Within- and between-person variation in morning testosterone is associated with economic risk-related decisions in athletic women across the menstrual cycle.

Literature suggests that women experience ovulatory shifts in risk-taking behaviours across different domains, which might be partly attributed to changes in testosterone (T). Thus, we investigated associations between menstrual variability in T concentrations and economic risk-related decisions among athletic women. Thirty-five women were monitored across three consecutive menstrual cycles. Testing occurred on day seven (D7), 14 (D14) and 21 (D21) following the onset of menses. The morning (7 to 8 am) assessment of salivary T (sal-T) and cortisol (sal-C) was followed by the economic Hawk-Dove game (11 am to 12 pm) played in pairs, where hawk decisions were used to index risk. Morning sal-T concentration increased from D7 to D14, before decreasing on D21 (p < 0.001), representing moderate effect size (ES) changes of 0.6 to 0.8. Morning sal-C did not vary over time. Hawk choices paralleled the sal-T results, being elevated on D14 (p < 0.001) with large ES changes of 1.8. Regression analyses revealed that morning sal-T concentration was positively related (p ≤ 0.01) to the number of hawks chosen between- (beta = 0.47) and within-participants (beta = 0.10) when controlling for training hours and menstrual day. In summary, the risk-related choices of athletic women during a dyadic contest covaried with morning sal-T concentrations across the menstrual cycle. Both outcomes were positively correlated on a within- and between-person level. Confirming the major sources of T variation across the menstrual cycle, whilst discerning its relationship with other risk-related behaviours, would be worthwhile avenues for research.

Assessment of potential biomarkers of pre-receptive and receptive endometrium in uterine fluid and a functional evaluation of the potential role of CSF3 in fertility.

The endometrium lines a women's uterus becoming receptive, and allowing embryo implantation to occur, for just a few days during the post-ovulatory mid-secretory phase of each menstrual cycle. We investigated whether concentrations of proposed receptivity biomarkers (VEGF, IL8, FGF2, CSF3 sFlt-1, sGP130 and PlGF) secreted by the endometrium into the uterine cavity and forming the microenvironment for embryo implantation is altered among a population of age-matched women with unexplained (idiopathic) infertility compared to fertile women during the receptive mid-secretory phase (n = 16 fertile, 18 infertile) and the prior pre-receptive early secretory phase (n = 19 fertile, 18 infertile) of their cycle. In the mid-secretory cohort significantly elevated concentrations of five biomarkers; PlGF (p = 0.001), IL8 (p = 0.004), sGP130 (p = 0.009), sFlt-1 (p = 0.021), and CSF3 (p = 0.029) was present in uterine fluid of infertile women during the mid-secretory phase, but only CSF3 was significantly elevated in the pre-receptive early secretory phase (p = 0.006). In vitro studies of glycosylated and non-glycosylated forms of CSF3 at representative fertile (20 ng/mL) and infertile (70 ng/mL) effects on endometrium and embryo behaviour were performed. Non-glycosylated CSF3 at fertile concentrations significantly (p < 0.001) elevated endometrial epithelial cell proliferation however chronic treatment or elevated (infertile) concentrations of CSF3 in glycosylated form abrogated the positive effects. Both forms of CSF3 increased trophoblast cell invasion (p < 0.001) regardless of concentration. Mouse embryo outgrowth was significantly (p < 0.01) increased at fertile but not at infertile concentrations. The study confirmed potential utility of five biomarkers of endometrial receptivity for future application in the mid-secretory phase while highlighting CSF3 is elevated in the earlier pre-receptive phase. Our data provides evidence that CSF3 acts on both human endometrium and embryo in a manner that is concentration and glycosylation dependent.

Perimenstrual exacerbation of symptoms in borderline personality disorder: evidence from multilevel models and the Carolina Premenstrual Assessment Scoring System.

BACKGROUND: Individuals with a borderline personality disorder (BPD) suffer from a constellation of rapidly shifting emotional, interpersonal, and behavioral symptoms. The menstrual cycle may contribute to symptom instability among females with this disorder. METHODS: Fifteen healthy, unmedicated females with BPD and without dysmenorrhea reported daily symptoms across 35 days. Urine luteinizing hormone and salivary progesterone (P4) were used to confirm ovulation and cycle phase. Cyclical worsening of symptoms was evaluated using (1) phase contrasts in multilevel models and (2) the Carolina Premenstrual Assessment Scoring System (C-PASS), a protocol for evaluating clinically significant cycle effects on symptoms. RESULTS: Most symptoms demonstrated midluteal worsening, a perimenstrual peak, and resolution of symptoms in the follicular or ovulatory phase. Post-hoc correlations with person-centered progesterone revealed negative correlations with most symptoms. Depressive symptoms showed an unexpected delayed pattern in which baseline levels of symptoms were observed in the ovulatory and midluteal phases, and exacerbations were observed during both the perimenstrual and follicular phases. The majority of participants met C-PASS criteria for clinically significant (⩾30%) symptom exacerbation. All participants met the emotional instability criterion of BPD, and no participant met DSM-5 criteria for premenstrual dysphoric disorder (PMDD). CONCLUSIONS: Females with BPD may be at elevated risk for perimenstrual worsening of emotional symptoms. Longitudinal studies with fine-grained hormonal measurement as well as hormonal experiments are needed to determine the pathophysiology of perimenstrual exacerbation in BPD.

Sex-Related Differences in GI Disorders.

Epidemiological studies indicate sex-related differences among functional gastrointestinal disorders (FGIDs) wherein females are more likely to receive a diagnosis than their male counterparts. However, the mechanism by which females exhibit an increased vulnerability for development of these pathophysiologies remains largely unknown, and therapeutic treatments are limited. The current chapter focuses on clinical research outlining our current knowledge of factors that contribute to the female predominance among FGID patients such as the menstrual cycle and sex hormones. In addition, we will discuss progress in preclinical research, including animal models, which serve as valuable tools for the investigation of the development and long term manifestation of symptoms observed within the patient population. Although much progress has been made, additional longitudinal studies in both clinical and preclinical research are necessary to identify more specific mechanisms underlying sex-related differences in FGIDs as well as targets for improved therapeutic approaches.

Endocrine assessment of ovarian cycle activity in wild female mountain gorillas (Gorilla beringei beringei).

Variability of fertility (i.e. number of births per female per year) has been reported in females of many primate species but only a few studies have explored the associated physiological and behavioral patterns. To investigate the proximate mechanisms of variability in fertility of wild female mountain gorillas (Gorilla beringei beringei), we quantified the occurrence of ovulation, matings, and successful pregnancies among females. We examined the profiles of immunoreactive pregnanediol-3-glucuronide (iPdG) for sixteen females (seven nulliparous and nine parous females, including one geriatric female; average sampling period for fecal sample collection and behavioral observations per female=175 days; SD=94 days, range=66-358 days) monitored by the staff of the Dian Fossey Gorilla Fund's Karisoke Research Center in Parc National des Volcans, Rwanda. We quantified ovarian cycles from iPdG profiles using an algorithm that we developed by adjusting the method of Kassam et al. (1996) to the characteristics of ovarian cycle profiles based on fecal hormone measurements. The mean length of ovarian cycles was 29±4 days (median: 28 days, N=13 cycles), similar to ovarian cycle lengths of other great apes and humans. As expected, we found that female mountain gorillas exhibit longer follicular phases (mean±SD: 21±3 days, N=13 cycles) than luteal phases (mean±SD: 8±3 days, N=13 cycles). We also found that the frequency of ovarian cycles was greater in parous females (i.e. 20 ovarian cycles across 44 periods of 28 days; 45.5%) than in nulliparous females (i.e. two ovarian cycles across 34 periods of 28 days; 6%). However, the frequency of days on which matings were observed did not differ significantly between parous and nulliparous females, nor between pregnant and non-pregnant females. Five pregnancies were detected with iPdG levels, but only three resulted in live births, indicating miscarriages of the other two. In sum, this study provides information on the underlying endocrine patterns of variation in fertility depending on parity, mating behavior, and pregnancy success in a critically endangered great ape.

Reductions in urinary collection frequency for assessment of reproductive hormones provide physiologically representative exposure and mean concentrations when compared with daily collection.

OBJECTIVE: To determine if reducing the frequency of urinary sample collection from daily to 5, 3, or 2 days per week during a menstrual cycle or 28-day amenorrheic monitoring period provide accurate representations of the reproductive hormone metabolites estrone-1-glucuronide (E1G) and pregnanediol glucuronide (PdG) exposure and mean concentrations. METHODS: Exercising women presenting with eumenorrhea or exercise-associated menstrual disturbances collected daily urine samples for the assessment of E1G and PdG concentrations. After enzyme immunoassay analysis of the daily samples, E1G and PdG data were systematically removed from each menstrual cycle or amenorrheic monitoring period to mimic three reduced collection frequencies, representing 5, 3, and 2 days per week. Exposure and mean concentration were calculated for both hormones and all four urinary collection frequencies. RESULTS: E1G and PdG exposure and mean cycle concentrations derived from reduced collection frequencies were not different from daily collection (P > 0.05), independent of whether menstrual cycles and monitoring periods were analyzed together or separately. Bland-Altman analysis indicated acceptable agreement between each reduced collection frequency and daily collection. CONCLUSIONS: Compared with daily urinary collection, a reduced collection frequency of 5, 3, or 2 days each week provides accurate E1G and PdG profiles of collection periods of various lengths and types of menstrual function. Reduction of urinary sample collection frequency may enable researchers to reduce participant burden and costs, increase compliance, and study a wider range of study populations.

Ethinyl estradiol and 17ß-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment.

The need to seek improved combined oral contraceptive (COC) efficacy, with fewer health risks and better acceptability, has been ongoing since the introduction of COCs more than 50 years ago. New progestin formulations combined with lower doses of ethinyl estradiol (EE), the predominant estrogenic component of COCs, have reduced the incidence of venous thromboembolism and other negative outcomes of COC treatment. Previous attempts to use endogenous 17ß-estradiol (E2) instead of EE were limited primarily by poor cycle control. The recent introduction of E2-based formulations has renewed interest to determine if there are potential benefits of using E2 in COCs. These formulations have been shown to have similar efficacy and cycle control as EE-based COCs. This review provides a brief summary of the pharmacology of EE and E2, including metabolism, pharmacokinetics and pharmacodynamics, as well as adverse effects of these estrogens.

Endometrial aspiration cytology by various techniques.

The demand for testing endometrium for detecting pathological as well as hormonal status is increasing and cytodiagnosis is extended very rapidly in malignant and non-malignant conditions. The gynaecologists have responded to this trend by providing cost effective care without compromising the quality. With this in mind, uterine aspiration curettage, ambulatory procedure, for endometrial sampling was studied. Dilatation and curettage (D&C) is probably most commonly performed gynaecological surgery. It accounts for large proportion of hospital bed use and operating room time, the cost is significant and patient also risks the complication of anaesthesia. Consequently various alternative procedures for endometrial sampling like endometrial brush, uterine lavage, jet wash vabra aspiration and endometrial biopsy have been reported.

Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study.

Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The "female" model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The "male" model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.

The impact of developmental conditions on adult salivary estradiol levels: why this differs from progesterone?

Women living in energetically stressful conditions have significantly lower baseline salivary steroid levels compared to those in affluent environments. Developmental hypotheses suggest that interpopulation variation in ovarian function results from contrasting environments experienced during growth. We use a migrant study of Bangladeshi women to test this hypothesis. We compared middle-class women (19-39 years) who migrated to London, UK, at different life-stages (pre and postmenarche), with Bangladeshi sedentees, second-generation British-Bangladeshis, and white British women living in similar London neighborhoods (total n = 227). We analyzed levels of salivary estradiol for one menstrual cycle, together with data on anthropometry, diet, lifestyle, and migration and reproductive histories. Results from multiple linear regression models, controlling for anthropometric and reproductive variables, show no significant differences in baseline estradiol levels between groups whether all cycles or just ovulatory cycles are analyzed. We also found no correlation between age at migration or time since migration on estradiol levels, nor between adult estradiol levels and age at menarche. Our results differ from previous reports of significantly lower salivary estradiol levels in populations living in more extreme ecological settings. They also contrast with our previous findings of significant intergroup differences in baseline levels of salivary progesterone. However, women who spent their childhood in Sylhet have a lower proportion of ovulatory cycles compared to women who developed in Britain. These group differences in ovulation frequency indicate more qualitative effects of contrasting developmental environments. We discuss possible explanations for differences in response between progesterone and estradiol, as well as broader implications of our findings.

Interpopulation, interindividual, intercycle, and intracycle natural variation in progesterone levels: a quantitative assessment and implications for population studies.

Methodological challenges in studying sex steroid hormones in premenopausal women result from the existence of variation at three levels: among women from the same population, among menstrual cycles recorded for women at different times of the year, and among days of the same cycle. We partitioned, for a Polish rural population, the natural, nonpathological, variation in salivary progesterone concentrations (measured during 14 days of the luteal phase) into the intracycle component (which accounts for 65% of the total variation) and the among-cycle component (the remaining 35% of the total variation). Out of the among-cycle variation in salivary progesterone, as much as 46% is expressed as differences among individual women (interindividual component); the remaining 54% of variation is due to differences among cycles of individual women (intercycle, within-women component). Such intercycle variation is probably caused by a seasonality of agricultural workload and is much higher than in nonseasonal, industrial populations. We also used bootstrap analyses to generate heuristic recommendations for choosing sample sizes of the number of subjects, number of cycles per woman, and number of days per cycle. Studies in populations with seasonal lifestyles should rely on measurements of at least three cycles per woman. Given the substantial intracycle amplitude in hormone levels to reliably assess biologically and medically relevant variation in ovarian function, at least 7-8 days/cycle should be measured.

Assessment of the proliferative status of epithelial cell types in the endometrium of young and menopausal transition women.

BACKGROUND: We determined protein and mRNA expressions of markers of normal human endometrial proliferation and hypothesized that dysregulation of the endometrial response to estradiol (E(2)) and progesterone would be observed in the older menopausal transition (MT) women compared with mid-reproductive age (MRA) controls. METHODS: Endometrial biopsies were prospectively obtained from MRA and MT non-randomized healthy volunteers during proliferative (+/- exogenous E(2)) and secretory (MRA only) menstrual cycle phases. mRNA and/or nuclear protein expressions of proliferative markers (MKI67, PCNA and MCM2), cell-cycle regulators (cyclins A1, E1 and D1 and cyclin dependent kinase Inhibitor B; CCNA1, CCNE1, CCND1 and CDKN1B) and sex-steroid receptors [estrogen receptor (ER) and progesterone receptor (PR)] were assessed in endometrial lumen, gland and stroma. RESULTS: MRA women had significantly higher proliferative than secretory expression of MKI67, PCNA, MCM2, CCNA1, CCNE1, ESR1 and PGR in lumen and gland (minimal stromal changes), whereas CDKN1B protein expression was higher during the secretory phase. E(2)-treatment of MT women led to relatively less MKI67 glandular protein expression compared with MRA women; no other age-related differences were observed. CONCLUSION: Although the MT does not appear to alter the proliferative cell phenotype of endometrial epithelium and stroma, the data suggest that prior to the MT, age is associated with a decrease in some proliferative markers and steroid receptor expression status within different endometrial cell types.

Resting energy expenditure in females with cystic fibrosis: is it affected by puberty?

OBJECTIVE: The aims of this study were to determine the effect of puberty and the menstrual cycle on resting energy expenditure (REE) in females with cystic fibrosis (CF). DESIGN: Cross-sectional study. All participants had measurements of REE, anthropometry and pubertal staging. The measurements in the postmenarche group were carried out both in the follicular and luteal phases of their menstrual cycle. SETTING: CF outpatient clinic at the Children's Hospital at Westmead. SUBJECTS: Fifty-six females with CF and pancreatic insufficiency (13 postmenarche) were recruited from the hospital clinic and 63 controls (21 postmenarche) were recruited through families and friends of hospital staff. RESULTS: Females with CF had a higher REE than controls (111.6+/-12.8% of predicted from controls P<0.001). There was a significant effect of menarche on REE with a decrease in the postmenarche -470 kJ/24 h compared with premenarche after adjustment for fat-free mass, fat mass and group (control or CF). There was no difference in REE between the follicular and luteal phases for either CF or controls. CONCLUSIONS: Females with CF had raised REE that appeared to be independent of menarche. This study implies all females with CF and pancreatic insufficiency may need more intensive dietary management, owing to raised REE, to maintain growth and nutritional status, and possibly improve survival.

Improved endometrial assessment using cyclin E and p27.

OBJECTIVE: To evaluate endometrial expression of cyclin E and p27 in fertile and infertile women. DESIGN: Retrospective clinical study. SETTING: University medical center and private practice. PATIENT(S): Thirty-three fertile volunteers, 83 women seeking infertility treatment, and 23 women undergoing mock cycles. INTERVENTION(S): Endometrial biopsy. MAIN OUTCOME MEASURE(S): Cyclin E and p27 immunohistochemistry. RESULT(S): Glandular cyclin E and p27 expression dramatically changed in intensity and subcellular localization throughout the menstrual cycle. In normal control biopsies, glandular cyclin E progressed from the basal to the lateral cytoplasm (midproliferative phase) to the nucleus (days 18 to 19) and was absent in biopsies after day 20. First appearing on days 17 to 19, p27 was found only in the nuclei. Cyclin E was more frequently seen after day 20 in infertility patients. In the hyperstimulated cycles, staining for cycle E in proliferative samples was more intense than in the natural cycles, but p27 staining was unchanged. CONCLUSION(S): Cyclin E and p27 may be clinically useful markers of development in the endometrium. As cell cycle regulators, cyclins reveal underlying biochemical processes driving endometrial progression and may partly represent the means by which estrogen and progesterone regulate this dynamic tissue.

[Assessment of the PCNA and P53 proteins expression in the proliferative, hyperplastic and neoplastic human endometrium]. / Immunohistochemiczna ocena ekspresji PCNA oraz onkoproteiny p53 we wzrostowym, rozrostowym i nowotworowym endometrium u kobiet.

In the current study, PCNA and p53 proteins were immunohistochemically studied in the proliferative (n = 5), hyperplastic (n = 4) and neoplastic (n = 20) human endometrium. PCNA immunostaining was noted in 2 out of 5 (40%) proliferative, 4 out of 4 (100%) hyperplastic, and in 18 out of 20 (90%) neoplastic slides. Concomitant PCNA and p53 expression was reported in 12 out of 20 (60%) malignant tumors. All non-endometrioid neoplasms were PCNA-positive, suggested this proliferative marker is commonly expressed in the unfavorable histological types of endometrial cancer.

Immunohistochemical assessment of superoxide dismutase expression in the endometrium in endometriosis and adenomyosis.

OBJECTIVE: To determine the expression of superoxide dismutase (SOD) in the endometrium during the menstrual cycle in endometriosis and adenomyosis. DESIGN: Immunohistochemical identification of SOD in endometrial tissues using the monoclonal antibody. SETTING: Department of obstetrics and gynecology in a university hospital. PATIENT(S): The subjects were divided into three groups: 36 patients with endometriosis, 38 patients with histologically proven adenomyosis, and 47 fertile control subjects. INTERVENTION(S): Endometrium was biopsied throughout the menstrual cycle. MAIN OUTCOME MEASURE(S): Semiquantitative immunostaining (evaluation nomogram) score for endometrial cells. RESULT(S): The analyses revealed phase-dependent changes in the expression of SODs in the glandular and surface epithelia during the menstrual cycle in fertile controls. Specifically, the expression of copper, zinc SOD was weakest in the early and midproliferative phases, then gradually increased, and was most marked in the early and midsecretory phases. The expression of manganese SOD reached a peak in the late secretory phase. The expression of both SODs in endometriosis and adenomyosis was persistently higher than the control levels throughout the menstrual cycle. CONCLUSION(S): The exaggerated expression of both SODs in the endometrium throughout the menstrual cycle suggests that superoxide plays a key role in infertility in endometriosis and adenomyosis.