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Journal of Ovarian Research Jan 2024For women of childbearing age, the biggest problem caused by polycystic ovary syndrome (PCOS) is infertility, which is mainly caused by anovulation, abnormal follicular...
BACKGROUND
For women of childbearing age, the biggest problem caused by polycystic ovary syndrome (PCOS) is infertility, which is mainly caused by anovulation, abnormal follicular development, proliferation of small antral follicles, and cystic follicles. The mechanism underlying its occurrence is not clear. The abnormal proliferation and development of follicles in PCOS patients is a complex process, which is affected by many factors. The objective of this study was to investigate the relationship between the Hippo pathway and follicular development in PCOS, and to further explore this relationship by using the YAP inhibitor verteporfin (VP).
METHOD
30 3-week-old BALB/C female rats were randomly divided into control group (n = 10), DHEA group (n = 10) and DHEA + VP group (n = 10). The morphology of ovary and the degree of follicular development were observed by HE staining, and the expression and location of AMH in ovarian follicles were observed by immunofluorescence. The ovarian reserve function index AMH, cell proliferation index PCNA and the ratio of Hippo pathway related proteins MST, LATS, YAP, P-YAP and P-YAP/YAP were detected by Western blot.
RESULTS
After dividing 30 3-week-old female mice into control, dehydroepiandrosterone (DHEA; model of PCOS), and DHEA + VP groups, we found that the number of small follicles increased in the DHEA group compared to the control group. Additionally, in the DHEA group compared to the control group, anti-müllerian hormone (AMH; ovarian reserve index) increased, proliferating cell nuclear antigen (PCNA; cell proliferation index) decreased, and upstream (MST and LATS) and downstream (YAP and p-YAP) proteins in the Hippo pathway increased, though the p-YAP/YAP ratio decreased. VP ameliorated the increases in AMH, MST, LATS, YAP and p-YAP, but did not ameliorate the decrease in the p-YAP/YAP ratio.
CONCLUSIONS
This study indicates that the increased small follicles in the ovaries and changes in ovarian reserve and cell proliferation may be closely related to Hippo pathway activation. This suggests that the Hippo pathway may be an important pathway affecting the proliferation and development of follicles and the occurrence of PCOS.
Topics: Humans; Female; Rats; Animals; Mice; Polycystic Ovary Syndrome; Proliferating Cell Nuclear Antigen; Hippo Signaling Pathway; Mice, Inbred BALB C; Anti-Mullerian Hormone; Dehydroepiandrosterone
PubMed: 38216976
DOI: 10.1186/s13048-023-01305-z -
BMC Endocrine Disorders Mar 2024Polycystic ovary syndrome (PCOS) is a serious health condition affecting women of reproductive age. High prevalence of PCOS and associated metabolic complications needs...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a serious health condition affecting women of reproductive age. High prevalence of PCOS and associated metabolic complications needs effective treatment and management. This study evaluated the efficacy of optimal nutraceutical combinations in improving PCOS characteristics using system biology-based mathematical modelling and simulation.
METHODS
A shortlisting of eight potent nutraceuticals was carried out with literature search. Menstrual cycle model was used to perform simulations on an in-silico population of 2000 individuals to test individual and combined effects of shortlisted nutraceuticals on five PCOS characteristics [oligomenorrhea, anovulation, hirsutism, infertility, and polycystic ovarian morphology (PCOM)] for a duration of 6 months. Efficacy was tested across lean and obese phenotypes and age groups.
RESULTS
Individual assessment of nutraceuticals revealed seven most potent compounds. Myo-inositol among them was observed to be the most effective in alleviating the PCOS characteristics. The in-silico population analysis showed that the combination of melatonin and ALA along with myo-inositol was efficacious in restoring the hormonal balance across age-groups and Body Mass Index (BMI) categories.
CONCLUSION
Supplementation with the combination of myo-inositol, melatonin, and ALA demonstrated potential in managing PCOS symptoms in our in-silico analysis of a heterogeneous population, including lean and obese phenotypes across various severities and age groups, over a 6-month period. Future clinical studies are recommended to validate these findings.
Topics: Female; Humans; Polycystic Ovary Syndrome; Melatonin; Dietary Supplements; Inositol; Obesity
PubMed: 38549084
DOI: 10.1186/s12902-024-01571-y -
Phytotherapy Research : PTR Sep 2023Polycystic ovary syndrome (PCOS) is most common in women of reproductive age, giving rise to androgen excess and anovulation, leading to infertility and non-reproductive...
Naringenin improves ovarian health by reducing the serum androgen and eliminating follicular cysts in letrozole-induced polycystic ovary syndrome in the Sprague Dawley rats.
Polycystic ovary syndrome (PCOS) is most common in women of reproductive age, giving rise to androgen excess and anovulation, leading to infertility and non-reproductive complications. We explored the ameliorating effect of naringenin in PCOS using the Sprague Dawley (SD) rat model and human granulosa cells. Letrozole-induced PCOS rats were given either naringenin (50 mg/kg/day) alone or in combination with metformin (300 mg/kg/day), followed by the estrous cycle, hormonal analysis, and glucose sensitivity test. To evaluate the effect of naringenin on granulosa cell (hGC) steroidogenesis, we treated cells with naringenin (2.5 μM) alone or in combination with metformin (1 mM) in the presence of forskolin (10 μM). To determine the steroidogenesis of CYP-17A1, -19A1, and 3βHSD2, the protein expression levels were examined. Treatment with naringenin in the PCOS animal groups increased ovulation potential and decreased cystic follicles and levels of androgens. The expression levels of CYP-17A1, -19A1, and 3βHSD2, were seen restored in the ovary of PCOS SD rats' model and in the human ovarian cells in response to the naringenin. We found an increased expression level of phosphorylated-AKT in the ovary and hGCs by naringenin. Naringenin improves ovulation and suppress androgens and cystic follicles, involving AKT activation.
Topics: Humans; Female; Rats; Animals; Polycystic Ovary Syndrome; Androgens; Rats, Sprague-Dawley; Letrozole; Proto-Oncogene Proteins c-akt; Follicular Cyst; Metformin; Disease Models, Animal
PubMed: 37165686
DOI: 10.1002/ptr.7860 -
BMC Women's Health Nov 2023The aim of this study was to compare the efficacy of the combination of clomiphene citrate (CC) and letrozole to that of CC alone in inducing ovulation in infertile... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The aim of this study was to compare the efficacy of the combination of clomiphene citrate (CC) and letrozole to that of CC alone in inducing ovulation in infertile women with ovulatory dysfunction.
METHODS
A randomized controlled trial was conducted at a single academic medical center between November 2020 and December 2021. Anovulatory infertility females, aged 18 to 40, were evenly distributed by a computer-generated block of four into two treatment groups. A "combination group" received a daily dose of CC (50 mg) and letrozole (2.5 mg), while a "CC-alone group" received a daily dose of CC alone (50 mg). The study medications were administered on days 3 through 7 of menstrual cycle. The primary outcome was the ovulation rate, defined by serum progesterone levels exceeding 3 ng/mL at the mid-luteal phase. The secondary outcomes were ovulation induction cycle characteristics, endometrial thickness, conception rate, and adverse events.
RESULTS
One hundred women (50 per group) were enrolled in the study. The mean age was not significantly different in both groups: 31.8 years in the combination group and 32.4 years in the CC-alone groups (P = 0.54). The prevalence of polycystic ovary syndrome in the combination and CC-alone groups was 48% and 44%, respectively (P = 0.841). According to intention-to-treat analysis, the ovulation rates were 78% and 70% in the combination and CC-alone groups, respectively (P > 0.05). There was no significant difference in the mean endometrial thickness or the number of dominant follicles of the groups. No serious adverse events were observed in either group.
CONCLUSIONS
Our study found no significant difference between the combination of CC and letrozole and CC alone in inducing ovulation in infertile women with ovulatory dysfunction in one cycle. The small number of live births precluded any meaningful statistical analysis. Further studies are needed to validate and extend our findings beyond the scope of the current study.
TRIAL REGISTRATION
The study was registered at https://www.thaiclinicaltrials.org with the following number: TCTR20201108004 and was approved on 08/11/2020.
Topics: Pregnancy; Female; Humans; Letrozole; Infertility, Female; Fertility Agents, Female; Pregnancy Rate; Clomiphene; Ovulation Induction; Polycystic Ovary Syndrome; Live Birth
PubMed: 37964246
DOI: 10.1186/s12905-023-02773-7 -
Reproductive Sciences (Thousand Oaks,... Jul 2024Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder that is frequently linked to anovulation in women who are experiencing infertility.... (Meta-Analysis)
Meta-Analysis Review
Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder that is frequently linked to anovulation in women who are experiencing infertility. Intestinal flora, also known as the "second genome" of the host, is closely associated with chronic metabolic diseases. Recently, there has been increasing attention on the connection between PCOS and the gut microbiome, and experiments have been conducted. However, the results were unsatisfactory and inconsistent. This review aims to provide a comprehensive overview of the literature investigating the associations between the gut microbiome and PCOS in adults. The goal is to identify whether there are changes in the composition of the gut microbiome in individuals with PCOS. This is the first systematic review to focus on functional alterations in the gut microbiome, which could provide insights into potential mechanisms of microbial involvement in the development of PCOS. We found that there was no significant change in gut microbiome biodiversity in PCOS. Meta-analyses of three studies revealed a significantly higher abundance of Proteobacteria (1.12, 95% CI, 0.21, 2.02, I = 0%) in adults with PCOS. At the genus level, Bacteroides, Enterococcus, and Escherichia-Shigella were found to be enriched in patients with PCOS. Species such as Ruminococcus gnavus group, Parabacteroides distasonis, and Bacteroides fragilis showed an increase in PCOS. Metabolic pathways associated with glucose, lipid metabolism, bile acid metabolism, and protein absorption were found to be enriched in individuals with PCOS. The gut microbiome in PCOS is not characterized by lower diversity, but the composition is altered at the phylum, family, genus, or species level. Consequently, the metabolic pathway differs according to the phenotype of PCOS.
Topics: Polycystic Ovary Syndrome; Humans; Gastrointestinal Microbiome; Female; Adult; Observational Studies as Topic
PubMed: 38212581
DOI: 10.1007/s43032-023-01440-4 -
Journal of Medicine and Life Jan 2024Polycystic ovary syndrome is the most common cause of oligo-ovulation and anovulation among women of reproductive age, contributing to infertility. This study aimed to... (Randomized Controlled Trial)
Randomized Controlled Trial
Polycystic ovary syndrome is the most common cause of oligo-ovulation and anovulation among women of reproductive age, contributing to infertility. This study aimed to compare the effects of green tea tablets and metformin on ovulation, menstrual cycle regularity, and antioxidant biomarkers in women with polycystic ovary syndrome (PCOS). In this clinical trial study, 94 women with PCOS were randomly assigned to three groups: green tea ( = 33), metformin ( = 29), and control ( = 32). Menstrual status and oxidative stress parameters, including total antioxidant capacity, thiol, and lipid peroxidation, were compared before and 3 months after the intervention among all three groups. Data analysis was conducted using SPSS software version 22 and employing the analysis of variance and paired t-tests. Following the intervention, the mean menstrual cycle duration in the green tea, metformin, and control groups was 32.22 ± 12.78, 48.72 ± 37.06, and 48.53 ± 31.04 days, respectively ( = 0.040). There was no statistically significant difference between the three groups in terms of biochemical, hormonal, and antioxidant indices before and after the intervention ( > 0.05). The intake of green tea tablets was associated with better outcomes in regulating the menstrual cycle in women with PCOS.
Topics: Humans; Polycystic Ovary Syndrome; Female; Metformin; Tea; Menstrual Cycle; Adult; Ovulation; Tablets; Young Adult; Antioxidants; Oxidative Stress
PubMed: 38737668
DOI: 10.25122/jml-2022-0066 -
Chronobiology International Aug 2023Environmental factors, such as sleep restriction, contribute to polycystic ovary syndrome (PCOS) by causing hyperinsulinemia, hyperandrogenism, insulin resistance, and...
Environmental factors, such as sleep restriction, contribute to polycystic ovary syndrome (PCOS) by causing hyperinsulinemia, hyperandrogenism, insulin resistance, and oligo- or anovulation. This study aimed to evaluate the effects of circadian rhythm disruption on reproductive and metabolic functions and investigate the potential therapeutic benefits of MitoQ10 and hot tub therapy (HTT). Sixty female rats were divided into six groups: control, MitoQ10, HTT, and three groups with PCOS induced by continuous light exposure(L/L). The reproductive, endocrine, and structural manifestations ofL/L-induced PCOS were confirmed by serum biochemical measurements, ultrasound evaluation of ovarian size, and vaginal smear examination at week 14. Subsequently, the rats were divided into the L/L (untreated), L/L+MitoQ10-treated, andL/L+HTT-treated groups. At the end of week 22, all rats were sacrificed. Treatmentwith MitoQ10 or HTT partially reversed the reproductive, endocrine, and structural features of PCOS, leading to a decreased amplitude of isolated uterine contractions, ovarian cystic changes and size, and endometrial thickness. Furthermore, both interventions improved the elevated serum levels of anti-Mullerian hormone (AMH), kisspeptin, Fibulin-1, A disintegrin and metalloproteinase with thrombospondin motifs 19 (ADAMTS-19), lipid profile, homeostatic model assessment for insulin resistance (HOMA-IR), oxidative stress markers, androgen receptors (AR) and their transcription target genes, FKBP52 immunostaining in ovarian tissues, and uterine estrogen receptor alpha (ER-α) and PRimmunostaining. In conclusion, MitoQ10 supplementation and HTT demonstrated the potential for ameliorating metabolic, reproductive, and structural perturbations associated with PCOS induced by circadian rhythm disruption. These findings suggest a potential therapeutic role for these interventions in managing PCOS in women.
Topics: Humans; Female; Rats; Animals; Polycystic Ovary Syndrome; Insulin Resistance; Hot Temperature; Circadian Rhythm; Hyperandrogenism
PubMed: 37548004
DOI: 10.1080/07420528.2023.2241902 -
Applied Physiology, Nutrition, and... May 2024Exercising women have a high prevalence of menstrual disturbances. In 2003, it was suggested that disruption in luteinizing hormone (LH) pulsatility occurs below a... (Review)
Review
Exercising women have a high prevalence of menstrual disturbances. In 2003, it was suggested that disruption in luteinizing hormone (LH) pulsatility occurs below a threshold of energy availability (EA) of 30 kcal/kg lean body mass (LBM)/day. This paper is a critical review of the evidence regarding the theory that disruptions to the reproductive axis and menstrual disturbances occur below the proposed threshold. Short-term laboratory studies demonstrated that 4-5 days of an EA below 30 kcal/kg LBM/day, induced with or without exercise, decreased serum triiodothyronine and LH pulse frequency, and increased LH pulse amplitude in sedentary, regularly menstruating women. Fewer studies have investigated downstream ovarian effects after long-term exposure to low EA. The Sargent Camp Study was the first randomized trial that induced luteal phase defects, delayed menses, and anovulation by causing weight loss (-4 ± 0.3 kg) with an abrupt increase in exercise volume for two menstrual cycles. The BioEnergetics Study was a randomized controlled trial that induced varying levels of energy deficits by manipulating energy intake and expenditure for three menstrual cycles. LH pulse frequency and triiodothyronine decreased, and 57% of women developed luteal phase defects, anovulation, and/or oligomenorrhea. An EA below 30 kcal/kg fat free mass/day increased the chance of experiencing a menstrual disturbance by 50%. However, menstrual disturbances were observed above and below that EA threshold, and changes in LH pulse frequency predicted only luteal phase defects, not oligomenorrhea or anovulation. The proposed EA threshold is not a cut-off below which menstrual disturbances occur, but represents an increased risk of experiencing menstrual disturbances.
Topics: Humans; Female; Menstruation Disturbances; Energy Metabolism; Luteinizing Hormone; Exercise; Energy Intake; Menstrual Cycle
PubMed: 38194640
DOI: 10.1139/apnm-2023-0418 -
Cytokine Jul 2024Polycystic ovarian syndrome (PCOS) is one of the most common (about 5-20%) reproductive disorders in women of reproductive age; it is characterized by polycystic...
AIMS
Polycystic ovarian syndrome (PCOS) is one of the most common (about 5-20%) reproductive disorders in women of reproductive age; it is characterized by polycystic ovaries, hyperandrogenism, and oligo/ anovulation. The levels and expression of ovarian adipokines are deregulated in the PCOS. Apelin is an adipokine that acts through its receptor (APJ) and is known to express in the various tissues including the ovary. It has also been suggested that apelin and APJ could be targeted as therapeutic adjuncts for the management of PCOS. However, no study has been conducted on the management of PCOS by targeting the apelin system. Thus, we aimed to evaluate its impact on combating PCOS-associated ovarian pathogenesis.
METHODS
The current work employed a letrozole-induced-hyperandrogenism PCOS-like mice model to investigate the effects of apelin13 and APJ, antagonist ML221. The PCOS model was induced by oral administration of letrozole (1 mg/kg) for 21 days. A total of four experimental groups were made, control, PCOS control, PCOS + aplein13, and PCOS + ML221. The treatment of apelin13 and ML221 was given from day 22 for two weeks.
KEY FINDINGS
The letrozole-induced PCOS-like features such as hyperandrogenism, cystic follicle, decreased corpus luteum, elevated levels of LH/FSH ratio, and up-regulation of ovarian AR expression were ameliorated by apelin13 and ML221 treatment. However, the PCOS-augmented oxidative stress and apoptosis were suppressed by apelin 13 treatments only. ML221 treatment still showed elevated oxidative stress and stimulated apoptosis as reflected by decreased antioxidant enzymes and increased active caspase3 and Bax expression. The expression of ERs was elevated in all groups except control. Furthermore, the PCOS model showed elevated expression of APJ and apelin13 treatment down-regulated its own receptor. Overall, observing the ovarian histology, corpus luteum formation, and decreased androgen levels by both apelin13 and ML221 showed ameliorative effects on the cystic ovary.
SIGNIFICANCE
Despite the similar morphological observation of ovarian histology, apelin13 and ML221 exhibited opposite effects on oxidative stress and apoptosis. Therefore, apelin13 (which down-regulates APJ) and ML221 (an APJ antagonist) may have suppressed APJ signalling, which would account for our findings on the mitigation of polycystic ovarian syndrome. In conclusion, both apelin13 and ML221 mediated mitigation have different mechanisms, which need further investigation.
Topics: Letrozole; Polycystic Ovary Syndrome; Animals; Female; Apelin Receptors; Mice; Apelin; Ovary; Oxidative Stress; Hyperandrogenism; Apoptosis; Disease Models, Animal
PubMed: 38733946
DOI: 10.1016/j.cyto.2024.156639 -
Human Reproduction (Oxford, England) Jan 2024The potential for repeated ovulation and menstruation is thought to have provided a Darwinian advantage during the Palaeolithic. Reproductive conditions remained...
The potential for repeated ovulation and menstruation is thought to have provided a Darwinian advantage during the Palaeolithic. Reproductive conditions remained relatively stable until the pre-industrial era, characterized by late menarche, very young age at first birth, multiple pregnancies, and prolonged periods of lactational amenorrhoea. For hundreds of thousands of years, menstruators experienced few ovulatory cycles, even though they were genetically adapted to ovulate and menstruate every month. In the post-industrial era, the age at menarche gradually declined, the age at first birth progressively increased, and breastfeeding became optional and often of short duration. This created a mismatch between genetic adaptation and socio-environmental evolution, so that what was initially a probable reproductive advantage subsequently contributed to increased susceptibility to diseases associated with lifetime oestrogen exposure, such as ovarian, endometrial and breast cancer and, hypothetically, also those associated with the number of ovulatory menstruations, such as endometriosis and adenomyosis. The incidence of endometriosis shows a steep and progressive increase around the age of 25 years, but given the consistently reported delay in diagnosis, the actual incidence curve should be shifted to the left, supporting the possibility that the disease has its roots in adolescence. This raises the question of whether, from an evolutionary point of view, anovulation and amenorrhoea should not still be considered the physiological state, especially in the postmenarchal period. However, an increase in the frequency of endometriosis in recent decades has not been demonstrated, although this deserves further epidemiological investigation. In addition, as endometriosis occurs in a minority of individuals exposed to retrograde menstruation, other important pathogenic factors should be scrutinised. Research should be resumed to explore in more detail the transtubal reflux of not only blood, but also endometrial cells, and whether they are systematically present in the peritoneal fluid after menstruation. If repetitive ovulatory menstruation during the early reproductive years is shown to increase the risk of endometriosis and adenomyosis development and progression in susceptible individuals, hormonal interventions could be used as secondary prevention in symptomatic adolescents.
Topics: Pregnancy; Female; Adolescent; Humans; Adult; Endometriosis; Adenomyosis; Amenorrhea; Secondary Prevention; Menstruation
PubMed: 37951243
DOI: 10.1093/humrep/dead229