Endogenous Testosterone Production Research Articles

Clomiphene Citrate Treatment as an Alternative Therapeutic Approach for Male Hypogonadism: Mechanisms and Clinical Implications

Male hypogonadism, which is characterized by low testosterone levels, has a significant impact on male sexual function, overall health, and fertility. Testosterone replacement therapy (TRT) is the conventional treatment for this condition, but it has potential adverse effects and is not suitable for men seeking to conceive. Testosterone plays an essential role in male sexual function, metabolism, mood, and overall well-being. Clomiphene citrate, a drug originally developed for female infertility, has recently gained attention as an off-label treatment for male hypogonadism. By blocking the negative feedback of estrogen on the hypothalamus and pituitary glands, clomiphene stimulates gonadotropin secretion, leading to increased endogenous testosterone production, which, in turn, improves sperm parameters and fertility and alleviates the symptoms of hypogonadism. Regarding the safety profile of clomiphene compared with TRT, clomiphene appears to confer a lower risk than TRT, which is associated with adverse effects such as polycythemia. Furthermore, combination therapy with clomiphene and anastrozole or human chorionic gonadotropin has been investigated as a potential approach to enhancing the effectiveness of treatments for improving hypogonadism symptoms. In conclusion, clomiphene citrate may offer a promising alternative to TRT for men with hypogonadism, particularly those desiring fertility preservations. However, its long-term efficacy and safety remain inadequately understood. Future research should focus on exploring the benefits of combination therapies and personalized treatment strategies based on individual patient characteristics.

Testosterone and male contraception.

Rates of unintended pregnancy have remained relatively stagnant for many years, despite a broad array of female contraceptive options. Recent restrictions on access to abortion in some countries have increased the urgency for expanding contraceptive options. Increasing data suggest men are keen to utilize novel reversible male contraceptives. Despite decades of clinical research in male contraception, no reversible hormonal product currently exists. Nestorone/testosterone, among other novel androgens, shows promise to finally move to pivotal Phase 3 studies and introduction to the marketplace. Hormonal male contraception utilizes androgens or androgen-progestin combinations to exploit negative feedback that regulates the hypothalamic-pituitary-testicular axis. By suppressing release of gonadotropins, these agents markedly decrease endogenous testosterone production, lower intratesticular testosterone and suppress spermatogenesis. The addition of a progestin enhances the degree and speed of sperm suppression. The androgen component preserves a state of symptomatic eugonadism in the male. There is growing demand and acceptance of male contraceptive options in various forms. As these formulations progress through stages of drug development, regulatory oversight and communication with developers around safety and efficacy standards and garnering industry support for advancing the production of male contraceptives will be imperative.

The influence of correction of carbohydrate metabolism and body weight on endogenous testosterone production in men with type 2 diabetes mellitus, obesity and hypogonadism

Male hypogonadism and type 2 diabetes mellitus (T2DM) are often combined and aggravate each other. Considering the pathogenetic relationship with the components of the metabolic syndrome (hyperglycemia, insulin resistance, obesity) and the potential reversibility of testosterone deficiency, as well as the wariness of doctors and patients regarding testosterone replacement therapy, it is interesting to study the effect of various methods for correcting carbohydrate metabolism and obesity on endogenous testosterone production. When analyzing the effect of lifestyle correction, drug therapy for T2DM and obesity, as well as metabolic surgery on testosterone production, encouraging results were obtained with regard to methods that provide, first of all, significant reduction in body weight (medications from the group of glucagon-like peptide-1 receptor agonists and bariatric surgery). As for other classes of new antidiabetic drugs, it is likely that all of them may have direct or indirect beneficial effects on male sexual function, mainly by reducing glucotoxicity and inflammation. However, this hypothesis requires studies on large samples of patients. In addition, there is still no convincing data on the significance of correction of carbohydrate metabolism, regardless of weight loss, in relation to endogenous testosterone production, and there is also no data on the degree of improvement in glycemic control required for a clinically significant increase in serum testosterone levels.

Effectiveness and Safety of Different Estradiol Regimens in Transgender Females: A Randomized Controlled Trial.

A goal of gender-affirming hormone therapy (GAHT) for transgender women is to use estradiol to suppress endogenous production of testosterone. However, the effects of different estradiol regimens and route of administration on testosterone suppression is unknown. This is the first open-label randomized trial comparing different GAHT regimens for optimal estradiol route and dosing. To evaluate 1 month and 6 months testosterone suppression <50 ng/dL with pulsed (once- or twice-daily sublingual 17-beta estradiol) and continuous (transdermal 17-beta estradiol) GAHT. This study was conducted at an outpatient adult transgender clinic. Thirty-nine transgender women undergoing initiation of GAHT were randomly assigned to receive either once-daily sublingual, twice-daily sublingual, or transdermal 17-beta estradiol. All participants received spironolactone as an antiandrogen. Doses were titrated at monthly intervals to achieve total testosterone suppression <50 ng/dL. Transdermal 17-beta estradiol resulted in more rapid suppression of total testosterone, lower estrone levels, with no differences in estradiol levels when compared to once-daily and twice-daily sublingual estradiol. Moreover, there was no difference in the mean estradiol dose between the once-daily and twice-daily sublingual 17-beta estradiol group. Continuous exposure with transdermal 17-beta estradiol suppressed testosterone production more effectively and with lower overall estradiol doses relative to once or twice daily sublingual estradiol. Most transgender women achieved cisgender women testosterone levels within 2 months on 1 or 2 0.1 mg/24 hours estradiol patches. Given no difference between once- or twice-daily sublingual estradiol, pulsed 17-beta estradiol likely provides no benefit for testosterone suppression.

OR25-03 Self-administration Of Post-cycle Therapy Is Associated With Increased Probability Of Subsequent Normalisation Of Reproductive Hormones Following Anabolic-androgenic Steroid Cessation In Men

Abstract Disclosure: B. Grant: None. J. Campbell: None. A. Pradeep: None. A.D. Burns: None. P. Bassett: None. P. Saket: None. S. Minhas: None. W.S. Dhillo: None. J. McVeigh: None. S. Bhasin: None. C.N. Jayasena: Grant Recipient; Self; Logixx Pharma Ltd. Context: Millions of men worldwide illicitly use anabolic-androgenic steroids (AAS) for muscle growth. However, AAS can cause death, cardiomyopathy, stroke, and psychosis. AAS use suppresses endogenous testosterone secretion for several months following cessation. Therefore, AAS cessation causes tiredness, low mood, insomnia, absent sexual function, and suicidality. There is currently no treatment recommended to reduce symptoms when men stop AAS. Some men empirically self-administer post-cycle therapy (PCT) drugs such as human chorionic gonadotrophin (hCG), selective oestrogen receptor modulators (SERM) and aromatase inhibitors (AI), aiming to restore endogenous testosterone. hCG directly stimulates endogenous testosterone production, while SERMs and AIs reduce the oestrogenic negative feedback on gonadotrophin secretion. Currently evidence is lacking to support the use of PCT in AAS-induced hypogonadism. Methods: Clinical audit from a single addiction service clinic, of 613 men stopping AAS in Scotland between 2015-2022. Men attended for a single, non-fasting, random blood test performed within 12 months of AAS cessation, with or without PCT use. Primary endpoint was the combination of reference range levels of serum LH, serum FSH and total testosterone, as a surrogate marker of biochemical recovery from hypogonadism. Results: PCT use was reported by 76% of men. Men using PCT had a significantly higher serum total testosterone following AAS cessation compared to men who did not (mean total testosterone nmol/L: 11.3 ± 6.7, no PCT; 12.8 ± 7.6, PCT; P=0.024). PCT use was associated with a higher probability (223/466, 48%, PCT; 56/147; 38%, no-PCT; P=0.04), and shorter time interval between stopping AAS and blood test of normalised reproductive hormones (13.3 ± 8.8 weeks, PCT;18.7 ± 12.0 weeks, no-PCT; P&amp;lt;0.01). The odds of biochemical normalisation during multivariable analysis were statistically significant when: (1) PCT was used (P=0.01); (2) fewer AAS were used (P=0.003); (3) shorter time of AAS use (P=0.02); (4) AAS used stopped for a longer time (P=0.03). Discussion: Our data provide primary evidence that self-administered PCT drugs may be associated with improved biochemical recovery from AAS-induced hypogonadism. These data require corroboration within an interventional study to determine causality. Nevertheless, these data may have important therapeutic implications for the future treatment of men who are motivated to stop AAS. Presentation Date: Saturday, June 17, 2023

Dose-dependent response to long-term clomiphene citrate in male functional hypogonadotropic hypogonadism.

Functional hypogonadotropic hypogonadism is a relatively common condition in middle-aged to elderly men that can significantly impair quality of life. Besides lifestyle optimisation, androgen replacement remains the mainstay of treatment; however, its adverse effects on spermatogenesis and testicular atrophy are undesirable. Clomiphene citrate is a selective oestrogen receptor modulator that acts centrally to increase endogenous testosterone without affecting fertility. Although it has demonstrated effectiveness in shorter-duration studies, its longer-term outcomes are less well-documented. In this study, we report the case of a 42-year-old male with functional hypogonadotropic hypogonadism who sustained an excellent dose-dependent, titratable clinical and biochemical response to clomiphene citrate with no known adverse effects for 7 years to date. This case highlights that clomiphene citrate has potential as a safe and titratable longer-term treatment option, and the need for further randomised control trials in therapy options to normalise androgen status. Functional hypogonadotropic hypogonadism is a relatively common, but likely underdiagnosed, condition in middle-aged to older males. Testosterone replacement is the current mainstay of endocrine therapy but can cause sub-fertility and testicular atrophy. Clomiphene citrate is a serum oestrogen receptor modulator that acts centrally to increase endogenous testosterone production without affecting fertility. It has potential as a safe and efficacious longer-term treatment option that can be titrated to increase testosterone and relieve clinical symptoms in a dose-dependent manner. Longitudinal prospective studies as randomised control trials evaluating alternatives to exogenous testosterone are required.

The Safety of Human Chorionic Gonadotropin Monotherapy Among Men With Previous Exogenous Testosterone Use.

Background and objectiveHuman chorionic gonadotropin (hCG) is homologous to luteinizing hormone (LH) and stimulates endogenous testosterone (T) production. Current American Urological Association (AUA) guidelines recommend hCG for T-deficient men who wish to preserve their fertility. However, there is no data available regarding the long-term efficacy and safety of hCG monotherapy in men with a history of exogenous T use. We hypothesized that transitioning to hCG would be a safe and effective option in this population.MethodologyWe performed a retrospective analysis involving 28 men with previous exogenous T use who were switched to hCG monotherapy and underwent follow-up lab work at least one month later. We evaluated changes in hormones [T, LH, follicle-stimulating hormone (FSH), and estradiol], hematocrit (HCT), glycated hemoglobin (HbA1c), and prostate-specific antigen (PSA).ResultsAmong the entire cohort, we found no significant change in mean hormone levels (including T), HbA1c, or PSA. There was a significant (p<0.05) decrease in HCT (45.27 ±4.06 to 44.16 ±3.48%, n=15). No thromboembolic events were reported. Additionally, among men who had their baseline labs completed outside their previous T therapy therapeutic time window prior to starting hCG monotherapy, there was a statistically significant increase in mean T levels (307.36 ±148.74 to 422.11 ±268.15 ng/dL, n=30 and 31, pre- and post-hCG, respectively) and a statistically significant decrease in mean PSA levels (0.91 ±0.35 to 0.69 ±0.23 ng/mL, n=5).ConclusionsThese results suggest that hCG is a safe and effective alternative to traditional T therapy for men with a history of exogenous T use and may lead to an advantageous decrease in HCT. hCG may serve as an alternative form of T therapy with a lower risk for secondary erythrocytosis, and further research is warranted to gain deeper insights into the topic.

Testosterone Deficiency in Sickle Cell Disease: Recognition and Remediation.

Hypogonadism is common in men with sickle cell disease (SCD) with prevalence rates as high as 25%. Testicular failure (primary hypogonadism) is established as the principal cause for this hormonal abnormality, although secondary hypogonadism and compensated hypogonadism have also been observed. The underlying mechanism for primary hypogonadism was elucidated in a mouse model of SCD, and involves increased NADPH oxidase-derived oxidative stress in the testis, which reduces protein expression of a steroidogenic acute regulatory protein and cholesterol transport to the mitochondria in Leydig cells. In all men including those with SCD, hypogonadism affects physical growth and development, cognition and mental health, sexual function, as well as fertility. However, it is not understood whether declines in physical, psychological, and social domains of health in SCD patients are related to low testosterone, or are consequences of other abnormalities of SCD. Priapism is one of only a few complications of SCD that has been studied in the context of hypogonadism. In this pathologic condition of prolonged penile erection in the absence of sexual excitement or stimulation, hypogonadism exacerbates already impaired endothelial nitric oxide synthase/cGMP/phosphodiesterase-5 molecular signaling in the penis. While exogenous testosterone alleviates priapism, it disadvantageously decreases intratesticular testosterone production. In contrast to treatment with exogenous testosterone, a novel approach is to target the mechanisms of testosterone deficiency in the SCD testis to drive endogenous testosterone production, which potentially decreases further oxidative stress and damage in the testis, and preserves sperm quality. Stimulation of translocator protein within the transduceosome of the testis of SCD mice reverses both hypogonadism and priapism, without affecting intratesticular testosterone production and consequently fertility. Ongoing research is needed to define and develop therapies that restore endogenous testosterone production in a physiologic, mechanism-specific fashion without affecting fertility in SCD men.

PD36-04 AROMATIZATION OF ENDOGENOUS TESTOSTERONE OCCURS PRIMARILY IN TESTICULAR LEYDIG CELLS

You have accessJournal of UrologyCME1 May 2022PD36-04 AROMATIZATION OF ENDOGENOUS TESTOSTERONE OCCURS PRIMARILY IN TESTICULAR LEYDIG CELLS Caroline Kang, Nahid Punjani, Jessica Marinaro, and Peter Schlegel Caroline KangCaroline Kang More articles by this author , Nahid PunjaniNahid Punjani More articles by this author , Jessica MarinaroJessica Marinaro More articles by this author , and Peter SchlegelPeter Schlegel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002594.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Endogenous testosterone (T) is produced by testicular Leydig cells that are rich in aromatase activity. Aromatization to estradiol (E2) can negatively regulate the hypothalamic-pituitary-testis (HPT) axis, thereby diminishing gonadotropin and T production as well as spermatogenesis. Exogenous T is exposed primarily to fat, muscle, and other peripheral tissues with limited exposure to testicular Leydig cells. We investigated the source of aromatization by comparing serum T:E2 ratios, as a surrogate for aromatase activity, in men with Klinefelter syndrome (KS) who have endogenous or exogenous testosterone production, that is, before and after the initiation of testosterone replacement therapy (TRT). METHODS: We performed a retrospective study of all adult men (> 20 years of age) with a diagnosis of KS undergoing sperm retrieval by microdissection testicular sperm extraction (mTESE) performed by a single surgeon at a tertiary infertility referral center between 1995-2020. Demographic data, along with hormone data (serum T and E2 levels) pre- and post-TRT were obtained from the electronic medical record. Patients not treated with TRT or with incomplete hormone data were excluded. Paired statistical analyses were completed to determine differences between hormone levels pre- and post-TRT initiation. RESULTS: A total of 35 men with KS were included in our final analysis. Median age was 32 years (interquartile range (IQR), 28 - 36), and median BMI was 25.9 kg/m2 (IQR, 24.6 - 30.8). The majority of our cohort was initiated on topical TRT (e.g., cream or gel; 26/35, 74.3%), while the remaining were treated with injectable or implanted TRT (9/35, 25.7%). Mean serum T increased from 239±134 ng/dL to 519±361 ng/dL (p=0.0003), while mean serum E2 increased from 30±22 pg/ml to 36±28 pg/ml (p=0.55) after initiation of TRT. Mean T:E2 ratio increased from 9.4±6.3 to 17.4±14.5 (p=0.0005) after initiation of TRT. CONCLUSIONS: Aromatization of T to E2 can result in suppression of the HPT axis and diminish both T production and spermatogenesis. After initiation of TRT, T:E2 ratios rose significantly due to an increase in T with relatively stable E2, suggesting that exogenous and endogenous T are not subject to the same cellular milieu and therefore differential aromatization. This finding has important implications in the treatment and counseling of men with infertility and abnormal hormone levels. Source of Funding: CK and JS are supported in part by the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e634 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Caroline Kang More articles by this author Nahid Punjani More articles by this author Jessica Marinaro More articles by this author Peter Schlegel More articles by this author Expand All Advertisement PDF DownloadLoading ...

Safety of Human Chorionic Gonadotropin Monotherapy for Men with Previous Exogenous Testosterone Use or Replacement Therapy

ABSTRACT Introduction Human chorionic gonadotropin (hCG) is homologous to luteinizing hormone (LH) and stimulates endogenous testosterone (T) production and may be an option for testosterone replacement therapy (TRT). Currently, hCG is recommended for hypogonadal men with fertility concern as it prevents azoospermia seen with exogenous testosterone use. It is unknown if hCG is as efficacious as T in improving symptoms. We hypothesized that hCG is an effective and safe treatment in males with a history of exogenous T use or TRT. Objective Our objective was to evaluate for changes in symptoms and side effects to assess hCG monotherapy as a possible method of TRT in adult males with a history of previous exogenous T use or TRT. Methods We retrospectively reviewed 50 charts using exogenous T (including testosterone cypionate, clomid, anastrozole, methandienone, and testosterone gel) and were switched to hCG monotherapy for at least 1 month with follow-up labs. We evaluated changes in hormones [T, LH, follicle stimulating hormone (FSH), and estradiol], hematocrit (HCT), glycated hemoglobin (A1c), and prostate specific antigen (PSA). Results presented as means standard deviation. Student t-test was used to compare pre- and post-treatment values, significance was set at p=0.05. We also evaluated for incidence of thromboembolic events, including stroke, deep vein thrombosis, and myocardial infarction. Results The average age was 43.3±10.2 years with a BMI of 29.4±3.9 kg/m2. Of the patient's reviewed, 46% had used clomid, 18% T cypionate, 15% anabolic steroids, 13% T gel, 4% T pellets, and 4% methandienone. Average follow-up after starting hCG therapy was 163 days, range 28 to 583 days. Average weekly hCG dosage was 2435 IU. Serum T experienced no significant change, from 402.54±281.34 ng/dL to 404.29 ±259.64 ng/dL (p=0.58, n=50). No change was seen in FSH (4.82±6.21 to 3.71±3.24 mIU/mL, n=25), LH (3.12±4.18 to 1.98±1.86 mIU/mL, n=25), PSA (0.79±0.39 to 0.64±0.25 ng/mL, n=6), estradiol (27.84±14.82 to 27.96±13.18 pg/mL, n=31), or A1c (5.51±0.41 to 5.41±0.0.43 %, n=8). There was a statistically significant decrease of HCT (45.05±4.87 to 43.91±4.48 %, n=15). When evaluated for improvement of erectile dysfunction (ED, n=30), low libido (n=30), and low energy (n=32), 57%, 63%, and 66% of patients reported improvement of each symptom, respectively. Only 41% of patients with ED were noted to be on another medication or therapy specifically for ED. No thromboembolic events were observed. Conclusions Weekly hCG dosing appears to have no significant effect on T levels in men with a history of exogenous T use or TRT. The majority of patients reported an improvement in their hypogonadal symptoms. No changes were noted in PSA and A1c. HCT was noted to have a small, but statistically significant decrease and no thromboembolic events were recorded. Disclosure No

Safety of Human Chorionic Gonadotropin Monotherapy for Men with Hypogonadal Symptoms and Testosterone >300 ng/dL

ABSTRACT Introduction Human chorionic gonadotropin (hCG) is homologous to luteinizing hormone (LH) and is known to stimulate endogenous testosterone (T) production and may be an option for testosterone replacement therapy (TRT). Current guidelines recommend TRT for men with two T levels &amp;lt;300 ng/dl and symptoms of low T. A challenging patient population are men with symptoms of low T who do not meet biochemical criteria for TRT as there are not current treatment recommendations. We hypothesize that hCG may be a safe and effective therapy for men with hypogonadal symptoms and T &amp;gt;300ng/dl. Objective Our objective was to evaluate for symptom improvement and side effects of hCG monotherapy in men with hypogonadal symptoms and T &amp;gt;300 ng/dL. Methods We retrospectively reviewed the charts of 31 men treated with hCG monotherapy for hypogonadal symptoms with a T average (latest two lab results) &amp;gt;300 ng/dL who had follow-up labs at least 1 month after initiation of hCG therapy. We evaluated changes in hormones [T, LH, follicle stimulating hormone (FSH), and estradiol], hematocrit (HCT), glycated hemoglobin (A1c), and prostate specific antigen (PSA). Results presented as means standard deviation. Student t-test was used to compare pre- and post-treatment values, significance was set at p=0.05. We also evaluated for incidence of thromboembolic events, including stroke, deep vein thrombosis, and myocardial infarction. Results The average age of patients was 49.0±15.8 years with a BMI of 28.6±4.8 kg/m2. Average follow-up after starting hCG therapy was 292 days, range 77 to 857 days. Average weekly hCG dosage was 1500 IU. Serum T increased from 431.27±117.22 ng/dL to 461.05 ±185.19 ng/dL (p=0.61, n=31). No change was seen in FSH (6.79±10.85 to 7.12±12.07 mIU/mL, n=8), PSA (1.55±1.44 to 1.90±1.81 ng/mL, n=10), HCT (43.43±2.27 to 44.48±2.86 %, n=12), estradiol (27.44±6.92 to 30.63±10.25 pg/mL, n=8), or A1c (6.15±0.95 to 6.33±0.93 %,n=4). A statistically significant decrease was seen in LH (4.93±1.98 to 3.66±1.85 mIU/mL,n=11). When evaluated for improvement of erectile dysfunction (ED, n=22), low libido (n=25), and low energy (n=19), 86%, 80%, and 79% of patients reported improvement of each symptom, respectively. All patients with ED were noted to be on another medication or therapy specifically for ED. No thromboembolic events were observed. Conclusions Weekly hCG dosing appears to safely improve hypogonadal symptoms even with baseline T levels &amp;gt;300 ng/dL. No changes were noted in HCT, PSA, A1c and no thromboembolic events were recorded. Disclosure No

Effect of aromatase inhibitors on infertile men and its relation to sexual desire

Background: Aromatase inhibitors (AI) can boost endogenous testosterone production without increasing circulating estrogen levels, as shown with estrogen receptor modulators, Aim and Objectives: The study's goal was to determine the efficacy of aromatase inhibitor medication in improving spermatogenesis in oligozoospemic and azoospermic males, as well as its relationship to sexuality. Subjects and methods: This study was done on eighty man subjects joining the outpatient clinic of Andrology, Kasr El Aini Hospital, Cairo University during the peroid from April 2018 – April 2020, and they were divided into (2) groups, 40 subjects in each group. Results: There was a statistically significant difference in serum total testosterone measured before and after treatment in normal FSH patients with a p value ≤ 0.05. There was a notably not important change in sexual desire questionnaire measured before and after treatment in normal FSH patients with a p value &gt; 0.05, Conclusion: ERs and aromatase share topographic sites in the brain with pheromones, indicating that estrogen influences both early sexual maturation and sexual behavior in adults. Estrogen can maintain libido while also influencing the number of serotonin receptors in the brain, which modulates mood, mental state, cognition, and emotion.

The effect of aromatase inhibitors on infertile men and its relation to sexual desire

Background: Aromatase inhibitors (AI) can boost endogenous testosterone production without increasing circulating estrogen levels, as shown with estrogen receptor modulators, Aim and Objectives: The study's goal was to determine the efficacy of aromatase inhibitor medication in improving spermatogenesis in oligozoospemic and azoospermic males, as well as its relationship to sexuality. Subjects and methods: This study was done on eighty man subjects joining the outpatient clinic of Andrology, Kasr El Aini Hospital, Cairo University during the peroid from April 2018 – April 2020, and they were divided into (2) groups, 40 subjects in each group. Results: There was a statistically significant difference in serum total testosterone measured before and after treatment in normal FSH patients with a p value ≤ 0.05. There was a notably not important change in sexual desire questionnaire measured before and after treatment in normal FSH patients with a p value &gt; 0.05, Conclusion: ERs and aromatase share topographic sites in the brain with pheromones, indicating that estrogen influences both early sexual maturation and sexual behavior in adults. Estrogen can maintain libido while also influencing the number of serotonin receptors in the brain, which modulates mood, mental state, cognition, and emotion.

Clinical question: How to manage symptoms of hypogonadism in patients after androgen abuse?

Androgen abuse is relatively common amongst young (amateur) bodybuilders. After cessation, the hypothalamic-pituitary-gonadal (HPG) axis-which has been suppressed by the androgens-needs time to recover. The endogenous testosterone production often recovers within 3 months, however, prolonged or permanent post-androgen abuse hypogonadism (PPAAH) has been described. There is no widely accepted definition nor is its pathogenesis completely elucidated. To date it is a subject of debate whether PPAAH is a separate entity, reflecting irreversible damage to essential components of the HPG axis inflicted by long-term exposure to high doses of androgens. Alternately, it may be the result of longer than expected suppressive effects of androgen depots, undisclosed ongoing androgen abuse or undiagnosed unrelated disorders. Due to the lack of scientific evidence, the management of PPAAH is challenging. By combining clinical experience with evidence from the recent literature, a suggested outline of the management of androgen-abuse-induced hypogonadism are given.

Semen quality, testosterone values, and testicular and accessory gland parameters in rams receiving sustained stimulation with low doses of buserelin

Context The use of buserelin, a gonadotropin-releasing hormone (GnRH) agonist, can improve semen quality. Nevertheless, the appropriate dosage, and frequency and time of application, remain to be established owing to the subsequent negative feedback on endogenous production of testosterone described so far. Aims This study aimed to propose a new buserelin application protocol for sperm improvement in Santa Inês rams. Methods Fifteen Santa Inês rams were divided into two experimental groups: the first group (n = 8) received 2.5 μg buserelin acetate; and the second group (n = 7) received saline solution. Treatments were applied for 21 days at intervals of 6 h, totalling four hormonal or saline applications per day. In all animals, macroscopic and microscopic seminal characteristics and freezability, plasma testosterone, pixels of testicular parenchyma, and biometric analysis of testicular and accessory sex glands by ultrasound were evaluated throughout the period of hormonal application and for a further 7 days. Key results Rams receiving buserelin showed a peak of testosterone after the first week (Day 7) of application, with a drop in values at Day 14, followed by negative feedback at Day 21 and return to basal concentrations at Day 28. They also showed improvement of kinetics parameters such as straight line velocity (μm/s: +buserelin 51.5 ± 1.5 &gt; control 46.6 ± 1.6) and linearity coefficient (%: +buserelin 53.5 ± 1.8 &gt; control 47.5 ± 1.9). Ultrasound parameters, pixels of testicular parenchyma, and freezability were not affected by treatment. Conclusions The administration of buserelin was able to improve some sperm kinetics parameters of Santa Inês rams. Implications Low doses of this GnRH analogue can be used; however, further adjustments to the hormonal protocol are needed to obtain an effective improvement in sperm quality.

MP35-16 DOES FEMINIZING HORMONE THERAPY REDUCE ACE2 RECEPTOR EXPRESSION?: A HISTOLOGIC STUDY USING TRANSGENDER WOMEN’S TESTICLE TISSUE AFTER ORCHIECTOMY, AND, IMPLICATIONS FOR POSSIBLE USE FOR COVID19 TREATMENT AND/OR PREVENTION

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Prostate & Genitalia (MP35)1 Sep 2021MP35-16 DOES FEMINIZING HORMONE THERAPY REDUCE ACE2 RECEPTOR EXPRESSION?: A HISTOLOGIC STUDY USING TRANSGENDER WOMEN’S TESTICLE TISSUE AFTER ORCHIECTOMY, AND, IMPLICATIONS FOR POSSIBLE USE FOR COVID19 TREATMENT AND/OR PREVENTION John M. Masterson, Chau Bui, Yi Zhang, Xiaopen Yuan, Carissa Huynh, Harneet Jawanda, Wohaib Hasan, Daniel Luthringer, Warren Tourtellotte, and Maurice Garcia John M. MastersonJohn M. Masterson More articles by this author , Chau BuiChau Bui More articles by this author , Yi ZhangYi Zhang More articles by this author , Xiaopen YuanXiaopen Yuan More articles by this author , Carissa HuynhCarissa Huynh More articles by this author , Harneet JawandaHarneet Jawanda More articles by this author , Wohaib HasanWohaib Hasan More articles by this author , Daniel LuthringerDaniel Luthringer More articles by this author , Warren TourtellotteWarren Tourtellotte More articles by this author , and Maurice GarciaMaurice Garcia More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002044.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Invasion of cells by SARS-CoV-2 is mediated by the ACE2 receptor (ACE2r), which is highly expressed in testicle tissue. It has been proposed that men hospitalized with COVID19 be treated with estrogen (E) or E and Progesterone (P), however results of these trials remain unknown. Transgender women (TW) (male to female) are routinely treated with E or E+P regimens for feminization. We analyzed differences in ACE2r expression in testicles of TW taking E or E+P. METHODS: Orchiectomy specimens were collected from TW undergoing gender-affirming surgery, who were taking E or E+P preoperatively. For controls, we used benign orchiectomy specimens from cis-gender men. All specimens were stained with H&E, Trichrome (fibrosis), insulin-liken3 antibody (INS) (Leydig cell), and ACE2r IHC. Cells per high-powered field (HPF) were counted by cell type (Leydig, Sertoli, Germ). Stain intensity was rated on a 0-2 scale. IHC scoring was performed in a blinded fashion by a senior GU Pathologist. Mean cell type/HPF and stain intensity were compared across cohorts using Student’s t-test (p<0.05). Intracohort findings were stratified by age (< or >40). RESULTS: On IHC for Leydig cells and ACE2r staining the EP cohort had fewer Leydig cells compared to controls. The EP cohort also had greater degree of tissue fibrosis compared to controls and the E cohort. On intra-cohort analysis, TW >age 40 had lower Sertoli cell (H&E, ACE2r) and Germ cell (ACE2r) counts, and lower ACE2r stain intensity on Leydig cells. The EP cohort of TW >age 40 also showed increased fibrosis to TW age <age 40. (Table 1) CONCLUSIONS: These findings have implications both for use of feminizing hormones to treat COVID19 in men and for TW seeking to preserve fertility after prolonged hormone therapy. Regarding COVID19: this work supports the hopeful possibility that a short course of P (or E+P) could downregulate ACE2r to protect men from COVID19 infection. Of separate interest to transitioning TW, this work suggests that fertility preservation after E+P may be challenging, given the significant seminiferous tubule fibrosis observed. Furthermore, E+P has the benefit of appearing to decrease endogenous Testosterone production more than E alone. Source of Funding: n/a © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e633-e633 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information John M. Masterson More articles by this author Chau Bui More articles by this author Yi Zhang More articles by this author Xiaopen Yuan More articles by this author Carissa Huynh More articles by this author Harneet Jawanda More articles by this author Wohaib Hasan More articles by this author Daniel Luthringer More articles by this author Warren Tourtellotte More articles by this author Maurice Garcia More articles by this author Expand All Advertisement PDF downloadLoading ...

Disruption and recovery of testicular function during and after androgen abuse: the HAARLEM study

What is the speed and extent by which endogenous testosterone production and spermatogenesis recover after androgen abuse? Testosterone concentrations normalized within 3 months after discontinuation of androgen abuse in most subjects but recovery of spermatogenesis took longer-approximately 1 year. An estimated 4-6% of amateur strength athletes use androgens. Abuse of supraphysiological doses of androgens completely suppresses endogenous testosterone production and spermatogenesis. Prospective and observational cohort study in which 100 male amateur athletes participated for 1 year. Subjects (≥18 years) were included if they had not used androgens for at least 3 months and intended to start an androgen cycle within 2 weeks. Clinic visits took place before (T0), at the end (T1), and 3 months after the end of the cycle (T2), and 1 year after start of the cycle (T3), and included a blood test for gonadotrophins and sex hormones, and semen analysis. During androgen abuse, 77% of subjects had a total sperm count (TSC) below 40 million. Three months after the end of the cycle (T2), total (-1.9 nmol/l, CI -12.2 to 8.33, P = 0.71) and free (-38.6 pmol/l, CI -476 to 399, P = 0.86) testosterone concentrations were not different compared to baseline, whereas mean TSC was 61.7 million (CI 33.7 to 90.0; P < 0.01) lower than baseline. At the end of follow-up (T3), there was no statistically significant difference for total (-0.82 nmol/l, CI -11.5 to 9.86, P = 0.88) and free (-25.8 pmol/l, CI -480 to 428, P = 0.91) testosterone compared to baseline, but there was for TSC (-29.7 million, CI -59.1 to -0.39, P = 0.05). In nine (11%) subjects, however, testosterone concentrations were below normal at the end of follow-up (T3), and 25 (34%) subjects still had a TSC below 40 million. The follow-up period (after the cycle) was relatively short, especially considering the long recovery time of spermatogenesis after discontinuation of androgens. Endogenous testosterone production and spermatogenesis recover following androgen abuse in the vast majority of users. Nevertheless, not all users achieve a normalized testicular function. This may especially be the case for athletes with a high past exposure to androgens. There is no conflict of interest. The study was funded by the Spaarne Gasthuis academy. N/A.

TSPO ligand FGIN-1-27 controls priapism in sickle cell mice via endogenous testosterone production.

Priapism, a prolonged penile erection in the absence of sexual arousal, is common among patients with sickle cell disease (SCD). Hypogonadism is also common in patients with SCD. While the administration of exogenous testosterone reverses hypogonadism, it is contraceptive. We hypothesized that the stimulation of endogenous testosterone production decreases priapism by normalizing molecular signaling involved in penile erection without decreasing intratesticular testosterone production, which would affect fertility. Treatment of SCD mice with FGIN-1-27, a ligand for translocator protein (TSPO) that mobilizes cholesterol to the inner mitochondrial membrane, resulted in eugonadal levels of serum testosterone without decreasing intratesticular testosterone production. Normalized testosterone levels, in turn, decreased priapism. At the molecular level, TSPO restored phosphodiesterase 5 activity and decreased NADPH oxidase-mediated oxidative stress in the penis, which are major molecular signaling molecules involved in penile erection and are dysregulated in SCD. These results indicate that pharmacologic activation of TSPO could be a novel, targetable pathway for treating hypogonadal men, particularly patients with SCD, without adverse effects on fertility.

MON-273 Retrospective Analysis of Gonadotropin-Mediated Pubertal Induction in Male Patients with Congenital Hypogonadotropic Hypogonadism (CHH)

CHH is a rare disease characterized by a failure to enter (complete forms) or to complete (partial forms) pubertal development. It has a strong genetic background and it needs a treatment to allow the puberty to complete. In male this goal could be achieved either by the classic testosterone replacement therapy or by the exogenous gonadotropins (Gn) administration which allows both the endogenous testosterone production and the testicular development. So far, only few studies have explored this latter therapeutic approach in inducing the CHH pubertal development and no internationally recognized protocols are available. Aim of this retrospective analysis is to (i) investigate clinical and biochemical predictors of testicular response to Gn-induced puberty in CHH; (ii) study the non-reproductive outcomes of this treatment (height, body proportions) and their determinants. A total of 19 CHH male patients, undergoing two years of Gn-mediated (FSH and hCG) puberty induction started between the ages of 14 and 23 years, were retrospectively evaluated. For each patient clinical history, physical examination, hormonal evaluation, and genetic analysis using Targeted Next Generation Sequencing for CHH genes was performed; 8 patients accepted to perform a semen analysis (SA) at the end of their treatment.Mann Whitney test and multiple regression analysis showed testicular volume after 24 months of Gn-mediated pubertal induction, to be significantly associated with: (i) the presence of cryptorchidism; (ii) the presence of a completely definable genetic cause for the disease; (iii) the presence of a complete CHH form. No significant association was found with the cumulative dose of hCG administered in 24 months. The statistical analyses regarding SA could not find the same associations. Multiple regression analyses investigating the eunuchoid habitus and a measure of the difference of subject’s final height from his target (deltaSDSth), showed a significant association with: (i) age at the beginning of the induction; (ii) the duration of growth during induction; (iii) and (for deltaSDSth) bone age before the induction. Duration of growth during induction resulted to be associated with previous testosterone priming and with partial CHH.In summary, our study confirms cryptorchidism and complete genetic forms of CHH as negative predictors of testicular response probably because they usually affect early phases of life with a complete GnRH deficiency. We also found that the eunuchoid habitus and deltaSDSth are associated not only with delayed treatment, but also with the duration of stature growth during the induction, apparently related to earlier androgenization.

A clinical algorithm for management of fertility in adolescents with the Klinefelter syndrome.

The review presents a clinical algorithm for the evaluation and treatment for adolescents with Klinefelter's syndrome who desire fertility preservation. Sperm is present in the ejaculate in around 8% of men with Klinefelter's syndrome. Although most are severely oligospermic/azoospermic, 43-45% of men will have sperm found during a testicular sperm extraction, reaching up to 70% in adolescents. Klinefelter's syndrome (47, XXY) causes hypogonadotophic hypogonadism and severe oligospermia/azoospermia rendering natural conception rare. During puberty, boys often require testosterone replacement therapy to develop secondary sexual characteristics, which can further decrease spermatogenesis. There is a progressive decrease of testicular germ cells after the onset of puberty, suggesting that fertility evaluation and preservation should begin shortly thereafter. In adolescents desiring fertility evaluation, any testosterone therapy should be discontinued, hormones and gonadotrophins measured, and a semen analysis obtained. Adolescents with low testosterone are administered aromatase inhibitors, selective estrogen receptors modulators and/or human chorionic gonadotropin to increase endogenous testosterone production. After testosterone levels are normalized, semen analysis is performed, and cryopreservation encouraged if sperm is present. For those without sperm in the ejaculate, a testicular sperm extraction is offered.