Associations Between Antral Ovarian Follicle Dynamics and Hormone Production Throughout the Menstrual Cycle as Women Age.

BACKGROUND: The physiological origins of age-related changes in hormone production during the menstrual cycle are uncertain. OBJECTIVE: The objective of the study was to test the hypothesis that changes in antral follicle dynamics are associated with changes in hormone production as women age. METHODS: A prospective, observational study was conducted in ovulatory women of midreproductive age (MRA; 18-35 y; n = 10) and advanced reproductive age (ARA; 45-55 y; n = 20). The numbers and diameters of all follicles of 2 mm or greater were quantified ultrasonographically every 1-3 days for one interovulatory interval; the growth profiles of individually identified follicles of 4 mm or greater were tabulated. Blood samples were assayed for FSH, LH, estradiol, progesterone, inhibin A and B, and anti-Mullerian hormone. RESULTS: Fifty percent of women in both the MRA and ARA groups developed one to two luteal-phase dominant follicles (LPDFs). MRA women with typical LPDFs had greater luteal-phase inhibin B (44.2 vs 17.0 ng/L) and estradiol (91.3 vs 51.7 ng/L) compared with those without LPDFs (P < .05). Luteal-phase estradiol was greater (184 vs 79 ng/L), inhibin B was greater (25.3 vs 12.7 ng/L), and progesterone was lower (6.98 vs 13.8 µg/L) in ARA women with atypical vs no LPDFs (P < .01). CONCLUSION: Changes in antral follicle dynamics are associated with changes in hormone production as women age. The development of LPDFs in women of MRA was associated with elevated luteal-phase estradiol. A similar but exaggerated elevation in late luteal-early follicular-phase estradiol, accompanied by lower progesterone, was observed in ARA women with atypically large and persistent LPDFs.

Hormone therapy in menopause: An update on cardiovascular disease considerations.

Cardiovascular disease (CVD) remains the number one cause of death and morbidity worldwide, and while overall CVD incidence rates declined in both genders between 1999 and 2007, age-specific data suggest that coronary risk factors in women are on the rise. While early observational data favored menopausal hormone therapy's (MHT's) role in primary CVD prevention, the initial interventional study data from the WHI did not. Further detailed analyses of both observational and interventional data have pointed to the possibility that MHT may play a role in primary CVD prevention if initiated within 10 years of menopause and less than 60 years of age (the timing hypothesis). Unanswered questions remain regarding the optimal route and dosage of estrogen in MHT. Data so far, favor transdermal estradiol over conventional-dose CEE with respect to CVD risk and oral estradiol over conventional-dose CEE with respect to stroke risk. Low-dose oral CEE may similarly have benefit over conventional-dose oral CEE for some CVD events. In addition, the transdermal route of delivery may avoid the excess risk of certain CVD events associated with MHT and lower doses of estrogen may have fewer adverse effects than the doses previously tested in WHI. Because questions regarding benefits versus risks remain, MHT is yet to be recommended for CVD prevention. However, it is indicated for menopausal symptom management in women within 10 years of menopause and under the age of 60 years, in whom it does not appear to carry increased cardiovascular risk. Additional research is ongoing and needed to confirm or refute the comparative safety of the various MHT options.

The perimenopausal woman: endocrinology and management.

This review focuses on the endocrine and physiological features of the transition to menopause, known as the menopausal transition or the perimenopause. The updated 2011 Stages of Reproductive Aging workshop (STRAW) system is presented with a discussion of the new subdivisions within stages -3 (late reproductive age) and +1 (postmenopause) and incorporation of FSH and other biomarkers in the supportive criteria. Ovarian follicle reserve and ovarian follicle dynamics are also discussed in terms of the changes that occur with reproductive aging, and the dramatic effect these changes have on the hypothalamic-pituitary-gonadal feedback system. Topics include the disruption of normal ovulatory function and related hormone secretion patterns, abnormal uterine bleeding, and the changes that occur in bone and the cardiovascular system. The review concludes with a discussion of management strategies. This article is part of a Special Issue entitled 'Menopause'.

Age-related changes in major ovarian follicular wave dynamics during the human menstrual cycle.

OBJECTIVE: Changes in antral follicle count, hormone production, and menstrual cyclicity as women age are well documented. However, age-related changes in ovarian follicular wave dynamics in women are not understood. The objective of this study was to test the hypothesis that major follicular wave dynamics (ie, those in which a dominant follicle develops) differ in women with age. METHODS: A prospective, cross-sectional, observational study was conducted in 58 women of mid-reproductive age (MRA; 18-35 y; n = 27), late reproductive age (LRA; 36-44 y; n = 10), and advanced reproductive age (ARA; 45-55 y; n = 21). The number and diameters of all follicles ≥ 2 mm were quantified ultrasonographically every 2 to 3 days for one complete interovulatory interval (IOI). Only ovulatory cycles were evaluated. Antral follicle count and major follicular wave dynamics during the IOI were compared among age groups using SPSS version 19.0 (α = 0.05). RESULTS: One (36/58, 62%) or two (22/58, 38%) major follicular waves were observed during the IOI in all women evaluated. The prevalence of follicular-phase dominant follicles (FPDFs) and luteal-phase dominant follicles (LPDFs) was not different among the MRA, LRA, and ARA groups (FPDFs: 27/27 [100%], 10/10 [100%], and 20/21 [95%], respectively; LPDFs: 10/17 [37%], 3/10 [30%], and 10/21 [48%], respectively; P > 0.050). All FPDFs were ovulatory. One LPDF ovulated during menses in the ARA group; all other LPDFs in the MRA, LRA, and ARA groups were anovulatory. On average, LPDFs emerged earlier relative to ovulation (days -6, -2, and -2; P = 0.049), grew longer (11, 3, and 6 d; P = 0.005), and developed to a larger diameter (24, 11, and 11 mm; P = 0.032) in the ARA group versus the MRA and LRA groups. In follicular-phase major waves, there was a tendency for a greater prevalence of polyovulation as women aged (ARA 3/21 [14%] vs MRA 0/27 [0%]; P = 0.070). CONCLUSIONS: One or two major follicular waves develop during the IOI, irrespective of age. The prevalence of LPDFs (range, 30%-50%) and FPDFs (range, 95%-100%) during the IOI does not differ with age. However, the growth dynamics of major waves change as women age. On average, LPDFs emerge earlier, grow for a longer period, and grow to a larger diameter in ovulatory women of advanced versus mid or late reproductive age. There is a greater tendency for polyovulation in the follicular-phase major wave as women age.

Changes in serum antimüllerian hormone levels across the ovulatory menstrual cycle in late reproductive age.

OBJECTIVE: The aim of this study was to assess the pattern of serum antimüllerian hormone (AMH) across the normal ovulatory menstrual cycle in women in late reproductive age when ovarian follicle reserve and, hence, serum AMH levels are reduced. METHODS: Serum AMH levels were determined by enzyme-linked immunosorbent assay across the ovulatory menstrual cycle from women in mid (n = 18) and late (n = 43) reproductive life, including the menopausal transition. RESULT: : No intracycle variation in AMH level was observed in women in mid reproductive life nor in 33% (n = 14) of women with normal ovulatory cycles in late reproductive age. In the remaining cycles, a significant 2-fold decrease (P < 0.01) in AMH in 11 cycles and a significant 4.2-fold increase (P < 0.01) in 10 cycles were observed between the follicular and luteal phases. In a further eight ovulatory cycles, AMH was below the level of assay detection. As ovarian follicle reserve decreases with age and AMH levels are reduced, separate patterns of AMH are detected in the follicular and luteal phases of ovulatory menstrual cycles, presumably reflecting the intermittent pattern of the emergence of follicles close to menopause. CONCLUSIONS: It is concluded that when AMH levels are substantially reduced, as in late reproductive age, they become less reliable as markers of ovarian reserve because of the changing patterns observed in some cycles.

The relationship of menopausal status and rapid menopausal transition with carotid intima-media thickness progression in women: a report from the Los Angeles Atherosclerosis Study.

CONTEXT: The onset of menopause has been associated with an increase in cardiovascular risk factors. However, little information is available about the rapidity of the menopausal transition and its relationship to the development of preclinical cardiovascular disease (CVD). OBJECTIVE: Our objective was to assess whether the rate of carotid intima-media thickness (cIMT) progression over time differs according to 1) menopausal status and 2) rapidity of the menopausal transition. DESIGN: We evaluated 203 community-based women aged 45-60 yr without previously diagnosed CVD who underwent three repeated measurements of cIMT as a measure of preclinical CVD over 3 yr. Menopausal status was ascertained at each visit based on menstrual cycle parameters and reproductive hormone profiles. Of these, 21 remained premenopausal, 51 transitioned, and 131 were postmenopausal throughout the observation period. RESULTS: Age-adjusted cIMT progression rates were similar among premenopausal, transitioning, and postmenopausal women. In the 51 transitioning women, age was not related to rate of cIMT progression. However, the rapidity of menopausal transition was related to cIMT progression: women transitioning from pre- to postmenopause within the 3-yr period had a higher rate of cIMT progression compared with women with a slower transition. Statistical adjustments for the significant covariates of systolic blood pressure, body mass index, race, cigarette smoking, or hormone therapy use did not alter the findings. CONCLUSIONS: Among healthy women undergoing repeated cIMT measurement, a more rapid menopausal transition was associated with a higher rate of preclinical CVD progression measured by cIMT. Further work is needed to explore potential mechanisms of this effect.

Quantitative measurements of menstrual blood loss in ovulatory and anovulatory cycles in middle- and late-reproductive age and the menopausal transition.

OBJECTIVE: To measure menstrual blood loss before and during the menopausal transition and to explore the relationships between menstrual blood loss and menstrual cycle irregularity and reproductive hormone levels. METHODS: Two consecutive menstrual blood loss measurements were performed in 77 healthy women aged 21-55 years, classified as midreproductive age (n=21, control group), late-reproductive age (n=17), early-menopausal transition (n=16), and late-menopausal transition (n=23). Serum hormone levels (estradiol [E2], progesterone, follicle-stimulating hormone, luteinizing hormone, and inhibins) were measured three times per week from the start of one menstrual period to the end of the subsequent menstrual period. RESULTS: There were nine, one, zero, and two anovulatory cycles captured in the late-menopausal transition, early-menopausal transition, late-reproductive age, and midreproductive age groups, respectively. The median (range) menstrual blood loss values after ovulatory cycles were 30 (142), 33 (147), 55.7 (105), and 68.9 (234) mL in the midreproductive age, late-reproductive age, early-menopausal transition, and late-menopausal transition groups, respectively. After anovulatory cycles in the late-menopausal transition group, menstrual blood loss was only 11.8 (97) mL. In the late-menopausal transition group, menstrual blood loss after an ovulatory cycle was significantly higher than when occurring after an anovulatory cycle (P=.008, Kruskal-Wallis). The highest menstrual blood loss measurements were in women in the late-menopausal transition group who experienced ovulatory cycles with abnormally high E2 levels and disturbed E2 secretion patterns. CONCLUSION: The onset of variability in menstrual blood loss was associated with the onset of irregular cycles. Excessive menstrual blood loss (greater than 250 mL) was associated with ovulatory cycles with high E2 levels and late menopausal transition. LEVEL OF EVIDENCE: III.

Atypical estradiol secretion and ovulation patterns caused by luteal out-of-phase (LOOP) events underlying irregular ovulatory menstrual cycles in the menopausal transition.

OBJECTIVE: The menopausal transition is characterized by irregular menstrual cycles and unpredictable hormone levels, including dramatic swings in estradiol (E2). An increasing number of studies have found variable high E2 and low luteal phase progesterone occur with progression of Stages of Reproductive Aging Workshop (STRAW)stage, but the cause remains unclear. To explore the causes of the erratic changes in E2, individual within-cycle secretion patterns of E2, progesterone, follicle-stimulating hormone, luteinizing hormone, inhibin A, and inhibin B were explored in detail. DESIGN: Blood samples taken three times per week over 1 1/3 menstrual cycles from 77 women aged 21 to 55 classified as mid-reproductive age (STRAW stages 5 and 4; n = 21), late-reproductive age (STRAW stages 4 and 3; n = 16), early menopausal transition (STRAW stage 2; n = 17), and late menopausal transition (STRAW stage 1; n = 23) were analyzed. RESULTS: Eleven of the 29 (37%) early and late menstrual transition ovulatory cycles exhibited a specific pattern of E2 secretion that was characterized by a second increase in E2 during the mid- and late luteal phases and that continued to a peak during the subsequent menstrual phase. This second rise and fall in E2 was typical in appearance of a normal follicular phase, except that it was superimposed on an existing ovulatory cycle(specifically during the luteal and menstrual phases). The pattern was therefore referred to as a luteal out-of-phase(LOOP) follicular event. In four of these LOOP cycles, a luteinizing hormone peak and ovulatory episode followed the second E2 peak early in the subsequent cycle. Compared with the typical ovulatory cycles, the cycles with LOOP events exhibited lower luteal phase progesterone, higher early cycle follicle-stimulating hormone, and lower early cycle inhibin B. They were also associated with abnormally short (<21 d) or long (>40 d) cycle length. CONCLUSIONS: Many of the marked increases in ovulatory cycle E2 and cycle irregularities during the menopausal transition may be due to LOOP events and appear to be triggered by prolonged high follicular phase follicle-stimulating hormone levels.

Interrelationships between ovarian and pituitary hormones in ovulatory menstrual cycles across reproductive age.

CONTEXT: Ovarian hormones regulate pituitary gonadotropin secretion across the menstrual cycle via negative and positive feedback mechanisms. The contribution of individual hormones is complex and is a continuing area of research. OBJECTIVE: The aim of the study was to identify relationships between LH/FSH and estradiol, progesterone, inhibin A, inhibin B, and anti-Mullerian hormone (AMH) in ovulatory menstrual cycles across reproductive age. DESIGN: Serum ovarian and pituitary hormones were studied in a group of young (<35 yr; n = 21) and older (>45 yr; n = 55) women. The slopes of the regression lines relating the ovarian and pituitary hormones were determined by multiple linear regression analysis and expressed with 95% confidence intervals for each ovarian hormone, with FSH and LH as independent variables. Both simultaneous and delayed (time lagged) relationships were examined. RESULTS: Clear associations were evident for the lagged prediction of FSH, with significant negative associations being evident with inhibin B and AMH in the follicular phase and with estradiol, inhibin B, progesterone, and AMH in the luteal phase. For the lagged prediction of LH, significant positive and negative associations were observed with estradiol and inhibin B, respectively, in the follicular phase and a negative association with progesterone and inhibin B in the luteal phase. CONCLUSIONS: It is concluded that in the follicular phase, inhibin B is a major feedback regulator of FSH and may also be a negative feedback regulator of LH. AMH may be indirectly involved in FSH regulation.

A proposed classification system for menstrual cycles in the menopause transition based on changes in serum hormone profiles.

OBJECTIVE: To characterize menstrual cycles in women in late reproductive age and the menopause transition, based on changes in serum hormone levels. DESIGN: Serum levels of estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone, inhibin A, inhibin B, and antimüllerian hormone, as previously reported as mean data grouped according to the Stages of Reproductive Aging Workshop proposals, were analyzed in 55 women aged 45 to 55 and compared with those in 21 women aged 21 to 35. RESULTS: The ovulatory cycles in the older women were divided into three types. Type 1 cycles (n = 14, 33%) were those with hormone concentrations similar to the women aged 21 to 35 except for 20-fold lower antimüllerian hormone levels. Type 2 cycles (n = 24; 53%) had increased FSH, decreased inhibin B, and increased FSH-to-inhibin B ratios but normal estradiol and progesterone levels. Type 3 cycles had the same characteristics as type 2 cycles (n = 5; 12%) in addition to lower luteal phase progesterone and increased luteinizing hormone. CONCLUSIONS: The changes in hormone levels indicated in cycle types 1 to 3 closely reflect the changes in ovarian-pituitary activity as menopause approaches and are likely to be directly attributable to a decrease in ovarian follicle reserve. The findings suggest that FSH-to-inhibin B ratios and antimüllerian hormone are distinct early indicators of the menopause transition and are likely to be useful biomarkers of impending menopause. Furthermore, this classification may provide an improved basis for the study of reproductive endocrine disorders associated with the menopause transition.

Cycle and hormone changes during perimenopause: the key role of ovarian function.

The menopausal transition is the stage in reproductive life commonly defined as commencing with the onset of menstrual irregularity. Classic studies of the endocrinology of the transition postulated the existence of inhibin in women to explain the observed increase in follicle-stimulating hormone (FSH) levels without a significant decrease in estradiol (E2). Descriptions were provided of cycle characteristics during the transition, emphasizing the unpredictability of the endocrine changes rather than the occurrence of an orderly and progressive decline in ovarian function. Women older than the age of 45 exhibited menstrual irregularity when the average number of primordial follicles per ovary decreased to approximately 100. Inhibin B is a major regulator of FSH secretion and a product of small antral follicles. Its levels respond to the early follicular phase increase and decrease in FSH. The age-related decrease in ovarian primordial follicle numbers, which is reflected in a decrease in the numbers of small antral follicles, leads to a decrease in inhibin B, which in turn leads to an increase in FSH, hypothesized to act as a stimulus to the maintenance of circulating E2 in the follicular phase until late in the transition. Concurrently, the concentrations of testosterone do not change significantly. Early follicular phase FSH levels in women reporting menstrual irregularity fluctuate markedly, with a more uniform increase in levels when no menses have occurred for at least 3 months. Anovulatory cycles occur at increased frequency in the last 30 months before final menses or menopause. In ovulatory cycles, FSH shows little, if any, increase, but anovulatory cycles are usually characterized by low levels of inhibin B, markedly increased levels of FSH, and low levels of E2. Thus, the heterogeneity of follicular phase FSH represents a mixture of ovulatory and anovulatory cycles. Longitudinal data indicate that both ovulatory and anovulatory cycles occur after entry into both the early and late menopausal transition and that ovulatory cycles occur even after final menses. There is no endocrine marker of menopause, which may be primarily an endometrial event. Using the hormonal concentrations in ovulatory cycles observed in women in mid-reproductive age as controls and comparing such concentrations in late reproductive age women older than 45 either continuing to cycle regularly or having entered the early or late menopausal transition, a gradual increase in follicular phase FSH and E2 and a decrease in inhibin B were observed in ovulatory cycles. Anovulatory cycles showed markedly increased FSH with low E2 and inhibin B. No specific endocrine change was characteristic of either the early or late menopausal transition, confirming the observations of previous studies regarding the unpredictability of cycle characteristics and hormone changes with the approach of menopause. Antimüllerian hormone correlates with follicle numbers and shows a large age-related decrease to reach undetectable levels at menopause. Thus, the marked decrease in follicle numbers during late reproductive age appears to predispose to erratic and unpredictable cycle characteristics, with normal ovulatory cycles continuing to occur episodically. There is no specific endocrine marker of the early or late transition, making measurements of FSH or E2 unreliable in attempting to stage an individual with regard to approaching menopause.

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.

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.

Phytoestrogens and lipoproteins in women.

OBJECTIVES: We undertook a study to evaluate relationships among blood phytoestrogen levels, lipoprotein levels, estrogen levels, and angiographically defined coronary artery disease in women. BACKGROUND: Evidence for a beneficial role and the potential mechanism(s) of plant estrogens (phytoestrogens) on blood lipoproteins in humans is controversial. METHODS: We evaluated 483 women enrolled in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation with coronary risk factors undergoing coronary angiography for evaluation for suspected ischemia for blood phytoestrogen levels (daidzein and genistein), lipoprotein levels [total cholesterol, triglycerides, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol (HDL-C)], estrogen levels (estradiol, bioavailable estradiol, estrone), and angiographic coronary artery disease using core laboratories. RESULTS: Higher blood levels of the phytoestrogen daidzein were associated with lower triglycerides (P = 0.01), higher HDL-C (P = 0.05) levels, and a beneficial total cholesterol to HDL-C ratio (P = 0.02). This beneficial association was evident among the subgroup of women with low [<184 pmol/liter (<50 pg/ml)] blood estradiol levels, regardless of age and lipoprotein levels. The phytoestrogen associations with lipoproteins were incrementally related to the magnitude of daidzein level and independent of other lipoprotein modulators. There were no detectable relationships between the phytoestrogen levels and angiographic coronary artery disease. CONCLUSIONS: Higher blood phytoestrogen daidzein levels are associated with beneficial lipoprotein levels in women with low estrogen levels, possibly by an estrogen receptor mechanism. These results suggest a potential explanation for the variable lipoprotein results observed in prior randomized controlled trials and call for investigation regarding subgroups of subjects who may preferentially benefit from dietary intake of food products, such as soy.

Isoflavone supplementation and endothelial function in menopausal women.

OBJECTIVE: Despite strong observational evidence for a beneficial role of oestrogen in cardiovascular disease, recent trial results suggest that hormone replacement therapy (HRT) may have adverse effects in menopausal women with established coronary heart disease. Isoflavones are oestrogen analogues found in plants with oestrogen-like properties and, because of a favourable side-effect profile, may be ideal alternatives to HRT with respect to cardiovascular benefits. Endothelial function is a marker of cardiovascular health. We aimed to determine the effect of isoflavones on endothelial function using the brachial artery reactivity test. DESIGN AND MEASUREMENTS: Twenty-nine healthy menopausal women underwent entry and exit brachial artery reactivity testing following randomization to 2 weeks of an oral soy isoflavone concentrate containing 80 mg of soy isoflavones (Archer Daniel Midland Inc., IL, USA) or placebo. RESULTS: At study exit, there was no difference between placebo and isoflavone groups with respect to flow-mediated dilation (%FMD(max)), change (entry to exit) in %FMD(max) or response to nitroglycerine (%TNG). Subgroup analyses assessing lipid and oestrogen effects did not produce any significant results. CONCLUSIONS: These results suggest that short-term oral isoflavone supplements do not improve endothelial function in healthy menopausal women.