Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins.

Effects of hormone replacement therapy on glucose and lipid metabolism in peri- and postmenopausal women with a history of menstrual disorders.

BACKGROUND: Previous studies have indicated that women with a history of menstrual disorders have an increased risk of metabolic and cardiovascular diseases. This has been attributed to the high proportion of polycystic ovary syndrome (PCOS) among this group. The favorable effects of hormone replacement therapy (HRT) on serum lipid profiles and glucose homeostasis in postmenopausal women is widely accepted. Whether HRT can also show positive effects on metabolic homeostasis in menopausal women with prior menstrual disorders (a putative PCOS phenotype) has not been reported yet. The aim of the study was to compare the effects of HRT on glucose and lipid metabolism in peri- and postmenopausal women with prior menstrual disorders and controls who did not have prior menstrual disorders. METHODS: A retrospective multicenter study was conducted including 595 peri- and postmenopausal women who received HRT at four hospitals in the Zhejiang Province from May 31, 2010 to March 8, 2021. Participants were divided into the Normal menstruation group and the Menstrual disorders group according to their prior usual menstrual cycle pattern. Glucose and lipid metabolism indicators were assessed at baseline and after HRT. The results were compared between and within the groups, and data from peri- and postmenopausal women were analyzed separately. RESULTS: HRT significantly decreased fasting insulin and homeostasis model assessment of insulin resistance in perimenopausal users, and fasting plasma glucose levels in postmenopausal users with prior menstrual disorders, compared with baseline. Furthermore, HRT decreased low-density lipoprotein cholesterol, total cholesterol, fasting insulin, fasting plasma glucose and homeostasis model assessment of insulin resistance in both peri- and postmenopausal controls, compared with baseline. Nevertheless, no significant differences were observed in any of the glucose or lipid metabolism indicators at baseline and follow-up, as well as changes from baseline levels between menopausal women with and without prior menstrual disorders. CONCLUSIONS: HRT shows more obvious within-group improvements in glucose and lipid metabolism in controls, but there is no significant between-group difference. Further prospective studies are required for confirmation.

A new hypothesis linking oxytocin to menstrual migraine.

OBJECTIVE: To highlight the emerging understanding of oxytocin (OT) and oxytocin receptors (OTRs) in modulating menstrual-related migraine (MRM). BACKGROUND: MRM is highly debilitating and less responsive to therapy, and attacks are of longer duration than nonmenstrually related migraine. A clear understanding of the mechanisms underlying MRM is lacking. METHODS: We present a narrative literature review on the developing understanding of the role of OT and the OTR in MRM. Literature on MRM on PubMed/MEDLINE database including clinical trials and basic science publications was reviewed using specific keywords. RESULTS: OT is a cyclically released hypothalamic hormone/neurotransmitter that binds to the OTR resulting in inhibition of trigeminal neuronal excitability that can promote migraine pain including that of MRM. Estrogen regulates OT release as well as expression of the OTR. Coincident with menstruation, levels of both estrogen and OT decrease. Additionally, other serum biochemical factors, including magnesium and cholesterol, which positively modulate the affinity of OT for OTRs, both decrease during menstruation. Thus, during menstruation, multiple menstrually associated factors may lead to decreased circulating OT levels, decreased OT affinity for OTR, and decreased expression of the trigeminal OTR. Consistent with the view of migraine as a threshold disorder, these events may collectively result in decreased inhibition promoting lower thresholds for activation of meningeal trigeminal nociceptors and increasing the likelihood of an MRM attack. CONCLUSION: Trigeminal OTR may thus be a novel target for the development of MRM therapeutics.

Endometrial epithelial-mesenchymal transition (EMT) by menstruation-related inflammatory factors during hypoxia.

Endometriosis is characterised by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal haemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, hypoxia is a well-known inducer of fibrosis that may be associated with epithelial-mesenchymal transition (EMT). However, the complex molecular interactions between hypoxia and proinflammatory menstruation-related factors, PGE2 and thrombin, a PAR1 agonist, on EMT in endometriosis have not been fully characterised. To explore the effects of hypoxia and proinflammatory factors on EMT-like changes in endometrial cells, we determined the effects of PGE2 and thrombin (P/T) on EMT marker expression and cell migration in three dimensional cultured human endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). Treatment of EECs with P/T under hypoxia stimulated cell migration, increased the expression of mesenchymal N-cadherin, vimentin and C-X-C chemokine receptor type 4 (CXCR4), and reduced the expression of epithelial E-cadherin. Furthermore, treatment with C-X-C motif chemokine ligand 12 (CXCL12), a ligand for CXCR4, increased EMT marker expression and cell migration. In ESCs, P/T or oestrogen treatment under hypoxic conditions increased the expression and secretion of CXCL12. Taken together, our data show that hypoxic and proinflammatory stimuli induce EMT, cell migration and inflammation in EECs, which was increased by CXCL12 derived from ESCs. These data imply that inflammatory mediators in retrograde menstrual fluid contribute to ectopic endometrial EMT and migration in the presence of peritoneal hypoxia.

Label-free proteomics uncovers SMC1A expression is Down-regulated in AUB-E.

BACKGROUND: While heavy menstrual bleeding (HMB) is a prevalent symptom among women with abnormal uterine bleeding caused by endometrial disorder (AUB-E) seeking gynecologic care, the primary endometrial disorder remains poorly understood. METHODS: Five human endometrial samples from women with AUB-E and the age-matched healthy women were selected, respectively. Proteins from the samples were analyzed by a linear ion trap (LTQ)-Orbitrap Elite mass spectrometer based label-free proteomic approach. The purpose protein was validated by western blot and immunohistochemistry staining. RESULTS: A total of 2353 protein groups were quantified under highly stringent criteria with a false discovery rate of < 1% for protein groups, and 291 differentially expressed proteins were significantly changed between the two groups. The results showed that the down-regulation of structural maintenance of chromosomes protein 1A (SMC1A) in AUB-E patients. Next, this change in the glandular epithelial cells was validated by immunohistochemistry. CONCLUSION: The results indicated a novel mechanism for the cause of AUB-E, as down-expression SMC1A potentially regulated the cell cycle progression in endometrial glandular epithelium further led to bleeding.

Dietary Supplementation of Lauric Acid Alleviates the Irregular Estrous Cycle and the Impaired Metabolism and Thermogenesis in Female Mice Fed with High-Fat Diet (HFD).

Lauric acid (LA) has been implicated in the prevention/treatment of obesity. However, the role of LA in modulating an obesity-related female reproductive disorder remains largely unknown. Here, female mice were fed a control diet, high-fat diet (HFD), or HFD supplemented with 1% LA. The results demonstrated that the HFD-induced estrous cycle irregularity and the reduction of serum follicle-stimulating hormone (FSH) were alleviated by LA supplementation. In possible mechanisms, LA supplementation led to significant increase in serum lipid metabolites such as sphingomyelin and lysophosphatidylcholine containing LA (C12:0) and the improvement of glucose metabolism in mice fed HFD. Moreover, impaired body energy metabolism and weakened brown adipose tissue (BAT) thermogenesis of HFD-fed mice were improved by LA supplementation. Together, these findings showed that LA supplementation alleviated HFD-induced estrous cycle irregularity, possibly associated with altered serum lipid metabolites, improved glucose metabolism, body energy metabolism, and BAT thermogenesis. These findings suggested the potential application of LA in alleviating obesity and its related reproductive disorders.

Reproductive health in women with type 2 diabetes mellitus.

As type 2 diabetes mellitus (T2DM) reaches epidemic proportions in the developed world and the age at diagnosis decreases, more women of reproductive age are being affected. In this article, we provide a synoptic view on potential mechanisms and relevant factors underlying menstrual cycle disorders and fertility issues in women with T2DM. The article discusses the function of the hypothalamic-pituitary-ovarian (HPO) axis, the central role of the hypothalamus in the homeostasis of this system, the central modulators of the axis, and the peripheral metabolic signals involved in neuroendocrine control of reproduction. The available literature on the relationship between T2DM and the female reproductive lifespan, menstrual cycle disorders, fertility issues, and gestational health in women with T2DM are also discussed. The data so far indicate that there is a "U-shaped" relationship between menarche, menopause, and T2DM, both early and late menarche/menopause being risk factors for T2DM. Hyperglycemia and its consequences may be responsible for the effects of T2DM on reproductive health in women, but the exact mechanisms are not as yet fully understood; thus, more studies are needed in order to identify factors causing disruption of the HPO axis.

Epidemiology and Treatment of Menstrual Migraine and Migraine During Pregnancy and Lactation: A Narrative Review.

The peak prevalence of migraine occurs in women of reproductive age, and women experience a higher burden of migraine symptoms and disability compared to men. This increased burden of migraine in women is related to both developmental and temporally variable activational effects of female sex hormones. Changing levels of female sex hormones affect the expression of migraine during pregnancy, and, to a lesser degree, lactation, and are the mechanism underlying menstrual migraine. This review describes the evidence for sex differences in the expression of migraine across the reproductive epoch; reviews the epidemiology of migraine during pregnancy, lactation, and menses; and summarizes the available evidence for safety and efficacy of acute treatments during pregnancy and lactation and for menstrual migraine. Areas of controversy in treatment of migraine during pregnancy, including the use of magnesium, triptans vs butalbital combination medications, and onabotulinum toxin, are also explored.

Energy Availability Is Associated With Luteinizing Hormone Pulse Frequency and Induction of Luteal Phase Defects.

OBJECTIVE: Determine the interrelations between reductions in energy availability (EA), luteinizing hormone (LH) pulse frequency, and the induction of menstrual disturbances in previously sedentary, ovulatory women. METHODS: Secondary analysis of a randomized controlled trial consisting of a 3-month controlled diet and supervised exercise program. EA was calculated daily by measured energy intake (kcal) and exercise energy expenditure (kcal) normalized to fat-free mass (kg) and averaged during baseline and each of 3 intervention menstrual cycles. Blood samples were obtained every 10 minutes for 24 hours in the early follicular phase before the intervention and after 3 months of diet and exercise (n = 14). LH pulse dynamics were assessed by Cluster. Linear mixed models determined whether EA predicts LH pulse frequency and LH pulse frequency predicts luteal phase defects (LPDs). RESULTS: Subjects were 20 ± 1 years old, 165.1 ± 1.4 cm tall, and weighed 58.9 ± 1.5 kg. LH pulse frequency decreased from 0.82 ± 0.06 pulses/h to 0.63 ± 0.09 pulses/h (P = 0.048) as a result of the intervention which produced modest (-3.2 ± 0.6 kg) weight loss. EA, averaged across a menstrual cycle, predicted LH pulse frequency (P = 0.003) such that a single-unit decrease in EA was associated with a 0.017 pulses/h decrease in LH pulse frequency. LH pulse frequency in cycles with LPDs was 49% of that observed in cycles with no menstrual disturbances and for every 0.1-unit decrease in LH pulse frequency, the odds of having an LPD were 22× greater than having an optimal ovulatory cycle (P = 0.01). CONCLUSIONS: Modest reductions in EA over a prolonged period are associated with decreased LH pulse frequency and the induction of menstrual disturbances.

Kisspeptin and LH pulsatile temporal coupling in PCOS patients.

PURPOSE: To evaluate the temporal coupling between spontaneous kisspeptin and luteinizing hormone (LH) pulsatile releases in polycystic ovary syndrome (PCOS) patients. METHODS: We examined 71 patients diagnosed with PCOS. A 2 h pulsatility study was performed to evaluate serum kisspeptin and LH pulse frequency and concentration, sampled every 10 min; baseline follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), cortisol, 17-hydroksy-progesterone (17OHP), testosterone (T), free testosterone index (FTI, and insulin levels were also measured. Detect and Specific Concordance (SC) algorithms were used to evaluate the temporal coupling associations between spontaneous episodic secretion of kisspeptin and LH. RESULTS: All PCOS patients demonstrated LH and kisspeptin pulsatile secretions. When the SC index was calculated across the sample of PCOS patients (n = 71), no temporal coupling was observed between kisspeptin and LH pulses. When PCOS patients were subdivided according to their menstrual cyclicity, oligomenorrheic patients demonstrated elevated kisspeptin pulse frequency. Additionally, the SC index reveled a temporal coupling between kisspeptin and LH secretory peaks only in eumenorrheic patients (n = 30, intermenstrual interval < 45 days). Oligomenorrheic PCOS patients (intermenstrual interval > 45 days) did not demonstrate temporal coupling between kisspeptin and LH secretory peaks. CONCLUSIONS: The study of the endogenous kisspeptin and LH pulsatile release revealed the temporal coupling of kisspeptin with LH secretory pulses only in eumenorrheic. This data supports the hypothesis that neuroendocrine impairments in PCOS affect the coupling of kisspeptin with LH pulses and potentially worsen as the disease progresses, becoming unequivocally evident in oligomenorrheic PCOS patients.

Understanding Menstrual Migraine.

PREMISE: Menstrual-related migraine is very prevalent, very disabling, yet very easy to manage given a good understanding of its cause. POSSIBLE SOLUTION: This article is intended to help with that understanding and to enable headache specialists to prescribe or create effective hormonal preventives of menstrual-related migraine.

Migraine in Women.

Migraine is one of the most common neurological disorders, affecting women disproportionally at a rate of 3:1. Prior to puberty, boys and girls are equally affected, but the female preponderance emerges after puberty. Migraine pathophysiology is not fully understood, and although the hormonal effect of estrogen is significant, other factors are at play. This article will focus on the hormonal influence on migraine in women. Here we review our most recent understanding of migraine and menstrual migraine, including epidemiology, pathophysiology, and treatment strategies for this challenging disorder, as well as migraine during pregnancy, postpartum period, breastfeeding, perimenopause, and menopause. We also review the risks and benefits of exogenous hormone use in this population and discuss stroke risk in women with migraine aura. By understanding these aspects of migraine in women, we hope to arm practitioners with the knowledge and tools to help guide treatment of this debilitating disorder in this large population.

Current Status of the Female Athlete Triad: Update and Future Directions.

PURPOSE OF REVIEW: This review provides an update on the primary clinical sequelae of the Female Athlete Triad. RECENT FINDINGS: Scientific advancements have contributed to improve understanding of Triad-related conditions, including leptin's role as a potential neuroendocrine link between energy status and reproductive function. Use of finite element analysis of HRpQCT imaging has provided a more accurate assessment of bone geometry and bone strength and may be clinically relevant. New perspectives aimed at developing and implementing a multi-disciplinary, personalized approach in the prevention and early treatment of triad-related symptoms are provided. The Female Athlete Triad is a multi-dimensional condition that affects active women across the lifespan. Energy availability impacts reproductive function and bone with implications for health and performance. Understanding the contributions of each individual component as well as their interconnected effects is necessary for progression and expansion of the Triad literature.

Three-step method for menstrual and oral contraceptive cycle verification.

OBJECTIVES: Fluctuating endogenous and exogenous ovarian hormones may influence exercise parameters; yet control and verification of ovarian hormone status is rarely reported and limits current exercise science and sports medicine research. The purpose of this study was to determine the effectiveness of an individualised three-step method in identifying the mid-luteal or high hormone phase in endogenous and exogenous hormone cycles in recreationally-active women and determine hormone and demographic characteristics associated with unsuccessful classification. DESIGN: Cross-sectional study design. METHODS: Fifty-four recreationally-active women who were either long-term oral contraceptive users (n=28) or experiencing regular natural menstrual cycles (n=26) completed step-wise menstrual mapping, urinary ovulation prediction testing and venous blood sampling for serum/plasma hormone analysis on two days, 6-12days after positive ovulation prediction to verify ovarian hormone concentrations. RESULTS: Mid-luteal phase was successfully verified in 100% of oral contraceptive users, and 70% of naturally-menstruating women. Thirty percent of participants were classified as luteal phase deficient; when excluded, the success of the method was 89%. Lower age, body fat and longer menstrual cycles were significantly associated with luteal phase deficiency. CONCLUSIONS: A step-wise method including menstrual cycle mapping, urinary ovulation prediction and serum/plasma hormone measurement was effective at verifying ovarian hormone status. Additional consideration of age, body fat and cycle length enhanced identification of luteal phase deficiency in physically-active women. These findings enable the development of stricter exclusion criteria for female participants in research studies and minimise the influence of ovarian hormone variations within sports and exercise science and medicine research.

11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency.

Context: Patients with 21-hydroxylase deficiency (21OHD) have long-term complications, resulting from poor disease control and/or glucocorticoid overtreatment. Lack of optimal biomarkers has made it challenging to tailor therapy and predict long-term outcomes. Objective: To identify biomarkers of disease control and long-term complications in 21OHD. Setting and Participants: Cross-sectional study of 114 patients (70 males), ages 2 to 67 years (median, 15 years), seen in a tertiary referral center. Methods: We correlated a mass-spectrometry panel of 23 steroids, obtained before first morning medication, with bone age advancement (children), adrenal volume (adults), testicular adrenal rest tumors (TART), hirsutism, menstrual disorders, and pituitary hormones. Results: Total adrenal volume correlated positively with 18 steroids, most prominently 21-deoxycortisol and four 11-oxygenated-C19 (11oxC19) steroids: 11ß-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11ketoA4), 11ß-hydroxytestosterone (11OHT), and 11-ketotestosterone (11ketoT) (r ≈ 0.7, P < 0.0001). Nine steroids were significantly higher (P ≤ 0.01) in males with TART compared with those without TART, including 11OHA4 (6.8-fold), 11OHT (4.9-fold), 11ketoT (3.6-fold), 11ketoA4 (3.3-fold), and pregnenolone sulfate (PregS; 4.8-fold). PregS (28.5-fold) and 17-hydroxypregnenolone sulfate (19-fold) levels were higher (P < 0.01) in postpubertal females with menstrual disorders. In males, testosterone levels correlated positively with all 11oxC19 steroids in Tanner stages 1 and 2 (r ≈ 0.7; P < 0.001) but negatively in Tanner stage 5 (r = -0.3 and P < 0.05 for 11ketoA4 and 11ketoT). In females, testosterone level correlated positively with all four 11oxC19 steroids across all Tanner stages (r ≈ 0.8; P < 0.0001). Conclusion: 11oxC19 steroids and PregS might serve as clinically useful biomarkers of disease control and long-term complications in 21OHD.

Reduced Transforming Growth Factor-ß Activity in the Endometrium of Women With Heavy Menstrual Bleeding.

Context: Heavy menstrual bleeding (HMB) is common and incapacitating. Aberrant menstrual endometrial repair may result in HMB. The transforming growth factor (TGF)-ß superfamily contributes to tissue repair, but its role in HMB is unknown. Objective: We hypothesized that TGF-ß1 is important for endometrial repair, and women with HMB have aberrant TGF-ß1 activity at menses. Participants/Setting: Endometrial biopsies were collected from women, and menstrual blood loss objectively measured [HMB >80 mL/cycle; normal menstrual bleeding (NMB) <80 mL]. Design: Immunohistochemistry and reverse transcription polymerase chain reaction examined endometrial TGF-ß1 ligand, receptors, and downstream SMADs in women with NMB and HMB. The function and regulation of TGF-ß1 were examined using cell culture. Results: TGFB1 mRNA was maximal immediately prior to menses, but no differences detected between women with NMB and HMB at any cycle stage. Histoscoring of TGFB1 revealed reduced staining in the stroma during menses in women with HMB (P < 0.05). There were no significant differences in TGFBR1/2 or TGFBR1/2 immunostaining. Cortisol increased activation of TGFB1 in the supernatant of human endometrial stromal cells (HES; P < 0.05) via thrombospondin-1. Endometrial SMAD2 and SMAD3 were lower in women with HMB during menstruation (P < 0.05), and decreased phosphorylated SMAD2/3 immunostaining was seen in glandular epithelial cells during the late secretory phase (P < 0.05). Wound scratch assays revealed increased repair in HES cells treated with TGF-ß1 versus control (P < 0.05). Conclusions: Women with HMB had decreased TGF-ß1 and SMADs perimenstrually. Cortisol activated latent TGF-ß1 to enhance endometrial stromal cell repair. Decreased TGF-ß1 activity may hinder repair of the denuded menstrual endometrium, resulting in HMB.

The role of estrogen receptor subtypes for induction of delayed effects on the estrous cycle and female reproductive organs in rats.

It has been reported that neonatal exposure to estrogens at relatively low doses can induce early onset anovulation as a delayed effect in female rats. Dysfunction of kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) was proposed to be a trigger for this effect. To determine the roles of estrogen receptor (ER) subtypes in the induction of delayed effects, we conducted a series of experiments using Donryu rats to examine whether neonatal injection of an ERα agonist (PPT), an ERß agonist (DPN) or an ERα antagonist (ICI) could induce delayed effects. Also, involvement of the kisspeptin neurons in the AVPV for induction of delayed effect by PPT and DPN was investigated. We observed that neonatal exposure to PPT, DPN and ICI induced the early onset of abnormal estrous cyclicity after sexual maturation, suggesting that the compounds capable of inducing delayed effects are not limited to ERα agonists. On the other hand, the data suggested the possibility that DPN and ICI functioned partially as ERα agonists in the neonatal brain. Regardless of the agents used, there is a possibility that dysfunction of kisspeptin neurons in the AVPV might contribute to induction of early onset anovulation.

Effects of icariin on the expression of ER, VEGF, and KDR in the endometrial cells of thin endometrium.

We explored the effects of icariin on the expression of estrogen receptor (ER), vascular endothelial growth factor (VEGF), and kinase insert domain receptor (KDR) in the endometrial cells of the thin endometrium. Primary endometrial cells were obtained and divided into a blank control group, a high-, a middle-, and a low-dose icariin groups, as well as an estrogen treatment group to undergo cellular identification by immunocytochemistry. The expression levels of ER, VEGF, and its receptor were estimated by western blotting. The expression levels of ER, VEGF, and KDR gradually increased from the control group to the estrogen (E2) treatment and icariin treatment groups; the differences were statistically significant. However, the differences were not statistically significant among the different icariin dose groups. The endometrium may be thickened by icariin treatment by increasing the expression levels of ER, VEGF, and KDR in endometrial cells.