Elevated Serum Testosterone Levels Research Articles

Abstract 5577: TRPM8 mediated Ca2+ signaling as a therapeutic target in prostate cancer

Abstract Prostate cancer (PC) is a prevalent and deadly malignancy, necessitating the development of innovative therapeutic strategies. Transient receptor potential melastatin 8 (TRPM8), an ion channel highly expressed in prostate epithelium, has emerged as a potential target. Our preliminary studies demonstrate that TRPM8 plays a crucial role in PC progression. We observed an initial increase in TRPM8 mRNA expression during early-stage PC, followed by a decline in advanced and androgen-independent prostate cancer (AIPC) stages. Additionally, TRPM8 knockout mice exhibited elevated serum testosterone levels, heightened androgen receptor (AR) activity, and increased cell cycle, invasion, and adhesion-related effects. In xenograft models, TRPM8 demonstrated potent antitumor properties in both AR+ and AR- contexts. Our research suggests that TRPM8 activation on the plasma membrane promotes calcium influx and induces apoptosis in PC cells. Conversely, TRPM8 internalization correlates with PC pathogenesis. By exploring the effects of TRPM8 on PTEN-mediated cellular signaling, we aim to uncover novel insights into the molecular mechanisms underlying TRPM8's role in PC. This abstract underscores the potential of targeting TRPM8-mediated Ca2+ signaling as a promising therapeutic approach to combat PC progression, offering hope for improved patient outcomes. Citation Format: Swapna Asuthkar, Kiran Velpula, Vander Don Griend. TRPM8 mediated Ca2+ signaling as a therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5577.

Uterine histopathology and steroid metabolism in a polycystic ovary syndrome rat model

The aim of this study was to investigate uterine lesions, uterine endocrine status and expression of genes involved in uterine differentiation in a rat model of polycystic ovary syndrome (PCOS). The possible involvement of the androgen receptor (AR) was also investigated. PCOS rats showed an increased incidence of uterine epithelial and glandular lesions and elevated serum testosterone level, which was not detected in uterine tissue. Uterine 17β-estradiol, estrone and progesterone were detected in 100%, 75% and 50% of the animals, respectively. This was associated with a decrease in Star and an increase in Hsd17b2, Srd5a1 and Cyp19a1, suggesting that uterine steroids are not synthesized de novo in PCOS and that alterations in these enzymes may explain the absence of testosterone and low progesterone. In addition, ESR2 decreased and AR increased, suggesting possible steroid receptor crosstalk. Genes associated with uterine differentiation, PTEN and WNT5a, also showed reduced expression. PCOS rats treated with flutamide, an AR antagonist, were similar to PCOS rats in terms of uterine lesions, serum steroid levels, ESR2, PTEN and WNT5a expression. However, testosterone, AR and aromatase levels were similar to control rats, with decreased expression of ESR1 and HOXA10, suggesting that these expressions are AR dependent. Our results suggest that the primary cause of the observed uterine lesions in the PCOS rat model is the altered endocrine status and consequently changes in genes related to uterine differentiation.

High-fat and high-sucrose diet impairs female reproduction by altering ovarian transcriptomic and metabolic signatures

BackgroundExcessive energy intake in modern society has led to an epidemic surge in metabolic diseases, such as obesity and type 2 diabetes, posing profound threats to women’s reproductive health. However, the precise impact and underlying pathogenesis of energy excess on female reproduction remain unclear.MethodsWe established an obese and hyperglycemic female mouse model induced by a high-fat and high-sucrose (HFHS) diet, then reproductive phenotypes of these mice were evaluated by examing sexual hormones, estrous cycles, and ovarian morphologies. Transcriptomic and precise metabolomic analyses of the ovaries were performed to compare the molecular and metabolic changes in HFHS mice. Finally, orthogonal partial least squares discriminant analysis was performed to compare the similarities of traits between HFHS mice and women with polycystic ovary syndrome (PCOS).ResultsThe HFHS mice displayed marked reproductive dysfunctions, including elevated serum testosterone and luteinizing hormone levels, irregular estrous cycles, and impaired folliculogenesis, mimicking the clinical manifestations of women with PCOS. Precise metabolomic overview suggested that HFHS diet disrupted amino acid metabolism in the ovaries of female mice. Additionally, transcriptional profiling revealed pronounced disturbances in ovarian steroid hormone biosynthesis and glucolipid metabolism in HFHS mice. Further multi-omics analyses unveiled prominent aberration in ovarian arginine biosynthesis pathway. Notably, comparisons between HFHS mice and a cohort of PCOS patients identified analogous reproductive and metabolic signatures.ConclusionsOur results provide direct in vivo evidence for the detrimental effects of overnutrition on female reproduction and offer insights into the metabolic underpinnings of PCOS.

Association between Serum Testosterone and Aortic Valve Stenosis: A Prospective Cohort Study.

Serum testosterone is associated with atherosclerotic cardiovascular disease, which shares risk factors with aortic stenosis (AS). The association between serum testosterone and AS has not been previously investigated. We aimed to assess the prospective association between serum testosterone and risk of AS. Serum testosterone was determined at baseline using a radioimmunoassay kit in 2577 men aged 42-61 years recruited into the Kuopio Ischemic Heart Disease prospective cohort study. Hazard ratios (HRs) with 95% confidence intervals (Cis) were estimated for AS. After a median follow-up of 27.2 years, 119 cases of AS were recorded. The risk of AS increased continuously with increasing serum testosterone across the range 25-39 nmol/L (p-value for nonlinearity = 0.49). In an analysis adjusted for age, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking status, history of type 2 diabetes, history of coronary heart disease, and alcohol consumption, the HR (95% CI) for AS was 1.39 (1.10-1.76) per 10 nmol/L increase in serum testosterone. When alcohol consumption was replaced with physical activity, the HR (95% CI) was 1.38 (1.09-1.74). Comparing the bottom versus top third of serum testosterone, the corresponding (adjusted) risk estimates were 1.76 (1.11-2.81) and 1.76 (1.10-2.80), respectively. In middle-aged and older Finnish men, elevated levels of serum testosterone were associated with an increased risk of AS. Further research is needed to replicate these findings and assess any potential relevance of serum testosterone in AS prevention.

Phytochemical-Based Study of Ethanolic Extract of Saraca asoca in Letrozole-Induced Polycystic Ovarian Syndrome in Female Adult Rats.

Polycystic ovarian syndrome (PCOS) is a complex metabolic and endocrine disorder which affects women of reproductive age. It is a condition in which ovaries produce an excessive amount of androgen (the male sex hormone). Saraca asoca (Roxb.) Willd. is a plant of the Fabaceae family. This plant has been traditionally used as a uterine tonic in leucorrhea and dysmenorrhea due to its various pharmacological activities. In this study, the ethanolic extract of S. asoca (EESA) was evaluated for its potential to be used for the management of PCOS. HPLC analysis revealed the presence of various phytoconstituents: kaempferol, rutin, (-)-epicatechin, salicylic acid, and gallic acid. For PCOS induction, 30 adult female rats were randomly divided into two groups: the control group (n = 5) and the PCOS group (n = 25). Letrozole (1 mg/kg/day) was administered per orally (p.o.) for a period of 7 weeks for the induction of disease. Weekly body weight measurements and daily vaginal cytology examinations were performed for disease confirmation. After disease induction, the PCOS group was further divided into five groups (n = 5), that is, disease control, metformin, and EESA (200, 400, and 600 mg/kg) groups, respectively, and given treatment doses for next 5 weeks. After the treatment period, all animals were weighed and euthanized humanly. Blood samples were collected for hormonal assays, lipid profiles, and liver function tests. For histological assessment of ovarian cysts, ovaries were dissected. Livers were preserved to evaluate EESA's antioxidant properties. Histopathology analysis revealed that EESA reduced body weight and the number of cystic follicles. Furthermore, it also lowered the elevated levels of serum testosterone, luteinizing hormone, insulin, and malonaldehyde in PCOS rats while increasing the levels of follicle-stimulating hormone, estradiol, progesterone, prolactin, and other antioxidant enzymes such as superoxide dismutase, glutathione, and catalase. It can be concluded that EESA exhibited beneficial effects in normalizing the perturbed hormonal profile and improved the ovary status by decreasing the cystic follicle and improving the ovulation status in a dose-dependent manner.

Emodin improves glucose metabolism and ovarian function in PCOS mice via the HMGB1/TLR4/NF-ĸB molecular pathway.

Polycystic ovary syndrome (PCOS) is a reproductive disorder with an unclear etiology. It affects 5-10% of women worldwide and is largely associated with impaired glucose metabolism and obesity. High mobility group box 1 (HMGB1) is a nuclear protein associated with impaired glucose metabolism and PCOS. We sought to investigate the potential therapeutic effects of emodin on glucose metabolism and ovarian functions in PCOS mice via the HMGB1 molecular pathway. A high-fat diet (HFD) and dehydroepiandrosterone (DHEA) induced PCOS mouse model comprising four experimental groups was established: control, PCOS, PCOS plus emodin, and PCOS plus vehicle groups. Emodin administration attenuated obesity, elevated fasting glucose levels, impaired glucose tolerance, and insulin resistance, and improved the polycystic ovarian morphology of PCOS mice. Additionally, it lowered elevated serum HMGB1, LH, and testosterone levels in PCOS mice. Elevated ovarian protein and mRNA levels of HMGB1 and TLR4 in PCOS mice were also lowered following emodin treatment. Furthermore, emodin lowered high NF-ĸB/65 protein levels in the ovaries of PCOS mice. Immunohistochemical staining of the ovaries revealed strong HMGB1, TLR4, and AR expressions in PCOS mice, which were lowered by emodin treatment. Moreover, emodin significantly increased GLUT4, Irs2, and Insr levels that were PCOS. Overall, our study showed that emodin alleviated the impaired glucose metabolism and improved ovarian function in PCOS mice, possibly via the HMGB1/TLR4/NF-ĸB signaling pathway. Thus, emodin could be considered a potential therapeutic agent in the management of PCOS.

AMH producing purely cystic virilizing adult granulosa cell tumor in 17 years old girl: a case report and review of literatures

BackgroundAndrogen-producing granulosa cell tumor in adolescent girl is rare condition and clinical characteristics are not fully elucidated.Case presentationSeventeen years old girl complained of secondary amenorrhea was referred to our out-patient consultation. Markedly elevated serum testosterone, LH, and AMH levels were noted. Mild hirsutism and clitoromegaly were presented. Transabdominal ultrasonography and MRI revealed cystic mass occupied pelvic cavity probably originated from left ovary. Right ovary showed polycystic appearance. Laparoscopic left ovarian cystectomy was performed. After the surgery, her menstruation resumed along with normalized hormonal parameters, and clinical hyperandrogenism were improved. Since the scarcity of cellular lining of inner cyst wall, definitive pathological diagnosis was difficult. After the consultation with gynecological pathologist, the tumor was diagnosed as sex cord stromal tumor, highly suspicious for adult granulosa cell tumor. Residual left salpingo-oophorectomy was performed by additional laparoscopic surgery. Her serum testosterone and AMH levels were remained low with regular menstrual cycles and no evidence of recurrence.ConclusionsAndrogen-producing cystic granulosa cell tumor is rare gynecological disorders, which need both gynecologic oncological and endocrinological approach. Its clinical manifestations may bring some clues to the pathogenesis of ovulatory dysfunctions, such as polycystic ovary syndrome.

Effects of time-restricted feeding on letrozole-induced mouse model of polycystic ovary syndrome

The present study aimed to investigate whether time-restricted feeding (TRF) ameliorates metabolic and reproductive phenotypes in a letrozole-induced mouse model of polycystic ovary syndrome (PCOS). Sixty female C57BL/6 N mice were randomly divided into two groups according to the type of food received: either a chow or a 60% high-fat diet. Those mice were subcutaneously implanted with letrozole or placebo pellets at four weeks of age. Then, letrozole-treated mice were randomly assigned to different feeding regimens: (1) TRF for 4 h (ZT12–ZT16) or (2) ad libitum diet. After 4 weeks of dietary intervention, estrous cycles were determined with daily vaginal smear examination, and serial tail-tip blood sampling was performed at 5-min intervals for 2 h to measure the luteinizing hormone (LH) pulse frequency, amplitude, and mean LH levels in the diestrus cycle stage. Letrozole-treated mice in the ad libitum group demonstrated multiple PCOS-like phenotypes including ovulatory dysfunction, polycystic ovaries, and increased body weight, parametrial fat weight, adipocyte size and inflammation, and higher expression of Cyp17, Cyp19, and Fshr in the ovary, and Kiss1r and Gnrh in the hypothalamus, elevated serum testosterone levels, and more rapid and elevated LH pulsatility, with increased pulse frequency, amplitude, and mean levels in the diestrus stage, compared with the controls. After TRF for 4 weeks, those phenotypes reverted to normal levels in letrozole-treated mice, except the percentage of diestrus cycles indicating the arrest of estrous cycling which did not differ between the TRF and ad libitum groups. Our results demonstrate that TRF has therapeutic effects on the reproductive and metabolic phenotypes of a letrozole-induced mouse model of PCOS.

Elevated Endogenous Testosterone Levels are not Associated With Significant Clinical Morbidity

ObjectiveTo investigate the association between elevated endogenous testosterone levels and deleterious effects associated with testosterone therapy. Elevated serum testosterone levels in men receiving testosterone therapy have been associated with side effects, though precise thresholds above which these occur are unknown. Data on the association between naturally elevated endogenous testosterone levels and their physiologic effects is sparse. MethodsWe examined National Health and Nutrition Examination Survey data between 2011 and 2016, analyzing men aged 18 and older not on testosterone or androgen ablation therapy, excluding men who had testosterone <300 ng/dL, to compare men with elevated testosterone (>800 ng/dL) to men with normal testosterone (300-800 ng/dL). We used multivariable logistic and linear regressions for comparison. ResultsAfter excluding men with testosterone levels <300 ng/dL, 3673 men met inclusion criterion. Only 146 (4%) of men had a testosterone >800 ng/dL. When compared to men with normal testosterone, men with high testosterone had similar rates of sleep disorders, urinary symptoms, and depression. Men with elevated testosterone had higher hematocrit regression coefficient (βi 1.30, 95% confidence interval [CI] 0.69-1.90 P < .01), AST (βi 8.48, 95% CI 0.31-16.66, P = .04) and ALT (βi 12.23, 95% CI 0.70-23.77, P = .04) compared to men with normal testosterone. ConclusionNo association was found between higher endogenous testosterone levels and adverse events associated with testosterone therapy. Men with higher testosterone had increased hematocrit, but this was not clinically significant. This challenges what is considered a safe target for testosterone therapy and prompts future prospective studies to delineate the safety of elevated endogenous and exogenous modulated levels of testosterone.

Protective Effect ofEthanolic Extract ofArgyreia Nervosa Leaves on Chronic-Diabetes Induced Testicular Alterations

Our objective is to evaluated the role of primary phytochemical constituents present in ethanol extracts of Argyreia nervosa, resulting in chronic diabetic males induced infertility. The current study aims to assess the protective role of ethanol extract of Argyreia Nervosa against Streptozotocin (STZ)caused alterations in blood glucose level and histopathology architectureof the testis. Phytochemical profiling of ethanolicextractArgyreiaNervosa was carried out. The diabetic model was created by giving animals 40 mg/kg/BW of STZ(intraperitoneally). Further, Argyreia nervosa was administered orally after the induction of STZ and confirmed blood glucose levels in experimental subjects. The drug dosage was (200,400 mg/kg/BW) daily for 60 days. Histopathological analysis of the removed testis at specified intervals was carried out. Ethanol extracts contain more phytochemical constituents such as tannins, phenolics, quercetin, saponins, flavonoids, beta carotene, etc. The components have more antioxidant properties when compared with methanol and petroleum ether extract. The results showed that blood glucose levels significantly decreased and noted elevated serum testosterone levels in Argyreia nervosa(400mg/kg) treated groups compared with the untreated Streptozotocin (STZ) induced group. The histopathological study revealed that the Argyreia nervosa (200&amp;400 mg/kg/BW) treated groups show significant changes in testis when compared with the STZ induced diabetic groups. This herbal has many antioxidants, anti-diabetic, anti-microbial, antifungal, and aphrodisiac. Ethanol extract of Argyreia nervosa lowers the blood glucose level in hyperglycemic patients due to its anti-diabetic property and aphrodisiac properties. Like an adaptogenic aphrodisiac, Argyreia nervosa extracts contain potent antioxidants, which enhance sperm density and sperm quality and minimize the damage to sperm cells by scavenging free radicals resulting from excessive oxidative damage.

A Clinico-etiological Evaluation of Hirsutism Patients: A Case Series

Background: Hirsutism is a condition of excess hair growth in females in male-like distribution. It is seen in almost 5-10% of women. Women having hirsutism have a negative impact on quality of life.&#x0D; Aim: All patients were subjected to ultrasound imaging (Sonography) and hormonal evaluation to establish possible causative factors.&#x0D; Methods: A prospective and retrospective study of hirsutism patients, who were evaluated at Samarpan medical research organization, Modasa, Gujarat from 2016 to 2019.&#x0D; Results: In this case series age and clinical presentation were studied in five female patients diagnosed with hirsutism. The patients age ranged from 16 to 22 years with a mean of 19.60 years. All these patients showed localized hair growth on the upper lip, chin, and cheek on the face. Ultrasound study revealed that one of the five patients had a right bulky ovary and four patients showed both ovaries with multiple follicles. In hormonal evaluation, in one of the three patients the LH: FSH ratio was found to be more than 3. Three out of the five patients showed elevated levels of 17-OHP and serum testosterone. Two out of the three patients showed an elevated level of serum insulin. The level of DHEAS, serum prolactin, serum cortisol, and serum TSH were found to be in a normal range.&#x0D; Conclusion: Ultrasonographic (USG) study revealed a positive correlation between PCOS and Hirsutism patients. Hirsutism patients were found to have higher levels of 17-OHP, serum testosterone, serum insulin, and a higher ratio of LH: FSH, one or more at a time suggesting a strong correlation between elevated levels of these hormones and hirsutism. The present study could not establish any meaningful correlation between the level of DHEAS, serum prolactin, serum cortisol, and serum TSH.

Short\u2010term rapamycin administration elevated testosterone levels and exacerbated reproductive disorder in dehydroepiandrosterone\u2010induced polycystic ovary syndrome mice

BackgroundPolycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy that affects reproduction and metabolism. Mammalian target of rapamycin (mTOR) has been shown to participate in female reproduction under physiological and pathological conditions. This study aimed to investigate the role of mTOR complex 1 (mTORC1) signaling in dehydroepiandrosterone (DHEA)-induced PCOS mice.ResultsFemale C57BL/6J mice were randomly assigned into three groups: control group, DHEA group, and DHEA + rapamycin group. All DHEA-treated mice were administered 6 mg/100 g DHEA for 21 consecutive days, and the DHEA + rapamycin group was intraperitoneally injected with 4 mg/kg rapamycin every other day for the last 14 days of the DHEA treatment. There was no obvious change in the expression of mTORC1 signaling in the ovaries of the control and DHEA groups. Rapamycin did not protect against DHEA-induced acyclicity and PCO morphology, but impeded follicle development and elevated serum testosterone levels in DHEA-induced mice, which was related with suppressed Hsd3b1, Cyp17a1, and Cyp19a1 expression. Moreover, rapamycin also exacerbated insulin resistance but relieved lipid metabolic disturbance in the short term.ConclusionsRapamycin exacerbated reproductive imbalance in DHEA-induced PCOS mice, which characterized by elevated testosterone levels and suppressed steroid synthesis. This underscores the need for new mTORC1-specific and tissue-specific mTOR-related drugs for reproductive disorders.

Classic CAH Presenting in Adulthood: Experience From a Tertiary Care Hospital in Eastern India

Abstract Classic CAH presenting in adulthood: Experience from a tertiary care hospital in Eastern India: Congenital adrenal hyperplasia(CAH) is one of the most common genetic disorders transmitted as an autosomal recessive trait. Of the various forms CAH due to 21-hydroxylase deficiency is most common. Based on the clinical phenotype CAH can be classified as classic and non-classic form. It is very rare for classic CAH to present in adulthood. We describe 3 patients with classic CAH presenting in adulthood. Case 1: 21 year old female presented with complaint of not attaining menarche. She had features of virilisation t with a modified Ferriman Gallwey(FG) score of 18/36, pubic hair stage 4 and atrophied breasts. Genital examination revealed clitoromegaly (CI-100 mm2) with Prader stage 2. Biochemical evaluation revealed elevated levels of serum testosterone (257.2 ng/dl), 17-hydroxy progesterone(332 ng/ml), DHEAS(417 µg/dl) and PRA of 34ng/ml/hr. Case 2: 30 year old female presented with complaint of primary infertility for 5 years. She had history of delayed menarche at 20 years and oligomenorrheic cycles since last 10 years. On examination there was hirsutism with a modified FG score of 15/36, pubic hair stage 5 with atrophied breasts. Genital examination revealed symmetrical genitalia with nonpalpable gonads, clitiromegaly(CI=135mm2) and a single urogenital opening (Prader stage 3). Biochemical evaluation revealed elevated levels of serum testosterone (812ng/dl), 17-hydroxy progesterone (164.8 ng/ml), DHEAS (503 µg/dl) and PRA of 42ng/ml/hr. Case 3: 26 year old female presented with complaint of noticing excessive hair growth in androgen dependent areas. On examination there was short stature,modified FG score 16/36, pubic hair stage 5 with atrophied breasts. Genital examination revealed clitoromegaly (CI=75mm2) with Prader stage 2. Biochemical evaluation revealed elevated levels of serum testosterone (254.2 ng/dl), 17-hydroxy progesterone (351.8 ng/ml), DHEAS (296.2 µg/dl) and PRA of 30ng/ml/hr. Karyotype in all the three patients was 46,XX. All our patients had serum testosterone values in tumorous range, however imaging studies didnot reveal any evidence of malignancy in the adrenals except for occurrence of a single right adrenal nodule of size 2×2.1cm with precontrast HU of &amp;lt;10 and absolute contrast washout of &amp;gt;60% in case 2. Based on clinical and biochemical findings a diagnosis of classic CAH was made. They were started on corticosteroid and mineralocorticoid replacement. In all of the above three patients none of them had been evaluated for the presenting complaints prior to visiting our centre. Failure of implementation of neonatal screening for CAH in many centres in India and the social stigma associated with genital ambiguity are contributory to the delay in diagnosis of CAH.

Androgen Secreting Adenoma Co- Secreting Cortisol First Diagnosed During Pregnancy

Background: Pure androgen secreting adenoma is rare (1) and rarer to have an adenoma that is co-secreting androgen and cortisol, and extremely rare to have it diagnosed during pregnancy. In female, an elevated serum testosterone level with normal adrenal androgens is usually regarded as ovary origin (2). Here we report an unusual case of pregnant woman with markedly elevated serum testosterone level and elevated cortisol that first presented during pregnancy. Clinical Case: A 32-year old lady who is 32 weeks pregnant, presented with signs and symptoms of Cushing and acute hirsutism developed and advanced during pregnancy. Clinically She had hypertension, gestational diabetes with sever hirsutism and virilization. Fasting total testosterone was high (52 nmoL/L n 0.2–2.9 nmoL/L), DHEAS (1.98 umol/L n 0.51–11 umol), 24 hours urine cortisol (1343 nmoL/24 hrs n 11.8–485 nmoL/24 hrs), ACTH (0.220 pmol/L n 1.6–13.9pmol/L). Adrenal MRI without contrast showed a large right adrenal mass of 6.5 x 6.2 x 5.3 cm, of heterogenous signal in all pulse sequences, with limited assessment due to the lack of IV contrast. During admission,the patient’s liver enzymes were gradually increasing which lead to the decision of an elective C-section at 34 weeks gestation followed by right robotic adrenalectomy after ruling out pheochromocytoma. The product was viable and healthy baby boy. The immediate post-op hormonal profile showed normalization of urinary cortisol and serum total testosterone level. Histopathology report confirmed an Adrenocortical adenoma. The patient was discharged on the 3rd day post-op on hydrocortisone replacement therapy. The hydrocortisone doses were gradually tapered down tell stopped. The course of follow up was uneventful, two years following the surgery, she got another pregnancy with no obvious complications.Conclusion: Co- existing testosterone and cortisol secreting adrenocortical adenoma is a rare tumor, diagnosis and management during pregnancy is challenging, with surgical resection being the only possible definite management.

Severe Virilization in a Girl With the Homozygous G200SNicotinamide Nucleotide Transhydrogenase Mutation Is Surprisingly Caused by Rare Bilateral Para-Overian Adrenal Rest Tumors

Background: Patients with NNT (Nicotinamide Nucleotide Transhydrogenase) gene mutations, a rare cause of glucocorticoid and mineralocorticoid deficiency require hormone replacement therapy. Adrenal Rest Tumor (ART) in females is very rare (<20 cases world-wide) and was reported only in noncompliant patients with congenital adrenal hyperplasia having extremely elevated ACTH levels. This study characterizes the clinical characteristics, the pathophysiology and the molecular ontogeny of a unique ART in a female with adrenal failure due to the G200S mutation in NNT. Clinical presentation and Method: A 15-year-old girl, with homozygous G200S NNT-mutation that caused adrenal insufficiency reappeared to follow-up after several years with severe virilization and elevated serum testosterone (28.3 nmol/l) and ACTH (> 1500 pmol/l) levels. Pelvic MRI and Ultrasound demonstrated one sided para-ovarian round tumor with pathological vascularization. Laparoscopic exploration revealed bilateral para-ovarian mesosalpinx masses involving the serosa of the Fallopian tube (3 and 1 cm in diameter); the testosterone level normalized within one day after removal of those masses (0.2 nmol/l). Results: Histopathology demonstrated a pattern of adrenal rest tissue with strong intracellular positive staining for adrenal markers such as SF-1, calretinin, MART1, inhibin and the pituitary corticotroph marker-ACTH. The staining for ovarian characteristic markers such as PAX 8 was negative. Studying mRNA extracted from the tissue by RT-PCR revealed the presence of CYP17A1, CYP21A2 and MC2R (ACTH receptor) cDNA confirming typical adrenocortical transcriptional pattern in the tissue. cDNA of POMC was not detected suggesting that in spite of dense ACTH staining the tissue is not classically originated from pituitary corticotrophs. Methylome studies to further characterise the tissue are underway. Conclusion: This study exemplifies severe virilization that resulted from a unique and rare type of ART in ovarian related tissue that was caused by incompliance to treatment in a patient with NNT gene mutation. Given the ubiquitous expression of NNT and its reported pathophysiology as free radicals scavenger in all adrenocortical layers, it is surprising to have high ACTH induced severe virilization in spite of severe NNT dysfunction and adrenal insufficiency. This study may indicate timely testosterone screening in females with NNT mutation and when increased they should probably be laparoscopically surveyed for ART even when not detected by imaging. How NNT mutation damages mineralo and glucocorticoid secreting cells while androgen secreting cells are rescued is a theme for further studies.

Updated Review of Testosterone Replacement Therapy in the Setting of Prostate Cancer

Since the 1940s, elevated serum testosterone (T) levels have been infamously suggested as a causal factor in the development of prostate cancer (PCa); this time was also the dawn of both surgically and pharmacologically induced castration. However, men suffering from primary or secondary hypogonadism and who are concomitantly paradoxically at risk for developing PCa cited the adverse effects of T deficiency. In the past 25 years, researchers have published on the genetic, biochemical, and clinical outcomes of testosterone replacement therapy (TRT) in hypogonadal men. The longstanding dogma of the deleterious effects of TRT has recently been challenged, and it now appears that TRT may have an important therapeutic role in the treatment of hypogonadism in those men with either low-risk, active, or previously treated PCa. This review summarizes the latest findings on the treatment of hypogonadal men with a history of PCa, emphasizing results of clinical research studies.

The traditional Chinese medicine, Monascus-fermented rice, prevents Zn deficiency-induced testis and sperms injury

Monascus purpureus is a fungus used in rice fermentation. Monascus-fermented rice is called red-mold rice (RMR) in Taiwan since the fermentation products contain a considerable amount of red pigments. The protective effects of RMR on oxidative stress in the testis and sperm were evaluated in this study. Zn deficiency was induced in rats by feeding them with a Zn-deficient diet for 12 weeks while the control rats were fed with a normal diet. The Zn-deficient rats were then divided into 6 groups, designated as Zn-deficient (ZD), Zn-compensated (ZC), 1R (151 mg RMR/kg), 5R (755 mg RMR/kg), 1R + ZC (1RZ), and 5R + ZC (5RZ). The animals were administered with the mentioned diet (RMR/Zn) for 8 weeks. In the ZD rats, no spermatid cell formation was observed in the seminiferous tubular epithelia, and testis necrosis/atrophy was apparent. However, 5R and 5RZ administration improved testicular antioxidant enzyme activity, elevated serum testosterone levels, and increased sperm number in ZD rats; this treatment also exhibited inhibitory effects on caspase activities and reactive oxygen species (ROS) levels in the ZD rats, suggesting that RMR attenuated ZD-induced oxidative stress and testis apoptosis. The preventive activity against ZD-induced reproductive damage was more apparent in the 1RZ and 5RZ groups than in the ZC group, suggesting that RMR can serve as a supplement in adjuvant therapy for diseases associated with Zn deficiency.

A Rare Case Report of Postmenopausal Virilization: Ovarian Steroid Cell Tumor

Ovarian steroid cell tumors are rare, life-threatening neoplasms that make about 0.1% of all primary ovarian tumors. They frequently present in premenopausal women with the manifestation of virilization. We report a 58-year-old postmenopausal woman that referred to our clinic with clinical manifestation of virilization. Laboratory findings showed markedly elevated serum testosterone level and ultrasound showed 2 follicles with 7 mm diameters in the left ovary. She treated by bilateral salpingo-oophorectomy and synchronous hysterectomy. Histological pathology confirmed a benign steroid cell tumor. The presentation of new-onset and rapid progressive hyperandrogenism is rare in postmenopausal women. In diagnosis, we must consider adrenal and ovarian malignancies. Stromal luteoma is a rare benign ovarian tumor, Which is treated with surgical treatment.

Metagenomic analysis identified microbiome alterations and pathological association between intestinal microbiota and polycystic ovary syndrome

To identify different microbial species in women with polycystic ovary syndrome (PCOS) and reveal a possible relationship between gut dysbiosis and pathological changes. Cross-sectional study. Academic institution. Reproductive-aged women with PCOS (n = 14) and controls (n = 14) from the Centre for Reproductive Medicine. Shotgun metagenomic sequencing on fecal samples from patients, and clinical parameters (including body mass index, endocrine hormone levels, and glycemia level) gathered for correlation analysis. Identification of different gut microbial strains and relativity between microbiota and clinical parameters. We found several microbial strains were statistically significantly more abundant in the PCOS group, including Parabacteroides merdae, Bacteroides fragilis, and strains of Escherichia and Shigella, whereas Faecalibacterium prausnitzii was enriched in the control group. Metagenomic species (MGS) analysis revealed that the microbes of the PCOS group were negatively correlated with those of the control group. Of note, we observed a positive correlation between MGS relevant to PCOS and endocrine disorders, including body mass index and elevated levels of serum testosterone, luteinizing hormone, and antimüllerian hormone. Functional alterations, reflected by Kyoto Encyclopedia of Genes and Genomes orthologues, could imply potential mechanisms of microbial involvement in the developmental progress of PCOS. Our findings suggest an intimate association and potential mechanisms linking microbial dysbiosis and the pathophysiologic changes of PCOS. We address the importance of monitoring and modulating microbial composition and functional shifts in future clinical practice.

SUN-LB15 A Case of Familial Male-Limited Precocious Puberty With a Novel Mutation

Introduction:Familial Male-Limited Precocious Puberty (FMPP), also known as testotoxicosis, is a rare cause of precocious puberty in males. It is caused by a mutation in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene, resulting in the receptor to be constitutively activated. This results in precocious puberty in males with rapid skeletal maturation and compromised final adult height if not treated. A combination on anti-androgens and aromatase inhibitors are the mainstay of treatment.Case:A 16-month-old male presented to our clinic due to concerns of precocious puberty. Pubic hair was noted at 6 months of age along with rapid growth acceleration. There was no known exposure to testosterone and no family history of early puberty or subnormal adult height. Upon presentation, his height was over the 99th percentile while his target height is at the 50th percentile. Physical examination revealed prepubertal testes with pubic hair at Tanner stage II. A bone age was reported as 12-18 months at a chronologic age of 12 months. Initial lab evaluation revealed normal serum levels of 17 OHP, androstenedione and DHEA-S with a slightly elevated serum LH (0.7mIU/ml), and very elevated serum testosterone level (289ng/dl). Leuprolide and ACTH stimulation tests as well as MRI of the abdomen and pelvis were normal. Serum levels of AFP, β-hCG and IGF-1 were also normal. Bone age advanced to 6 years at a chronological age of 21 months and to 8 years by 26 months of age. At 26 months of age, his stretched penile length measured 11cm. LH receptor testing was obtained, which revealed a novel heterozygous missense mutation in the LHCGR gene (c.1733A>C; p.Asp.578Ala). The mutation was reported to be a variant of unknown significance though likely in the pathological end of the spectrum by variant analysis with SIFT and PolyPhen. He was started on treatment with anastrozole 1 mg daily and bicalutamide 25 mg daily at 2 and 9/12 years of age. Pubertal progression, linear growth and skeletal maturation slowed down with treatment. His bone age remained stable at 13 years from the age of 2 and 10/12 years to 4 years old. Pubertal stage and stretched penile length have also remained stable on treatment. He is tolerating treatment well.Conclusion:We report a novel mutation in the LHCGR gene causing FMPP in a 6-month-old male who is responding very well to a combination of bicalutamide and anastrazole with marked decrease in growth velocity, pubertal progression and skeletal advancement.