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Background/Objectives: Vitamin D deficiency is common in women with polycystic ovary syndrome (PCOS) and may be associated with metabolic and endocrine disorders as well as ovulatory dysfunction. Vitamin D supplementation may improve ovarian dysfunction and follicular development by effecting gene expression. The aim of the present study was to investigate the effects of vitamin D supplementation in women with PCOS through a prospective, randomized, two-phase, parallel design, placebo-controlled trial. Methods: We assessed the impact on ovarian morphology, cycle length, and ovulatory dysfunction. Transvaginal ultrasonography (TVUS) examinations and clinical laboratory assessments were conducted at the baseline, and again after 12 and 24 weeks. The participants received vitamin D (30,000 IU/week) or a placebo (without concurrent metformin use) for 12 weeks, supplemented with calcium, followed by an additional 12 weeks of vitamin D treatment. Results: The treatment resulted in improvements in ovarian morphology and regularity of menstrual cycles in more than half of the patients. Additionally, vitamin D3 was associated with a significant increase in the ovulation rate. A statistically significant reduction in mean testosterone levels was observed in the subgroup of patients with an LH/FSH ratio greater than 2. Conclusions: Our results suggest that vitamin D3 treatment could function as either a standalone or an adjunctive therapy in the management of PCOS.

Mitochondrial dysfunction is present in the ovaries of patients with polycystic ovary syndrome (PCOS). Melatonin (MT) has shown promise in treating PCOS by improving mitochondrial dysfunction, though the underlying mechanisms remain unclear. In this study, we first assessed the levels of proteins associated with mitochondrial autophagy and dynamics in ovary granulosa cells (GCs) of PCOS patients and in the ovaries of DHEA-induced PCOS mice. We found abnormal expression of these proteins, indicating the presence of mitochondrial dysfunction in PCOS ovaries. Notably, the expression of the circadian gene Clock and melatonin synthetic enzymes were also decreased in the ovaries of PCOS patients. Studies have suggested a potential role of circadian rhythm genes in the pathogenesis and progression of PCOS. We subsequently observed that pretreatment with MT could ameliorate the abnormal levels of mitochondrial-related proteins, reverse the low expression of CLOCK, and reduce pyroptosis in PCOS ovaries. Given the potential interaction between MT and Clock, we focused on whether exogenous MT improves mitochondrial dysfunction in PCOS ovaries by regulating the expression of the circadian gene Clock. Through in vitro culture of the human ovarian granulosa cell line KGN, we further found that when CLOCK levels were inhibited, the beneficial effects of MT on abnormal mitochondrial autophagy, disturbed mitochondrial dynamics, and mitochondrial dysfunction in PCOS ovaries were not significant, and there was no notable improvement in ovary GCs pyroptosis. Our study suggests that MT may improve ovary mitochondrial dysfunction by regulating circadian gene Clock while also reducing GCs pyroptosis in PCOS.

Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989–1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.

Polycystic ovary syndrome (PCOS) is a prevalent hormonal disorder of premenopausal women worldwide and is characterized by reproductive, endocrine, and metabolic abnormalities. The clinical manifestations of PCOS include oligomenorrhea or amenorrhea, hyperandrogenism, ovarian polycystic changes, and infertility. Women with PCOS are at an increased risk of suffering from type 2 diabetes; me\\tabolic syndrome; cardiovascular events, such as hypertension, dyslipidemia; gynecological diseases, including infertility, endometrial dysplasia, endometrial cancer, and ovarian malignant tumors; pregnancy complications, such as premature birth, low birthweight, and eclampsia; and emotional and mental disorders in the future. Although numerous studies have focused on PCOS, the underlying pathophysiological mechanisms of this disease remain unclear. Mitochondria play a key role in energy production, and mitochondrial dysfunction at the cellular level can affect systemic metabolic balance. The recent wide acceptance of functional mitochondrial disorders as a correlated factor of numerous diseases has led to the presupposition that abnormal mitochondrial metabolic markers are associated with PCOS. Studies conducted in the past few years have confirmed that increased oxidative stress is associated with the progression and related complications of PCOS and have proven the relationship between other mitochondrial dysfunctions and PCOS. Thus, this review aims to summarize and discuss previous and recent findings concerning the relationship between mitochondrial dysfunction and PCOS.

Abstract Disclosure: Y. Soejima: None. K. Yamamoto: None. N. Iwata: None. K. Motohashi: None. A. Suyama: None. Y. Nakano: None. F. Otsuka: None. The transforming growth factor (TGF)-β superfamily, including bone morphogenetic protein (BMP), plays a pivotal role in reproductive function. TGF-β and BMP bind to their receptors and induce expression of target genes through Smad-mediated signaling. Smad6 and Smad7, also known as inhibitory Smads, function as negative regulators of TGF-β and BMP signaling. Although it has been reported that Smad6 and Smad7 are expressed in the ovary, their direct effects on follicular steroidogenesis have not been fully elucidated. In the present study, we investigated the influence of inhibitory Smads on ovarian BMP signaling and follicular steroidogenesis by using human granulosa cell tumor-derived KGN cells and primary cultured rat ovarian granulosa cells. In KGN cells, it was confirmed that knockdown (KD) of Smad6 and Smad7 by siRNA suppressed Smad6 and Smad7 mRNA expression, respectively. Under Smad6 KD or Smad7 KD conditions, BMP receptor signaling, detected by Id-1 mRNA levels, was enhanced in the presence of BMP-15. Under Smad6 KD conditions, BMP-15 stimulation suppressed forskolin-induced StAR and P450scc mRNA levels, enhanced 3βHSD expression, but did not affect P450arom expression. On the other hand, under Smad7 KD conditions, BMP-15 stimulation suppressed the expression of StAR and P450scc, while the expression of 3βHSD and P450arom was not affected. The expression of 20α-HSD, a progesterone degradation enzyme, remained unchanged by BMP-15 stimulation under Smad6 KD conditions but was increased under Smad7 KD conditions. Furthermore, BMP-15 stimulation suppressed the expression of clock genes including Clock and Bmal1b under the KD effects of Smad6 but not that of Smad7. Notably, in the primary culture of rat ovarian granulosa cells, simultaneous KD of Smad6 and Smad7 significantly suppressed progesterone synthesis levels, whereas it did not affect estradiol production. Collectively, it was revealed that the coexistence of inhibitory Smad6 and Smad7 regulates BMP receptor signaling in ovarian granulosa cells, which may lead to the integrated modulation of follicular steroidogenesis by BMP-15. Presentation: Monday, July 14, 2025

Polycystic ovarian syndrome (PCOS) is a prevalent endocrine condition associated with hormonal and metabolic abnormalities, as well as behavioral modifications. This research assesses the impact of the chemically profiled Pluchea dioscoridis ethanolic extract and metformin in a letrozole-induced polycystic ovary syndrome rat model. Thirty female Sprague Dawley rats were allocated into five groups: Control, P. dioscoridis (100 mg/kg), PCOS (letrozole, 1 mg/kg), PCOS + Metformin (300 mg/kg), and PCOS + P. dioscoridis (100 mg/kg), letrazole was given for 8 weeks followed by metformin or P. dioscoridis for 21 days. Behavioral assessments, hormone analyses, and dopamine quantifications in the brain were performed. Ovarian histology and immunohistochemical analysis were conducted. Letrozole-induced PCOS resulted in heightened depression- and anxiety-like behaviors, along with significant hormonal imbalances compared to the control group (P < 0.05%). Both P. dioscoridis and metformin therapies significantly ameliorated these changes, with P. dioscoridis demonstrating better efficacy. P. dioscoridis medication regulated luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estrogen levels, concurrently enhancing cerebral dopamine levels. Histological analysis revealed less cystic follicles and a reinstated normal ovarian architecture in rats treated with P. dioscoridis compared to PCOS group (P < 0.05%). Several flavonoids, nitrogenous compounds and hydroxy cinnamic acid esters were detected in P. dioscoridis samples for the first time utilizing UPLC-ESI-MS analysis. The P. dioscoridis ethanolic extract exhibited potential medicinal properties that are equivalent to or surpass those of metformin for treating behavioral, hormonal, and ovarian structural abnormalities produced by PCOS. It significantly improved dopamine levels, hormonal balance, and ovarian histology, rendering it a suitable alternative or complementary treatment for PCOS.

Background This study investigates whether ovarian structural and hormonal changes over a 13-year period differ between women diagnosed with polycystic ovary syndrome (PCOS) and healthy controls within an unselected population. Methods This prospective nested cohort study followed up on a prevalence study conducted in 2009 in an unselected-population. A total of 41 women with PCOS (≥ 35 years-old, diagnosed using the Rotterdam criteria) and 43 age- and body-mass-index-(BMI)-matched healthy controls were included from this cohort. The relationship between ovarian structure and hormonal profiles was tracked over 13 years. Antral follicle count (AFC) and ovarian volume (OV) were assessed by transvaginal/pelvic ultrasonography. Anti-Mullerian hormone (AMH), total testosterone (TT), sex hormone-binding globulin (SHBG), free androgen index (FAI), and dehydroepiandrosterone sulfate (DHEAS) were measured. The cardiometabolic profile of these aging women in same cohort was reported in a recent study. Results The mean age (44.1 ± 6.5 vs. 46.4 ± 4.2 years, p  = 0.06), BMI (24.7; IQR:21.9–27.8 vs. 25.2; IQR:23.2–28.9, p  = 0.16), and proportion of women in postmenopausal stage (75.6% vs. 62.8%, p  = 0.24) were comparable between PCOS and control groups. Ovarian volume and AFC were significantly higher in the aging women with PCOS. At 13 years follow-up, PCOS group experienced a greater decline in AFC, AMH, and TT but retained higher levels of AMH, TT, FAI, and DHEAS than controls. An AMH cutoff of 1.17 ng/mL showed moderate diagnostic reliability for diagnosing PCOS in aging women, with an area under curve of 0.71 (95% CI:0.60–0.83). Conclusions Aging women with PCOS show greater declines in AFC, OV, AMH, and TT but maintain higher ovarian and hormonal levels than controls. Serum AMH provides moderate diagnostic utility for diagnosing PCOS in aging women. Highlights • The significant differences in the clinical and biochemical profiles between reproductive age PCOS and healthy control groups appear to diminish with advancing age. • Aging women with PCOS exhibit higher levels of OV and AFC than aging healthy women. • A cut-off for AMH value could be used at a moderate reliability level, helping in the diagnosis of PCOS in aging women. • Both clinical and biochemical hyperandrogenism findings are still more pronounced in aging women with PCOS when compared to aging healthy women.