Menstrual bleeding, hormones, and the menopausal transition

The perimenopause represents a time of great variability in reproductive hormone dynamics and menstrual cycle characteristics, but age-related changes begin prior to this. These changes include a gradual increase in follicle stimulating hormone (FSH) levels, a gradual shortening of mean cycle length, and a decline in the number of ovarian follicles. The onset of perimenopause is thought to occur with the first break in menstrual cycle regularity. With the onset of cycle irregularities, hormone concentrations exhibit large increases in variability and unpredictability, rather than following a gradual trend with the approach of menopause, the final menstrual period. Abrupt spikes in gonadotropins and considerable fluctuations in estradiol and inhibin levels have been observed. Variability is the norm in the perimenopause, with hormonal fluctuations contributing to the visible signs of menstrual cycle and bleeding irregularities. To date there is no single endocrine indicator to serve as an adequate marker of menopausal status. This paper provides a review of research to date on patterns of reproductive hormones and menstrual bleeding during the menopausal transition. An understanding of such patterns can contribute to a better ability to distinguish "normal" transitional events from more serious pathology.     

Regulation and function of inhibins in the normal menstrual cycle

The development of assays specific for dimeric inhibin A and inhibin B defined the distinct physiology of these two hormones in the normal menstrual cycle. Inhibin A and inhibin B expression and secretion along with their differential regulation by gonadotropins explain their unique serum patterns and their potential endocrine and ovarian autocrine-paracrine functions. There is evidence that inhibin A and inhibin B play an endocrine role in the negative regulation of follicle-stimulating hormone (FSH) in nonhuman primates and humans. However, some studies suggest that estradiol is a more important, if not the only, negative feedback regulator of FSH in women. There is also evidence from animal models that inhibins and activins play a critical role in follicle development. Future work will be necessary to define further the relative role of the inhibins, estradiol, and other autocrine-paracrine factors in these important reproductive functions.     

Inhibin A and B as markers of menopause: a five-year prospective longitudinal study of hormonal changes during the menopausal transition

OBJECTIVES: A more direct and precise hormonal marker of the menopause has been required for some time. The aim of this study was to identify the most accurate marker of the menopause, based on analyses of inhibin A and B, FSH, LH and estradiol (E(2)), among 59 healthy women without hormonal treatment during the perimenopause and early postmenopause. METHODS: Fifty-nine women, aged 46-56 years (mean age 51.2 years), were examined annually for 5 years during the menopausal transition and had venous blood drawn simultaneously for later analyses of the above-mentioned hormones. RESULTS: Inhibin A showed a steady decline from at least 4 years before the final menstrual period (FMP) until 1 year before menopause, whereas inhibin B had a shorter lasting decline from year 3 to year 2 before menopause, concomitant with a rise in FSH and LH. CONCLUSION: The present study confirmed previous observations that inhibin A had a continuous decline starting before the decline of inhibin B, suggesting that an increasing part of the cycle was anovulatory. The fall in inhibin B and the increase in FSH constitute markers of ovarian aging. One year prior to menopause neither inhibin A nor inhibin B could be detected. The disappearance of these peptide hormones is an important predictor of the approaching menopause.     

Follicular phase hormone levels and menstrual bleeding status in the approach to menopause

OBJECTIVE: (1) Characterize the relationship between follicular phase hormone levels and menstrual bleeding patterns in the approach to menopause; (2) identify racial differences in hormone levels; (3) determine independent contributions of menstrual status, race, age, BMI, and smoking to hormone levels. DESIGN: Randomly identified, population-based cohort, stratified to obtain equal numbers of African American and Caucasian women, prospectively followed for 5 years. SETTING: Women in Philadelphia County, PA, identified by random-digit telephone dialing. PARTICIPANT(S): Women aged 35 to 47 years with regular menstrual cycles at enrollment (N = 436). DATA COLLECTION: Blood sampling twice in each of 7 assessment periods during days 1-6 of the cycle, menstrual dates identified through structured interview and daily symptom reports, anthropometric measures and standardized questionnaires at each assessment period. MAIN OUTCOME MEASURE(S): Serum levels of follicular E(2), FSH, inhibin B, and LH. RESULT(S): The mean levels of E(2), FSH, inhibin B, and LH were differentially associated with the 5 menstrual status groups defined by changes in bleeding patterns. Significant changes in hormone levels occurred prior to missed menstrual cycles for inhibin B, FSH, and LH. All hormones had a highly significant interaction between menstrual status and BMI. African American women had significantly lower levels of E(2) and LH compared to Caucasian women in univariate analyses. The interaction of race, menstrual status, and BMI was highly significant (P<.001) for E(2), with African American women having lower E(2) levels until postmenopause, when E(2) levels were higher in AA women with BMI > or =25 and BMI > or =30. CONCLUSION(S): Levels of E(2), FSH, LH, and inhibin B are significantly associated with menstrual bleeding patterns in late reproductive age women and differentiate the earliest stages of the menopausal transition. Racial differences in mean levels of E(2) appear strongly mediated by BMI.     

正常月经周期中尿液LH、FSH、E_2和P的变化

本文介绍了用放射免疫法测定20例育龄妇女正常月经周期晨尿中LH、FSHE_2和P、的逐日变化,并和同日收集的血清样品中这些激素的变化相比较。其结果显示:(1)血,尿激素逐日平均值呈正相关:LH,r=0.7224,p<0.0001;FSH,r=0.8493,p<0.0001;E_2,r=0.8744,p<0.0001;P,r=0.9225,p<0.0001。(2)血、尿激素在月经周期各期的浓度变化特点基本一致。因此,测定月经周期中尿液生殖激素的变化有可能成为观察女性内分泌功能的另一个重要手段裨。     

Initial analysis of variability among basal hormone biomarkers of ovarian reserve

The most commonly used biomarker tests of ovarian reserve are basal hormone measurements during the early follicular phase, including mainly FSH but also oestradiol, FSH:LH ratio, and inhibin B. This study was designed to assess prospectively the intra- and inter-cycle variability of serum values of those hormone biomarkers in the early follicular phase of consecutive cycles in a group of women candidates for assisted reproduction. Fifty eumenorrhoeic women underwent blood sampling for hormone measurement on cycle day 3 for three consecutive cycles, and during the first study cycle, daily samples were obtained on cycle days 2, 3, 4 and 5. No significant difference was detected among FSH concentrations and FSH:LH ratios during cycle days 2-5; in contrast, oestradiol and inhibin B were not constant through the early follicular phase. No difference in FSH or inhibin B serum concentrations and FSH:LH ratio on cycle day 3 during three consecutive cycles was noted; however, significant inter-cycle variability for oestradiol serum concentration on cycle day 3 was detected. FSH and inhibin serum concentrations, and FSH:LH ratio varied significantly less than oestradiol on cycle day 3, but inter-cycle variability was similar for the first three hormonal biomarkers of ovarian reserve. There was significantly less intra-cycle variability of FSH serum concentration and FSH:LH ratio than oestradiol and inhibin B serum concentrations. Basal FSH serum concentrations (or FSH:LH ratio) during the early follicular phase showed neither significant inter-cycle nor intra-cycle variability when measured during 3 consecutive months in an assisted reproduction patient population, thus offering greater flexibility of pretreatment sampling.     

年龄与卵巢功能——对卵巢衰老的认识

女性生育力高峰出现在20~30岁的中、晚阶段,此后生育力逐渐降低直到绝经。生育力下降发生在FSH水平上升,抑制素B下降和月经周期长度改变之前。抗苗勒管激素是较抑制素B出现更早的标志物。窦卵泡数的变化和月经周期长度可变性增强反映生殖衰老加速。生殖衰老过程,在人群存在一个普遍适用的规律;但每个个体的衰老进程是她所受多种复杂因素相互作用的结果。     

Impact of obesity and leptin levels on the secretion of estradiol, inhibin A and inhibin B during ovarian stimulation with gonadotropins.

We examined the impact of high leptin levels on the secretion of estradiol, inhibin A and inhibin B in obese and lean women during ovarian stimulation. Patients undergoing long-term pituitary suppression, ovarian stimulation and in vitro fertilization for non-endocrine reasons were included in this case-control study. Obese women (body mass index (BMI) > 28 kg/m(2); n = 17) were individually matched with lean women (BMI 20-25 kg/m(2); n = 17) for age and baseline follicle stimulating hormone and luteinizing hormone concentrations. Blood samples were collected in a previous menstrual cycle and 1-3 days apart throughout ovarian stimulation. Serum levels of estradiol, leptin, inhibin A and inhibin B were measured. Obese and lean women had similar serum concentrations of estradiol, inhibin A and inhibin B in the follicular and luteal phases of the spontaneous menstrual cycle, and throughout ovarian stimulation. Serum levels of leptin were higher in obese than in lean women, and increased during stimulation in both groups. In the obese group, area-under-the-curve (AUC) leptin levels correlated with AUC inhibin A levels. In the lean group, there was no correlation between AUC leptin levels and AUC levels of ovarian hormones. The results suggest that high leptin concentrations in vivo are not associated with impaired secretion of estradiol and dimeric inhibins during ovarian stimulation.     

The menopause transition: endocrine changes and clinical symptoms

Several biological changes take place during the menopause transition. The number of oocytes declines progressively from before birth but reaches a critically low level by the time of the menopause. The regular pattern of the menstrual cycle becomes disrupted and the frequency of normal ovulatory cycles declines. Rising gonadotrophin levels, particularly of follicle stimulating hormones (FSH), and declining estrogen levels are thought to characterize the menopausal transition. It now appears that declining levels of inhibin may play an important role in maintaining estrogen levels until just before the menopause, while causing increased levels of gonadotrophins. Wide variations in hormonal profiles between and within individuals occur. The clinical responses to this endocrine instability include vasomotor symptoms, psychological symptoms, sexual dysfunction and irregular menstrual bleeding. Estradiol deficiency induces a rapid phase of increased bone turnover in the early postmenopausal period, which can contribute to osteoporosis later in life. Similarly, changes in lipid profiles, particularly high-density lipoprotein (HDL) and triglycerides, can also occur.     

Aging women with polycystic ovary syndrome who achieve regular menstrual cycles have a smaller follicle cohort than those who continue to have irregular cycles

OBJECTIVE: To examine whether follicle loss due to ovarian aging is responsible for the occurrence of regular menstrual cycles in aging women with polycystic ovary syndrome (PCOS), the size of the FSH-sensitive follicle cohort was estimated by the exogenous follicle-stimulating hormone ovarian reserve test (EFORT) and related to the follicle count as measured by ultrasound. DESIGN: Prospective study. SETTING: Reproductive endocrinology unit of an academic medical center. PATIENT(S): Twenty-seven aging women with PCOS (35.8-49.4 years): 20 with regular menstrual cycles and 7 with oligomenorrhea or amenorrhea. INTERVENTION(S): EFORT and transvaginal ultrasound. MAIN OUTCOME MEASURE(S): Baseline (cycle day 2, 3, or 4) FSH, androstenedione (A), T, E(2), and inhibin B levels, the E(2) and inhibin B increment after the EFORT, and the follicle count. RESULT(S): After correction for the body mass index (BMI), the inhibin B increment was higher in the irregular menstrual group, but the E(2) increment did not differ significantly between the two groups. Ultrasound showed a median follicle count of 8.5 (4.0-18.0) in women with regular menstrual cycles (n = 16), compared with 18.0 (8.0-35.0) in irregularly menstruating women (n = 7). The follicle count was significantly correlated to the FSH-induced E(2) increment (r = 0.656) as well as to the inhibin B increment (r = 0.654). The regularly menstruating group was significantly older, had a higher basal FSH concentration, and had lower androgens than the irregularly menstruating group. CONCLUSION(S): The smaller follicle count, the older age, the higher FSH concentration, and the lower FSH-induced inhibin B increment found in women with PCOS and a regular menstrual cycle confirm that a decrease in the size of the follicle cohort due to ovarian aging is largely responsible for the regular menstrual cycles in aging PCOS women.     

Concentrations of inhibins and activin in women undergoing stimulation with recombinant follicle-stimulating hormone for in vitro fertilization treatment

OBJECTIVE: To investigate the influence of human recombinant follicle-stimulating hormone (FSH) on circulating serum concentrations of the ovarian proteohormones inhibin A, inhibin B, pro alpha-C, and activin A and serum levels of estradiol after down-regulation with GnRH analogue. DESIGN: Serum concentrations of ovarian proteohormones and estradiol. SETTING: Academic clinical practice. PATIENT(S): 30 women who underwent assisted reproductive techniques. INTERVENTION(S): Blood samples were analyzed for inhibin A, inhibin B, pro alpha-C, activin A, and estradiol during IVF treatment at points coinciding with pituitary down-regulation, stimulation with recombinant FSH, ovulatory triggering, and the luteal phase of the cycle. RESULT(S): Activin A levels did not change with recombinant FSH stimulation. In women with a sonographically detected leading follicle >17 mm in diameter, levels of inhibin A, pro alpha-C, and estradiol increased significantly (P<.05). The increase in inhibin B level was not statistically significant. In patients without adequate follicle development during FSH stimulation, serum levels of inhibins remained low and did not significantly deviate from values measured before stimulation. CONCLUSION(S): Inhibin A and pro alpha-C are effective markers of follicular development and may be effective additions to estradiol as a marker.     

Impact of obesity and leptin levels on the secretion of estradiol,inhibin A and inhibin B during ovarian stimulation with gonadotropins

We examined the impact of high leptin levels on the secretion of estradiol, inhibin A and inhibin B in obese and lean women during ovarian stimulation. Patients undergoing long-term pituitary suppression, ovarian stimulation and in vitro fertilization for non-endocrine reasons were included in this case-control study. Obese women (body mass index (BMI) > 28 kg/m²; n = 17) were individually matched with lean women (BMI 20-25 kg/m²; n = 17) for age and baseline follicle stimulating hormone and luteinizing hormone concentrations. Blood samples were collected in a previous menstrual cycle and 1–3 days apart throughout ovarian stimulation. Serum levels of estradiol, leptin, inhibin A and inhibin B were measured. Obese and lean women had similar serum concentrations of estradiol, inhibin A and inhibin B in the follicular and luteal phases of the spontaneous menstrual cycle, and throughout ovarian stimulation. Serum levels of leptin were higher in obese than in lean women, and increased during stimulation in both groups. In the obese group, area-under-the-curve (AUC) leptin levels correlated with AUC inhibin A levels. In the lean group, there was no correlation between AUC leptin levels and AUC levels of ovarian hormones. The results suggest that high leptin concentrations in vivo are not associated with impaired secretion of estradiol and dimeric inhibins during ovarian stimulation.     

绝经过渡期妇女血清抑制素水平的研究

目的　分析绝经过渡期妇女血清抑制素A(Inh A)、抑制素B(Inh B)水平的变化及其与其他生殖激素水平变化的时间关系。方法　测定 10例正常育龄妇女月经周期各期血清Inh A、Inh B水平 ;测定 40例绝经过渡期妇女月经周期第 3天的血清Inh B、促卵泡激素 (FSH)、促黄体生成素(LH)、雌二醇 (E2 )水平 ,经前 5～ 9d(经前期 )血清Inh A、孕酮 (P)水平 ;测定 10例绝经后妇女的血清Inh A、Inh B、FSH、E2 水平。分析各项激素水平变化之间的时间关系。结果　育龄妇女月经周期中Inh A、Inh B水平的变化曲线各不相同。绝经过渡期妇女中 ,黄体功能正常者占 48% ,经前期Inh A水平低于育龄妇女 ,分别为 ( 2 4 7± 13 0 )及 ( 42 9± 12 1)ng/L ,两者比较 ,差异有显著性 (P =0 0 17) ,Inh B水平改变差异无显著性 (P >0 0 5 ) ;黄体功能不足与无排卵者的Inh A水平进一步显著下降 ,分别为 ( 12 4± 10 2 )及 ( 5 3± 3 8)ng/L(P分别为 0 0 3 3及 <0 0 0 0 1) ,绝经后妇女则皆未检出。与育龄妇女比较 ,月经周期第 3天Inh B水平的下降仅在无排卵与绝经后妇女差异有极显著性 (P =0 0 0 1)。月经周期第 3天 ,FSH≥ 10IU/L者Inh B水平显著低于FSH <10IU/L者 ,分别为 ( 16 2± 4 0 )及 ( 62 0±43 8)ng/L(P <0 0 0     

Heterozygosity for the classical galactosemia mutation does not affect ovarian reserve and menopausal age

Female patients with classical galactosemia (galactose-1-phosphate uridyltransferase [GALT] deficiency) frequently suffer from premature ovarian failure, despite treatment with a galactose-restricted diet. Earlier research has suggested an association between heterozygosity for GALT mutations and early menopause. This study evaluates the effect of carriership for classical galactosemia on ovarian reserve and menopausal age. Proven female carriers of classical galactosemia were recruited via the Dutch Galactosemia Society. All 58 participants underwent a structured interview regarding fertility, smoking status, and menopause. To determine ovarian reserve, 42 premenopausal GALT carriers underwent ovarian antral follicle count (AFC) by transvaginal ultrasound and early follicular phase blood sampling for hormonal measurement of follicle-stimulating hormone (FSH), inhibin B, and anti-Müllerian hormone (AMH). These ovarian reserve parameters were compared with a cohort of proven fertile women (n = 166). The mean age at menopause in GALT carriers was 49.7 years, which is not different from the mean age at menopause in the general population in the Netherlands. There was no difference in FSH, inhibin B, and AMH levels or in the AFC (when corrected for age and smoking status) between 42 premenopausal GALT carriers and controls. The authors conclude that there is no evidence that GALT mutation carriership affects ovarian reserve or menopausal age.     

TRH-induced hyperprolactinemia and pituitary-ovarian function

To elucidate the role of prolactin in the control of pituitary-ovarian function, eight healthy women were given 80 mg of synthetic thyrotropin-releasing hormone (TRH) orally on two consecutive days during the luteal phase of their menstrual cycle. TRH elevated serum prolactin to a mean concentration of 43.8 ng/ml on the first day and to 15.5 ng/ml on the second day. The reduced response to the second TRH dose was statistically significant (p < 0.05). Accompanying changes in concentrations of gonadotropins or ovarian steroids were not consistent. Short-term oral administration of TRH and/or the temporary hyperprolactinemia induced by its use do not modify the pituitary-ovarian function during the luteal phase of the menstrual cycle.     

Side of ovulation and its effects on uterine and ovarian stromal blood flow and reproductive hormones

OBJECTIVE: Effect of the side of ovulation on uterine, ovarian, and follicular blood flow parameters and various hormone levels. DESIGN: Prospective, observational study. SETTING: Fertility Clinic, St. George's Hospital. PATIENT(S): Nineteen women with regular menstrual cycles. Pulsed Doppler measurements and serum hormonal concentrations during midfollicular, periovulatory, and midluteal phase for three successive cycles. MAIN OUTCOME MEASURE(S): Doppler blood flow and serum hormones. RESULT(S): Doppler blood flow of the ovarian stroma and follicular and uterine arteries showed no differences in the three phases between the right and left sides. Left-side uterine peak systolic velocity (PSV) (right-side PSV, 31.51cm/s; left-side PSV, 37.38 cm/s) during the periovulatory phase tended to be higher in the nondominant ovary; however, this was not quite significant. The serum hormone concentration showed no significant differences. CONCLUSION(S): The side of ovulation did not influence the Doppler blood flow to the ovarian stroma or follicular and uterine arteries. The side of ovulation had no effect on serum FSH, LH, 17beta-estradiol, P, inhibin A, or inhibin B levels.     

Inhibin B and anti-Mullerian hormone: markers of ovarian response in IVF/ICSI patients?

OBJECTIVE: The objective of this study was to investigate whether follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH) and inhibin B could be useful in predicting the ovarian response to gonadotrophin stimulation in assisted reproduction patients who are considered to be poor responders. DESIGN: Prospective study. SETTING: Fertility unit. SAMPLE: Blood samples were collected on day five or six in the early follicular phase of an untreated menstrual cycle. Samples were collected from 69 patients. METHODS: Serum samples were assayed for FSH, AMH and inhibin B using commercial immunoassay kits. MAIN OUTCOME MEASURES: Response to gonadotrophin stimulation and number of eggs collected. RESULTS: Among the 69 patients, 52 patients completed an IVF cycle and 17 patients had to cancel the cycle because of poor ovarian response to gonadotrophin stimulation. Mean FSH levels were significantly higher (P < 0.05) in the cancelled group (10.69 +/- 2.27 mIU/mL) compared with the cycle-completed group (7.89 +/- 0.78 mIU/mL). Mean AMH levels were significantly lower (P < 0.01) in the cancelled group (0.175 +/- 0.04 ng/mL) compared with the cycle-completed group (1.13 +/- 0.2 ng/mL). Mean inhibin B levels were significantly lower (P < 0.001) in the cancelled group (70 +/- 12.79 pg/mL) compared with the completed group (126.9 +/- 8.8 pg/mL). Predictive statistics show that AMH is the best single marker and that the combination of FSH, AMH and inhibin B is modestly better than the single marker. Linear regression analysis in the cycle completed patients shows that although FSH (r= 0.25, P < 0.05) and inhibin B (r= 0.35, P < 0.05) have a significant linear association with the number of eggs collected, AMH has the greatest association (r= 0.69, P < 0.001) with the number of eggs collected among the parameters measured. CONCLUSION: In this particular group of IVF patients, AMH is the best single marker of ovarian response to gonadotrophin stimulation. The combined markers modestly improved the prediction.     

Role of inhibin in polycystic ovarian syndrome

The possible role of inhibin in the etiology of polycystic ovarian syndrome (PCO) was studied. In rats PCO was induced by thiouracil and human chorionic gonadotropin (hCG). These animals were grouped under different treatment schedules: inhibin; antibodies to inhibin; ovine follicle stimulating hormone (FSH). In rats treated with antibodies to inhibin, there was a decrease in ovarian weight concomitant with specific increase in serum FSH levels. No changes in serum luteinizing hormone (LH) and prolactin levels were observed. However, testosterone levels were significantly decreased. Histological examination of the ovaries showed a marked arrest in the cyst formation with new growing follicles. In animals treated with inhibin, testosterone levels increased without any accompanying changes in ovarian weight. The circulating levels of prolactin and LH were unaffected. A decrease in serum FSH levels was accompanied by an increase in the number of cysts. The study corroborates the hypothesis that inhibin is involved in the development of PCO syndrome. Hence, an antagonist to inhibin may prove useful for the treatment of women with this condition.     

血清抑制素含量在月经周期中的变化及其与卵泡刺激素的相关性

目的了解育龄妇女在月经周期中血清抑制素(INH)含量的变化规律及其与卵泡刺激素(FSH)、黄 体生成素(LH)、雌二醇(E2)及孕酮(P)的相关性。方法建立一种改良的INH放射免疫测定法(RIA),对育龄妇 女正常月经周期中及绝经后妇女血清INH含量的变化进行监测;同时测定血清FSH、LH、E     

Comparison of Basal and Clomiphene Citrate Induced FSH and Inhibin B, Ovarian Volume and Antral Follicle Counts as Ovarian Reserve Tests and Predictors of Poor Ovarian Response in IVF

PURPOSE: To compare basal and clomiphene citrate (CC) induced follicle-stimulating hormone (FSH), estradiol (E2), and inhibin B levels with ultrasound indices of ovarian reserve in infertile women and to test the prognostic value of these tests on response to ovarian stimulation in in vitro fertilization (IVF). METHODS: Fifty-six patients had basal and CC induced serum hormone levels and ultrasound measured mean ovarian volume (MOV) and mean antral follicle counts (MFC). Thirty-two patients were then appropriately selected to have a total of 41 cycles of IVF/ICSI treatment. RESULTS: Women with diminished ovarian reserve had lower MOV, MFC, day 3 and day 10 inhibin B levels (p < 0.001). Only basal and CC induced FSH and inhibin B correlated with MOV and MFC. Poor responders in IVF/ICSI had higher basal FSH (p < 0.05), lower basal and induced inhibin B levels (p < 0.05), and lower MOV and MFC (p < 0.01) than normal responders. Ovarian volume alone was better than age and basal hormones in predicting poor ovarian response, while abnormal CC test was the only independent significant factor in predicting ovarian response. However, age was the only independent predictor of pregnancy in IVF as compared to hormonal and ultrasound indices of ovarian reserve. CONCLUSION: CC test and ovarian volume are better than other hormonal and sonographic tests in predicting the response to ovarian stimulation in IVF cycles.