Challenges in Diagnosis and Treatment of Male Hypogonadism.

Hypogonadism is a condition characterized by diminished or absent production of sex hormones by the testicles in men and the ovaries in women. Hypogonadism is classified into primary and secondary hypogonadism. Each type of hypogonadism can be caused by congenital and acquired factors. There are many factors that contribute to the occurrence of hypogonadism, including genetic and developmental disorders, infection, kidney disease, liver disease, autoimmune disorders, chemotherapy, radiation, surgery, and trauma. This represents the considerable challenge in diagnosing hypogonadism.The goals of treatment include restore sexual functionality and well-being, initiating and sustaining virilization, osteoporosis prevention, normalize growth hormone levels in elderly men if possible, and restoring fertility in instances of hypogonadotropic hypogonadism. The main approach to treating hypogonadism is hormone replacement therapy. Male with prostate cancer, breast cancer, and untreated prolactinoma are contraindicated for hormone replacement therapy. When selecting a type of testosterone therapy for male with hypogonadism, several factors need to be considered, such as the diversity of treatment response and the  type of testosterone formulation. The duration of therapy depends on individual response, therapeutic goals, signs and symptoms, and hormonal levels. The response to testosterone therapy is evaluated based on symptoms and signs as well as improvements in hormone profiles in the blood. Endocrine Society Clinical Practice Guideline recommend therapeutic goals based on the alleviation of symptoms and signs, as well as reaching testosterone levels between 400 - 700 ng/dL (one week after administering testosterone enanthate or cypionate) and maintaining baseline hematocrit.Hormone therapy is the primary modality in the management of hypogonadism. The variety of signs and symptoms makes early diagnosis of this condition challenging. Moreover, administering hypogonadism therapy involves numerous considerations influenced by various patient factors and the potential for adverse effects. This poses a challenge for physicians to provide targeted hypogonadism therapy with minimal complications.

Fertility outcomes in male adults with congenital hypogonadotropic hypogonadism treated during puberty with human chorionic gonadotropin and recombinant follicle stimulating hormone.

AIM: Hormone replacement therapy with testosterone for pubertal induction in boys with congenital hypogonadotropic hypogonadism (CHH) achieves virilization but not spermatogenesis. By contrast, human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) provides both virilization and spermatogenesis. Fertility outcomes of boys treated with recombinant therapy during adolescence have been infrequently described. We report fertility induction and pregnancy outcomes in CHH patients treated with recombinant gonadotropins during puberty. METHODS: Data of six subjects with CHH (n = 3 Kallmann syndrome & n = 3 Isolated hypogonadotropic hypogonadism) treated with hCG and FSH for pubertal induction were reviewed. Of these, five underwent subsequent fertility induction while one desired fertility at the end of pubertal induction. RESULTS: Partners of all subjects achieved pregnancies using hCG and rFSH, all with full term live births. All infants were clinically normal. CONCLUSION: This study provides early evidence of proof of concept of use of gonadotropin induction of puberty being beneficial in subsequent fertility outcome.

Effect of topical testosterone on pre-diabetes and diabetes.

Overview of: Bhasin S, Lincoff AM, Nissen SE, et al. Effect of testosterone on progression from prediabetes to diabetes in men with hypogonadism: a substudy of the TRAVERSE randomized clinical trial. JAMA Intern Med. 2024. doi: 10.1001/jamainternmed.2023.7862. [Epub ahead of print 5 February 2024].

Classes and predictors of reversal in male patients with congenital hypogonadotropic hypogonadism: a cross-sectional study of six international referral centres.

BACKGROUND: Although some male patients with congenital hypogonadotropic hypogonadism (CHH) undergo spontaneous reversal following treatment, predictors of reversal remain elusive. We aimed to assemble the largest cohort of male patients with CHH reversal to date and identify distinct classes of reversal. METHODS: This multicentre cross-sectional study was conducted in six international CHH referral centres in Brazil, Finland, France, Italy, the UK, and the USA. Adult men with CHH (ie, absent or incomplete spontaneous puberty by age 18 years, low serum testosterone concentrations, and no identifiable cause of hypothalamic-pituitary-gonadal [HPG] axis dysfunction) were eligible for inclusion. CHH reversal was defined as spontaneous recovery of HPG axis function off treatment. Centres provided common data elements on patient phenotype, clinical assessment, and genetics using a structured, harmonised data collection form developed by COST Action BM1105. Latent class mixture modelling (LCMM) was applied to establish whether at least two distinct classes of reversal could be identified and differentially predicted, and results were compared with a cohort of patients without CHH reversal to identify potential predictors of reversal. The primary outcome was the presence of at least two distinct classes of reversal. FINDINGS: A total of 87 male patients with CHH reversal and 108 without CHH reversal were included in the analyses. LCMM identified two distinct reversal classes (75 [86%] in class 1 and 12 [14%] in class 2) on the basis of mean testicular volume, micropenis, and serum follicle-stimulating hormone (FSH) concentration. Classification probabilities were robust (0·998 for class 1 and 0·838 for class 2) and modelling uncertainty was low (entropy 0·90). Compared with class 1, patients in class 2 had significantly larger testicular volume (p<0·0001), no micropenis, and higher serum FSH concentrations (p=0·041), consistent with the Pasqualini syndrome (fertile eunuch) subtype of CHH. Patients without CHH reversal were more likely to have anosmia (p=0·016), cryptorchidism (p=0·0012), complete absence of puberty (testicular volume <4 cm³; p=0·0016), and two or more rare genetic variants (ie, oligogenicity; p=0·0001). Among patients who underwent genetic testing, no patients (of 75) with CHH reversal had a rare pathogenic ANOS1 variant compared with ten (11%) of 95 patients without CHH reversal. Individuals with CHH reversal had a significantly higher rate of rare variants in GNRHR than did those without reversal (nine [12%] of 75 vs three [3%] of 95; p=0·025). INTERPRETATION: Applying LCMM to a large cohort of male patients with CHH reversal uncovered two distinct classes of reversal. Genetic investigation combined with careful clinical phenotyping could help surveillance of reversal after withdrawing treatment, representing the first tailored management approach for male patients with this rare endocrine disorder. FUNDING: National Institutes of Health National Center for Advancing Translational Sciences; Ministry of Health, Rome, Italy; Ministry of University, Rome, Italy; National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the Josiah Macy Jr Foundation. TRANSLATION: For the Italian translation of the abstract see Supplementary Materials section.

Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism: A Substudy of the TRAVERSE Randomized Clinical Trial.

Importance: The effect of testosterone replacement therapy (TRT) in men with hypogonadism on the risk of progression from prediabetes to diabetes or of inducing glycemic remission in those with diabetes is unknown. Objective: To evaluate the efficacy of TRT in preventing progression from prediabetes to diabetes in men with hypogonadism who had prediabetes and in inducing glycemic remission in those with diabetes. Design, Setting, and Participants: This nested substudy, an intention-to-treat analysis, within a placebo-controlled randomized clinical trial (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men [TRAVERSE]) was conducted at 316 trial sites in the US. Participants included men aged 45 to 80 years with hypogonadism and prediabetes or diabetes who were enrolled in TRAVERSE between May 23, 2018, and February 1, 2022. Intervention: Participants were randomized 1:1 to receive 1.62% testosterone gel or placebo gel until study completion. Main Outcomes and Measures: The primary end point was the risk of progression from prediabetes to diabetes, analyzed using repeated-measures log-binomial regression. The secondary end point was the risk of glycemic remission (hemoglobin A1c level <6.5% [to convert to proportion of total hemoglobin, multiply by 0.01] or 2 fasting glucose measurements <126 mg/dL [to convert to mmol/L, multiply by 0.0555] without diabetes medication) in men who had diabetes. Results: Of 5204 randomized participants, 1175 with prediabetes (mean [SD] age, 63.8 [8.1] years) and 3880 with diabetes (mean [SD] age, 63.2 [7.8] years) were included in this study. Mean (SD) hemoglobin A1c level in men with prediabetes was 5.8% (0.4%). Risk of progression to diabetes did not differ significantly between testosterone and placebo groups: 4 of 598 (0.7%) vs 8 of 562 (1.4%) at 6 months, 45 of 575 (7.8%) vs 57 of 533 (10.7%) at 12 months, 50 of 494 (10.1%) vs 67 of 460 (14.6%) at 24 months, 46 of 359 (12.8%) vs 52 of 330 (15.8%) at 36 months, and 22 of 164 (13.4%) vs 19 of 121 (15.7%) at 48 months (omnibus test P = .49). The proportions of participants with diabetes who experienced glycemic remission and the changes in glucose and hemoglobin A1c levels were similar in testosterone- and placebo-treated men with prediabetes or diabetes. Conclusions and Relevance: In men with hypogonadism and prediabetes, the incidence of progression from prediabetes to diabetes did not differ significantly between testosterone- and placebo-treated men. Testosterone replacement therapy did not improve glycemic control in men with hypogonadism and prediabetes or diabetes. These findings suggest that TRT alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism. Trial Registration: ClinicalTrials.gov Identifier: NCT03518034.

Management of Male Fertility in Hypogonadal Patients on Testosterone Replacement Therapy.

Testosterone is crucial in regulating several body functions in men, including metabolic, sexual, and cardiovascular functions, bone and muscle mass, and mental health. Therefore, optimizing testosterone levels in men is an important step to maintaining a healthy body and mind, especially as we age. However, traditional testosterone replacement therapy has been shown to lead to male infertility, caused by negative feedback in the hypothalamic-pituitary-gonadal (HPG) axis. Recent advances in research have led to the discovery of many new methods of administration, which can have more or less suppressive effects on the HPG axis. Also, the usage of ancillary medications instead of or after testosterone administration might help maintain fertility in hypogonadal patients. The goal of this narrative review is to summarize the newest methods for optimizing fertility parameters in patients undergoing treatment for hypogonadism and to provide the necessary information for healthcare providers to make the right treatment choices.

APHRODITE criteria: addressing male patients with hypogonadism and/or infertility owing to altered idiopathic testicular function.

RESEARCH QUESTION: Can a novel classification system of the infertile male - 'APHRODITE' (Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function) - stratify different subgroups of male infertility to help scientists to design clinical trials on the hormonal treatment of male infertility, and clinicians to counsel and treat the endocrinological imbalances in men and, ultimately, increase the chances of natural and assisted conception? DESIGN: A collaboration between andrologists, reproductive urologists and gynaecologists, with specialization in reproductive medicine and expertise in male infertility, led to the development of the APHRODITE criteria through an iterative consensus process based on clinical patient descriptions and the results of routine laboratory tests, including semen analysis and hormonal testing. RESULTS: Five patient groups were delineated according to the APHRODITE criteria; (1) Hypogonadotrophic hypogonadism (acquired and congenital); (2) Idiopathic male infertility with lowered semen analysis parameters, normal serum FSH and normal serum total testosterone concentrations; (3) A hypogonadal state with lowered semen analysis parameters, normal FSH and reduced total testosterone concentrations; (4) Lowered semen analysis parameters, elevated FSH concentrations and reduced or normal total testosterone concentrations; and (5) Unexplained male infertility in the context of unexplained couple infertility. CONCLUSION: The APHRODITE criteria offer a novel and standardized patient stratification system for male infertility independent of aetiology and/or altered spermatogenesis, facilitating communication among clinicians, researchers and patients to improve reproductive outcomes following hormonal therapy. APHRODITE is proposed as a basis for future trials of the hormonal treatment of male infertility.

Testosterone Replacement Therapy in Orthopaedic Surgery.

Testosterone replacement therapy (TRT) is an indicated treatment of several medical conditions including late-onset hypogonadism, congenital syndromes, and gender affirmation hormonal therapy. Increasing population age, medical benefits, and public awareness of TRT have resulted in increased prevalence of its utilization. However, TRT is not without concern for adverse risks including venous thromboembolic complications, cardiovascular events, and prostate issues. In the field of orthopaedic surgery, research is beginning to delineate the complex relationship between TRT and the development of orthopaedic conditions and potential effects on surgical interventions and outcomes. In this review, we discuss current literature surrounding TRT and subsequent development of osteoarthritis, incidence of total joint arthroplasty, musculotendinous pathology, postoperative infection risk, improvements in postoperative rehabilitation metrics, enhancement of osseous healing, and increased bone-implant integration. The authors suggest future areas of investigation that may provide guidance on how surgeons can mitigate adverse risks while optimizing benefits of TRT in the orthopaedic patient.

An updated systematic review and meta-analysis of the effects of testosterone replacement therapy on erectile function and prostate.

Introduction: Testosterone replacement therapy (TRT) is a generally accepted method treating for aging-related late-onset hypogonadism (LOH). However, the efficacy and safety of TRT remain controversial. An updated systematic review and meta-analysis aimed to determine the effectiveness and security of TRT treating for LOH. Methods: Randomized controlled trials (RCTs) of TRT for LOH were searched in the databases of Pubmed, Embase, Clinicaltrials.gov and Cochrane from 1990 to 2023 and an updated meta-analysis was conducted. Results: The results of 28 RCTs involving 3461 patients were included and scrutinized in this analysis. Among these, 11 RCTs were of long-term duration (≥12 months), while 18 RCTs were short-term studies (<12 months) comparing TRT with a placebo. TRT modalities comprised injection, oral administration, and transdermal administration. International Index of Erectile Function (IIEF) (Weighted Mean difference (WMD) 3.26; 95%; 95% confidence interval (CI) 1.65-4.88; P<0.0001) was obviously improved in the TRT group. International Prostate Symptom Score (IPSS) (WMD 0.00; 95% CI -0.45-0.45; P=1.0), Prostate Volume (PV) (WMD 0.38; 95% CI -0.64-1.41; P=0.46), Maximum Flow Rate (Qmax) (WMD 1.86; 95% CI -0.98-4.69; P=0.20), Postvoid Residual Urine Volume (PVR) (WMD 3.20; 95% CI -5.87-12.28; P=0.49) and Prostate-Specific Antigen (PSA) (WMD 0.08; 95% CI -0.00-0.17; P=0.06) were not significantly statistical between two groups. Conclusion: This meta-analysis reveals that TRT could improve the IIEF score of hypogonadal men without detriment to the IPSS score, PV, Qmax, PVR and PSA regardless of the administration method or duration of treatment.The meta-analysis was registered at PROSPERO (CRD42023413434).

Treatment Options for Male Hypogonadism.

Male hypogonadism is a common condition widely associated with the aging process. Understanding of this condition is continuing to grow as new information is available. Pharmacists are in a very unique position to work with patients and physicians in achieving better diagnosis and treatment plans for the hundreds of thousands of men in the U.S. who are hypogonadal. This article discusses various methods that can be employed to restore testosterone in men and the varying expectations associated with each treatment method.

Hormone Treatment Options for Males: What to do for Men with Low Testosterone.

Male hypogonadism is a condition that is receiving increasing medical scrutiny, resulting in research producing results favorable to the consideration of maintaining physiological levels of testosterone. As healthcare professionals interested in the health and welfare of a significant portion of the population, surely compounding pharmacists are interested in what can be done for men with this condition to help these patients improve their quality of life and long-term health. This article discusses the various ways that men's testosterone levels can be raised and provides insight into the importance of androgen-estrogen balance.

Advocating hormonal treatment to prevent adult in-fertility in patients diagnosed with congenital un-descended testes.

In 2007 the Nordic group came to the following unanimous conclusions: In general, hormonal treatment is not recommended, considering the poor immediate results and the possible long-term adverse effects on spermatogenesis. Thus, surgery is to be preferred. However, defective mini puberty inducing insufficient gonadotropin secretion is one of the most common causes of nonobstructive azoospermia in men suffering from congenital isolated unilateral or bilateral cryptorchidism. The extent of alteration in the unilateral undescended testis correlate with the contralateral descended testis, indicating that unilateral cryptorchidism is a bilateral disease. Idiopathic central hypogonadism explains the phenomenon of defective mini puberty in otherwise healthy cryptorchid boys. We therefore recommend hormonal treatment for cryptorchid boys with defective mini puberty. Gonadotropin releasing hormone agonist (GnRHa) treatment following surgery to correct cryptorchidism restores mini puberty via endocrinological and transcriptional effects and prevents adult infertility in most cases. Several genes are important for central hypogonadotropic hypogonadism in mammals, including many that are transcribed in both the brain and testis. At the molecular level, there is no convincing evidence that heat shock is responsible for the observed pathological testicular changes. Thus, impaired transformation of gonocytes is not the result of temperature stress but rather a hormonal imbalance. Cryptorchidism should therefore be considered a serious andrological problem that cannot be successfully treated by early orchidopexy alone.