Luteinizing hormone-independent rise of progesterone as the physiological trigger of the ovulatory gonadotropins surge in the human.

The current ovarian cycle paradigm postulates that ovulation is triggered by a critically sustained elevation of estradiol. However, an in-depth look into the published data reveals considerable uncertainty about the relative roles of progesterone and estradiol in the ovulation process.This review provides compelling evidences that the role of estradiol in ovulation has been misinterpreted and that the true physiological trigger of ovulation is a luteinizing hormone-independent preovulatory progesterone surge in the circulation to approximately 0.5 ng/mL. Furthermore, the current work reconciles the ability of progesterone to trigger ovulation, with its well-established ability to block ovulation during pregnancy, or when administered in the form of a synthetic progestin in birth control formulations and with experimental data that estradiol benzoate triggers ovulation in the complete absence of progesterone.

Folate, homocysteine and the ovarian cycle among healthy regularly menstruating women.

STUDY QUESTION: How are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women? SUMMARY ANSWER: Higher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone. WHAT IS KNOWN ALREADY: Higher folate levels as well as some variants in genes relevant to one-carbon metabolism, are associated with improved reproductive outcomes and responses to fertility treatment, but only a few small studies have explored the relationship between markers of one-carbon metabolism and menstrual cycle characteristics. STUDY DESIGN, SIZE, DURATION: The BioCycle Study (2005-2007) is a prospective, longitudinal cohort of 259 regularly menstruating women not using hormonal contraceptives or dietary supplements who were followed for up to two menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum folate and reproductive hormones were measured up to eight times per cycle and plasma homocysteine up to three times. Linear mixed models were used to estimate associations between serum folate or plasma homocysteine and log-transformed reproductive hormone levels while accounting for multiple observations and cycles per woman. Generalized estimating equations were used to examine risk of sporadic anovulation. All models were adjusted for age, race, body mass index, cigarette and alcohol use, and energy and fiber intake. MAIN RESULTS AND THE ROLE OF CHANCE: Higher plasma homocysteine concentrations were associated with lower total estradiol across the cycle (adjusted percent change per unit increase in homocysteine [aPC] -2.3%, 95% CI: -4.2, -0.03), higher follicle stimulating hormone around the time of expected ovulation (aPC 2.4%, 95% CI: 0.2, 4.7) and lower luteal phase progesterone (aPC -6.5%, 95% CI: -11.1, -1.8). Higher serum folate concentrations were associated with higher luteal phase progesterone (aPC per unit increase in folate 1.0%, 95% CI: 0.4, 1.6). Higher homocysteine concentrations at expected ovulation were associated with a 33% increased risk of sporadic anovulation. We observed no risk associated with decreased folate concentrations, but a higher ratio of folate to homocysteine at ovulation was associated with a 10% decreased risk of anovulation. LIMITATIONS, REASONS FOR CAUTION: Our results are generalizable to healthy women with adequate serum folate levels. The independent influence of homocysteine should be confirmed in larger cohorts and among women with folate deficiency or increased risks of anovulation. WIDER IMPLICATIONS OF THE FINDINGS: If these findings are confirmed, it is possible that lowering homocysteine with B-vitamins through diet or supplementation could improve ovulatory function in some women. Study FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract numbers: HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose.

Endocrinology of the Menopause.

In women, age-related changes in ovarian function begin in the mid-30s with decreased fertility and compensatory hormonal changes in the hypothalamus-pituitary-gonadal axis that maintain follicle development and estrogen secretion in the face of a waning pool of ovarian follicles. The menopause transition is characterized by marked variability in follicle development, ovulation, bleeding patterns, and symptoms of hyper- and hypoestrogenism. The menopause, which is clinically defined by the last menstrual period, is followed by the consistent absence of ovarian secretion of estradiol.

Neuroendocrine control of ovulation.

Modern methods of diagnosis have made the distinction between hypothalamic failure and ovarian failure routine. Failure of the orderly progression of hypothalamic gonadotrophin-releasing hormone (GnRH) → pituitary gonadotrophins → ovarian steroids and inhibin → hypothalamus/pituitary results in anovulation/amenorrhea. The hypothalamic connections that regulate the pattern and amplitude of GnRH pulses are plastic and respond to external/psychological conditions and internal/metabolic factors that may affect the hypothalamic substrate on which estrogen levels can act. We trace the neuroendocrine regulation of the ovarian cycle, concentrating on hypothalamic connections that underlie negative and positive feedback control of GnRH and the complementary role of the adenohypophysis. The main hormone regulating this "central axis" and the development of the endometrium is estradiol which is exported from the developing ovarian follicles and thereby closes the feedback loop with follicle development. Progesterone and inhibin are also involved. Neuroendocrine responses to internal and external factors can cause anovulation and amenorrhea. Generally, these are accompanied by abnormal negative feedback between estradiol and the gonadotrophins; coexistence of low estradiol and luteinizing hormone/follicle-stimulating hormone. There are three main causes: (1) genetic diseases that interfere with the migration of GnRH cells into the brain or result in misfolding of GnRH; (2) input from the brain that interrupts normal feedback (e.g. stress and weight loss amenorrhea); and (3) the effect of agents which alter central neurotransmission and hypothalamic function (e.g. elevated prolactin and psychotropic medications). All types of hypothalamic insufficiency result in insufficient stimulation of the ovaries. In addition to amenorrhea, this central alteration also results in other complications (downstream disease) that make hypothalamic amenorrhea of greater consequence than simply reproductive failure. Thus, there may be more at stake in the diagnosis and treatment of hypothalamic failure than brings the patient to her caregiver.

Increased sensitivity to light-induced melatonin suppression in premenstrual dysphoric disorder.

Increased sensitivity to light-induced melatonin suppression characterizes some, but not all, patients with bipolar illness or seasonal affective disorder. The aim of this study was to test the hypothesis that patients with premenstrual dysphoric disorder (PMDD), categorized as a depressive disorder in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), have altered sensitivity to 200 lux light during mid-follicular (MF) and late-luteal (LL) menstrual cycle phases compared with normal control (NC) women. As an extension of a pilot study in which the authors administered 500 lux to 8 PMDD and 5 NC subjects, in the present study the authors administered 200 lux to 10 PMDD and 13 NC subjects during MF and LL menstrual cycle phases. Subjects were admitted to the General Clinical Research Center (GCRC) in dim light (<50 lux) to dark (during sleep) conditions at 16:00 h where nurses inserted an intravenous catheter at 17:00 h and collected plasma samples for melatonin at 30-min intervals from 18:00 to 10:00 h, including between 00:00 and 01:00 h for baseline values, between 01:30 and 03:00 h during the 200 lux light exposure administered from 01:00 to 03:00 h, and at 03:30 and 04:00 h after the light exposure. Median % melatonin suppression was significantly greater in PMDD (30.8%) versus NC (-0.2%) women (p = .040), and was significantly greater in PMDD in the MF (30.8%) than in the LL (-0.15%) phase (p = .047). Additionally, in the LL (but not the MF) phase, % suppression after 200 lux light was significantly positively correlated with serum estradiol level (p = .007) in PMDD patients, but not in NC subjects (p > .05).

Alteration in auditory function during the ovarian cycle.

This study investigates whether physiological variations in ovarian hormones during the ovarian cycle (OC) are associated with changes in auditory function. Sixteen women with normal hearing underwent auditory tests and simultaneous measurements of the hormone levels four times during OC. The auditory tests included recording of otoacoustic emissions (OAEs), the medial olivocochlear (MOC) suppression and auditory brainstem responses (ABRs). The OC was defined by oestradiol and progesterone serum levels and menstrual cycle dating. A significant spontaneous OAE frequency shift [F(3,114.6)=15.8, p<0.001], with the greatest shift in the late follicular phase (highest oestrogen levels), was observed. Transient evoked OAE levels showed a consistent tendency in an increase in all frequency bands in the late follicular/early luteal stage and a decrease in the late follicular stage; TEOAE inter-session comparison indicated very small statistical differences. The MOC suppression changed significantly during OC [F(3,33.8)=3.2, p=0.036], with significant inter-session difference, lower in session 2 than in session 1 (p=0.019) and lower in session 4 than in session 1 (p=0.007). The ABR wave V absolute latency changed significantly during OC [F(3,33)=3.3, p=0.03], longer in the late follicular phase. There was also a significant positive correlation of TEOAEs and ABR (wave V latency and III-V interval) and significant negative correlation of MOC suppression with oestradiol levels in the follicular phase. The results of this study reflect very small changes in auditory function during OC, and they are suggestive of an increased hearing sensitivity around the time of ovulation.

Metformin versus acarbose therapy in patients with polycystic ovary syndrome (PCOS): a prospective randomised double-blind study.

The objective of this study was to investigate the effect of metformin versus acarbose in terms of ovulation rate, their impact on hormonal and metabolic status and tolerability of both drugs in patients with polycystic ovary syndrome (PCOS). Seventy-five patients with PCOS were included in this prospective randomised controlled double-blinded clinical study. According to randomisation, patients were allocated to receive either metformin 2550 mg/day (n = 37) or acarbose 300 mg/day (n = 38) for 12 weeks. Primary study outcomes were ovulation rate, restoration of a regular menstrual cycle and the incidence of side effects. Secondary outcomes included treatment-related hormonal and metabolic changes. Comparable high rates of regular menstrual cycles as well as ovulation could be achieved in both groups (70% and 73% for metformin vs. 78% and 59% for acarbose, p = 0.330 and p = 0.185, respectively). In contrast, only in patients treated with metformin a statistically significant decrease in fasting insulin and cholesterol levels as well as BMI was observed. However, comparing both groups at the end of treatment, no significant differences in metabolic and/or hormonal parameters could be detected. Regarding side effects, the rate of flatulence and/or diarrhoea was significantly lower for acarbose compared to metformin (38% vs. 80%, p < 0.001).

Lower levels of prepulse inhibition in luteal phase cycling women in comparison with postmenopausal women.

Menopause denotes the end of the reproductive period in a woman's life and is characterized by gradually declining plasma levels of ovarian hormones. Mounting evidence suggests that prepulse inhibition (PPI) is sensitive to fluctuations in estradiol and progesterone. Deficits in PPI are associated with conditions characterized by increased levels of ovarian steroids, such as the mid-luteal phase of the menstrual cycle and the third trimester of pregnancy. The aim of the current study was to further elucidate ovarian steroid-related effects on PPI by examining 43 women with regular menstrual cycles, 20 healthy postmenopausal women without hormone replacement treatment (HRT) and 21 healthy postmenopausal women with ongoing estradiol-only or estradiol and progesterone therapy (EPT). Cycling women were tested during the late luteal phase of the menstrual cycle while postmenopausal women were tested on any arbitrary day. The PPI was measured by electromyography. Cycling women exhibited lower levels of PPI than postmenopausal women (p<0.05). There were no differences in PPI between postmenopausal HRT users and non-users. However, postmenopausal women with estradiol serum concentrations in the cycling range had lower PPI than postmenopausal women with low estradiol concentrations (groupxPPI interaction, p<0.05). In conclusion, the results further suggest a role for the ovarian steroids in PPI regulation as PPI is increased in postmenopausal women in comparison to regularly menstruating women examined during the late luteal phase. Furthermore, postmenopausal women with estradiol levels in the cycling range had lower PPI than postmenopausal women with low estradiol levels.

Late, but not early, wake therapy reduces morning plasma melatonin: relationship to mood in Premenstrual Dysphoric Disorder.

Wake therapy improves mood in Premenstrual Dysphoric Disorder (PMDD), a depressive disorder in DSM-IV. We tested the hypothesis that the therapeutic effect of wake therapy in PMDD is mediated by altering sleep phase with melatonin secretion. We measured plasma melatonin every 30 min (18:00-09:00 h) in 19 PMDD and 18 normal control (NC) women during mid-follicular (MF) and late luteal (LL) menstrual cycle phases, and during LL interventions with early wake therapy (EWT) (sleep 03:00-07:00 h)(control condition) vs. late wake therapy (LWT) (sleep 21:00-01:00 h)(active condition). Melatonin offset was delayed and duration was longer in the symptomatic LL vs. asymptomatic MF phase in both NC and PMDD subjects. LWT, but not EWT, advanced offset and shortened duration vs. the LL baseline, although they improved mood equally. Later baseline LL morning melatonin offset was associated with more depressed mood in PMDD patients, and longer melatonin duration in the MF phase predicted greater mood improvement following LWT. That LWT, but not EWT, advanced melatonin offset and shortened duration while they were equally effective in improving mood suggests that decreasing morning melatonin secretion is not necessary for the therapeutic effects of wake therapy in PMDD.

Variations in plasma selenium levels as a result of the menstrual cycle and pregnancy in healthy Japanese women.

Plasma levels of selenium (Se) were determined consecutively during a menstrual cycle of six women in three phases (i.e., menses, follicular, and luteal). To detect possible differences in relation to normal pregnancy, plasma levels of Se were also determined in paired samples of maternal and umbilical cord blood from 12 pregnant women. No periodic changes in the plasma Se levels were observed during the menstrual cycle. The intraindividual variation, estimated by coefficients of variation, ranged from 1.9% to 9.9% among the menstrual phases of the subjects. The plasma Se level during pregnancy did not differ significantly from those of nonpregnant women, and those in the second trimester and at delivery were at similar levels (1.58+/-.14 and 1.48+/-.20 mmol/L, respectively). Compared to the levels of maternal Se at delivery, the fetal cord plasma at birth had a significant lower Se level (1.23+/-.34 mmol/L, p<.05).

Consumption of Lactobacillus acidophilus and Bifidobacterium longum do not alter urinary equol excretion and plasma reproductive hormones in premenopausal women.

OBJECTIVE: To confirm the results of an earlier study showing premenopausal equol excretors to have hormone profiles associated with reduced breast cancer risk, and to investigate whether equol excretion status and plasma hormone concentrations can be influenced by consumption of probiotics. DESIGN: A randomized, single-blinded, placebo-controlled, parallel-arm trial. SUBJECTS: In all, 34 of the initially enrolled 37 subjects completed all requirements. INTERVENTION: All subjects were followed for two full menstrual cycles and the first seven days of a third cycle. During menstrual cycle 1, plasma concentrations of estradiol (E(2)), estrone (E(1)), estrone-sulfate (E(1)-S), testosterone (T), androstenedione (A), dehydroepiandrosterone-sulfate (DHEA-S), and sex-hormone-binding globulin (SHBG) were measured on cycle day 2, 3, or 4, and urinary equol measured on day 7 after a 4-day soy challenge. Subjects then received either probiotic capsules (containing Lactobacillus acidophilus and Bifidobacterium longum) or placebo capsules through day 7 of menstrual cycle 3, at which time both the plasma hormone concentrations and the post-soy challenge urinary equol measurements were repeated. RESULTS: During menstrual cycle 1, equol excretors and non-excretors were not significantly different with respect to subject characteristics, diet, or hormone concentrations. Significant inverse correlations were found between E(2) and body mass index (BMI) (P=0.02), SHBG and BMI (P=0.01), DHEA-S and dietary fiber (P=0.04), and A and protein:carbohydrate ratio (P=0.02). Probiotic consumption failed to significantly alter equol excretor status or hormone concentrations during menstrual cycle 3, although there were trends towards decreased concentrations of T (P=0.14) and SHBG (P=0.10) in the probiotic group. CONCLUSIONS: We were unable to verify a previously reported finding of premenopausal equol excretors having plasma hormone concentrations different from those of nonexcretors. Furthermore, a 2-month intervention with probiotic capsules did not significantly alter equol excretion or plasma hormone concentrations.

Investigating sleep disturbances in adults with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and joint involvement. Most adults with RA experience sleep disturbances, including longer times before falling asleep, numerous awakenings during the night, and early morning wakening, resulting in excessive daytime sleepiness and fatigue. This article will review what is known about sleep disturbances and the biologic basis in adults with RA, the influence of ovarian hormone levels in women with RA, how medications may influence sleep in RA, and complementary and alternative therapies that may be useful in reducing sleep disturbances.

Plasma selenium and plasma and erythrocyte glutathione peroxidase activity increase with estrogen during the menstrual cycle.

OBJECTIVE: This study was designed to determine the timing and magnitude of changes in selenium status in relation to the fluctuation of 17-beta-estradiol during the menstrual cycle and the effect of different phases of the menstrual cycle on dietary selenium intake. METHODS: Plasma 17-beta-estradiol and plasma and erythrocyte selenium and glutathione peroxidase (GPx) activity were measured in fasting blood samples collected in the morning at four times over three phases of the menstrual cycle: early follicular (EF: days 1-3 menstruation), periovulatory (PO; E-1: 1 day before estrogen peak and E: during estrogen peak) and mid-luteal (ML: 7-9 days after ovulation) in healthy women (n = 14) aged 21 to 39 years and with regular menstrual cycles (26 to 30 days). The estrogen peak was confirmed by measurement of the luteinizing hormone surge. Dietary records (three-day) coincided with blood collection for each phase. RESULTS: Plasma selenium and plasma and erythrocyte GPx activity were greatest during the periovulatory phase, coinciding with the estrogen peak. No differences were observed for erythrocyte selenium or dietary selenium throughout the cycle. A linear relationship existed between estradiol and plasma selenium (p < 0.0027), plasma GPx activity (p < 0.0001), and erythrocyte GPx activity (p < 0.0001). CONCLUSIONS: These results indicate that blood selenium parameters fluctuate during the menstrual cycle such that the phase of the cycle should be considered when assessing selenium status.

Comparative measurements of serum estriol, estradiol, and estrone in non-pregnant, premenopausal women; a preliminary investigation.

Little to no data exists in the literature for serum estriol values in non-pregnant, premenopausal women. The current medical community opinion holds that estriol has no significant role in non-pregnant women relative to the other estrogens. It is a possibility that estriol's primary function has yet to be discovered. Accordingly, the first step is to understand cycle-dependent serum estriol concentrations. We have made a preliminary investigation for serum estriol concentration of 26 women during the known cycle peaks of estrone and estradiol. Five of the women were also tested for serum estriol on various days throughout the cycle in order to develop a cycle-dependent concentration profile. The result of these experiments show that serum estriol was always significantly higher than the sum of estrone and estradiol and less fluctuating. We conclude that estriol is probably a significant estrogen component.

The phase of the menstrual cycle has no influence on the disease-free survival of patients with mammary carcinoma.

We evaluated the outcome of treatment for mammary carcinoma in 89 premenopausal women in relation to the phase of the menstrual cycle. The phase of the cycle was determined on the basis of serum concentrations of 17 beta-oestradiol and progesterone. The serum samples were collected 1 day prior to or on the day of operation. After a median follow-up of 4.1 years no significant differences in disease-free survival were found between the preovulatory (proliferative), periovulatory and post-ovulatory (luteal) groups. No differences in survival were found in these subgroups between the N0 and N1 subgroup. On the basis of this study we cannot confirm that the phase of the menstrual cycle during surgery has any effect on the eventual outcome in mammary carcinoma patients. However larger studies of this type are required before definitive conclusions can be reached.

Prospective study of the hypothalamic-pituitary axis in thalassaemic patients who developed secondary amenorrhoea.

OBJECTIVE: We aimed to prospectively evaluate during 10 years the GnRH-gonadotrophin secretory dynamics in a cohort of 15 menstruating girls with beta-thalassaemia major to determine whether they sustained progressive damage to this axis. DESIGN: Patients were characterized by 12-hour gonadotrophin profiles (by sampling blood at 15-minute intervals) and assessment of gonadotrophin responses to 100 micrograms GnRH bolus (by sampling blood at 20-minute intervals for 1 hour and at 2 hours) sequentially during the follicular and luteal phases of their menstrual cycles, 12-14 months and 5-6 years after the onset of secondary amenorrhoea. SUBJECTS: We studied 15 post-menarcheal thalassaemic girls and five age-matched control subjects who were the healthy siblings of the patients. MEASUREMENTS: FSH and LH assays were determined using commercial RIA systems and double antibody techniques. Pulse detection used the Pulsar technique of Merriam and Wachter. RESULTS: We demonstrated that during their amenorrhoeic period, all thalassaemic patients had gonadotrophin pulse abnormalities and low-normal GnRH-stimulated gonadotrophin levels indicating that they had GnRH-gonadotrophin secretory insufficiency. During the subsequent 10 years there was progressive deterioration of hypothalamic-pituitary function in all patients; 66% became apulsatile and all had marked reduction in their GnRH-stimulated gonadotrophin levels. CONCLUSIONS: Our investigation suggests that thalassaemic patients with secondary amenorrhoea had severe and progressive damage to their hypothalamic-pituitary axes despite intensive chelation therapy.

Serum osteocalcin in normal menstrual cycle.

Serum osteocalcin (OC) was serially measured along an ovulatory menstrual cycle in 4 healthy unmedicated volunteers (age 33-38 years). During the study the women maintained their normal diet and daily physical activity. Starting at days 4-5 of the cycle, blood samples were taken between 09-11 AM every 2 or 3 days for OC, FSH, LH, E2 and P determinations. Daily ultrasound assessment of ovulation was performed in all subjects between days 7-18 of the cycle. Hormone determinations and OC were performed by RIA. While blood levels of FSH, LH, E2 and P changed during the cycle, according to the expected ovulatory pattern, serum OC concentrations remained stable during the cycle in each subject. In conclusion, serum OC is independent of the gonadotropin and ovarian steroid variations during the normal menstrual cycle.

Endothelin-1 levels are not influenced by tokishakuyakusan and keishibukuryogan treatment in women.

The effect of Tokishakuyakusan (TS) or Keishibukuryogan (KB) on endothelin-1 (ET-1), a newly identified peptide, in plasma and amniotic fluid from TS- or KB-treated women or normal pregnant women following TS or KB treatment was studied during the menstrual cycle, gestation, delivery and the post-partum period. ET-1 levels during and/or after TS or KB treatment had no significant changes when compared with those in TS- or KB-untreated women. These results suggest that TS or KB has no effects on the ET-1 level during the menstrual cycle, gestation and the post-partum period.