Increased Androgen Levels Research Articles

BIOCHEMICAL FACTORS INFLUENCING FAMILIAL HIRSUTISM IN THE SOUTHERN REGION OF KPK

Familial hirsutism is a prevalent disorder marked by excessive hair growth in women, often arising from genetic and physiological influences. This research seeks to examine the molecular factors contributing to familial hirsutism in the southern region of Khyber Pakhtunkhwa (KPK), Pakistan. A cross-sectional analysis was conducted involving female participants with a familial history of hirsutism. Biochemical markers such as androgen levels (testosterone, dehydroepiandrosterone sulphate), indicators of insulin resistance, and hormonal profiles were assessed. The results demonstrate increased androgen levels and insulin resistance in the affected individuals relative to the control group. Family pedigree analysis revealed a significant hereditary pattern related to genetic predisposition. The findings indicate that hormonal imbalances and genetic variables are pivotal in the occurrence of familial hirsutism within this community. Comprehending these characteristics might facilitate the formulation of focused treatments and enhance management techniques for impacted persons. Additional investigation is advised to examine the fundamental genetic pathways and possible environmental factors.

Serum ferritin levels in women with polycystic ovary syndrome.

To study ferritin levels, and potential factors influencing them, in women with polycystic ovary syndrome (PCOS) and investigate potential associations between ferritin levels and other parameters in these women. Longitudinal general population-based cohort study, including data from both questionnaires and clinical measurements. The study was conducted with data from the participants of the Women's Health Study, including a total of 1,918 Finnish women aged approximately 35 years. Polycystic ovary syndrome was defined according to the Rotterdam criteria by the presence of at least 2 of the following findings: oligomenorrhea/amenorrhea, hyperandrogenism (clinical or biochemical), and polycystic ovarian morphology. Serum ferritin levels and other parameters were determined from the cohort data, and the associations between ferritin levels and other investigated parameters were investigated with linear regression models. Women with PCOS had significantly higher median ferritin levels than those without PCOS (51.43 μg/L vs. 44.85 μg/L). Low ferritin levels were less common among women with PCOS who had oligomenorrhea or amenorrhea compared with those among women who did not (1.5% vs. 11.8%). The median ferritin levels were also found to be lower in hyperandrogenic women with PCOS than in those with normoandrogenemia (49.96 μg/L vs. 73.50 μg/L). Women with PCOS had higher fasting insulin levels than those without PCOS (8.85 mU/L vs. 7.60 mU/L), and a positive association between fasting insulin and ferritin levels was found in the whole population (effect size, 0.0619; 95% confidence interval, 0.005-0.119). Finally, associations between ferritin levels and history of infertility were investigated in both the total population and women with PCOS; however, no significant associations were found. Our results suggest that women with PCOS have higher ferritin levels than those without PCOS and that both the decreased blood loss from irregular menstruation and increased androgen levels can influence ferritin levels in women with PCOS. A metabolic connection was also found because the serum insulin levels were associated positively with the serum ferritin levels in the total population, whereas the history of infertility did not seem to be associated with the serum ferritin levels in any of the study groups.

Multiple effects of kisspeptin on neuroendocrine, reproduction, and metabolism in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a highly prevalent and heterogeneous disease characterized by a combination of reproductive and endocrine abnormalities, often associated with metabolic and mental health disorders. The etiology and pathogenesis of PCOS remain unclear, but recent research has increasingly focused on the upstream mechanisms underlying its development. Among these, kisspeptin (KISS) signaling has emerged as a pivotal component in the regulation of the hypothalamic-pituitary-gonadal axis, with significant roles in reproductive function, energy regulation, and metabolism. Women with PCOS commonly exhibit disruptions in gonadotropin secretion, including elevated luteinizing hormone (LH) levels, imbalanced LH/follicle-stimulating hormone (FSH) ratios, and increased androgen levels, all of which are usually parallel with abnormal KISS signaling. Furthermore, alterations in the KISS/KISS1R system within the central and circulatory systems, as well as peripheral tissues, have been implicated in the development of PCOS. These changes affect multiple pathophysiological domains, including reproductive function, energy regulation, metabolic homeostasis, inflammatory response, and emotional disorders, and are further influenced by lifestyle and environmental factors. This review aims to comprehensively summarize the existing experimental and clinical evidence supporting these roles of KISS in PCOS, with the goal of establishing a foundation for future research and potential clinical applications.

Effects of Concurrent Administration of Spironolactone in Veterans with Metastatic Prostate Cancer Receiving Abiraterone: A Real-World Retrospective Study.

Prostate cancer is the most common cancer in men in the United States with low survival rates once metastasized. Abiraterone is approved for use in castrate-sensitive and castrate-resistant prostate cancer and is used extensively in the Veterans Affairs (VA) healthcare system. Spironolactone, a diuretic used to treat heart failure, edema, ascites, and hypertension, may increase androgen levels and reduce effectiveness of abiraterone when used concurrently to treat prostate cancer patients. While previous case studies support this, no large epidemiology studies have been conducted. The current study utilizes the large, VA prostate cancer data core and evaluates the effect of concomitant spironolactone on efficacy of abiraterone treatment in metastatic prostate cancer patients. The study selected 18,943 veterans with metastatic prostate cancer on abiraterone treatment. Of these, 581 patients (3.1%) were also on concomitant spironolactone. The concomitant treatment group, abiraterone + spironolactone, significantly differed from the abiraterone-only group in body mass index, prevalence rates of heart failure and liver disease, and being previously treated with docetaxel. A 1:1 propensity score matching method was used to balance sample sizes and baseline traits between the two treatment groups, abiraterone versus abiraterone + spironolactone. Kaplan-Meier curves and Cox proportional hazard model were used to compare 5-year overall survival and all-cause mortality outcomes, respectively, between the two groups. After propensity score matched, the abiraterone + spironolactone group was treated with abiraterone significantly longer than the abiraterone-only group (mean ± standard deviation days 549.0 ± 552.3 vs. 435.5 ± 474.1; p = 0.0002) and had a higher 5-year overall survival rate (44% vs. 37%; p = 0.0116). Veterans with metastatic prostate cancer treated with abiraterone + spironolactone also had a lower 5-year all-cause mortality compared to those only on abiraterone (hazard ratio 0.80, 95% confidence intervals 0.61-0.96; p = 0.012). This large VA observational study suggests that concomitant use of spironolactone does not compromise cancer control or survival of metastatic prostate cancer patients treated with abiraterone.

7886 Impact of Withania somnifera (Ashwagandha) Supplement on Androgen Signalling Pathways

Abstract Disclosure: I.S. Barata: None. J. Yakubu: None. T. Du Toit: None. A.V. Pandey: None. Supplements derived from plant extracts are often used as alternatives to pharmaceutical drugs. These products are often perceived as safe despite the absence of scientific evidence regarding their efficacy and safety and are less strictly regulated than pharmaceutical products. Winter cherry (Withania somnifera, commonly known as ashwagandha) is used as a testosterone booster supplement in multiple countries. Withania somnifera extract was found to increase testosterone and androgen precursors in a small clinical study. However, there is a lack of data regarding effects of Withania somnifera on the steroidogenic pathways. Steroidogenesis impacts not only sexual differentiation, reproduction, and fertility but also other physiological processes, including hypertension and obesity. Moreover, the modulation of hormone signaling is an important target in hormone-responsive pathogenesis, and overproduction of androgens has been implicated in the pathogenesis of prostate cancer (PCa) and polycystic ovarian syndrome (PCOS). In humans, testosterone is mainly produced in the testes after conversion of pregnenolone to 17-hydroxypregnenolone (17-OHPreg) and dehydroepiandrosterone (DHEA, the precursor of androgens) by adrenal CYP17A1, which catalyzes both the 17-hydroxylation of steroids for cortisol production and the breakage of 17,20 bonds (17,20 lyase) in 17-OHPreg to produce DHEA. The intake of substances that may increase androgen levels by people with PCa or PCOS or with predisposition to these conditions may trigger pathogenesis or worsen prognosis by accelerating disease progression. We investigated the effects of Withania somnifera in modulating the adrenal steroidogenic pathway and the possible consequences on the pathogenesis of androgen-responsive conditions, specifically PCa. Adrenal cells were treated with the extract of Withania somnifera to characterize its effect on adrenal steroid profile and CYP17A1 hydroxylase and lyase activities. Prostate cancer proliferation was assessed by direct incubation of prostate cancer cells with extracts as well as with conditioned media from adrenal cells treated for 48h, to simulate natural steroidogenesis. The results suggest that adrenal steroid hormone biosynthesis can be altered by the intake of Withania somnifera extract and that this supplement may affect proliferation of PCa cells. Moreover, the reported testosterone booster effect of Withania somnifera supplementation does not appear to be through increased adrenal androgen production. Presentation: 6/1/2024

7886 Impact of Withania somnifera (Ashwagandha) Supplement on Androgen Signalling Pathways

Abstract Disclosure: I.S. Barata: None. J. Yakubu: None. T. Du Toit: None. A.V. Pandey: None. Supplements derived from plant extracts are often used as alternatives to pharmaceutical drugs. These products are often perceived as safe despite the absence of scientific evidence regarding their efficacy and safety and are less strictly regulated than pharmaceutical products. Winter cherry (Withania somnifera, commonly known as ashwagandha) is used as a testosterone booster supplement in multiple countries. Withania somnifera extract was found to increase testosterone and androgen precursors in a small clinical study. However, there is a lack of data regarding effects of Withania somnifera on the steroidogenic pathways. Steroidogenesis impacts not only sexual differentiation, reproduction, and fertility but also other physiological processes, including hypertension and obesity. Moreover, the modulation of hormone signaling is an important target in hormone-responsive pathogenesis, and overproduction of androgens has been implicated in the pathogenesis of prostate cancer (PCa) and polycystic ovarian syndrome (PCOS). In humans, testosterone is mainly produced in the testes after conversion of pregnenolone to 17-hydroxypregnenolone (17-OHPreg) and dehydroepiandrosterone (DHEA, the precursor of androgens) by adrenal CYP17A1, which catalyzes both the 17-hydroxylation of steroids for cortisol production and the breakage of 17,20 bonds (17,20 lyase) in 17-OHPreg to produce DHEA. The intake of substances that may increase androgen levels by people with PCa or PCOS or with predisposition to these conditions may trigger pathogenesis or worsen prognosis by accelerating disease progression. We investigated the effects of Withania somnifera in modulating the adrenal steroidogenic pathway and the possible consequences on the pathogenesis of androgen-responsive conditions, specifically PCa. Adrenal cells were treated with the extract of Withania somnifera to characterize its effect on adrenal steroid profile and CYP17A1 hydroxylase and lyase activities. Prostate cancer proliferation was assessed by direct incubation of prostate cancer cells with extracts as well as with conditioned media from adrenal cells treated for 48h, to simulate natural steroidogenesis. The results suggest that adrenal steroid hormone biosynthesis can be altered by the intake of Withania somnifera extract and that this supplement may affect proliferation of PCa cells. Moreover, the reported testosterone booster effect of Withania somnifera supplementation does not appear to be through increased adrenal androgen production. Presentation: 6/1/2024

12325 Adrenocortical Carcinoma Masquerading As Pheochromocytoma In A Patient With Congenital Adrenal Hyperplasia

Abstract Disclosure: E.M. Niedzialkowska: None. A.A. Banka: None. Introduction: The development of adrenocortical carcinoma (ACC) in patients with congenital adrenal hyperplasia (CAH) is rare. The patients with CAH are at increased risk of adrenal tumors which is attributed to ACTH stimulation of adrenal gland if the disease is not appropriately treated. ACC cases mistaken for pheochromocytomas have been reported in the literature and are attributed to the variety of immunohistochemical markers expressed by the tumors. Case description:59 y.o female with salt-wasting CAH diagnosed at the age of 2 (21-hydroxylase deficiency) on hydrocortisone supplementation reported to the hospital due to episodes of sweating, tachycardia and hypertension. Work up revealed mildly elevated plasma normetanephrine 1 nmol/l (N <0.9), urine normetanephrine 1762 mcg (N<899), VMA 11.2 mcg/24hr (N 3.3-7.2). MRI of the abdomen revealed 2 left adrenal masses of 3.7 and 2.4 cm, right adrenal gland hyperplasia and low T1 and T2 enhancement. I-123 MIBG revealed increased activity and thickness of the right adrenal gland and no significant uptake on the left with nodular masses. The patient underwent left adrenalectomy with pathological report consistent with pheochromocytoma due to positive chromogranin and synaptophysin staining and moderate Ki activity. A year later follow up imaging showed an enhancing mass up to 7 cm at the suprarenal fossa invading the left kidney that was positive for nodular adrenocortical hyperplasia per pathology report. The patient continued to have elevated 17-OH- progesterone (2740 ng/l, N <51) despite compliance with her steroid therapy and suppressed ACTH. She underwent mass resection along with nephrectomy, splenectomy, partial colectomy and partial pancreatectomy. Pathology report was positive for adrenocortical carcinoma (positive chromogranin, synaptophysin, CAM 5.2, polycystic cytokeratin, Ki positive in greater than 10% of the tumor cells) with renal and regional lymph node invasion and colonic metastases. The patient was started on mitotane therapy but a year later PET scan was positive for liver and omental metastases and was subsequently started on carboplatin/etoposide followed by streptozocin/adriamycin with initial good response, however repeat PET a year afterwards showed progression of the liver lesions, metastases to omentum and metastatic lesion to calvarium and the patient expired soon afterwards. Discussion: CAH predisposes patients to adrenal tumors which is attributed to increased ACTH stimulation of the adrenal gland but ACC in this population is extremely rare. In very rare cases ACC can present clinically as pheochromocytoma with elevated catecholamine levels and positive synaptophysin and chromogranin staining which poses a clinical challenge. Both CAH and ACC can lead to increased androgen levels and ACTH levels can help to differentiate the origin of the hyperandrogenemia. Presentation: 6/2/2024

Association between infertility and risk of cardiovascular diseases in young women

Scientists and medical experts are beginning to understand the significant role that a woman’s past reproductive experiences play in her potential risk of developing heart disease. Reproductive history is seldom considered when assessing the cardiovascular risk. Infertility, high blood pressure, and hypertension are risk factors for heart disease. Additional analyses were conducted to determine whether the apparent increase in risk could be influenced by other risk factors associated with infertility such as irregular menstruation, thyroid conditions, and waist circumference. This study aimed to investigate the association between cardiovascular risk and infertility in women and those who are fertile. The objectives of this study were to estimate the levels of serum creatinine kinase (MB) in both infertile and fertile control groups, as well as to estimate the LDL and HDL levels in the same groups. The study group comprised 78 participants, of which 39 were fertile and 39 were infertile. CK (MB), HDL, LDL, Uric acid, and high sensitivity C reactive Protein (hs-CRP) levels were analyzed. In this study, we discuss how infertility may share common pathways with cardiovascular diseases. Numerous mechanisms may be involved in mediating infertility, including ovulatory abnormalities, endometriosis, and uterine fibroids. For example, in addition to having lower HDL levels, women with polycystic ovary syndrome (PCOS) are more likely to have higher levels of total cholesterol, triglycerides, and LDL. PCOS patients typically exhibit elevated UA levels and hyperuricemia, which are commonly associated with increased androgen levels.

Production of fertile YY pseudofemales in Nile tilapia with LG23 as the sex chromosome

Nile tilapia display conspicuous differences in growth rates between genders, as males tend to outpace and outgrow females. The production of all male Nile tilapia populations using genetically male tilapia (GMT) technology represents the most efficient and scientifically grounded approach. Most of the Nile tilapia stocks in aquaculture use LG23 as sex chromosome. The crux of GMT lies in the acquisition of YY supermales and YY pseudofemales (pF). Nonetheless, the utilization of GMT is impeded by the lower fertility and even infertility of feminized YY-pF. In this study, we found that YY-pF exhibited male-like genital papillae, and exhibited significantly higher androgen levels and lower E2 levels compared with that of fertile XY-pF. YY-pF carries two copies of Amhy but lacks Amh, and XY-pF possesses one Amhy and one Amh. In XY-pF, the expression of Amh/Amhy was only observed in granulosa cells of phase I and II follicles, while in YY-pF, Amhy expression persisted from phase I to IV. On the contrary, Cyp19a1a was found to be highly expressed in granulosa cells of phase III and IV follicles in XY-pF, but significantly reduced in granulosa cells of phase III and IV follicles in YY-pF, exhibiting a reciprocal expression pattern with Amhy. Consistently, YY-pF with one copy of Amhy mutation (YY-Amhy+/−-pF) were fertile. These results indicated that prolonged expression of Amhy led to a decrease in the expression of Cyp19a1a, followed by a decrease in serum E2 levels and an increase in androgen levels. Based on these data, we treated YY-pF with both E2 and trilostane (androgen synthetase inhibitors) simultaneously at the vitellogenic stage to make it fertile. The acquisition of fertile YY-pF laid the foundation for the widespread application of GMT.

Unveiling the Nuances of Adult Female Acne: A Comprehensive Exploration of Epidemiology, Treatment Modalities, Dermocosmetics, and the Menopausal Influence.

Previously considered a skin disease exclusively affecting adolescents, characterized by inflammatory and non-inflammatory skin lesions, acne vulgaris is now increasingly observed in adult life, including post-menopause. Today, adult female acne (AFA) is a common chronic inflammatory disease of the pilosebaceous unit, with polymorphic lesions presenting as open or closed comedones, papules, pustules, and even nodules or cysts, often with the presence of sequelae. AFA may persist from adolescence or manifest de novo in adulthood. Its etiology is multifactorial, involving genetic, hormonal, dietary, and environmental factors, yet still incompletely understood. Increased sebum production, keratinocyte hyper-proliferation, inflammation, and reduced diversity of Cutibacterium acnes strains are the underlying disease mechanisms. During menopausal transition, a relative increase in androgen levels occurs, just as estrogens begin to decline, which can manifest itself as acne. Whereas most AFA exhibit few acne lesions with normo-androgenic serum levels, baseline investigations including androgen testing panel enable associated comorbidities to be eliminated, such as polycystic ovarian syndrome, congenital adrenal hyperplasia, or tumors. Another interesting feature is AFA's impact on quality of life, which is greater than in adolescents, being similar to other chronic diseases like asthma. The therapeutic approach to AFA depends on its severity and associated features. This review investigates the intricate facets of AFA, with a specific focus on incidence rates, treatment modalities, and the curious impact of menopause. Utilizing insights from contemporary literature and scientific discussions, this article seeks to advance our understanding of AFA, offering new perspectives to shape clinical practices and improve patient outcomes.

Virtual Insights into Natural Compounds as Potential 5α-Reductase Type II Inhibitors: A Structure-Based Screening and Molecular Dynamics Simulation Study.

Androgenic alopecia (AGA) is a dermatological disease with psychosocial consequences for those who experience hair loss. AGA is linked to an increase in androgen levels caused by an excess of dihydrotestosterone in blood capillaries produced from testosterone by 5α-reductase type II (5αR2), which is expressed in scalp hair follicles; 5αR2 activity and dihydrotestosterone levels are elevated in balding scalps. The diverse health benefits of flavonoids have been widely reported in epidemiological studies, and research interest continues to increase. In this study, a virtual screening approach was used to identify compounds that interact with active site residues of 5αR2 by screening a library containing 241 flavonoid compounds. Here, we report two potent flavonoid compounds, eriocitrin and silymarin, that interacted strongly with 5αR2, with binding energies of -12.1 and -11.7 kcal/mol, respectively, which were more significant than those of the control, finasteride (-11.2 kcal/mol). Molecular dynamic simulations (200 ns) were used to optimize the interactions between compounds and 5αR2 and revealed that the interaction of eriocitrin and silymarin with 5αR2 was stable. The study shows that eriocitrin and silymarin provide developmental bases for novel 5αR2 inhibitors for the management of AGA.

Serum Testosterone and Dihydrotestosterone and Incidence and Progression of Lower Urinary Tract Symptoms: Results From the REDUCE Study.

Though the pathogenesis of benign prostatic hyperplasia is unclear, it was previously believed that increasing androgen levels contributed, though not all data support this idea. We tested if elevated serum testosterone or dihydrotestosterone were risk factors for lower urinary tract symptoms incidence in asymptomatic men and for lower urinary tract symptoms progression in symptomatic men. A post hoc analysis of REDUCE was performed in 3009 asymptomatic men and in 2145 symptomatic men. REDUCE was a randomized trial of dutasteride for prostate cancer prevention in men with an elevated prostate-specific antigen and negative prestudy biopsy. We estimated multivariable adjusted hazard ratios and 95% confidence intervals using Cox models to test the association between quintiles of serum testosterone and dihydrotestosterone at baseline and lower urinary tract symptoms incidence and progression and tested for interaction by treatment arm (dutasteride vs placebo). In asymptomatic men, there was no evidence serum testosterone or dihydrotestosterone were related to lower urinary tract symptoms incidence (P = .9, P = .4). In symptomatic men, there was no evidence serum testosterone or dihydrotestosterone were related to lower urinary tract symptoms progression (P = .9, P = .7). Results were similar in both placebo and dutasteride arms (all P interaction ≥ .3). In REDUCE, higher serum testosterone and higher serum dihydrotestosterone were not associated with either lower urinary tract symptoms incidence in asymptomatic men or lower urinary tract symptoms progression in symptomatic men. These data do not support the hypothesis that serum androgens in middle-aged men are associated with lower urinary tract symptoms.

FRI151 Combined Maternal Hyperandrogenemia And Maternal Western Diet Consumption Programs Hypertension In Adult Female Offspring That Is Associated With Increased Leptin Levels

Abstract Disclosure: N.M. Shawky: None. R.M. Quin: None. K. Davenport: None. Funding: P20GM121334, AHA Career Development Award 938320 Background: Polycystic ovary syndrome (PCOS) is the major cause of hyperandrogenemia and the most common endocrinopathy in women of reproductive age. There is still a great controversy on whether daughters of PCOS women develop PCOS themselves. PCOS is commonly associated with increased blood pressure (BP) and obesity. We utilize a hyperandrogenemic female (HAF) rat model that develops a 3-fold increase in androgen levels to study the cardiometabolic consequences in the offspring (off.). We have previously shown that adult female off. of HAF rats consuming regular chow do not develop hypertension (HTN) or obesity. Consumption of western diet (WD) aggravates the reproductive phenotype of PCOS. We have shown that WD consumption also promotes further increase in BP, early onset obesity and hyperleptinemia in HAF rats, an effect that was not seen in normoandrogenemic controls. The current study was performed to test the hypothesis that WD consumption in HAFs (model of PCOS with worsened cardiometabolic phenotype) will program HTN, hyperandrogenemia and obesity in adult female off. Methods: At 4 wks of age, female Sprague Dawley (SD) rats were implanted with either 5α-dihydrotestosterone (7.5 mg, s.c.; HAF) or placebo (controls; CON) pellets, that were replaced every 85 days. HAF and CON rats were alsostarted on WD (high fat and high sucrose) or control diet (CD), thus forming 4 groups; CON-CD, CON-WD, HAF-CD and HAF-WD. At 10-13 wks of age, females were paired with SD males and allowed to get pregnant and lactate their off. At 16 wks of age, body composition (EchoMRI), plasma leptin (ELISA) and serum testosterone (T) [LC/MS] were determined in female off. (n=4-12). Another set of female off. were implanted with radiotelemetry transmitters to measure mean arterial pressure (MAP) [n=4-5]. All studies were done using 1 off./litter/group. Results: Despite the similar fat mass in all groups, plasma leptin was significantly higher in female off. from HAF-WD compared to female off. from CON-WD (1.5-fold, p<0.05). Serum T was significantly higher (p<0.05) in female off. from HAF-CD compared to female off. from CON-CD (4-fold), CON-WD (3-fold) and HAF-WD (3-fold). MAP was significantly higher in female off. from HAF-WD compared to female off. from CON-CD and HAF-CD (113 ± 3 vs 104 ± 2 and 103 ± 5 mmHg, p<0.05). Yet, MAP was similar between female off. from CON-WD, CON-CD and HAF-WD. Conclusion: Our results indicate that independent mechanisms program hyperandrogenemia and HTN in adult female off. Combined maternal hyperandrogenemia and WD could program HTN in female off. that is associated with hyperleptinemia. This suggests that daughters of PCOS women with worsened cardiometabolic phenotype could be at risk of hyperleptinemia and HTN as adults. Our future studies will aim at addressing the role of hyperleptinemia in mediating HTN in the female off. Presentation: Friday, June 16, 2023

P-682 Androgen and Inhibin B levels during ovarian stimulation before and after eight weeks of low dose hCG priming in women with low ovarian reserve

Abstract Study question Does eight weeks of low dose human chorionic gonadotropin (hCG)-priming affect androgen or Inhibin B levels in serum and follicular fluid during IVF/ICSI treatment? Summary answer Inhibin B was reduced on stimulation day 1 in the IVF/ICSI cycle following hCG-priming. Androgen levels in serum and follicular fluid was not increased. What is known already In our recently published pilot study, eight weeks of low-dose hCG-priming was used to stimulate the intraovarian androgen synthesis in women with AMH <6.29 pmol/L. Priming resulted in more retrieved oocytes and more follicles sized 2-5 mm and less sized 6-10 mm at the start of stimulation. Stimulation time and FSH consumption was increased after priming. HCG priming potentially stimulate the intraovarian androgen synthesis causing upregulation of FSH receptors on granulosa cells, and therefore it was unexpected that the antral follicles were smaller and stimulation time longer following priming. This might indicate a different mechanism of action than previously thought. Study design, size, duration A prospective, paired, non-blinded, single-center study including 20 women conducted between January 2021 and July 2021 at a tertiary referral hospital. Participants underwent two identical IVF treatments: a Control cycle including elective freezing of all blastocysts and a Study cycle with fresh blastocyst transfer. The Control and Study cycles were separated by eight weeks (two menstrual cycles) of hCG-priming by daily injections of 260 IE hCG (details in our previously published paper). Participants/materials, setting, methods Women aged 18-40 years with cycle lengths of 23-35 days and AMH <6.29 pmol/L. Control and Study IVF cycles were performed in a fixed GnRH-antagonist protocol. Blood samples were taken on stimulation day 1, stimulation day 5-6, trigger day, day of oocyte pick up (OPU), and trigger day + 7 days in the Control and Study cycles. Follicular fluid was collected from the first aspirated follicle on both sides during OPU in both cycles. Main results and the role of chance Inhibin B serum levels were significantly lower on stimulation day 1 after hCG-priming, but no other significant differences in serum Inhibin B or androgen levels were seen. The concentrations of Inhibin B and androstenedione in the follicular fluid from the Study and Control cycle did not vary but testosterone was significantly lower in the Study cycle. A lower Inhibin B in the Study cycle corresponds with the antral follicles being significantly smaller after priming, and this probably led to a longer stimulation time in the Study cycle. This contradicts the theory that androgen priming causes more FSH receptors on developing (antral up to preovulatory) follicles. Instead, we hypothesize that androgen priming rescued some small antral follicles that would have otherwise undergone atresia by the end of the previous menstrual cycle. The mechanism of action was likely an increase in androgen levels and FSH receptor expression within these small follicles, however, not enough to elevate androgen levels in serum. We retrieved significantly more oocytes in the Study cycle and the production of estradiol per follicle ≥10 mm on trigger day was comparable in the Study and Control cycle, suggesting that the rescued follicles were competent in producing oocytes and steroid hormones. Limitations, reasons for caution The sample size was small, and androgen and Inhibin B levels were not the primary outcome. We have not demonstrated a higher androgen level or FSH receptor expression in small antral follicles following hCG-priming. Wider implications of the findings The results make us question the mechanism of action behind hCG-priming prior to IVF. It is important to design a study with retrieval of small antral follicles immediately after priming to investigate the proposed hypothesis and to confirm improved cycle outcomes i.e., more retrieved oocytes in a larger study population. Trial registration number NCT04643925

A Testicular Leydig Cell Tumor; An Uncommon Cause of Precocious Puberty: A Case Report With Secondary Central Precocious Puberty

Sexual precocity in boys is defined as any sign of secondary sexual characteristics present before the age of 9. Leydig cell tumors of the testes are a rare cause of peripheral precocious puberty in boys. Here, we report 8 years and 4-month-old boys with signs of peripheral precocious puberty because of a testicular Leydig cell tumor that developed true precocious puberty after surgical removal. Examination of genitalia showed Tanner 4 hair growth. The penis length was 14.5 cm with a 2.5 cm width. The right testis was enlarged but the left testis was measured at 2cm in length and 1 cm in width. Laboratory results showed low serum gonadotropin levels and increased androgen levels. Testicular sonography reported one solid mass measured 31×28×15 millimeters. With a presumptive diagnosis of Leydig cell tumor, the patient underwent radical orchiectomy. Pathologic evaluation confirmed it. Two months after surgery, the diagnosis of central precocious puberty was confirmed according to physical examination and rising of serum gonadotropins. We started treatment with a Gonadotropin-releasing hormone (GnRH) agonist. Leydig cell tumor in children is an uncommon cause of precocious puberty. In every boy with the sign of peripheral precocious puberty and asymmetrical testicular enlargement, the testicular tumor should be considered. It may induce central precocious puberty after surgical resection and this diagnosis should be considered in the patient’s follow-up in the next visits.

PD02-06 SERUM TESTOSTERONE AND DIHYDROTESTOSTERONE AND INCIDENCE AND PROGRESSION OF LOWER URINARY TRACT SYMPTOMS IN REDUCTION BY DUTASTERIDE OF PROSTATE CANCER EVENTS TRIAL

You have accessJournal of UrologyCME1 Apr 2023PD02-06 SERUM TESTOSTERONE AND DIHYDROTESTOSTERONE AND INCIDENCE AND PROGRESSION OF LOWER URINARY TRACT SYMPTOMS IN REDUCTION BY DUTASTERIDE OF PROSTATE CANCER EVENTS TRIAL James Daniels, James Mirocha, Daniel Moreira, Gerald Andriole, and Stephen Freedland James DanielsJames Daniels More articles by this author , James MirochaJames Mirocha More articles by this author , Daniel MoreiraDaniel Moreira More articles by this author , Gerald AndrioleGerald Andriole More articles by this author , and Stephen FreedlandStephen Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003219.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is common in older men, with many developing lower urinary tract symptoms (LUTS) that impair quality of life. Though the pathogenesis of BPH is unclear, it was previously believed that increasing androgen levels had a role, though not all data support this idea. We tested if elevated serum testosterone and elevated serum DHT are risk factors for LUTS incidence in asymptomatic men and for LUTS progression in symptomatic men. METHODS: A post-hoc analysis of REDUCE was carried out in 3009 asymptomatic men with baseline International Prostate Symptom Score (IPSS) <8 and in 2145 symptomatic men with baseline IPSS≥8 not taking α-blockers or 5α-reductase inhibitor medications. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial was a randomized trial of dutasteride for prostate cancer prevention in men with an elevated PSA and negative pre-study biopsy. IPSS was measured every 6 months over the 4-year study. We estimated multivariable adjusted hazard ratios (adj-HRs) and 95% confidence intervals (CIs) using Cox models to test the association between quintiles of serum testosterone and quintiles of serum dihydrotestosterone (DHT) at baseline and LUTS incidence and progression. Among asymptomatic men, incident LUTS was defined as the first report of medical treatment, surgery or sustained clinically significant LUTS (i.e., 2 reports of IPSS>14). Among symptomatic men, LUTS progression was defined as an IPSS increase of ≥4 points from baseline, any surgical procedure for BPH, or the start of a new BPH medication. RESULTS: In asymptomatic men, relative to the lowest quantile, all quintiles of serum testosterone and all quintiles of DHT were unrelated to LUTS incidence (all p≥0.25). In symptomatic men, relative to the lowest quantile, all quintiles of serum testosterone and all quintiles of DHT were unrelated to LUTS progression (all p≥0.17). There was no significant interaction between treatment with dutasteride and serum testosterone or DHT when predicting LUTS; as such, data were not stratified by treatment assignment. CONCLUSIONS: In the REDUCE study, higher serum testosterone and higher serum DHT were not associated with either incident LUTS in asymptomatic men or progression of LUTS in symptomatic men. These data do not support the hypothesis that serum androgen levels in middle-aged men are associated with LUTS. Source of Funding: Dr. Daniels is funded by the NIH grants TL1 DK132768 and U2C DK129496 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e71 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information James Daniels More articles by this author James Mirocha More articles by this author Daniel Moreira More articles by this author Gerald Andriole More articles by this author Stephen Freedland More articles by this author Expand All Advertisement PDF downloadLoading ...

Serum adiponectin in Indian women with polycystic ovary syndrome.

Poly Cystic Ovary Syndrome (PCOS) is mainly characterised by reproductive hormonal imbalance and increased androgen levels, ovulatory dysfunction and polycystic appearing ovaries on ultrasonography. The obesity is common factor to cause PCOS and this adipocytokines play an important role to cause obesity related disorders. Hence, the present study aimed to evaluate the role of adiponectin in women with PCOS compared them with healthy controls. This case control study included total eighty (80) subjects out of this fourty subjects with PCOS and remaining fourty (40) age and body mass index matched healthy controls. The fasting, post parandial blood sugars, glycated haemoglobin, lipid profile and adiponectin levels were measured and data was recorded. There was a significantly elevated levels of total cholesterol, triacylglycerol, very low density lipoprotein, low density lipoprotein (p = 0.0001**) and there were no significant levels of fasting and post parandial blood sugars, glycated haemoglobin levels were observed in women with PCOS than in controls. Additionally, we also observed significantly decreased levels of high density lipoprotein and adiponectin in women with PCOS when compared to healthy controls (p = 0.0001**). The adiponectin shown a positive correlation with age, high density lipoprotein and negative correlation with total cholesterol, triacylglycerol, very low density lipoprotein and low density lipoprotein (p = 0.0001**). The altered adiponectin levels in polycystic ovary syndrome appear to form an important link between obesity and the complications of PCOS.

Oral administration of VDAC1-derived small molecule peptides increases circulating testosterone levels in male rats.

Cholesterol is the precursor of all steroid hormones, and the entry of cholesterol into the mitochondria is the rate-limiting step of steroidogenesis. Voltage-dependent anion channel (VDAC1) is an outer mitochondrial protein part of a multiprotein complex that imports cholesterol. We previously reported that intratesticular administration of a 25 amino acid peptide blocking the interaction between 14-3-3ϵ with VDAC1 increased circulating levels of testosterone. This fusion peptide was composed of a HIV-1 transactivator of transcription (TAT) protein transduction domain cell-penetrating peptide, a glycine linker, and amino acids 159-172 of VDAC1 (TV159-172). Here, we describe the development of a family of small molecules that increase circulating testosterone levels after an oral administration. We first characterized an animal model where TV159-172 was delivered subcutaneously. This subcutaneous model allowed us to study the interactions between TV159-172 and the hypothalamus-pituitary-gonadal axis (HPG) and identify the biologically active core of TV159-172. The core consisted of the tetrapeptide RVTQ, which we used as a platform to design synthetic peptide derivatives that can be administered orally. We developed a second animal model to test various derivatives of RVTQ and found 11 active compounds. Dose-response experiments identified 4 synthetic peptides that robustly increased androgen levels in a specific manner. We selected RdVTQ as the leading VDAC1-core derivative and profiled the response across the lifespan of Brown-Norway rats. In summary, we present the development of a new class of therapeutics that act within the HPG axis to increase testosterone levels specifically. This new class of small molecules self-regulates, preventing abuse.

Sex and gender-specific aspects in prediabetes and diabetes mellitus-clinical recommendations (Update 2023)

Metabolic diseases dramatically affect the life of men and women from infancy up to old age in different and manifold ways and are amajor challenge for the healthcare system. The treating physicians are confronted with the different needs of women and men in the clinical routine. Gender-specific differences affect pathophysiology, screening, diagnostic and treatment strategies of diseases as well as the development of complications and mortality rates. Impairments in glucose and lipid metabolism, regulation of energy balance and body fat distribution and therefore the associated cardiovascular diseases, are greatly influenced by steroidal and sex hormones. Furthermore, education, income and psychosocial factors play an important role in the development of obesity and diabetes differently in men and women. Males appear to be at greater risk of diabetes at ayounger age and at alower body mass index (BMI) compared to women but women feature adramatic increase in the risk of diabetes-associated cardiovascular diseases after the menopause. The estimated future years of life lost owing to diabetes is somewhat higher in women than men, with ahigher increase in vascular complications in women but ahigher increase of cancer deaths in men. In women prediabetes or diabetes are more distinctly associated with ahigher number of vascular risk factors, such as inflammatory parameters, unfavourable changes in coagulation and higher blood pressure. Women with prediabetes and diabetes have amuch higher relative risk for vascular diseases. Women are more often morbidly obese and less physically active but may have an even greater benefit in health and life expectation from increased physical activity than men. In weight loss studies men often showed ahigher weight loss than women; however, diabetes prevention is similarly effective in men and women with prediabetes with arisk reduction of nearly 40%. Nevertheless, along-term reduction in all cause and cardiovascular mortality was so far only observed in women. Men predominantly feature increased fasting blood glucose levels, women often show impaired glucose tolerance. Ahistory of gestational diabetes or polycystic ovary syndrome (PCOS) as well as increased androgen levels and decreased estrogen levels in women and the presence of erectile dysfunction or decreased testosterone levels in men are important sex-specific risk factors for the development of diabetes. Many studies showed that women with diabetes reach their target values for HbA1c, blood pressure and low-density lipoprotein (LDL)-cholesterol less often than their male counterparts, although the reasons are unclear. Furthermore, sex differences in the effects, pharmacokinetics and side effects of pharmacological treatment should be taken more into consideration.

The Effect of L-carnitine on Apoptotic Markers (Annexin V and Clusterin) in Polycystic Ovarian Syndrome Women undergoing ICSI

Background: Despite abnormal apoptosis of granulosa cells is believed to have a role in the pathophysiology of polycystic ovarian syndrome (PCOS), the cellular and molecular processes behind this are unknown. Atresia occurs in developing PCOS follicles, likely facilitated by increased androgen levels. Atretic follicles are eliminated in the absence of tissue injury or inflammation, suggesting that programmed cell death may be the mechanism behind this process. Aim of the Study: The current study evaluated the protective effect of L-carnitine (LC) against programmed cell death and, eventually, endometrial receptivity. Patients and Methods: This prospective case-control research was performed at the Al-Nahrain University’s high institute for infertility diagnosis and assisted reproductive technologies and the Al-Farah Specialist Fertility Center. Sixty women diagnosed with the polycystic ovarian syndrome were recruited in this research and began their IVF/ICSI cycle; clusterin and annexin V were measured as apoptotic markers in the early follicular phase of the cycle CD2-in the serum and in the follicular fluid on the day of ova pickup. Endometrial thickness was assessed by ultrasound examination.Results: Both serum annexin V and clusterin were decreased significantly after treatment (p&lt; 0.05). The mean endometrial thickness in all enrolled women was 5.30 ± 0.70 mm. There was no significant difference in mean endometrial thickness between the study and placebo groups, 5.43 ± 0.63 versus 5.37 ± 0.66 mm, respectively (p = 0.441). There was no significant difference in mean serum annexin V (p = 0.101), but follicular fluid annexin V and serum and follicular fluid clusterin were lower in the study group than in the placebo group in a significant manner (p