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.

[Natural 5α-reductase inhibitors in treatment of benign prostatic hyperplasia].

Benign prostatic hyperplasia(BPH) is a common disease of the male urinary system, and its incidence rate in China is increasing. However, the mechanism underlying the pathogenesis of BPH remains unclear. Some studies demonstrated that the incidence of BPH was related to the change in the levels of steroid hormones. Too high content of dihydrotestosterone(DHT) in the body may cause BPH and other related diseases. Testosterone(T) is converted to DHT by 5α-reductase(SRD5A). By inhibiting the activity of this enzyme, the production of DHT can be reduced, and then the incidence of BPH can be lowered. Therefore, it has drawn great attention to screen and discover safer and more effective 5α-reductase inhibitors from natural medicines to treat prostatic hyperplasia without affecting the physiological function of men. This review summarizes the characteristics and tissue distribution of 5α-reductase, the discovery of 5α-reductase inhibitors in traditional Chinese medicine and natural medicines, 5α-reductase inhibitors commonly used in clinical practice and their side effects, as well as the animal models of prostatic hyperplasia and common detection indicators, aiming to provide a reference for more in-depth understanding and research about BPH and development of drugs.

Penile erection and cardiovascular function: effects and pathophysiology.

Penile erection (PE) is a hemodynamic event that results from a neuroendocrine process, and it is influenced by the cardiovascular status of the patient. However, it may also modulate an individual's cardiovascular events. The present study provides the mechanisms involved in the association of PE and cardiovascular function. Erection upsurges the cardiac rate, blood pressure, and oxygen uptake. Sex-enhancing strategies, such as phosphodiesterase inhibitors, alprostadil, and testosterone also promote vasodilatation and cardiac performance, thus preventing myocardial infarction. More so, drugs that are used in the treatment of hypertensive heart diseases (such as angiotensin system inhibitors and ß-blockers) facilitate vasodilatation and PE. These associations have been linked with nitric oxide- and testosterone-dependent enhancing effects on the vascular endothelium. In addition, impaired cardiovascular function may negatively impact PE; therefore, impaired PE may be a pointer to cardiovascular pathology. Hence, evaluation of the cardiovascular status of an individual with erectile dysfunction (ED) is essential. Also, employing strategies that are used in maintaining optimal cardiac function may be useful in the management of ED.

CLINICAL AND ENDOCRINE ALTERATIONS IN WOMEN WITH POLYCYSTIC OVARY SYNDROME.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder that affects women of reproductive age. Aim - to determine the association between body mass index, hirsutism, acne, and hormonal status with Polycystic ovary syndrome. This cross-sectional study included 55 women with PCOS, between the ages of 18 and 39 who attended the Obstetrics and Gynecology Clinic at the University Clinical Center of Kosovo (UCCK). Body mass index (BMI) was calculated and luteinizing hormone (LH), follicle stimulating hormone (FSH), LH/FSH ratio, testosterone and dehydroepiandrosterone sulfate (DHEA-S) values were determined. All the data were analyzed after the clinic-endocrine profile was assessed. The average age of women with PCOS was 21.36±4.29. Hirsutism and acne were quite conspicuous, as well as testosterone and DHEA-S values. Moreover, women with PCOS had higher values of LH and LH/FSH ratio (8.17±9.66 and 2.86±2.74) but not FSH values (4.16±2.97) that showed a positive correlation with polycystic ovary syndrome. Thus, PCOS is a multifaceted endocrine and metabolic disorder, which needs early recognition and treatment to prevent long-term complications.

Effect of testosterone replacement therapy on scar quality in gender-affirming mastectomies.

BACKGROUND: The term transgenders refer to people who sense discordance between their gender identity and the sex assigned to them at birth. Some transgenders receive hormonal therapy, which may lead to specific skin conditions. The purpose of the present study was to determine whether a causal relationship exists between hormonal therapy (specifically testosterone therapy) and unsatisfying surgical scarring, including hypertrophic and keloid scars. In addition, this study may serve as a basis for future studies, which may test means that aim to reduce such undesired effects. METHODS: In this retrospective, observational cohort study, data were collected regarding 170 patients who underwent mastectomy as a gender-affirming surgery by the senior author between 2003 and 2021. The medical records were analysed to obtain personal, medical (including the duration of testosterone treatment) and surgical information from the patients' medical files. A blinded evaluator assessed the surgical scars by reviewing the postoperative clinical pictures of the patients. The scars were rated using the validated Stony Brook Scar Evaluation Scale (SBSES). The use of pictures to assess surgical scars is described in the validation study of the SBSES and is, therefore, accepted. RESULTS: In total, 63 patients were included in the testosterone group and 63 were included in the non-testosterone treated group. The averages of the SBSES score were 2.74 and 2.66, respectively. The difference between the two averages was not statistically significant. CONCLUSION: In our retrospective cohort study, we did not find the effect of testosterone therapy on post-operative surgical scars to be significant. EVIDENCE BASED MEDICINE (EBM) LEVEL: 3.

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.

One-third of amenorrheic transmasculine people on testosterone ovulate.

Transmasculine people usually reach amenorrhea within 6 months of adequate testosterone treatment. It is often assumed that no ovulation occurs during amenorrhea. However, in this study, we report recent ovulatory activity in amenorrheic transmasculine people on testosterone therapy at gender-affirming oophorectomy. Histological signs of recent ovulatory activity, including the presence of ovulatory follicles, corpus luteum, and corpus albicans, are observed in 17 of 52 individuals (33%). This is not significantly correlated to the duration, testosterone serum levels, or type of testosterone used. These results suggest that amenorrhea does not equal anovulation in transmasculine people on adequate testosterone therapy, emphasizing the importance of contraception for people who engage in sexual activity that can result in pregnancy.

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.

Real-world effectiveness and safety of goserelin 10.8-mg depot in Chinese patients with localized or locally advanced prostate cancer.

OBJECTIVE: Real-word data on long-acting luteinizing hormone-releasing hormone (LHRH) agonists in Chinese patients with prostate cancer are limited. This study aimed to determine the real-world effectiveness and safety of the LHRH agonist, goserelin, particularly the long-acting 10.8-mg depot formulation, and the follow-up patterns among Chinese prostate cancer patients. METHODS: This was a multicenter, prospective, observational study in hormone treatment-naïve patients with localized or locally advanced prostate cancer who were prescribed goserelin 10.8-mg depot every 12 weeks or 3.6-mg depot every 4 weeks with or without an anti-androgen. The patients had follow-up evaluations for 26 weeks. The primary outcome was the effectiveness of goserelin in reducing serum testosterone and prostate-specific antigen (PSA) levels. The secondary outcomes included testosterone and PSA levels, attainment of chemical castration (serum testosterone <50 ng/dL), and goserelin safety. The exploratory outcome was the monitoring pattern for serum testosterone and PSA. All analyses were descriptive. RESULTS: Between September 2017 and December 2019, a total of 294 eligible patients received ≥ 1 dose of goserelin; 287 patients (97.6%) were treated with goserelin 10.8-mg depot. At week 24 ± 2, the changes from baseline [standard deviation (95% confidence interval)] in serum testosterone (n = 99) and PSA (n = 131) were -401.0 ng/dL [308.4 ng/dL (-462.5, -339.5 ng/dL)] and -35.4 ng/mL [104.4 ng/mL (-53.5, -17.4 ng/mL)], respectively. Of 112 evaluable patients, 100 (90.2%) achieved a serum testosterone level < 50 ng/dL. Treatment-emergent adverse events (TEAEs) and severe TEAEs occurred in 37.1% and 10.2% of patients, respectively. The mean testing frequency (standard deviation) was 1.6 (1.5) for testosterone and 2.2 (1.6) for PSA. CONCLUSIONS: Goserelin 10.8-mg depot effectively achieved and maintained castration and was well-tolerated in Chinese patients with localized and locally advanced prostate cancer.

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).