fall in AMH, a marginal fall in INHB, a rise in early cycle FSH, and a decrease in ovulatory cycle length. Menstrual cycles remain regular, and steroid hormone levels are unchanged. With progression to STRAW stage 2 and then to stage 1, there is a further rise in FSH and more clear-cut falls in INHB and AMH. Although not conclusive, the data in this relatively small cross-sectional study suggest that both INHB and AMH may be superior to FSH in predicting STRAW stage with respect to the onset and progression of the menopause transition. Future analyses of the early cycle hormone measurements throughout reproductive aging such as those from the SWAN may be more conclusive in this regard.


   Acknowledgments
 
We praise the substantial time and effort that each of the study participants contributed to this study. Acknowledgments are also due to Jerilynn C. Prior, M.D., and Christine Hitchcock for their invaluable contribution and support in the planning stages of this study; the research staff at the Family Planning New South Wales, Ashfield, for their support in the gynecological procedures; Frank Manconi and Georgina Luscombe for their invaluable logistical and statistical assistance; the staff in the Endocrine Laboratory at the Westmead Children’s Hospital; and Enid Pruysers at Prince Henry Institute.


   Footnotes
 
This work was supported by grants from the Australasian Menopause Society (2002 and 2004), National Health and Medical Research Council (NHMRC) Fellowship Scholarship Program, DSL-Beckman Coulter, and the NHMRC of Australia Program Grant 241000 and Research Fellowship (D.M.R.) 169201.

Authors Disclosure Information: G.E.H., X.Z., C.L.H., and I.S.F. have nothing to disclose. H.G.B. and D.M.R. are inventors on patents AU85/00119 and AU86/00097.

First Published Online June 5, 2007

Abbreviations: AMH, Anti-Mullerian hormone; BBT, basal body temperature; CV, coefficient of variation; E2, estradiol; EMT, early menopause transition; FREEDOM, Fertility Recognition and Enabling Early Detection of Menopause; INHA, inhibin A; INHB, inhibin B; LMT, late menopause transition; LRA, late reproductive age; MRA, mid-reproductive age; P, progesterone; PdG, pregnanediol 3-glucuronide; STRAW, Stages of Reproductive Aging Workshop; SWAN, Study of Women’s Health Across the Nation.

Received January 11, 2007.

Accepted May 24, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Dennerstein L, Randolph J, Taffe J, Dudley E, Burger H 2002 Hormones, mood, sexuality, and the menopausal transition. Fertil Steril 77(Suppl 4):S42–S48
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