Circulating insulin-like factor 3 (INSL3) in healthy and infertile women.

STUDY QUESTION: How does insulin-like factor 3 (INSL3) concentration in blood vary across the menstrual cycle in women? SUMMARY ANSWER: INSL3 is secreted by the theca interna cells of growing antral follicles and is phasic in its expression. WHAT IS KNOWN ALREADY: The relaxin-like hormone INSL3 is known to be expressed in follicles of several mammal species, and was recently shown in cows to be specifically secreted into the bloodstream by growing antral follicles, corresponding to follicular waves. In males INSL3 is known to be acutely independent of the hormones of the hypothalamic-pituitary-gonadal axis, suggesting that in women INSL3 might be a novel biomarker for antral follicle recruitment and development. STUDY DESIGN, SIZE, DURATION: Two cohorts of women were studied. First, 18 healthy women of reproductive age were followed longitudinally for one and a half cycles, with blood sampling and hormone measurement every 2-3 days. A second cohort comprised a cross-sectional study of 909 women attending an infertility clinic, with a single blood sample taken at entry, together with other clinical and hormonal parameters. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples from both retrospective cohorts were analyzed for INSL3 using a highly sensitive time-resolved fluorescent immunoassay, and data were analyzed in comparison with other clinical and hormonal parameters. MAIN RESULT AND THE ROLE OF CHANCE: For young healthy women of reproductive age, we showed a phasic expression of INSL3 corresponding to antral follicle growth in both the follicular and luteal phases of the cycle, which was significantly (P < 0.05) elevated compared with that during menses. For women attending an infertility clinic, those with diagnosed polycystic ovarian syndrome indicated significantly (P < 0.0005) greater circulating INSL3 levels and those with low ovarian reserve showed significantly (P < 0.002) decreased INSL3 values. LIMITATIONS, REASONS FOR CAUTION: These were retrospective studies and the results were obtained from natural cycles only, with their inherent variability. WIDER IMPLICATIONS OF THE FINDINGS: We show for the first time that INSL3 in women does vary across the menstrual cycle, and appears to reflect the number of growing antral follicles recruited within both follicular and luteal phases. STUDY FUNDING/COMPETING INTEREST(S): The present retrospective study was largely supported by departmental funds. There were no competing interests.

Hormonal changes and biomarkers in late reproductive age, menopausal transition and menopause.

This chapter describes current definitions of the climacteric, perimenopause, menopausal transition and menopause, and discusses the 2001 Stages of Reproductive Aging (STRAW) criteria in relation to more recently proposed categorization criteria for reproductive aging. Data from endocrine studies on women throughout the menopausal transition are discussed from earliest to most recent. The earlier studies focused on the changes in levels of steroid hormones and gonadotrophins, and established that follicle-stimulating hormone undergoes the first detectable change while menstrual cycles remain regular. Erratic and less predictable changes in steroid hormones follow, especially with the onset of irregular cycles. Later serum hormone studies on the inhibins and anti-Mullerian hormone established that diminishing ovarian follicle number contributes to the endocrine changes with advancing reproductive age. A classification system of cycle types incorporating all available endocrine data and their associated menstrual cycle patterns is proposed, and the application of biological markers as diagnostic tools for reproductive staging is discussed.

A review of hormonal changes during the menopausal transition: focus on findings from the Melbourne Women's Midlife Health Project.

The menopause, defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity, marks the end of natural female reproductive life. It is preceded by a period of menstrual cycle irregularity, the menopausal transition, which usually begins in the mid-40s and is conventionally divided into early and late phases. The endocrine changes, which underlie the transition, are predominantly the consequence of a marked decline in ovarian follicle numbers. The most significant changes include a decrease in early cycle inhibin B and in anti-Mullerian hormone (AMH) levels. The decline in inhibin B results in an increase in FSH, which appears to be an important factor in the maintenance of estradiol (E2) concentrations until late in reproductive life. In the post-menopause, FSH levels are markedly raised, E2 levels are low, whereas inhibin B and AMH are undetectable. The menopausal transition is a time of marked hormonal instability. The Melbourne Women's Midlife Health Project has been an extremely productive study in which it has been possible to describe longitudinal changes in hormone levels throughout the menopause transition and to separate the effects of hormone change from the effects of ageing on a number of endpoints. This review provides the background for an accompanying manuscript in which a novel approach to modelling the hormonal changes during the transition is described.

Cyclicity of breast tenderness and night-time vasomotor symptoms in mid-life women: information collected using the Daily Perimenopause Diary.

OBJECTIVE: The purpose was to explore cyclicity of breast tenderness and vasomotor symptoms in menstruating mid-life women using the Daily Perimenopause Diary. METHODS: Untreated mid-life women from a convenience sample completed the Daily Perimenopause Diary for clinical (n = 14) or research (n = 10) assessments. Breast tenderness, sleep disturbance and day and night vasomotor intensity were rated on a 0-4 scale with vasomotor number as a count. Daily oral temperature data were analyzed using the Quantitative Basal Temperature algorithm to assess ovulation and estimate luteal phase length. Analysis of variance tested cyclicity using the mean of three 3-day windows (during flow, at mid-cycle and premenstrually). RESULTS: Ninety-eight complete flow-to-flow diaries (from 24 women, mean age 47 years, cycle length 27 +/- 6.4 (standard deviation) days) were available, with quantitative temperature data for 60 cycles in 16 women. Of assessed cycles, 90% were ovulatory; 25% had luteal phases < 10 days. Breast tenderness was maximal in the premenstrual window overall (p < 0.0001) and in the ovulatory subset. Night sweats were maximal premenstrually (p = 0.0035) except in anovulatory cycles. Daytime flushes were not cyclic (p = 0.1333) except in ovulatory cycles (p = 0.031). CONCLUSION: Daily Perimenopause Diaries from mid-life women show premenstrual increases in breast tenderness and night sweats.

A double-blind randomized study on the effects of red clover isoflavones on the endometrium.

OBJECTIVE: To assess the effects of a red clover-derived isoflavone extract on the Ki-67 proliferative marker of endometrial biopsies in 45-to 50-year-old perimenopausal women. We hypothesized that we would be able to detect a decrease in the Ki-67 proliferative index during the late follicular phase after a 3-month course of approximately 50 mg red clover isoflavones. Isoflavones have been found to have some antiestrogenic effects, and an antiproliferative effect during the perimenopausal period may be especially useful owing to the excessive endometrial proliferation often characteristic of this period. DESIGN: In a double-blind, randomized, controlled study, 30 women between the ages of 45 and 50 years consented to an endometrial biopsy before and after a 3-month course of either placebo or active isoflavone extract. The biopsies were timed as close as possible to days 7-11 of the menstrual cycle, and simultaneous measurements of transvaginal endometrial thickness, uterine artery Doppler, hormone profiles, lipids, and bone markers were performed. RESULTS: Of 30 women, 2 did not return for a second biopsy, and a third had an unsuccessful second biopsy. Four subjects were excluded from the Intention to Treat analysis because they did not have a menstrual bleed within the time frame of the study (3 subjects) or were tested on day 13 instead of between days 7 and 11 of the cycle (1 subject). There was no change in the Ki-67 proliferation index after treatment in either group. Eight subjects in the placebo group and eight in the P-07 group had proliferative endometrial biopsies that were synchronized with estradiol levels at baseline and post-treatment, and analysis of these subjects revealed no detectable change in the relationship between estradiol levels and Ki-67 with treatment in either group. There was no change in fasting lipids, bone markers, uterine Doppler resistance, or pulsatility index. CONCLUSION: In this small pilot study, we did not find, using immunohistochemical quantification of the Ki-67 antigen, that red clover isoflavones had an antiproliferative effect in the endometrium. Small sample size, examination of a relatively short interval in the menstrual cycle, and isoflavone formulation may have contributed to our lack of findings; however, we believe that the issue of isoflavones and their possible antiproliferative effect is deserving of further study. A simpler physiological model with less hormonal variability, such as healthy, recently menopausal women on predetermined doses of estrogen, may prove to be more informative.

Galactose metabolism and ovarian toxicity.

Galactose is an energy-providing nutrient and also a necessary basic substrate for the biosynthesis of many macromolecules in the body. Metabolic pathways for galactose are important not only for the provision of these pathways but also for the prevention of galactose and galactose metabolite accumulation. Problems with galactose metabolism can cause a variety of clinical manifestations in animals and humans. It has been found that the mammalian ovary is particularly susceptible to damage from the accumulation of galactose and galactose metabolites. The galactose metabolites Gal-1-P, galactitol, and UDPgal are all considered to be important in this toxicity and proposed mechanisms include interference with ovarian apoptosis and gonadotrophin signaling. This review addresses the most recent scientific findings regarding the possible mechanisms of galactose-induced ovarian toxicity and also the possible protective role of hormonal and antioxidant therapy. In addition, the available epidemiologic and scientific evidence linking galactose intake with risk of ovarian cancer is discussed.

Glomerulonephritis secondary to Barmah Forest virus infection.

Clinical infection with Barmah Forest virus (BFV) is becoming increasingly recognised with serological testing. We report the first case of glomerulonephritis after BFV infection. The patient required diuretic and antihypertensive therapy, but made an almost complete recovery. BFV infection should be considered in the differential diagnosis of glomerulonephritis.