A select group of investigators attended a structured workshop, the Stages of Reproductive Aging Workshop (STRAW), at Park City, Utah, USA, in July 2001, which addressed the need in women for a staging system as well as the confusing nomenclature for the reproductive years.

MicroRNAs (miRNAs), a class of small noncoding RNAs that regulate gene expression, have fundamental roles in biological processes, including cell differentiation and proliferation. These small molecules mainly direct either target messenger RNA (mRNA) degradation or translational repression, thereby functioning as gene silencers. Epithelial cells of the uterine lumen and glands undergo cyclic changes under the influence of the sex steroid hormones estradiol-17beta and progesterone. Because the expression of miRNAs in human endometrium has been established, it is important to understand whether miRNAs have a physiological role in modulating the expression of hormonally induced genes. The studies herein establish concomitant differential miRNA and mRNA expression profiles of uterine epithelial cells purified from endometrial biopsy specimens in the late proliferative and midsecretory phases. Bioinformatics analysis of differentially expressed mRNAs revealed cell cycle regulation as the most significantly enriched pathway in the late proliferative-phase endometrial epithelium (P = 5.7 x 10(-15)). In addition, the WNT signaling pathway was enriched in the proliferative phase. The 12 miRNAs (MIR29B, MIR29C, MIR30B, MIR30D, MIR31, MIR193A-3P, MIR203, MIR204, MIR200C, MIR210, MIR582-5P, and MIR345) whose expression was significantly up-regulated in the midsecretory-phase samples were predicted to target many cell cycle genes. Consistent with the role of miRNAs in suppressing their target mRNA expression, the transcript abundance of predicted targets, including cyclins and cyclin-dependent kinases, as well as E2F3 (a known target of MIR210), was decreased. Thus, our findings suggest a role for miRNAs in down-regulating the expression of some cell cycle genes in the secretory-phase endometrial epithelium, thereby suppressing cell proliferation.

We measured serum reproductive hormone concentrations in a community-based, multiethnic population of premenopausal and early perimenopausal women to determine whether there are ethnic differences in hormones that can be explained by host factors. We studied 2930 participants in the Study of Women's Health Across the Nation who were aged 42-52 yr and self-identified as African-American (27.6%), Caucasian (47.1%), Chinese (7.4%), Hispanic (8.8%), or Japanese (9.0%) at 7 clinical sites. Outcome measures from this baseline assessment of a longitudinal study were serum estradiol (E2), FSH, testosterone (T), dehydroepiandrosterone sulfate, and SHBG concentrations and calculated estimates of free steroid availability, free testosterone index, and free E2 index from serum collected primarily in the early follicular phase of a spontaneous menstrual cycle. The primary explanatory variables were race/ethnicity, menopausal status, age, body mass index, day of the cycle, smoking, alcohol use, and physical activity. Chinese women had lower unadjusted E2 and SHBG levels, and Hispanic women had lower unadjusted T levels than other ethnic groups. Unadjusted serum FSH levels did not differ by race/ethnicity. E2 levels adjusted for host characteristics, particularly body size, did not differ by race/ethnicity. Adjusted FSH levels were higher, and adjusted T levels were lower in African-American and Hispanic women. Serum E2 and FSH concentrations were highly variable. Serum FSH levels, but no other hormone concentrations, were positively correlated with menopausal status. Serum dehydroepiandrosterone sulfate levels were negatively correlated with age, but not menopausal status. All hormone concentrations were significantly correlated with body mass index. We conclude that serum sex steroid, FSH, and SHBG levels vary by ethnicity, but are highly confounded by ethnic disparities in body size. to reproductive senescence in women is characterized by a progressive loss of ovarian response to pituitary stimulation as ovarian follicles lose the ability to develop, mature, and ovulate reproductively competent oocytes. Endocrinologically, this process of reproductive aging is characterized by a progressive rise in serum FSH levels associated with a decrease in serum estradiol (E2) levels (1), although current evidence suggests stage-specific variation in this general pattern (2). In contrast, serum dehydroepiandrosterone sulfate (DHEAS) levels decrease steadily with age without any known relationship to the loss of ovarian folliculogenesis (3, 4), leading to consideration of DHEAS as a marker of somatic aging. Once again, evidence is emerging that menopause stage-specific data are at variance with that pattern (5).No study, whether cross-sectional (6) or longitudinal (1,7,8), has investigated ethnic differences in reproductive hormones in midlife women. However, ethnic variation in hormone concentrations has been observed in menopausal women, as serum E2 levels are lower in Chinese women than in Caucasian women (9). In addition, host facto...

Objective. To study the relationship of HIV infection and drug use with the onset of natural menopause. Methods. Our analyses used the World Health Organization's definition of menopause (i.e., the date of the last menstrual period is confirmed after 12 months of amenorrhea) and baseline data from a prospective study. Semiannual interviews were conducted. Levels of HIV antibody and CD4 + cell counts were obtained. Menopause was identified at baseline or during 12 months of follow-up. Women ingesting reproductive hormones were excluded. Logistic regression analyses were used to assess factors associated with menopause.Results. Of 571 women, 53% were HIV infected, and 52% had used heroin or cocaine in the previous 5 years. The

Medical therapy for women in the perimenopausal period is controversial, in part due to varying degrees of ovarian hormone secretion characteristic of this time of life. To extend our understanding of the reproductive endocrine milieu of perimenopausal women, we studied 6 cycling women, aged 47 yr and older, for 6 months with daily collections of first morning voided urine. Five additional older reproductive aged (43-47 yr old) women were studied with daily urine and serum sampling for a single menstrual cycle; their urinary hormone data were combined with the former group for menstrual cycle comparisons. Urine was assayed for LH, FSH, estrone conjugates, and pregnanediol glucuronide and normalized for creatinine (Cr). Eleven midreproductive aged (19-38 yr old) normally cycling women, 5 women with well defined premature ovarian failure, and 5 women aged 54 yr and older who were at least 1 yr postmenopausal were used for comparison. Perimenopausal women had shorter follicular phases (11 +/- 2 days vs. 14 +/- 1 days; P = 0.031) and, hence, shorter menstrual cycles than midreproductive aged controls. FSH excretion in perimenopausal women was greater than that in younger women (range of means, 4-32 vs 3-7 IU/g Cr; P = 0.0005). LH secretion was overall greater than that in younger normal subjects (range of means, 1.4-6.8 vs. 1.1-4.2 IU/g Cr; P < 0.026). Overall mean estrone conjugate excretion was greater in the perimenopausal women compared to that in the younger women [76.9 ng/mg Cr (range, 13.1-135) vs. 40.7 ng/mg Cr (range, 22.8-60.3); P = 0.023] and was similarly elevated in both follicular and luteal phases. Luteal phase pregnanediol excretion was diminished in the perimenopausal women compared to that in younger normal subjects (range for integrated pregnanediol, 1.0-8.4 vs. 1.6-12.7 microg/mg Cr/luteal phase; P = 0.015). Compared to postmenopausal women, perimenopausal women had more overall estrone excretion (2.5-6.2 ng/mg Cr in postmenopausal women; P = 0.02) and lower mean FSH (range of means for postmenopause, 24-85 IU/g Cr; P = 0.017) and LH (range for postmenopause, 4.3-14.8 IU/g Cr; P = 0.041). Compared to women with premature menopause, perimenopausal women again had lower FSH (range of means for premature menopause, 36-82 IU/g Cr; P = 0.0022), lower LH (range of means for premature menopause, 5.5-23.8 IU/g Cr; P = 0.0092), borderline higher mean estrone conjugates (range of means for premature menopause, 4-44 ng/mg Cr; P = 0.064), and far longer periods of ovarian activity (one to two cycles in prematurely menopausal women vs. three to six cycles in perimenopausal women). We conclude that altered ovarian function in the perimenopause can be observed as early as age 43 yr and include hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion. These hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes this period of life.

Context:Female obesity is linked to abnormal menstrual cycles, infertility, reproductive wastage, and deficient LH, FSH, and progesterone secretion. Objective and Design:To elucidate the reproductive defects associated with obesity, we sampled 18 eumenorrheic (nonpolycystic ovary syndrome) women with a mean Ϯ SEM body mass index of 48.6 Ϯ 1.4 kg/m 2 with daily, first morning voided urine collections, seven of whom also had early follicular phase 12-h, every 10-min blood sampling to assess LH pulses. Daily hormones were compared with 11 eumenorrheic, normal-weight controls. A separate control group of 12 eumenorrheic, normal-weight women was used for the LH pulse studies. Main Outcome Measures:Assays for LH (serum and urine) and FSH, and estradiol and progesterone metabolites (estrone conjugate and pregnanediol glucuronide; urine) were performed. Daily hormones were meaned and normalized to a 28-d cycle length. LH pulsations were determined using two objective methods. Group means were compared using t tests. Results:Reduced whole-cycle mean, normalized pregnanediol glucuronide was observed in obese (38.2 Ϯ 2.1 g/mg creatine) compared with normal-weight women (181.3 Ϯ 35.1 g/mg creatine; P ϭ 0.002), without significant differences in LH, FSH, or estrone conjugate. Early follicular phase LH pulse frequency did not differ from normalweight women, but both amplitude and mean LH were dramatically reduced in obese women (0.8 Ϯ 0.1 and 2.0 Ϯ 0.3 IU/liter) compared with controls (1.6 Ϯ 0.2 and 3.4 Ϯ 0.2 IU/liter; P Ͻ 0.01). 10 -15% induces reversible deficits in reproductive function that have been well characterized (1). The effects of increased body weight on the reproductive axis are not as well understood, but the association of obesity with lower gonadotropins and reduced levels of sex steroids has been established (2, 3). One large, recent epidemiological study of 848 women used daily urinary sampling over the course of a menstrual cycle and observed longer follicular phases, lower LH and FSH, lower estradiol metabolites, and lower progesterone metabolites by 33% in overweight/obese [body mass index (BMI) of Ͼ25 kg/m 2 ] compared with normalweight women (4). Conclusions:We hypothesized that the reduced reproductive hormones in ovulatory, regularly cycling obese women are attributable to a deficient central neural reproductive drive. We studied morbidly obese (baseline BMI of Ͼ35 kg/m 2 ) women scheduled to undergo bariatric surgery before weight loss and compared menstrual cycle urinary hormone excretion and serum LH secretory patterns using frequent blood sampling to infer the characteristics of GnRH secretion. In this study, we compared our findings in the high-BMI women with normal-weight historical controls. Patients and Methods ParticipantsNineteen participants were recruited through a weight-loss surgery support group at the Montefiore Medical Center and Beth Israel Medical Center (New York, NY). Participants were aged 35-50 yr at enrollment and had to meet the following criteria: 1) BMI of at least 35 kg/m ...

Circulating SHBG and androgens are most strongly associated with physical characteristics and the metabolic syndrome in women in this community-based cohort. Androgens are related weakly to physical functioning and other symptoms to which they commonly are attributed, such as sexual desire, sexual arousal, and well-being.

These observations underscore differences between cross-sectional and longitudinal studies and the importance of considering ovarian status. Additional investigations regarding adrenal contribution to sex steroids in mid-aged women are warranted.