Circulating Testosterone Levels Research Articles

SARS-CoV-2 impairs male fertility by targeting semen quality and testosterone level: A systematic review and meta-analysis.

Since the discovery of COVID-19 in December 2019, the novel virus has spread globally causing significant medical and socio-economic burden. Although the pandemic has been curtailed, the virus and its attendant complication live on. A major global concern is its adverse impact on male fertility. This study was aimed to give an up to date and robust data regarding the effect of COVID-19 on semen variables and male reproductive hormones. Literature search was performed according to the recommendations of PRISMA. Out of the 852 studies collected, only 40 were eligible for inclusion in assessing the effect SARS-CoV-2 exerts on semen quality and androgens. More so, a SWOT analysis was conducted. The present study demonstrated that SARS-CoV-2 significantly reduced ejaculate volume, sperm count, concentration, viability, normal morphology, and total and progressive motility. Furthermore, SARS-CoV-2 led to a reduction in circulating testosterone level, but a rise in oestrogen, prolactin, and luteinizing hormone levels. These findings were associated with a decline in testosterone/luteinizing hormone ratio. The current study provides compelling evidence that SARS-CoV-2 may lower male fertility by reducing semen quality through a hormone-dependent mechanism; reduction in testosterone level and increase in oestrogen and prolactin levels.

Steroidomics in Men with Schizophrenia.

Schizophrenia is associated with numerous abnormalities, including imbalances in all hormonal axes, among which steroids play a major role. Steroidomic studies therefore represent a promising tool for early diagnosis and appropriate treatment of schizophrenia. A total of 51 adult male schizophrenics aged 27 (22, 34) years (shown as median with quartiles) and 16 healthy controls (HCs) aged 28 (25, 32) years were enrolled into this study. Our results showed the effective differentiation of men with schizophrenia from controls based on steroidomic profiles. We also found an altered metabolic pathway from pregnenolone and its sulfate (PREG/S) to cortisol in schizophrenics with several metabolic bottlenecks such as lower PREG levels due to increased PREG sulfation and/or suppressed PREGS desulfation and attenuated conversion of 17-hydroxy-PREG to 17-hydroxy-progesterone, as well as the results suggestive of suppressed CYP11B1 activity. In contrast, steroid molar ratios suggested two counterregulatory steps involving increased conversion of PREG/S to 17-hydroxy-PREG/S and decreased conversion of cortisol to cortisone, which may maintain unchanged basal cortisol levels but may not ensure a sufficient cortisol response to stress. Our data also indicated a trend to higher 7α-, 7β-, and 16α-hydroxylation that may counteract the autoimmune complications and proinflammatory processes accompanying schizophrenia. Finally, a possible suppression of HSD17B3 activity was suggested, resulting in decreased circulating testosterone levels with increased androstenedione levels.

Targeted inhibition of kisspeptin neurons reverses hyperandrogenemia and abnormal hyperactive LH secretion in a preclinical mouse model of polycystic ovary syndrome.

Do hyperactive kisspeptin neurons contribute to abnormally high LH secretion and downstream hyperandrogenemia in polycystic ovary syndrome (PCOS)-like conditions and can inhibition of kisspeptin neurons rescue such endocrine impairments? Targeted inhibition of endogenous kisspeptin neuron activity in a mouse model of PCOS reduced the abnormally hyperactive LH pulse secretion and hyperandrogenemia to healthy control levels. PCOS is a reproductive disorder characterized by hyperandrogenemia, anovulation, and/or polycystic ovaries, along with a hallmark feature of abnormal LH hyper-pulsatility, but the mechanisms underlying the endocrine impairments remain unclear. A chronic letrozole (LET; aromatase inhibitor) mouse model recapitulates PCOS phenotypes, including polycystic ovaries, anovulation, high testosterone, and hyperactive LH pulses. LET PCOS-like females also have increased hypothalamic kisspeptin neuronal activation which may drive their hyperactive LH secretion and hyperandrogenemia, but this has not been tested. Transgenic KissCRE+/hM4Di female mice or littermates Cre- controls were treated with placebo, or chronic LET (50 µg/day) to induce a PCOS-like phenotype, followed by acute (once) or chronic (2 weeks) clozapine-N-oxide (CNO) exposure to chemogenetically inhibit kisspeptin cells (n = 6 to 10 mice/group). Key endocrine measures, including in vivo LH pulse secretion patterns and circulating testosterone levels, were assessed before and after selective kisspeptin neuron inhibition and compared between PCOS groups and healthy controls. Alterations in body weights were measured and pituitary and ovarian gene expression was determined by qRT-PCR. Acute targeted inhibition of kisspeptin neurons in PCOS mice successfully lowered the abnormally hyperactive LH pulse secretion (P < 0.05). Likewise, chronic selective suppression of kisspeptin neuron activity reversed the previously high LH and testosterone levels (P < 0.05) down to healthy control levels and rescued reproductive gene expression (P < 0. 05). N/A. Ovarian morphology was not assessed in this study. Additionally, mouse models can offer mechanistic insights into neuroendocrine processes in PCOS-like conditions but may not perfectly mirror PCOS in women. These data support the hypothesis that overactive kisspeptin neurons can drive neuroendocrine PCOS-like impairments, and this may occur in PCOS women. Our findings complement recent clinical investigations using NKB receptor antagonists to lower LH in PCOS women and suggest that pharmacological dose-dependent modulation of kisspeptin neuron activity may be a valuable future therapeutic target to clinically treat hyperandrogenism and lower elevated LH in PCOS women. This research was supported by NIH grants R01 HD111650, R01 HD090161, R01 HD100580, P50 HD012303, R01 AG078185, and NIH R24 HD102061, and a pilot project award from the British Society for Neuroendocrinology. There are no competing interests.

Effects of Aerobic Training on Sex Hormones in A Cuprizone Rat Model of Multiple Sclerosis.

Central nervous system damage in multiple sclerosis (MS) leads to severe physical disability and neurological defects. Sexual dysfunction and infertility in patients with MS have often been neglected in previous studies. Aerobic exercise is suggested to improve circulating testosterone levels and sexual function. Therefore, the purpose of this study was to investigate the effect of aerobic exercise on sex hormone levels in a cuprizone rat model of MS. In this experimental study, 30 male rats (aged 70 days, 154.55 ± 18.1 g) were randomly divided into five groups: MS, exercise-MS (EX-MS), MS-EX, EX-MS-EX, and normal control (control). MS was induced by feeding cuprizone pellets (0.2%) to the rats for six weeks. The exercise groups performed an aerobic exercise protocol on a treadmill five days/week for six weeks before and during the induction of the MS model. Serum testosterone, follicle stimulating hormone (FSH), and luteinising hormone (LH) levels were measured using the ELISA method with standard kits (ZellBio Germany). Luxol fast blue staining (LFB) of the corpora collosa were performed. The results showed a significant decrease in the serum levels of testosterone, FSH, and LH in the MS groups compared to the control group (P<0.05). There was a significant increase in the serum levels of testosterone, FSH, and LH in the EX-MS-EX, and EX-MS groups compared to the MS group (P<0.05). Aerobic exercise could improve the level of sex hormones in the cuprizone rat model of MS and may be used to attenuate sexual dysfunction in patients with MS.

Short Adult Height After Rapid-tempo Puberty: When is it too Late to Treat?

A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment.

Associations of tubal ligation and hysterectomy with serum androgen and estrogen metabolites among postmenopausal women in the Women's Health Initiative Observational Study.

Hysterectomy is associated with subsequent changes in circulating hormone levels, but the evidence of an association for tubal ligation is unclear. We evaluated whether circulating concentrations of androgens and estrogens differ by tubal ligation or hysterectomy status in postmenopausal women from the Women's Health Initiative (WHI)-Observational Study (OS). Serum androgens and estrogens were measured in 920 postmenopausal women who did not use menopausal hormone therapy at the time of blood draw, of whom 139 self-reported a history of tubal ligation and 102 reported hysterectomy (with intact ovaries). Geometric mean hormone concentrations (GMs) and 95% confidence intervals (CIs) associated with a history of tubal ligation or hysterectomy (ever/never), as well as time since procedures, were estimated using adjusted linear regression with inverse probability of sampling weights to account for selection. Circulating levels of 12 androgen/androgen metabolites and 20 estrogen/estrogen metabolites did not differ by tubal ligation status. Among women reporting prior hysterectomy compared to women without hysterectomy, we observed lower levels of several androgens (e.g., testosterone (nmol/L): GMyes 0.46 [95% CI:0.37-0.57] vs. GMno 0.62 [95% CI:0.53-0.72]) and higher levels of estrogen metabolites, for example, 2-hydroxyestrone-3-methyl ether (GMyes 11.1 [95% CI:8.95-13.9] pmol/L vs. GMno 8.70 [95% CI:7.38-10.3]) and 4-methoxyestrone (GMyes 6.50 [95% CI:5.05-8.37] vs. GMno 4.92 [95% CI:4.00-6.05]). While we did not observe associations between prior tubal ligation and postmenopausal circulating hormone levels, our findings support that prior hysterectomy was associated with lower circulating testosterone levels and higher levels of some estrogen metabolites, which may have implications for future hormone-related disease risks.

Analysis of androgen receptor expression and activity in the mouse brain

Androgen deprivation therapy (ADT) is the core treatment for advanced prostate cancer (PCa), with a proven survival benefit. ADT lowers circulating testosterone levels throughout the body, but with it comes a variety of reported side effects including fatigue, muscle wastage, weight gain, hot flushes and importantly cognitive impairment, depression, and mood swings. Testosterone has a key role in brain masculinization, but its direct effects are relatively poorly understood, due both to the brain’s extreme complexity and the fact that some of testosterone activities are driven via local conversion to oestrogen, especially during embryonic development. The exact roles, function, and location of the androgen receptor (AR) in the adult male brain are still being discovered, and therefore the cognitive side effects of ADT may be unrecognized or under-reported. The age of onset of several neurological diseases overlap with PCa, therefore, there is a need to separate ADT side effects from such co-morbidities. Here we analysed the activity and expression level of the AR in the adult mouse brain, using an ARE-Luc reporter mouse and immunohistochemical staining for AR in all the key brain regions via coronal slices. We further analysed our data by comparing to the Allen Mouse Brain Atlas. AR-driven luciferase activity and distinct nuclear staining for AR were seen in several key brain areas including the thalamus, hypothalamus, olfactory bulb, cerebral cortex, Purkinje cells of the cerebellum and the hindbrain. We describe and discuss the potential role of AR in these areas, to inform and enable extrapolation to potential side effects of ADT in humans.

The influence of trinucleotide repeats in the androgen receptor gene on androgen-related traits and diseases.

Trinucleotide repeats in the androgen receptor have been proposed to influence testosterone signaling in men, but the clinical relevance of these trinucleotide repeats remains controversial. To examine how androgen receptor trinucleotide repeat lengths affect androgen-related traits and disease risks and whether they influence the clinical importance of circulating testosterone levels. We quantified CAG and GGC repeat lengths in the androgen receptor (AR) gene of European-ancestry male participants in UK Biobank from whole-genome and whole-exome sequence data using ExpansionHunter, and tested associations with androgen-related traits and diseases. We also examined whether the associations between testosterone levels and these outcomes were affected by adjustment for the repeat lengths. We successfully quantified the repeat lengths from whole-genome and/or whole-exome sequence data in 181,217 males. Both repeat lengths were shown to be positively associated with circulating total testosterone level and bone mineral density, whereas CAG repeat length was negatively associated with male-pattern baldness, but their effects were relatively small and were not associated with most of the other outcomes. Circulating total testosterone level was associated with various outcomes, but this relationship was not affected by adjustment for the repeat lengths. In this large-scale study, we found that longer CAG and GGC repeats in the AR gene influence androgen resistance, elevate circulating testosterone level via a feedback loop and play a role in some androgen-targeted tissues. Generally, however, circulating testosterone level is a more important determinant of androgen action in males than repeat lengths.

Association of genetically determined chronotype with circulating testosterone: a Mendelian randomization study.

Low testosterone levels in men have been linked to decreased physical and mental function, as well as a reduced quality of life. Previous prospective observational studies have suggested an association between testosterone and sleep traits, but the causality of this relationship remains unclear. We aimed to explore the potential causal link between genetically determined sleep traits and testosterone levels in men using Mendelian randomization (MR) analysis from the UK Biobank dataset. Our exposures were genetic variants associated with sleep traits (chronotype and sleep duration), whereas our outcomes were traits of sex steroid hormones (total testosterone, TT; bioavailable testosterone, BAT; and sex hormone-binding globulin, SHBG). We employed inverse variance weighted (IVW) and weighted median (WM) methods to assess the causal associations. The IVW method offers a robust estimate of causality, whereas the WM method provides reliable results even when some genetic variants are invalid instruments. Our main analysis involving sex steroid hormones and chronotype identified 155 chronotype-related variants. The primary findings from the analysis, which used chronotype as the exposure and sex steroid hormones as the outcomes, showed that a genetically predicted chronotype score was significantly associated with an increased levels of TT (association coefficient β, 0.08; 95% confidence interval [CI], 0.02-0.14; P = 0.008) and BAT (β, 0.08; 95% CI, 0.02-0.14; P = 0.007), whereas there was no significant association with SHBG (β, 0.01; 95% CI, -0.02-0.03; P = 0.64). Meanwhile, MR analysis of sex steroid hormones and sleep duration was performed, and 69 variants associated with sleep duration were extracted. There were no significant association between sleep duration and sex steroid hormones (TT, P = 0.91; BAT, P = 0.82; and SHBG, P = 0.95). Our data support a causal association between chronotype and circulating testosterone levels in men. These findings underscore a potential causal relationship between chronotype and testosterone levels in men, suggesting that lifestyle adjustments are crucial for men's health. Recognizing factors that influence testosterone is essential. One limitation of this study is the use of one-sample MR, which can introduce potential bias due to non-independence of genetic associations for exposure and outcome. In conclusion, our findings indicate that a morning preference is correlated with circulating testosterone levels, emphasizing the potential impact of lifestyle habits on testosterone levels in men.

Abstract 3440: Etiology of prostate cancer with the TMPRSS2:ERG fusion: A systematic review of risk factors

Abstract Background: The TMPRSS2:ERG gene fusion is the most common somatic alteration in primary prostate cancer and an early event in carcinogenesis. There are emerging data highlighting etiologic differences in prostate cancer by TMPRSS2:ERG status. This systematic review synthesized evidence from epidemiologic studies on prostate cancer risk factors for tumors with and without the TMPRSS2:ERG fusion. Methods: A systematic literature search was performed in Ovid MEDLINE, EMBASE, and Web of Science without language restriction for studies published by September 27, 2022. Studies that assessed associations between epidemiologic and genetic factors and prostate cancer risk by tumor TMPRSS2:ERG (ERG) fusion status in human populations were included. Results: Of 3,071 records identified, 20 publications comprising prospective cohort and case-control studies from five study populations (published 2009-2022) were included. Risk factors included germline genetic variants, circulating hormones, diet, lifestyle factors, and medications. The included studies suggested that taller height and higher total and free circulating testosterone levels tended to be associated with higher risk of ERG-positive, but not ERG-negative prostate cancer. CAG repeat length in the androgen receptor (AR) gene, related inversely to transcriptional activity, appeared to be associated with a lower risk of ERG-positive, but not ERG-negative prostate cancer. There was statistical evidence for etiologic differences for several germline single nucleotide polymorphisms (SNPs) by ERG status. Excess body weight, greater vigorous physical activity, greater lycopene intake, and calcium channel blocker use appeared to specifically be associated with a lower risk of ERG-positive tumors. Associations of other potential etiologic factors, including diabetes mellitus, baldness, aspirin use, circulating antioxidant levels, and sex hormones other than testosterone, with ERG-positive prostate cancer were null or inconclusive. Most associations had low precision, and the results were based on few distinct study populations, highlighting a need for replication. Conclusions: Prostate cancer with the TMPRSS2:ERG fusion may be an etiologically distinct subtype impacted by certain modifiable and hormonally-acting risk factors that align with the established mechanistic role of this gene fusion in androgen, insulin, and growth factor pathways. The findings suggest a potentially distinct genetic predisposition to prostate cancer with or without the TMPRSS2:ERG fusion. More broadly, these findings suggest that considering molecular subtypes of prostate cancer, beyond TMPRSS2:ERG, may strengthen etiologic understanding of prostate cancer and evidence for prevention. Citation Format: Colleen B. McGrath, Alaina H. Shreves, Megan R. Shanahan, Hannah E. Guard, Manelisi V. Nhliziyo, Kathryn L. Penney, Tamara L. Lotan, Michelangelo Fiorentino, Konrad H. Stopsack, Lorelei A. Mucci. Etiology of prostate cancer with the TMPRSS2:ERG fusion: A systematic review of risk factors [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 3440.

(134) Early Impact of Androgen Deprivation Therapy on Endothelial Function and Metabolic Parameters in Prostate Cancer Patients: A Prospective Study

Abstract Introduction Androgen deprivation therapy (ADT) is considered one of the mainstays in the treatment of prostate cancer. ADT slows cancer progression, alleviates cancer-related symptoms, and is associated with survival gains. Despite these proven benefits, this treatment is related to several side effects, such as increased cardiovascular risk, changes in body composition and various metabolic changes. Although the well-established association between circulating testosterone level and endothelial integrity, the direct effects of ADT on endothelial function remain controversial. Objective This study aimed to investigate the impact of ADT on endothelial function, through the analysis of vascular parameters of the brachial artery and measurement of serum inflammatory markers. It was also our aim to evaluate the early impact of ADT on body composition and metabolic parameters. Methods We prospectively evaluated men with moderate to high-risk prostate cancer treated with ADT from January to December 2022 at our institution. Smokers and those who quit smoking less than five years ago, decompensated diabetics (glycated hemoglobin &amp;gt; 9%) and those who had already had a cardiovascular event were excluded. High-resolution B-mode ultrasound was used to assess vascular diameter and endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. Our metabolic and inflammatory profile included measurement of serum total cholesterol and fractions, triglycerides, fasting glucose, glycated hemoglobin, basal insulin, C-reactive protein and assessment of body fat distribution through bioelectrical impedance. Subjects were evaluated at baseline and 3 months after starting ADT with goserelin acetate 10.80 mg. Results A total of 32 men were included. The mean age was 69 years and the prevalence of diabetes was 31.25%. FMD demonstrated a worsening trend after ADT, which did not reach statistical significance after 3 months (mean 3.39 ± 6.83 vs 1.16 ± 7.65; p = 0.14) (figure 1). Baseline brachial artery diameter also showed a tendency to worsen with ADT compared to baseline (0.44 ± 0.06 vs 0.42 ± 0.06; p = 0.06). With regard to the metabolic profile, ADT significantly increased insulin resistance: fasting glucose (mean 104.10 ± 18.96 vs 110.60 ± 25.29; p = 0.01), fasting insulin levels (mean 13.05 ± 8.76 vs 16.82 ± 11.36; p = 0.003), glycated hemoglobin (mean 5.89% ± 0.46 vs 6.15% ± 0.67; p = 0.008) and homeostatic model assessment insulin resistance (mean 3.47 ± 2.55 vs 5.05 ± 4.50; p = 0.005) increased significantly after 3 months. Triglycerides concentrations (mean 142.30 ± 69.66 vs 165.50 ± 93.04; p = 0.03) were higher after 3 months of ADT. Abdominal circumference (mean 98.66 ± 10.16 vs 99.76 ± 9.39; p = 0.02) and body mass index (mean 27.46 ± 4.06 vs 27.76 ± 3.89; p = 0.02) also increased after ADT. Conclusions Although not statistically significant, the present study demonstrated a trend towards a decrease in brachial artery FMD. We also observed an important and surprisingly early worsening of the metabolic profile with ADT, especially increased insulin resistance and dyslipidemia, which represent well-established risk factors for cardiovascular events. Disclosure No.

Neonatal Aromatase Inhibition Blocked Defeminization of AVPV Kiss1 Neurons and LH Surge-Generating System in Male Rats.

The neuroendocrine system that controls the preovulatory surge of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH), which triggers ovulation in female mammals, is sexually differentiated in rodents. A transient increase in circulating testosterone levels in male rats within a few hours of birth is primarily responsible for the defeminization of anteroventral periventricular nucleus (AVPV) kisspeptin neurons, which are critical regulators of the GnRH/LH surge. The present study aimed to determine whether neonatal estradiol-17β (E2) converted from testosterone by aromatase primarily causes the defeminization of AVPV kisspeptin neurons and the surge of GnRH/LH in male rodents. The results of the present study showed that the neonatal administration of letrozole (LET), a nonsteroidal aromatase inhibitor, within 2 hours of birth rescued AVPV Kiss1 expression and the LH surge in adult male rats, while the neonatal administration of testosterone propionate (TP) irreversibly attenuated AVPV Kiss1 expression and the LH surge in adult female rats. Furthermore, the neonatal LET-treated Kiss1-Cre-activated tdTomato reporter males exhibited a comparable number of AVPV Kiss1-Cre-activated tdTomato-expressing cells to that of vehicle-treated female rats, while neonatal TP-treated females showed fewer AVPV Kiss1-Cre-activated tdTomato-expressing cells than vehicle-treated females. Moreover, neonatal TP administration significantly decreased the number of arcuate Kiss1-expressing and Kiss1-Cre-activated tdTomato-positive cells and suppressed LH pulses in adult gonadectomized female rats; however, neonatal LET administration failed to affect them. These results suggest that E2 converted from neonatal testosterone is primarily responsible for the defeminization of AVPV kisspeptin neurons and the subsequent GnRH/LH surge generation in male rats.

Exploring Hematological and Biochemical Disparities in Same-Sex and Opposite-Sex Females: A Cross-Sectional Twin Study in a Ghanaian Population.

There are sex-dependent differences in hematological and biochemical variables in adulthood attributed to the predominant effects of testosterone in males and estrogen in females. The Twin Testosterone Transfer (TTT) hypothesis proposes that opposite-sex females may develop male-typical traits due to exposure to relatively higher levels of prenatal testosterone than same-sex females. Additionally, prenatal testosterone exposure has been suggested as a correlate of current circulating testosterone levels. Consequently, opposite-sex females might exhibit male-typical patterns in their hematological and biochemical variables. Despite this hypothesis, routine laboratory investigations assign the same reference range to all females. Our cross-sectional study, conducted in Tamale from January to September 2022, included 40 twins, comprising 10 opposite-sex (OS) males (25%), 10 OS females (25%), and 20 same-sex (SS) females (50%), all aged between 18 and 27 years. Fasting venous blood samples were collected and analyzed using automated hematology and biochemistry laboratory analyzers. Results indicated that levels of hemoglobin, serum creatinine, gamma-glutamyl transferase, total protein, globulins, and total testosterone were significantly higher in OS males than OS females. Conversely, total cholesterol and low-density lipoprotein cholesterol were significantly higher in OS females than OS males. Unexpectedly, levels of low-density lipoprotein cholesterol and total testosterone were significantly higher in SS females than OS females. Contrary to expectations, opposite-sex females did not exhibit male-typical patterns in their hematological and biochemical variables. This suggests that the TTT effect may not occur or may not be strong enough to markedly affect hematological and biochemical variables in OS females.

Androgen deficiency is associated with a better prognosis in glioblastoma

BackgroundThe androgen receptor (AR) has been demonstrated to play a role in the pathogenesis of glioblastoma; however, the implications of circulating testosterone levels in the biology of glioblastoma remain unknown.AimThis study aimed to analyze the association between circulating testosterone levels and the prognosis of patients with glioblastoma.MethodsForty patients with primary glioblastoma were included in the study. The main prognostic endpoint was progression-free survival (PFS). Circulating testosterone levels were used to determine the state of androgen deficiency (AD). AR expression was analyzed by reverse-transcriptase polymerase chain reaction, Western blot, and immunofluorescence. Survival analysis was performed using the log-rank test and univariate and multivariate Cox regression analysis.ResultsMost of the patients showed AR expression, and it was mainly located in the cytoplasm, as well as in the nucleus of tumor cells. Patients with AD presented a better PFS than those patients with normal levels (252.0 vs. 135.0 days; p = 0.041). Furthermore, normal androgenic status was an independent risk factor for progression in a multivariate regression model (hazard ratio = 6.346; p = 0.004).ConclusionCirculating testosterone levels are associated with the prognosis of glioblastoma because patients with AD show a better prognosis than those with normal androgenic status.

Morin hydrate ameliorates heat-induced testicular impairment in a mouse model.

Heat stress is known to adversely affect testicular activity and manifest the pathogenesis of spermatogenesis. Morin hydrate is a plant-derived compound, which contains a wide range of biological activities. Thus, it is hypothesized that morin hydrate might have an ameliorative effect on heat-induced testicular impairment. There has not been any research on the impact of morin hydrate on heat-induced testicular damage. The experimental mice were divided into four groups, groups1 as the normal control group (CN), and the second which underwent heat stress (HS) by immersing the lower body for 15min in a thermostatically controlled water bath kept at 43°C (HS), and third and fourth heat-stressed followed by two different dosages of morin hydrate 10mg/kg (HSM10) and 100mg/kg (HSM100) for 14days. Morin hydrate treatment at 10mg/kg improved, circulating testosterone levels (increases 3βHSD), and oxidative stress along with improvement in the testis and caput and corpus epididymis histoarchitecture, however, both doses of morin hydrate improved sperm parameters. Morin hydrate treatment significantly increases germ cell proliferation, (GCNA, BrdU staining), expression of Bcl2 and decreases expression of active caspase 3. Heat stress also decreased the expression of AR, ER- α, and ER-β, and Morin hydrate treatment increased the expression of these markers in the 10mg/kg treatment group. Morin hydrate ameliorates heat-induced testicular impairment modulating testosterone synthesis, germ cell proliferation, and oxidative stress. These effects could be manifested by regulating androgen and estrogen receptors. However, the two doses showed differential effects of some parameters, which requires further investigations.

Fabrication of silastic testosterone enanthate implants to achieve virilizing levels of serum testosterone in swine

The aim of this study was to create a continuous drug delivery system that would yield serum testosterone levels in sexually mature, female pigs consistent with serum testosterone levels of human transgender men. Testosterone enanthate was mixed with medical grade silicone at a ratio of 20 % by weight, placed in silastic tubing to cure at room temperature for 24 h, then removed from the tubing mold and stored at 4 °C until surgical implantation. Testosterone enanthate oxidizes at high temperatures which is why the implants had to be stored cold. Each implant was 9 cm long and contained 0.56 g of testosterone enanthate. A minimum of one implant (0.56 g testosterone enanthate) and a maximum of four implants (2.24 g testosterone enanthate) were placed in the cervical subcutaneous fat of each pig. After implantation, serum testosterone was assessed over 40 days. Silastic testosterone enanthate implants increase serum testosterone and maintain it in a relatively constant state in a dose-dependent manner for ∼ 21–25 days post-implantation.•Effective method for subcutaneous delivery of large quantities of testosterone or testosterone metabolites in compact implants to large animal biomedical model species.•Maintains increased circulating testosterone levels for up to 3, 4 weeks post-implantation in pigs.

Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer

BackgroundProstate cancer is regulated by steroid hormones, even in castration-resistant disease. ODM-208, a novel inhibitor of cytochrome P450 11A1 (which catalyzes the first step of steroid-hormone biosynthesis), was investigated in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC).MethodsCYPIDES is a first-in-human phase 1 (3 + 3 design) and phase 2 study. We administered ODM-208 twice daily with glucocorticoid/mineralocorticoid replacement and ongoing androgen deprivation therapy to adults with previously treated mCRPC, regardless of androgen receptor gene (AR) ligand-binding domain mutations (phase 1) and with activating AR ligand-binding domain mutations (ARmut; phase 2). Safety, pharmacokinetics, steroid-hormone pharmacodynamics, and preliminary efficacy were the key outcomes.ResultsNinety-two patients received one or more doses of ODM-208: 47 in phase 1 (20 [42.6%] with ARmut) and 45 in phase 2 (all ARmut). A dose of ODM-208 of 5 mg twice a day with dexamethasone 1 mg/fludrocortisone 0.1 mg provided a balance between decreased steroidogenesis and toxicity. Treatment-related adrenal insufficiency was the most common toxicity in phase 1 (n=17, 36.2%; necessitating ODM-208 discontinuation in one patient); this toxicity occurred in six patients (13.3%) at 5 mg twice a day in phase 2. Median circulating testosterone levels declined from 3.0 ng/dl (interquartile range, 1.3 to 6.2 ng/dl) at baseline to undetectable levels within the first week of ODM-208 5 mg twice a day treatment in 46 of 53 (87%) patients. A decrease in prostate-specific antigen levels of 50% or more occurred in 14 of 19 (73.7%) patients with ARmut and 2 of 23 (8.7%) patients with AR wild type in phase 1 and in 24 of 45 (53.3%) patients with ARmut in phase 2.ConclusionsODM-208 potently inhibited steroid-hormone biosynthesis with the expected toxicity of adrenal insufficiency. Evidence of antitumor activity was observed in this heavily pretreated mCRPC population, especially in those with ARmut. (Funded by Orion Pharma; ClinicalTrials.gov number, NCT03436485.)

Development of external genitalia during mini-puberty: is it related to somatic growth or reproductive hormones?

Although hypothalamo-pituitary-gonadal axis is active during mini-puberty, its relationship with somatic growth and the role on the development of external genitalia has not been fully elucidated. We aimed to evaluate the effects of somatic growth and reproductive hormones on the development of external genitalia during mini-puberty. Anthropometric data, pubertal assesment, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), sex-hormone binding globulin (SHBG), estradiol (E2) and inhibin-B, testosterone (T), and anti-Mullerian Hormone (AMH) of healthy infants aged 1-4months were evaluated. Free sex hormone index was calculated as T/SHBG for boys and E2/SHBG for girls. The mean age of 148 (74 female) infants included in the study was 2.31 ± 0.76months. Tanner stage 2-3 sex steroid and gonadotropin levels were observed. A statistically significant difference was found between the weight, height, BMI, weight gain and serum FSH, LH, and A4 measurements of girls and boys (p < 0.05). Penile length was associated with weight (r = 0.24, p = 0.03), height (r = 0.25, p = 0.02), and AMH (r = 0.3, p = 0.01), but not with testosterone (p = 0.56 respectively). A negative correlation was found between weight and serum LH (r = - 0.26, p = 0.2) and T/SHBG levels in males (r = - 0.38, p = 0.015 respectively). Weight-SDS was negatively correlated with testosterone in males (r = - 0.25, p = 0.02). Testicular size and breast stage did not correlate with any of the hormonal and anthropometric parameters. Conclusions: External genitalia in males during mini-puberty is related more to somatic growth rather than reproductive hormones. Similar to pubertal developmental stages, both total and free testosterone are negatively associated with higher weight during mini-puberty. What is Known: • Mini-puberty allows early assessment of HPG axis function in infancy. • There is an inverse relationship between the amount of adipose tissue and circulating testosterone levels in males during puberty and adulthood. • The potential effect of somatic growth and reproductive hormones on external genital development during mini-puberty remains unclear. What is New: • During mini-puberty, males' external genitalia is more related to somatic growth than to reproductive hormones, but this relationship is not observed in girls. • Both total and free testosterone are negatively associated with higher weight during mini-puberty, similar to the pubertal developmental stages.

Correlation of serum circulating testosterone levels with stress urinary incontinence in postmenopausal women.

Our study aimed to elucidate the possible relationship between endogenous circulating testosterone and the beginning and development of stress urinary incontinence (SUI) in postmenopausal women. The clinical data of female patients with SUI who underwent surgery at our hospital from January 2014 to February 2023 and healthy female volunteers recruited during the same period were retrospectively analyzed according to age and body mass index (BMI). Venous blood samples were taken from all subjects, and levels of estradiol, luteinizing hormone, prolactin, follicle-stimulating hormone, progesterone, and testosterone were measured by radioimmunoassay. After adjusting for age, BMI, hypertension, mode of delivery, hysterectomy, and profession, multiple logistic regression analysis was used to determine the relationship between SUI and serum testosterone levels in postmenopausal women. Serum testosterone levels were significantly lower in women with SUI than in healthy control women (0.92 ± 0.67 vs. 1.28 ± 1.10; P < 0.05). Further comparison of testosterone levels between postmenopausal SUI women and healthy postmenopausal women in postmenopausal subjects revealed that testosterone levels were significantly lower in postmenopausal SUI women than in healthy postmenopausal women (0.84 ± 0.64 vs. 1.23 ± 1.10; P < 0.05). This difference in testosterone levels remained significant after controlling for age, BMI, hypertension, mode of delivery, hysterectomy, and profession in postmenopausal women. The results of the present study indicate that low levels of serum testosterone are associated with an increased likelihood of stress urinary incontinence in women. Low serum testosterone levels may be a risk factor for SUI in postmenopausal women.

FRI309 Functional Gonadotrophin Secreting Adenoma With Elevated Testosterone—A Rare Entity

Abstract Disclosure: S. Bulchandani: None. S. Syal: None. E. Sloan: None. S.T. Sharma: None. Introduction: Gonadotroph adenomas are a common type of pituitary neuroendocrine tumor (PitNET). However, most do not lead to elevated sex hormone levels1. Presenting symptoms include headache, visual field deficits, and hypopituitarism.2-3. Gonadotropin-secreting PitNET leading to high circulating testosterone levels are extremely rare. We report a case of a male patient with a gonadotroph PitNET causing hypersecretion of testosterone. Case Report: 53-year-old male with history of hypertension presented for evaluation of dystonia. He also reported fatigue and an episode of diplopia. He had normal libido and sexual function, no mood fluctuations. MRI of the spine performed for evaluation of dystonia revealed a 2.8 cm sellar mass. MRI Pituitary showed a 31 mm in height by 24 mm in width by 19 mm in depth sellar mass suggestive of a pituitary adenoma with compression of the optic chiasm and extension into the left cavernous sinus. Laboratory evaluation revealed an elevated follicle stimulating hormone level (FSH) of 73.6 mIU/ml (1.6-8.0), luteinizing hormone (LH) 13.3mIU/ml (1.5-9.3), elevated total testosterone of 2176 ng/dl (250-1100) and Free testosterone 367.7 pg/mL (35-155), Sex hormone binding globulin of 68 nmol/L, Alpha subunit of 3ng/mL, prolactin 23 ng/ml (4-15.2), no increase with dilution, TSH 2.24 iIU/ml, free thyroxine level 0.9 ng/dL, and AM Cortisol 6.4 mcg/dl. A Cosyntropin stimulation test revealed adrenal insufficiency and treatment with hydrocortisone was initiated. Ophthalmology evaluation revealed left &amp;gt;right asymmetric bitemporal hemianopia. He underwent transsphenoidal resection of the pituitary tumor. Post-operative laboratory evaluation revealed testosterone level of 43.65ng/dL and FSH of 6.6mIU/ml. Pathology showed a gonadotroph PitNet with diffuse nuclear positivity for SF1 and patchy cytoplasmic positivity for FSH with Ki-67 index of 2-3%. Discussion and Conclusion: Most gonadotropinomas are nonfunctional2 and clinically present with hypopituitarism and often low or normal sex hormone levels. We present a rare case of gonadotroph PitNet with elevated testosterone levels not associated with a recognizable clinical syndrome of sex hormone excess. The standard therapy for gonadotropin-secreting macroadenomas is trans-sphenoidal surgery.2-3 Early diagnosis is essential for timely and appropriate management. Presentation: Friday, June 16, 2023