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PLoS Computational Biology Apr 2023Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to...
Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to attain this state to achieve contraception. However, large doses are associated with adverse effects such as increased risk for thrombosis and myocardial infarction. This study utilizes optimal control theory on a modified menstrual cycle model to determine the minimum total exogenous estrogen/progesterone dose, and timing of administration to induce anovulation. The mathematical model correctly predicts the mean daily levels of pituitary hormones LH and FSH, and ovarian hormones E2, P4, and Inh throughout a normal menstrual cycle and reflects the reduction in these hormone levels caused by exogenous estrogen and/or progesterone. Results show that it is possible to reduce the total dose by 92% in estrogen monotherapy, 43% in progesterone monotherapy, and that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. Finally, we show that by combining estrogen and progesterone the dose can be lowered even more. These results may give clinicians insights into optimal formulations and schedule of therapy that can suppress ovulation.
Topics: Female; Humans; Progesterone; Luteinizing Hormone; Estradiol; Anovulation; Estrogens; Contraception
PubMed: 37053167
DOI: 10.1371/journal.pcbi.1010073 -
International Journal of Molecular... Mar 2023Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts,... (Review)
Review
Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers-myo-Inositol and D-Chiro-Inositol-have recently been pharmacologically effective in managing many PCOS symptoms while rescuing ovarian fertility. However, some disappointing clinical results prompted the reconsideration of their specific biological functions. Surprisingly, D-Chiro-Ins stimulates androgen synthesis and decreases the ovarian estrogen pathway; on the contrary, myo-Ins activates FSH response and aromatase activity, finally mitigating ovarian hyperandrogenism. However, when the two isomers are given in association-according to the physiological ratio of 40:1-patients could benefit from myo-Ins enhanced FSH and estrogen responsiveness, while taking advantage of the insulin-sensitizing effects displayed mostly by D-Chiro-Ins. We need not postulate insulin resistance to explain PCOS pathogenesis, given that insulin hypersensitivity is likely a shared feature of PCOS ovaries. Indeed, even in the presence of physiological insulin stimulation, the PCOS ovary synthesizes D-Chiro-Ins four times more than that measured in control theca cells. The increased D-Chiro-Ins within the ovary is detrimental in preserving steroidogenic control, and this failure can easily explain why treatment strategies based upon high D-Chiro-Ins have been recognized as poorly effective. Within this perspective, two factors emerge as major determinants in PCOS: hyperandrogenism and reduced aromatase expression. Therefore, PCOS could no longer be considered a disease only due to increased androgen synthesis without considering the contemporary downregulation of aromatase and FSH receptors. Furthermore, these findings suggest that inositols can be specifically effective only for those PCOS phenotypes featured by hyperandrogenism.
Topics: Humans; Female; Polycystic Ovary Syndrome; Inositol; Hyperandrogenism; Aromatase; Androgens; Insulin Resistance; Insulin; Follicle Stimulating Hormone; Estrogens
PubMed: 37047265
DOI: 10.3390/ijms24076296 -
Healthcare (Basel, Switzerland) Mar 2023Polycystic ovary syndrome (PCOS) is a chronic endocrinopathy characterized by oligo- or anovulation, clinical and/or biochemical markers of hyperandrogenism, and...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a chronic endocrinopathy characterized by oligo- or anovulation, clinical and/or biochemical markers of hyperandrogenism, and polycystic ovaries, and it is associated with an increased prevalence of depression. Research conducted on psychiatric patients has shown correlations between depression and decreased cognitive function. The aim of this study was to examine the possible mediation of the time perspective (TP) in the development of depressive symptoms in patients with PCOS.
METHODS
A study was conducted on 83 patients with PCOS and 65 healthy women. Standardized questionnaires were used to assess depressive symptoms (Beck Depression Inventory-BDI-II) and time perspective (Zimbardo Time Perspective Inventory-ZTPI).
RESULTS
Our study revealed an indirect influence of depressive symptoms on PCOS through the positive future time perspective. In the logistic regression model, which included depression and a given time perspective as predictors of PCOS, only the future TP (β = -0.004, < 0.003, OR = 1.004, 95% CI [1.001, 1.008]) was significantly independently related to the occurrence of PCOS.
CONCLUSIONS
Our result is another argument for the role of psychoeducation and appropriate communication with a patient from the risk group in a way that builds hope and allows to regain influence on life situation.
PubMed: 37046920
DOI: 10.3390/healthcare11070993 -
European Review For Medical and... Mar 2023Oxytocin (OXT) controls appetite, promotes diet-induced energy expenditure, and may protect against obesity. Furthermore, the oxytocin system controls ovarian follicle...
OBJECTIVE
Oxytocin (OXT) controls appetite, promotes diet-induced energy expenditure, and may protect against obesity. Furthermore, the oxytocin system controls ovarian follicle luteinization and steroidogenesis as well as adrenal steroidogenesis, which if impaired might lead to anovulation and hyperandrogenism, signs found in women with polycystic ovarian syndrome (PCOS). PCOS is a common complex endocrine disorder of reproductive-age women, and it often presents with impaired glucose metabolism, insulin resistance (IR), and type 2 diabetes (T2D). The oxytocin receptor gene (OXTR) may confer a risk for PCOS, conceivably through dysregulation of metabolism, ovarian follicle maturation, and ovarian and adrenal steroidogenesis. Therefore, we aimed to investigate whether OXTR variants confer risk for PCOS.
SUBJECTS AND METHODS
In 212 Italian subjects with T2D and PCOS, we have analyzed 22 single nucleotide polymorphisms (SNPs) within the OXTR gene for linkage to and/or linkage disequilibrium (LD, i.e., association) with PCOS. We tested whether the significant risk variants were independent or part of an LD block.
RESULTS
We found 5 independent variants significantly linked to/in LD with PCOS within the peninsular families.
CONCLUSIONS
This is the first study to report OXTR as a novel risk gene in PCOS. Functional and replication studies are needed to confirm these results.
Topics: Female; Humans; Diabetes Mellitus, Type 2; Hyperandrogenism; Insulin Resistance; Oxytocin; Polycystic Ovary Syndrome; Receptors, Oxytocin
PubMed: 37013781
DOI: 10.26355/eurrev_202303_31800 -
Cureus Mar 2023Polycystic ovary syndrome (PCOS) is a common endocrine disorder often leading to anovulatory infertility. PCOS pathophysiology is still unclear and several potential...
Association Between Follicle-Stimulating Hormone Receptor (FSHR) rs6166 and Estrogen Receptor 1 (ESR1) rs2234693 Polymorphisms and Polycystic Ovary Syndrome Risk, Phenotype, and Reproductive Outcomes in an Infertile Portuguese Population.
INTRODUCTION
Polycystic ovary syndrome (PCOS) is a common endocrine disorder often leading to anovulatory infertility. PCOS pathophysiology is still unclear and several potential genetic susceptibility factors have been proposed. The effect of polymorphisms in two genesrelated to follicular recruitment and development, the follicle-stimulating hormone receptor () and the estrogen receptor 1 (), have been studied in different populations with contradictory results.
AIMS
To evaluate the influence of rs6166 (c.2039A>G) and of rs2234693 (Pvull c.453-397 T > C) polymorphisms on PCOS risk, phenotype, and response to controlled ovarian stimulation (COS).
MATERIALS AND METHODS
Genotyping of the rs6166 and the rs2234693 polymorphisms was performed in PCOS women and a control group undergoing in vitro fertilization (IVF). Demographic, clinical, and biochemical data, genotype frequency, and IVF outcomes were compared between groups.
RESULTS
We evaluated 88 PCOS women and 80 controls. There was no significant difference in the genotype distribution of rs6166 polymorphism between PCOS women and controls (AA 31.8%/AS 48.9%/SS 19.3% in PCOS women vs AA 37.5%/AS 40.0%/SS 22.5% in controls; p = 0.522). The same was true for the rs2234693 (CC 24.1%/CT 46.0%/TT 29.9% in PCOS women vs CC 18.8%/CT 48.8%/TT 32.5% in controls; p = 0.697). In PCOS women, we found higher follicle-stimulating hormone (FSH) levels on the third day of the menstrual cycle associated with the SS variant of the polymorphism (9.2 vs6.2 ± 1.6 and 5.6 ± 1.6 mUI/mL; p = 0.011). We did not find other associations between the baseline hormonal parameters, antral follicle count, and response measures to COS with or genotypes. We found, however, a need for higher cumulative doses of FSH for COS in patients with the SS variant of the rs6166 polymorphism (1860.5 ± 627.8 IU for SSvs1498.1 ± 359.3 for AA and 1425.4 ± 474.8 for SA; p = 0.046 and p = 0.046).
CONCLUSION
Our data suggest that in the population, rs6166and polymorphisms do not influence the risk of developing PCOS nor do they influence the patient's phenotype and IVF success. However, the SS variant of the rs6166 polymorphism may be associated with FSH resistance requiring higher FSH doses for COS.
PubMed: 37012960
DOI: 10.7759/cureus.35690 -
JDS Communications Mar 2023The objective of this observational prospective cohort study was to evaluate the combined effect of purulent vaginal discharge (PVD) and anovulation (ANOV) on the...
The objective of this observational prospective cohort study was to evaluate the combined effect of purulent vaginal discharge (PVD) and anovulation (ANOV) on the reproductive performance of a large multi-state population of Holstein cows. Data were prospectively collected from 11,729 cows in 16 herds located in 4 regions in the United States [Northeast (4 herds), Midwest (6), Southeast (1), and Southwest (5)]. Cows were enrolled at calving and monitored weekly for disease occurrence, reproductive events, and survival. Prevalence of PVD was evaluated at 28 ± 3 d in milk and defined by the presence of mucopurulent to fetid vaginal discharge. Resumption of ovarian cyclicity was determined via transrectal ultrasonography at 40 ± 3 and 54 ± 3 d postpartum. Pregnancy diagnosis was performed by ultrasonography on d 32 ± 3 after artificial insemination (AI) and reconfirmed at d 60 ± 3 of gestation. Pregnancy loss (PL) was defined as a cow diagnosed pregnant at 32 ± 3 but nonpregnant at 60 ± 3 d after AI. The association of PVD and ANOV with pregnancy traits was analyzed using 4 PVD-cyclicity categories that considered the following combinations: NPVD-CYC = absence of PVD and cycling; PVD-CYC = presence of PVD and cycling; NPVD-ANOV = absence of PVD and anovular; and PVD-ANOV = presence of PVD and anovular. Multiple logistic regression and Cox proportional regression were used for the analysis of potential associations between PVD and cyclicity categories and pregnancy at first AI (PAI1), days from calving to pregnancy, and PL at first AI. The odds (95% confidence intervals) of pregnancy increased from cows in the PVD-ANOV category (reference category) to cows in NPVD-ANOV [2.09 (1.62-2.50)], PVD-CYC [2.52 (2.02-3.14)], and NPVD-CYC [3.46 (2.84-4.23)]. Similarly, days from calving to pregnancy were less for NPVD-CYC, followed by PVD-CYC, NPVD-ANOV, and PVD-ANOV (121.4, 137.2, 137.3, and 157.4 d, respectively). On the contrary, no clear association was identified between groups and PL. The results indicate that both PVD and ANOV had a negative impact on PAI1 and days from calving to pregnancy. The results indicated a variable magnitude in the negative impact on the reproductive traits analyzed when both conditions were combined.
PubMed: 36974209
DOI: 10.3168/jdsc.2022-0271 -
Frontiers in Endocrinology 2023Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Its clinical characteristics are mainly oligo-ovulation or anovulation,... (Review)
Review
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Its clinical characteristics are mainly oligo-ovulation or anovulation, hyperandrogenemia (HA) and insulin resistance (IR). PCOS is considered to be one of the main causes of infertility in women of childbearing age, and its pathogenesis is still unclear. Intestinal flora, known as the "second genome" of human beings, is closely related to metabolic diseases, immune diseases and infectious diseases. At the same time, mounting evidence suggests that intestinal flora can regulate insulin synthesis and secretion, affect androgen metabolism and follicular development, and is involved in the occurrence of chronic inflammation and obesity. The imbalance of intestinal flora is caused by the abnormal interaction between intestinal flora and host cells caused by the change of intestinal microbial diversity, which is related to the occurrence and development of PCOS. The adjustment of intestinal flora may be a potential direction for the treatment of PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Gastrointestinal Microbiome; Hyperandrogenism; Insulin Resistance; Anovulation
PubMed: 36967808
DOI: 10.3389/fendo.2023.1151723 -
BMC Women's Health Mar 2023Polycystic ovary syndrome (PCOS) is characterized by anovulation, insufficient progesterone, hyperandrogenism, and insulin resistance. These factors can disrupt the...
Polycystic ovary syndrome is associated with a higher risk of premalignant and malignant endometrial polyps in premenopausal women: a retrospective study in a tertiary teaching hospital.
BACKGROUND
Polycystic ovary syndrome (PCOS) is characterized by anovulation, insufficient progesterone, hyperandrogenism, and insulin resistance. These factors can disrupt the endometrium of PCOS patients and can lead to chronic low-grade inflammation in the endometrium, endometrial hyperplasia, or even endometrial cancer.
OBJECTIVE
The aim of this study was to investigate the prevalence of premalignant and malignant endometrial polyps in premenopausal women and to further explore whether PCOS is associated with premalignant and malignant changes in endometrial polyps.
METHODS
This study was conducted by retrieving the medical data of 4236 premenopausal women who underwent hysteroscopic polypectomies between January 2015 and December 2021. Demographic and clinical data regarding age, height, weight, parity, hormone replacement therapy, oral contraceptives, abnormal uterine bleeding, hypertension, diabetes mellitus, PCOS, number of polyps, and size of polyps were collected, and their associations with premalignant and malignant changes in endometrial polyps were analysed.
RESULT
Among the endometrial polyps removed by hysteroscopic polypectomy in premenopausal women, the prevalence of premalignant and malignant polyps was 2.15%, which comprised hyperplasia with atypia at 1.13% and endometrial carcinoma at 1.02%. PCOS was associated with a higher risk of premalignant and malignant endometrial polyps in premenopausal women after adjustment for potential confounding factors.
CONCLUSION
PCOS is associated with a higher risk of premalignant and malignant endometrial polyps in premenopausal women. Therefore, it is important to evaluate the endometrium in PCOS patients with ultrasonography or hysteroscopy, and active management involving hysteroscopic polypectomy should be offered to PCOS patients diagnosed with endometrial polyps regardless of symptoms.
Topics: Pregnancy; Humans; Female; Retrospective Studies; Polycystic Ovary Syndrome; Uterine Neoplasms; Uterine Diseases; Endometrial Neoplasms; Precancerous Conditions; Endometrium; Hysteroscopy; Hospitals, Teaching; Polyps
PubMed: 36964546
DOI: 10.1186/s12905-023-02269-4 -
Bioactive Materials Aug 2023The bio-engineered ovary is an essential technology for treating female infertility. Especially the development of relevant models could be a critical step in a drug...
The bio-engineered ovary is an essential technology for treating female infertility. Especially the development of relevant models could be a critical step in a drug study. Herein, we develop a semi-opened culturing system (SOCS) strategy that maintains a 3D structure of follicles during the culture. Based on the SOCS, we further developed micro-cavity ovary (MCO) with mouse follicles by the microsphere-templated technique, where sacrificial gelatin microspheres were mixed with photo-crosslinkable gelatin methacryloyl (GelMA) to engineer a micro-cavity niche for follicle growth. The semi-opened MCO could support the follicle growing to the antral stage, secreting hormones, and ovulating cumulus-oocyte complex out of the MCO without extra manipulation. The MCO-ovulated oocyte exhibits a highly similar transcriptome to the counterpart (correlation of 0.97) and can be fertilized. Moreover, we found that a high ROS level could affect the cumulus expansion, which may result in anovulation disorder. The damage could be rescued by melatonin, but the end of cumulus expansion was 3h earlier than anticipation, validating that MCO has the potential for investigating ovarian toxic agents . We provide a novel approach for building an ovarian model to recapitulate ovarian functions and test chemical toxicity, suggesting it has the potential for clinical research in the future.
PubMed: 36936809
DOI: 10.1016/j.bioactmat.2023.02.029 -
Journal of the Endocrine Society Mar 2023Polycystic ovary syndrome (PCOS) is an endocrinopathy characterized by hyperandrogenism, anovulation, and polycystic ovaries, in which hyperandrogenism manifests by...
Polycystic ovary syndrome (PCOS) is an endocrinopathy characterized by hyperandrogenism, anovulation, and polycystic ovaries, in which hyperandrogenism manifests by excess androgen and other steroid hormone abnormalities. Mitochondrial fusion is essential in steroidogenesis, while the role of mitochondrial fusion in granulosa cells of hyperandrogenic PCOS patients remains unclear. In this study, mRNA expression of mitochondrial fusion genes mitoguardin1, -2 () was significantly increased in granulosa cells of hyperandrogenic PCOS but not PCOS with normal androgen levels, their mRNA expression positively correlated with testosterone levels. Dihydrotestosterone (DHT) treatment in mice led to high expression of MIGA2 in granulosa cells of ovulating follicles. Testosterone or forskolin/ phorbol 12-myristate 13-acetate treatments increased expression of MIGA2 and the steroidogenic acute regulatory protein (StAR) in KGN cells. MIGA2 interacted with StAR and induced StAR localization on mitochondria. Furthermore, MIGA2 overexpression significantly increased cAMP-activated protein kinase A (PKA) and phosphorylation of AMP-activated protein kinase (pAMPK) at T172 but inhibited StAR protein expression. However, MIGA2 overexpression increased , and mRNA expression. As a result, MIGA2 overexpression decreased progesterone but increased estradiol synthesis. Besides the androgen receptor, testosterone or DHT might also regulate MIGA2 and pAMPK (T172) through LH/choriogonadotropin receptor-mediated PKA signaling. Taken together, these findings indicate that testosterone regulates MIGA2 via PKA/AMP-activated protein kinase signaling in ovarian granulosa cells. It is suggested mitochondrial fusion in ovarian granulosa cells is associated with hyperandrogenism and potentially leads to abnormal steroidogenesis in PCOS.
PubMed: 36936714
DOI: 10.1210/jendso/bvad034