Increased Androgen Production Research Articles

A comprehensive meta-analysis of in vitro studies on polycystic ovary syndrome cell lines

Introduction: Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age. In vitro studies using PCOS cell lines have been instrumental in understanding the pathophysiology and identifying potential therapeutic targets. This meta-analysis aims to synthesize and evaluate the existing literature on PCOS cell line research. Methods: A systematic search of PubMed, Scopus, and Web of Science databases up to January 2024, using relevant keywords and medical subject headings. Inclusion criteria were original research articles in English, focusing on PCOS cell lines and reporting quantitative data. Data extraction included study design, cell line model, outcomes, and main findings. Results: A total of 48 studies met the inclusion criteria, involving human granulosa-derived (KGN, COV434), theca-derived (HsTE-1, HsTE-10), and ovarian surface epithelial (IOSE-80) cell lines. These studies focused on the evaluation of hormonal imbalances, insulin resistance, and inflammation. The meta-analysis revealed that PCOS cell lines exhibited increased androgen production, elevated insulin resistance markers, and pro-inflammatory cytokine expression compared to control cell lines. Conclusion: In vitro studies using PCOS cell lines have provided valuable insights into the molecular mechanisms underlying PCOS pathogenesis. These cell lines serve as valuable tools for understanding the complex interplay between hormonal dysregulation, insulin resistance, and inflammation.

The Effect of BMI and Lipid Metabolism on Pregnancy Outcomes of PCOS Patients Treated with ICSI_IVF.

Polycystic ovary syndrome is a highly prevalent and important cause of infertility. This complication demonstrates relationships with obesity, increased androgen production, and insulin resistance. The typical pattern of dyslipidemia in women with PCOS is a decrease in high-density lipoprotein and an increase in triglycerides. On the other hand, fat people are at a higher risk of hyperandrogenism, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and infertility compared to ordinary people. In this cross-sectional study, 150 patients under 40 years suffering from PCOS based on the Rotterdam criteria, who were candidates for in vitro fertilization (IVF), were examined at Yas Hospital (Tehran, Iran) from April to September 2022. In addition to demographic information, lipid profile, body mass index, obstetric, fasting blood sugar (FBS), beta HCG (negative or positive), and ultrasound were also checked and pregnancy status was checked six weeks later. The rate of clinical and chemical pregnancy in women with a normal BMI was about two times that of women with a BMI above 25kg/m2. In addition, the pregnancy rate in women with dyslipidemia was significantly lower than that in ordinary women. The amount of FBS was substantially lower in people with positive pregnancies. The probability of pregnancy in PCOS women with a BMI is higher than normal women, and dyslipidemia is lower than that in ordinary people. Therefore, enhancing BMI and dyslipidemia in these women before starting infertility treatment is recommended.

Beyond Prostate Cancer: An Androgen Receptor Splice Variant Expression in Multiple Malignancies, Non-Cancer Pathologies, and Development.

Multiple studies have demonstrated the importance of androgen receptor (AR) splice variants (SVs) in the progression of prostate cancer to the castration-resistant phenotype and their utility as a diagnostic. However, studies on AR expression in non-prostatic malignancies uncovered that AR-SVs are expressed in glioblastoma, breast, salivary, bladder, kidney, and liver cancers, where they have diverse roles in tumorigenesis. AR-SVs also have roles in non-cancer pathologies. In granulosa cells from women with polycystic ovarian syndrome, unique AR-SVs lead to an increase in androgen production. In patients with nonobstructive azoospermia, testicular Sertoli cells exhibit differential expression of AR-SVs, which is associated with impaired spermatogenesis. Moreover, AR-SVs have been identified in normal cells, including blood mononuclear cells, neuronal lipid rafts, and the placenta. The detection and characterization of AR-SVs in mammalian and non-mammalian species argue that AR-SV expression is evolutionarily conserved and that AR-SV-dependent signaling is a fundamental regulatory feature in multiple cellular contexts. These discoveries argue that alternative splicing of the AR transcript is a commonly used mechanism that leads to an expansion in the repertoire of signaling molecules needed in certain tissues. Various malignancies appropriate this mechanism of alternative AR splicing to acquire a proliferative and survival advantage.

The Effects of Plant-Derived Phytochemical Compounds and Phytochemical-Rich Diets on Females with Polycystic Ovarian Syndrome: A Scoping Review of Clinical Trials.

Polycystic ovarian syndrome (PCOS) is an endocrine condition that impacts nutritional status, metabolic, and hormonal function in females of reproductive age. This condition is associated with increased androgen production (hyperandrogenism) and decreased insulin sensitivity, which often leads to insulin resistance and hyperinsulinemia. This increase in androgen production and insulin resistance is strongly associated with a high incidence of obesity, type-2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), and certain types of gonad-related cancers among females who suffer from this condition. As research continues to grow, it has been demonstrated that PCOS is a complex condition, and some of its characteristics vary among the females that have this disorder. However, it has been suggested that oxidative stress and low-grade chronic inflammation could play an important role in the development of PCOS. Current evidence suggest that phytochemicals could potentially help with weight-loss by reducing oxidative stress and low-grade inflammation, as well as aid in metabolic and hormonal regulation due to their antioxidant properties. Some of the bioactive compounds found in plants that have shown positive effects in the attenuation of PCOS include flavonoids, polyphenols, phytoestrogen, and polyunsaturated fatty acids (PUFAs). Thus, a review of the current literature published on PCOS and phytochemicals was conducted in PubMed, Google Scholar, and the Academy of Nutrition and Dietetics databases for articles published between 2013 and 2023 with a study duration of 1 to 3 months and adequate sample sizes. The main purpose of this review of literature was to investigate the metabolic effects of phytochemical compounds and phytochemical-rich diets on females with PCOS by comparing the results of several randomized clinical trials.

Salt-inducible kinases regulate androgen synthesis in theca cells by enhancing CREB signaling

Ovulation is the pinnacle of folliculogenesis, a process that requires an interplay between the oocyte, the granulosa cells, and the theca cells (TCs). TCs are the only source of ovarian androgens, which play a vital role in female fertility. However, abnormally elevated androgen levels reduce fertility. Therefore, uncovering novel mechanisms regulating androgen synthesis in TCs is of great significance. We have shown that salt-inducible kinases (SIKs) regulate granulosa cell steroidogenesis. Here, we investigated whether SIKs regulate androgen production in TCs. SIK2 and SIK3 were detected in the TCs of mouse ovaries and isolated TCs. Next, TCs in culture were treated with luteinizing hormone (LH) in the presence or absence of a highly specific SIK inhibitor. SIK inhibition enhanced the stimulatory effect of LH on steroidogenic gene expression and androgen production in a concentration-dependent manner. SIK inhibition alone stimulated the expression of steroidogenic genes and increased androgen production. Activation of adenylyl cyclase with forskolin or emulation of increased intracellular cyclic AMP levels stimulated steroidogenesis, an effect that was enhanced by the inhibition of SIK activity. The stimulatory effect of downstream targets of cyclic AMP was also significantly augmented by SIK inhibition, suggesting that SIKs control targets downstream cyclic AMP. Finally, it is shown that SIK2 knockout mice have higher circulating testosterone than controls. This evidence shows that TCs express SIKs and reveal novel roles for SIKs in the regulation of TC function and androgen production. This information could contribute to uncovering therapeutic targets to treat hyperandrogenic diseases.

The inhibition of steroid hormones determines the fate of IPC-366 tumor cells, highlighting the crucial role of androgen production in tumor processes

Inflammatory mammary cancer (IMC) is a disease that affects female dogs. It is characterized by poor treatment options and no efficient targets. However, anti-androgenic and anti-estrogenic therapies could be effective because IMC has a great endocrine influence, affecting tumor progression. IPC-366 is a triple negative IMC cell line that has been postulated as a useful model to study this disease. Therefore, the aim of this study was to inhibit steroid hormones production at different points of the steroid pathway in order to determine its effect in cell viability and migration in vitro and tumor growth in vivo. For this purpose, Dutasteride (anti-5αReductase), Anastrozole (anti-aromatase) and ASP9521 (anti-17βHSD) and their combinations have been used. Results revealed that this cell line is positive to estrogen receptor β (ERβ) and androgen receptor (AR) and endocrine therapies reduce cell viability. Our results enforced the hypothesis that estrogens promote cell viability and migration in vitro due to the function of E1SO4 as an estrogen reservoir for E2 production that promotes the IMC cells proliferation. Also, an increase in androgen secretion was associated with a reduction in cell viability. Finally, in vivo assays showed large tumor reduction. Hormone assays determined that high estrogen levels and the reduction of androgen levels promote tumor growth in Balb/SCID IMC mice. In conclusion, estrogen levels reduction may be associated with a good prognosis. Also, activation of AR by increasing androgen production could result in effective therapy for IMC because their anti-proliferative effect.

ODP375 Absence of Virilization With Completely Normal Phenotype in a Newborn Female With Salt-Wasting Classical CAH

Abstract Background Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that leads to the disruption of adrenal steroidogenesis. 21-hydroxylase deficiency is the most common form and is caused by the mutations in the 21-hydroxylase (CYP21A2) gene. Deficiency in the 21-hydroxylase enzyme can affect aldosterone and cortisol production and shift the pathway to increased androgen production. It is classified as classical and nonclassical depending on the severity of enzyme deficiency. The classical form can present as a life-threatening salt-wasting or a milder form of simple virilizing CAH. Female patients with classical 21-hydroxylase deficiency present with ambiguous genitalia secondary to increased androgen production. We present a case of salt-wasting classical CAH in a female patient with no signs of virilization that was diagnosed based on newborn screening. Case presentation A four-day-old full-term female was referred to our hospital for elevated 17 hydroxyprogesterone (17-OHP) on a newborn screen. She was born via normal vaginal delivery with an uncomplicated prenatal and postnatal course. Her newborn screen was drawn at day 1 of life resulted in 17-OHP of 128.20 nmol/L (normal cutoff of 85 nmol/L). Otherwise, she was active, feeding well with no other concerns. On admission, her vital signs were within normal, with an unremarkable physical examination. Specifically, the genitourinary exam demonstrated normal female external genitalia with no evidence of virilization, no clitoromegaly with a clitoris length of 12 mm and width 1-2 mm, no hyperpigmentation, and with normal-appearing vaginal orifice and urethral meatus. Confirmatory 17-OHP by mass spectrometry was sent along with the metabolic panel, and her initial electrolytes were within normal. Since there was a low suspicion for salt-wasting CAH given her normal labs and unremarkable physical exam, medication was not started, and the patient was admitted for monitoring. The potassium level trended up abnormally to 6.3 mmol/L, which prompted the initiation of empiric treatment with a physiologic dose of Hydrocortisone and Florinef on day of life 7, pending confirmatory 17-OHP level. Confirmatory17-OHP was 1242 ng/dL (normal <78) and following stimulation with Cosyntropin a markedly elevated 17-OHP 27,929.31 ng/dL (normal expected 7-106) and low cortisol level 2 mcg/dL, for which definitive treatment with hydrocortisone and Florinef were initiated. Subsequent genetic testing confirmed the diagnosis of 21-hydroxylase deficiency with mutations in the CYP21A2 gene for I172N, R356W, and c. *13G>A. Further genetic workup to explain the complete lack of virilization, including assessment of an androgen insensitivity panel and whole-exome sequencing, was unremarkable. Conclusion This case illustrates the critical importance of heel-stick newborn screening for CAH to prevent a life-threatening salt-wasting crisis as female patients with classical CAH can present with a phenotypic complete lack of virilization that could be misleading and fatal if not recognized. Presentation: No date and time listed

Polycystic Ovary Syndrome in Girls With Type 2 Diabetes

Source: Cioana M, Deng J, Nadarajah A, et al. Prevalence of polycystic ovary syndrome in patients with pediatric type 2 diabetes a systematic review and meta-analysis. JAMA Netw Open. 2022;5(2):e2147454. doi:10.1001/jamanetworkopen.2021.47454Investigators from multiple institutions conducted a meta-analysis to estimate the prevalence of polycystic ovary syndrome (PCOS) in girls with type 2 diabetes (T2D). For the meta-analysis, systematic search procedures were used to identify studies in which the prevalence of PCOS in girls diagnosed with T2D when they were ≤18 years old was estimated. Studies included could have cross-sectional, retrospective, or prospective cohort designs, if they had a minimum sample of 10 patients. No specific criteria for the diagnosis of PCOS were required. The prevalence of PCOS in each included study was determined, and a pooled prevalence was calculated. A secondary analysis that included studies in which specific criteria were required for the diagnosis of PCOS also was conducted. For studies with the available data, the prevalence of PCOS among girls with T2D from different racial groups was calculated.The authors screened 722 articles to identify 6 studies that met the inclusion criteria; 5 of these were retrospective cohort studies. Data on 470 girls were included in the meta-analysis. The mean age at diagnosis of T2D among participants in the included studies ranged from 12.9 years to 16.1 years. Overall, the pooled prevalence of PCOS among adolescent females with T2D was 19.58% (95% CI, 12.02%, 27.14%). Three studies required a history of persistent oligomenorrhea and clinical and/or biochemical hyperandrogenism for a diagnosis of PCOS. Among 87 girls with T2D included in these studies, the pooled prevalence of PCOS was 24.04% (95% CI, 15.07%, 33.01%). There were 2 studies in which the prevalence of PCOS by race was reported; reported prevalence was 17% among 36 white females, 23.10% in Indian adolescent females (N = 195), and 2.0% in indigenous females in Canada (N = 64).The authors conclude that approximately 1 in 5 girls with T2D had PCOS.Dr. Fechner has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.It is not surprising that 1 in 5 girls with T2D have PCOS, as insulin resistance with hyperinsulinemia increases androgen production by the ovary, leading to PCOS.1 While the diagnosis of PCOS in adult women requires 2 of 3 criteria: androgen excess, oligo/anovulation or polycystic ovaries,2 the presence of polycystic ovaries on ultrasound and anovulatory symptoms may be normal in the early post-menarchal years. Thus, a history of anovulation and an ultrasound with polycystic ovaries may be normal during the period after menarche. A consensus statement on the pathophysiology, diagnosis, and treatment of PCOS in adolescence in 2017 suggested the diagnostic criteria of clinical and/or biochemical hyperandrogenism with irregular menses/oligomenorrhea at least 2 years post-menarche.3As in adults, it is important to exclude other etiologies such as non-classic congenital adrenal hyperplasia, hyperprolactinemia, and thyroid disease. PCOS has many of the same co-morbidities as T2D. In addition, there is increased infertility and increased risk of endometrial cancer as well as possible increased androgen exposure to the female fetus leading to ambiguous genitalia in the fetus.2 Treatment of PCOS overlaps T2D treatment, with lifestyle management to lose weight as a primary intervention. Adolescents with PCOS may also benefit from the use of an oral contraceptive to decrease androgens and improve acne, hirsutism, anovulatory symptoms, and to prevent pregnancy. Metformin for those unsuccessful with lifestyle management may also benefit both PCOS and T2D management.3It is important to gather menstrual history and look for signs of hyperandrogenism in females with T2D as PCOS appears to be a relatively common morbidity in girls with T2D.

Non-PCOS Hyperandrogenic Disorders in Adolescents

Hyperandrogenism-clinical features resulting from increased androgen production and/or action-is not uncommon in peripubertal girls. Hyperandrogenism affects 3 to 20% of adolescent girls and often is associated with hyperandrogenemia. In prepubertal girls, the most common etiologies of androgen excess are premature adrenarche (60%) and congenital adrenal hyperplasia (CAH; 4%). In pubertal girls, polycystic ovary syndrome (PCOS; 20-40%) and CAH (14%) are the most common diagnoses related to androgen excess. Androgen-secreting ovarian or adrenal tumors are rare (0.2%). Early pubic hair, acne, and/or hirsutism are the most common clinical manifestations, but signs of overt virilization in adolescent girls-rapid progression of pubic hair or hirsutism, clitoromegaly, voice deepening, severe cystic acne, growth acceleration, increased muscle mass, and bone age advancement past height age-should prompt detailed evaluation. This article addresses the clinical manifestations of and management considerations for non-PCOS-related hyperandrogenism in adolescent girls. We propose an algorithm to aid diagnostic evaluation of androgen excess in this specific patient population.

Deconstructing a Syndrome: Genomic Insights Into PCOS Causal Mechanisms and Classification.

Polycystic ovary syndrome (PCOS) is among the most common disorders in women of reproductive age, affecting up to 15% worldwide, depending on the diagnostic criteria. PCOS is characterized by a constellation of interrelated reproductive abnormalities, including disordered gonadotropin secretion, increased androgen production, chronic anovulation, and polycystic ovarian morphology. It is frequently associated with insulin resistance and obesity. These reproductive and metabolic derangements cause major morbidities across the lifespan, including anovulatory infertility and type 2 diabetes (T2D). Despite decades of investigative effort, the etiology of PCOS remains unknown. Familial clustering of PCOS cases has indicated a genetic contribution to PCOS. There are rare Mendelian forms of PCOS associated with extreme phenotypes, but PCOS typically follows a non-Mendelian pattern of inheritance consistent with a complex genetic architecture, analogous to T2D and obesity, that reflects the interaction of susceptibility genes and environmental factors. Genomic studies of PCOS have provided important insights into disease pathways and have indicated that current diagnostic criteria do not capture underlying differences in biology associated with different forms of PCOS. We provide a state-of-the-science review of genetic analyses of PCOS, including an overview of genomic methodologies aimed at a general audience of non-geneticists and clinicians. Applications in PCOS will be discussed, including strengths and limitations of each study. The contributions of environmental factors, including developmental origins, will be reviewed. Insights into the pathogenesis and genetic architecture of PCOS will be summarized. Future directions for PCOS genetic studies will be outlined.

INFERTILITY TREATMENT USING HUMAN MESENCHYMAL STEM CELL DERIVED EXTRACELLULAR VESICLE IN LETROZOLE INDUCED PCOS MOUSE MODEL

Polycystic ovary syndrome (PCOS) is the most common metabolic and endocrine disorder in reproductive-age women. Excessive inflammation and increased androgen production from ovarian theca cells are key features of PCOS. We and others have recently reported that human bone marrow mesenchymal stem cells (MSC) can reverse PCOS conditions both in vitro and in vivo models. Recent studies reported that MSC secreted extracellular vesicles (EV), also known as exosome, play a key role in the reparative paracrine effect of MSC in various disease. Here we evaluated the therapeutic efficacy of MSC-EV in both in vitro and in an in vivo PCOS mouse models. We hypothesize that MSC-EV treatment can reverse the PCOS related features such as insulin resistance, altered androgen production, and infertility. We used commercialized MSC-EV (EV-pure+, Vitti lab) which isolated from Human Umbilical Cord Tissue derived MSC. For in vitro experiment, we treated MSC-EV to androgen producing H293R cells, and analyzed androgen producing gene expression. For in vivo experiment, three different concentration of MSC-EV were injected into Letrozole (LTZ) induced mouse PCOS model through intravenous injection (3X107, 1.5X108, 7.5 X108 particles). Effect in both in vitro and in vivo model were assessed by monitoring cell proliferation (immunohistochemistry), steroidogenic gene expression (qRT-PCR), animal tissue assay (H&E staining), and fertility by mating and pregnancy/delivery outcomes. MSC-EV significantly reduced gene expression Cyp11a1 (0.75±0.03 fold), Cyp17a1 (0.58±0.04 fold), and Dennd1 (0.72±0.06 fold) in H293R cells. In our in vivo model, abnormal serum glucose level in PCOS mice (231.5±16.3 mg/dL) were significantly decreased by all MSC-EV tested doses treatment (186.5±3.54, 194.0±0.00, 188.0±5.66 mg/dL) at same time point after glucose injection (60 min). In breeding experiment, PCOS mice (n=4) delivered only one offspring while healthy mice (n=4) delivered 33 pups. Interestingly, average number of pups in each MSC-EV treated group(n=4) were 13, which is significantly increased compared to untreated PCOS mice. The pups did not show any visible abnormalities and exhibited normal growth rate. Our study demonstrates the efficacy of intra venous injection of MSC-EV for potential treatment of infertility in PCOS mouse model. Our work suggests that MSC-EV can potentially be a safer therapeutic option for women with PCOS as cell-free biomedicine. Further preclinical and pilot clinical trials are required to further evaluate and validate this novel treatment option for this common female reproductive disorder.

CLINICAL COURSE OF PERIMENOPAUSAL PERIOD IN WOMEN WITH HYPERANDROGENISM SYNDROME

Hyperandrogenism is a disorder of endocrine status caused by excess production of androgens. The syndrome is a consequence of increased androgen production both in the ovaries and adrenal glands. However, such a division is very arbitrary, as increased production of androgens in the adrenal glands may increase production in the ovaries and vice versa. Androgens in women are synthesized by ovaries, adrenal glands and peripheral tissues, which also participate in metabolism.The set of androgens in both womenand men includes dehydroepiandrosterone-sulfate, dehydroepiandrosterone, androstenedione, testosterone and 5-alpha-dihydrotestosterone (5-alpha-DHT). Still, unlike men, women have a higher concentration of the first three hormones than the lasttwo. Androgen synthesis in the adrenal glands in women is regulated by adrenocorticotropic and in the ovaries by luteinizing hormone (LH) and some other intraglandular autoparacrine mechanisms. According to recent studies, in addition to the basic biological, previously commonly known effects of androgens, their new mechanisms of influence on the female body have been discovered. Keywords: hyperandrogenism, hormones, ovaries, adrenal glands, reproductive disorders

A study on steroidogenic elaborations of stroma and their regulation in response to ovarian hormones in goats

Stromal tissue is an essential componenlt of the ovary not only for providing structural support but also for contributing to the early follicular growth with their bi-directional paracrine signaling. Estradiol is a major female hormone mainly secreted by the follicular cells in the ovary. To examine the relationship between 17β-estradiol and the factors involved in androgen production in stromal cells, ovarian stromal cells were cultured in the graded concentrations (50 and 100 ng/mL) of 17β-estradiol for varying time periods (24 and 48 h). The cells were processed for transmission electron microscopy to study the changes in steroidogenic functions of the cells. The effect of estradiol treatment was also evaluated on the quantity of androgen production and abundance of steroidogenic enzymes and proteins. The results indicated 17β-estradiol increased androgen production in ovarian stromal cells. In addition to enhanced androstenedione and testosterone production, estradiol stimulation was also based on the marked increase in abundance of mRNA transcript of steroidogenic enzymes [Star (Steroidogenic Acute Regulatory Protein), Cyp11a1, Cyp17a1, and hsd3b1 (3β-hydroxysteroid dehydrogenase)], as well as abundances of StAR and CYP11A1 protein. Thus, 17β-estradiol enhanced steroidogenesis in ovarian stromal cells. This study provided a basis for further exploration of regulation of steroidogenesis in ovarian stromal cells and the feedback mechanisms in association with estradiol.

Polymorphism in the Androgen Biosynthesis Gene (CYP17), a Risk for Prostate Cancer: A Meta-Analysis.

Gene polymorphism is one of the few factors that increases the risk of prostate cancer. T to C substitution in the 5’ promoter region of the CYP17 gene is hypothesized to increase the rate of gene transcription, increase androgen production, and thereby increase the risk of prostate cancer. Nevertheless, the inconsistencies originating from studies on CYP17 polymorphism and prostate cancer prompted this meta-analysis, to decipher the association between CYP17 polymorphism and prostate cancer. Most case-control studies addressing CYP17 polymorphism and prostate cancer were exhaustively searched from Web of Science, Google Scholar, and PubMed. The various genotype distributions as well as the minor allele distributions were retrieved. Pooled odds ratios (ORs) with their 95% CI and estimates of the Hardy–Weinberg Equilibrium were calculated. Analyses were performed using the RevMan v.5.3 software and SPSS v.21. There was high-pooled heterogeneity (I2 = 87.0%, OR = .42, CI [.39, .45], and p < .001) among the A2 versus A1 allele. With the per-allele model (A2 versus A1), ethnicity was a major risk factor to prostate cancer, with Asians recording the highest risk (OR = 12.61, 95% CI [8.77, 18.12]). From the genotype models, A1/A1 versus A2/A2 (OR = 3.02, 95% CI [2.65, 3.44]) and A1/A2 versus A2/A2 (OR = 4.39, 95% CI [3.86, 5.00]) were all significantly associated with prostate cancer. Although some genotype models were associated with the risk of prostate cancer, we should be mindful when interpreting the results of this study because of the limited number of studies and the small sample size used.

Assessment of relationship between hormones and insulin resistance in PCOS

Introduction: Polycystic ovarian syndrome (PCOS) is the most common heterogenous disorder of reproductive age. Increased frequency of GnRH pulses from hypothalamus elevates LH levels this in turn causes increased androgen production. The chronic hyperandrogenic state have multiple long and short term complications which includes DM and CVD. Insulin resistance can be characterized as impaired action of insulin on glucose metabolism which increases risk of developing T2DM. Hyperandrogenism with hyperinsulinemia also leads to dyslipidemia. Aim: To estimate LH/FSH ratio, testosterone in PCOS patients and to correlate its significance with the insulin resistance. Materials and Methods: This case-control study was conducted on clinically, diagnosed 50 PCOS patients, aged 15 to 35 years were included as cases. Age-matched 50 apparently heal thy women were included as controls. Serum leutinising hormone(LH), Follicle stimulating hormone(FSH), testosterone, serum insulin were analysed by chemiluminiscence immunoassay(CLIA) on Maglumi 1000. Mindray BS 300, fully automated analyser was used for estimation of Total cholesterol(TC), High density lipoprotein(HDL), Triglyceride(TG), Fasting Blood Glucose (FBG), Low density lipoprotein (LDL) was calculated using Friedewald’s formula. Insulin resistance was assessed by HOMA IR. Descriptive statistics analysis was done using unpaired student’s t-test. Chi-square/ Fisher Exact test has been used to find the significance of study parameters on categorical scale. Pearson’s correlation coefficient was applied to analyse the correlation. p value Results: In our study the LH /FSH ratio, HOMA IR and Testosterone was increased in cases compared to controls with p 0.01 and for testosterone p 0.001. In contrast HDL decreased in cases compared to controls (p and Total cholesterol were not significantly increased in cases however we can find that LDL was still increased in cases. Average BMI was within the normal range (p=0.06). On correl

Neurotransmitter, neuropeptide and gut peptide profile in PCOS-pathways contributing to the pathophysiology, food intake and psychiatric manifestations of PCOS.

Polycystic ovary syndrome (PCOS) is a major health problem with a heterogeneous hormone-imbalance and clinical presentation across the lifespan of women. Increased androgen production and abnormal gonadotropin-releasing hormone (GnRH) release and gonadotropin secretion, resulting in chronic anovulation are well-known features of the PCOS. The brain is both at the top of the neuroendocrine axis regulating ovarian function and a sensitive target of peripheral gonadal hormones and peptides. Current literature illustrates that neurotransmitters regulate various functions of the body, including reproduction, mood and body weight. Neurotransmitter alteration could be one of the reasons for disturbed GnRH release, consequently directing the ovarian dysfunction in PCOS, since there is plenty evidence for altered catecholamine metabolism and brain serotonin or opioid activity described in PCOS. Further, the dysregulated neurotransmitter and neuropeptide profile in PCOS could also be the reason for low self-esteem, anxiety, mood swings and depression or obesity, features closely associated with PCOS women. Can these altered central brain circuits, or the disrupted gut-brain axis be the tie that would both explain and link the pathogenesis of this disorder, the occurrence of depression, anxiety and other mood disorders as well as of obesity, insulin resistance and abnormal appetite in PCOS? This review intends to provide the reader with a comprehensive overview of what is known about the relatively understudied, but very complex role that neurotransmitters, neuropeptides and gut peptides play in PCOS. The answer to the above question may help the development of drugs to specifically target these central and peripheral circuits, thereby providing a valuable treatment for PCOS patients that present to the clinic with GnRH/LH hypersecretion, obesity or psychiatric manifestations.

Inflammatory Stimuli Trigger Increased Androgen Production and Shifts in Gene Expression in Theca-Interstitial Cells.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by theca cell hyperplasia and excessive androgen production. An increasing body of evidence has pointed to a close association between PCOS and low-grade chronic systemic inflammation. However, the mechanistic basis for this linkage is unknown. Therefore, we evaluated the effects of the inflammatory agents lipopolysaccharide (LPS) and IL-1β on rat theca-interstitial cells (TICs). We found that incubation with either LPS or IL-1β elicited a dose-dependent increase in both TIC viability and androgen production. Using RNA sequencing analysis, we found that both of these inflammatory agents also triggered profound and widespread shifts in gene expression. Using a stringent statistical cutoff, LPS and IL-1β elicited differential expression of 5201 and 5953 genes, respectively. Among the genes upregulated by both LPS and IL-1β were key regulatory genes involved in the cholesterol and androgen biosynthesis pathways, including Cyp17a1, Cyp11a1, Hsd3b, and Hmgcr. This provides a molecular explanation for the mechanism of action of inflammatory agents leading to increased androgen production. Gene ontology and pathway analysis revealed that both LPS and IL-1β regulated genes highly enriched for many common functions, including the immune response and apoptosis. However, a large number of genes (n = 2222) were also uniquely regulated by LPS and IL-1β, indicating that these inflammatory mediators have substantial differences in their mechanism of action. Together, these findings highlight the potential molecular mechanisms through which chronic low-grade inflammation contributes to the pathogenesis of androgen excess in PCOS.

Quantification of Leydig cells and stromal hyperplasia in the postmenopausal ovary of women with endometrial carcinoma

Endometrioid endometrial carcinomas (EECs) are correlated with high serum levels of androgens and estrogen. We hypothesized that Leydig cells and ovarian stromal hyperplasia contribute to postmenopausal ovarian androgen production and are observed more frequently in EEC patients. Ovaries of postmenopausal women with EEC (n = 36) or non-endometrioid endometrial carcinoma (NEEC; n = 19) were examined for the presence of hilar Leydig cells and compared with ovaries resected for benign conditions (n = 22). Leydig cells were counted manually, and a Leydig cell density was calculated per millimeter squared hilar surface. Ovarian stromal hyperplasia was scored as atrophic, moderate hyperplastic, or marked hyperplastic. In all endometrial carcinomas, these findings were correlated with the serum levels of sex steroids and hormone receptor expression in their endometrial carcinomas. In EEC patients, mean number of Leydig cells was 282.8 cells compared with 76.3 cells in NEEC patients and 66.4 cells in controls. Leydig cells, marked stromal hyperplasia, and combined presence were observed more frequently in EEC patients compared with NEEC and controls. Combined presence was associated with higher serum sex steroid levels and increased tumor expression of estrogen and progesterone receptor. A cutoff value for Leydig cell hyperplasia could be proposed at a total of 300 Leydig cells bilaterally, examining a representative cross section of both hili. Concluding, we have quantified hilar Leydig cells and demonstrated that Leydig cells may contribute to the development of EEC by increased androgen production in postmenopausal women. The correlation between sex hormone levels and Leydig cell hyperplasia may support endometrial pathology screening in these women.

Paeoniflorin extract reverses dexamethasone-induced testosterone over-secretion through downregulation of cytochrome P450 17A1 expression in primary murine theca cells

Ethnopharmacological relevancePolycystic Ovarian Syndrome (PCOS) is a complex endocrine and reproductive disorder. A main hallmark includes increased androgen production. The root of Paeonia lactiflora Pall. (Bai Shao) is used in Chinese herbal medicine for reproductive disorders, however its effects and mechanisms on ovarian theca cells has not yet been fully elucidated. Aim of the studyThe aim of this study was to evaluate effect of paeoniflorin extract (PFE), the main constituents of Bai Shao, on androgen production in ovarian theca cells. Materials and methodsPrimary murine theca cells were treated with concentrations of PFE (1–100 µg/mL) in the presence of dexamethasone (10 µM) with media-only treated cells used as the control. After 24 h, culture media was collected for biochemistry assays of testosterone and progesterone. Expression of key steroidogenic enzymes, cholesterol side-chain cleavage (CYP11A1) and 17α-hydroxylase (CYP17A1) was characterized using immunofluorescence staining, immunoblotting and qRT-PCR. ResultsDexamethasone significantly enhanced testosterone secretion (P < 0.05 vs. the control cells). PFE reversed over-production of testosterone induced by dexamethasone in a dose-dependent manner. The treatment with PFE also normalized production of progesterone in dexamethasone-treated cells. Expression of CYP11A1 and CYP17A1 in the theca cells were visualised by immunofluorescence staining. All doses of PFE significantly inhibited CYP17A1 expression detected by immunoblotting, but only 100 µg/mL of PFE downregulated CYP11A1 expression and reduced CYP11A1 significantly in dexamethasone-treated theca cells. ConclusionsPFE may reduce over-secretion of testosterone in theca cells through downregulation of CYP17A1 and CYP11A1. These findings provide scientific evidence to treat ovarian hyperandrogenism with the root of Paeonia lactiflora Pall.

Diverged Effects of Piperine on Testicular Development: Stimulating Leydig Cell Development but Inhibiting Spermatogenesis in Rats

Background: Piperine is the primary pungent alkaloid isolated from the fruit of black peppercorns. Piperine is used frequently in dietary supplements and traditional medicines. The objective of the present study was to investigate the effects of piperine on the testis development in the pubertal rat.Methods: Piperine (0 or 5 or 10 mg/kg) was gavaged to 35-day-old male Sprague-Dawley rats for 30 days. Serum levels of testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured. The development of adult Leydig cell population was also analyzed 65 days postpartum. For in vitro studies, immature Leydig cells were isolated from 35-day-old male rats and treated with 50 μM piperine in the presence of different steroidogenic stimulators/substrates for 24 h.Results: Thirty-day treatment of rats with piperine significantly increased serum T levels without affecting LH concentrations. However, piperine treatment reduced serum FSH levels. Consistent with increase in serum T, piperine increased Leydig cell number, cell size, and multiple steroidogenic pathway proteins, including steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase 1, 17α-hydroxylase/20-lyase, and steroidogenic factor 1 expression levels. Piperine significantly increased the ratio of phospho-AKT1 (pAKT1)/AKT1, phosphos-AKT2 (pAKT2)/AKT2, and phospho-ERK1/2 (pERK1/2)/ERK1/2 in the testis. Interestingly, piperine inhibited spermatogenesis. Piperine in vitro also increased androgen production and stimulated cholesterol side-chain cleavage enzyme and 17α-hydroxylase/20-lyase activities in immature Leydig cells.Conclusion: Piperine stimulates pubertal Leydig cell development by increasing Leydig cell number and promoting its maturation while it inhibits spermatogenesis in the rat. ERK1/2 and AKT pathways may involve in the piperine-mediated stimulation of Leydig cell development.