Disrupted puberty in males may result from self-limiting constitutional delay of growth and puberty (CDGP) or abiding hypogonadism (ie, congenital hypogonadotropic hypogonadism, CHH). This article provides an overview of normal puberty, CDGP, and CHH and synthesizes current evidence on health and wellbeing outcomes. Particular attention is given to the drivers of disparities in outcomes and discussion of future directions to advance the care of males with disrupted puberty.

Testosterone has a pivotal role in spermatogenesis, erectile function, libido and expression of secondary sexual characteristics. The prevalence of symptomatic, laboratory-proven testosterone deficiency increases with age and is often treated with testosterone replacement therapy (TRT). Treatment with exogenous androgens suppresses gonadotropin levels, inhibits endogenous testosterone production and drastically reduces intratesticular testosterone, consequently impairing spermatogenesis. Sperm production often slowly resumes after TRT cessation. However, the rate of recovery shows highly variable kinetics that might complicate family planning. Medical therapies (including aromatase inhibitors and selective oestrogen receptor antagonists) and exogenous gonadotropins (including human chorionic gonadotropin and follicle-stimulating hormone) may be used to preserve or restore spermatogenesis in select populations receiving TRT. Exogenous testosterone is contraindicated in men trying to conceive, but new short-acting formulations, including oral testosterone undecanoate and nasal testosterone gel, might incompletely suppress the hypothalamic-pituitary-gonadal axis and partially preserve spermatogenesis.

To present a summary of the updated 2025 European Association of Urology (EAU) Guidelines on Sexual and Reproductive Health (SRH) on male infertility, providing practical recommendations on the clinical work-up with a focus on diagnosis, treatment and follow-up.

For the 2025 SRH guidelines, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences.

Key recommendations emphasise the importance of a thorough urological assessment of all men seeking medical help for fertility problems to ensure appropriate treatment. The guidelines also stress the clinical relevance of a parallel investigation of the female partner during the diagnostic and management work-up of the infertile couple, to promote shared-decision making in terms of timing and therapeutic strategies. Furthermore, the guidelines recommend to counsel all infertile men and men with abnormal semen parameters on the associated health risks. Key changes in the male infertility guidelines for 2025 include: the addition of two new sections addressing exome sequencing and probiotic treatment; and significant update of the evidence base and recommendations for the diagnostic work-up of male infertility.

This overview of the 2025 SHR guidelines offers valuable insights into the diagnosis, classification, treatment and follow-up of male factor infertility and are designed for effective integration into clinical practice.

Infertility is defined as the inability to conceive after 1 year of unprotected intercourse, affecting approximately 15-20% of couples in Western countries. It is a shared problem within the couple; when the main issue lies with one of the partners, it is preferable to refer to "male factor" or "female factor" infertility rather than simply male or female infertility. Despite male factor infertility accounting for half of all couple infertility cases, the clinical approach to the male partner is not uniformly standardized across international guidelines.

To provide an expert overview, we have comprehensively reviewed and critically analyzed the most up-to-date literature on this sensitive topic, leading to the development of a proposal for tailored assessment of the diagnostic-therapeutic pathway and preventive strategies. The diagnostic approach also considers that infertile men are objectively less healthy than their fertile counterparts of the same age and ethnicity.

This article discusses the diagnostic flow, the classification of male factor infertility, the definition of idiopathic infertility, the involvement of general health, and treatment recommendations, emphasizing follicle-stimulating hormone treatment in selected groups of patients.

We provide expert opinion on current drawbacks and future perspectives in this field, with practical advice for the clinical practice of general practitioners and expert in reproductive medicine.

Hypogonadotropic hypogonadism (HH) represents a relatively rare cause of nonobstructive azoospermia (NOA), but its knowledge is crucial for the clinical andrologists, as it represents a condition that can be corrected with medical therapy in 3 quarters of cases. There are forms of congenital HH, whether or not associated with an absent sense of smell (anosmic HH or Kallmann syndrome, and normosmic HH, respectively), and forms of acquired HH. In congenital HH, complete absence of pubertal development is characteristic. On the other hand, if the deficit occurs after the time of pubertal development, as in acquired HH patients, infertility and typical symptoms of late-onset hypogonadism are the main reasons for seeking medical assistance. Gonadotropin-releasing hormone (GnRH) or gonadotropin replacement therapy is the mainstay of drug therapy and offers excellent results, although a small but significant proportion of patients do not achieve sufficient responses.

To evaluate whether there was a difference in outcome between pulsatile gonadotropin releasing hormone (GnRH) therapy and human chorionic gonadotropin/human menopausal gonadotropin (hCG/HMG) therapy for induction of spermatogenesis in post-pubertal male patients with congenital hypogonadotropic hypogonadism (CHH).

This was a single-center retrospective cohort study conducted at the Andrology Center of a university hospital. A total of 155 postpubertal CHH patients who met the inclusion criteria underwent spermatogenic induction at the same andrology center. All patients used pulsatile GnRH therapy or hCG/HMG therapy for at least 6 months. The effects of spermatogenic induction therapy and testicular growth were evaluated. Logistic regression analysis was used to identify statistically significant factors which could predict the outcome of treatment.

There was no difference in the efficiency of successfully inducing spermatogenesis between pulsatile GnRH therapy and hCG/HMG therapy (82.1% vs. 75.8%, P: 0.356), nor was there a difference in sperm concentration category (SCC) (P: 0.284). However, the mean time required for pulsatile GnRH therapy was shorter (12.34 vs. 14.74 months, P: 0.038). At the treatment endpoint, total testicular volume (TTV) was greater with pulsatile GnRH therapy compared with hCG/HMG therapy (15 vs. 12 ml, P: 0.010), and there was still no difference in SCC (P: 0.310). Multivariate logistic regression analysis showed that only baseline TTV was statistically significant predictor of induced spermatogenic success (odds ratio, OR: 1.156, 95% confidence interval, CI: 1.013, 1.319). The area under receiver operating characteristic curve was 0.635, a sensitivity of 0.661, and a specificity of 0.588. In addition, multiple linear regression analysis demonstrated that younger age at treatment initiation and higher baseline TTV were significantly associated with increased sperm concentration at the end of treatment.

Pulsatile GnRH therapy was similar to hCG/HMG therapy in inducing spermatogenesis in post-pubertal CHH patients, but it took less time and was more beneficial to testicular development. Larger baseline TTV may mean a better spermatogenic outcome. It was necessary for patients to have more information about spermatogenesis therapy in order to make reasonable medical decisions.

Chinese Clinical Trial Registry. ChiCTR2400086876. Retrospectively registered on July 5, 2024.

Hypogonadotropic hypogonadism (HH) is a treatable cause of nonobstructive azoospermic male infertility. Gonadotropin treatment can successfully induce spermatogenesis in most patients, although comprehensive quantitative summary data on spermatogenic outcomes like those required to induce pregnancy is lacking in the literature.

Systematic review and meta-analysis of outcomes related to male reproductive function following gonadotropin treatment.

Our search strategy identified 41 studies encompassing 1673 patients with a mean age of 25 (± 5) years. Average sperm concentration achieved after a median of 18 months of gonadotropin treatment was 11.6 M/mL of ejaculate (95% CI 8.4-14.9). Sperm concentrations > 0, > 1, > 5, > 10 and > 20 M/mL were achieved by 78%, 55%, 36%, 24% and 15% of patients, respectively. Mean sperm output and the proportion of patients achieving all sperm thresholds were significantly greater following combined hCG/FSH treatment compared with hCG monotherapy. When compared by diagnosis, patients with congenital HH (CHH) had significantly lower mean sperm output compared with patients with hypopituitarism or mixed patient cohorts that did not differentiate between CHH and hypopituitarism. Treatment-related increases in testosterone and testicular volume (TV) were not different between hCG and combined hCG/FSH treated patients, although increases in TV were lower in men with CHH compared with those with hypopituitarism.

Gonadotropin treatment successfully induced spermatogenesis in most men with pathological gonadotropin deficiency. Sperm outputs more consistent with those typically needed to induce a natural pregnancy were less commonly achieved. Despite similar effects on serum testosterone and TV, combined hCG/FSH appeared more efficacious than hCG alone at inducing spermatogenesis.

Male hypogonadism is a clinical syndrome that results in low testosterone levels and frequently leads to infertility. The syndrome occurs due to disruption at one or more levels of the hypothalamic-pituitary-gonadal axis. Testosterone replacement therapy (TRT) is the most common treatment utilised for male hypogonadism. However, long-acting forms of TRT leads to infertility and so is inappropriate for patients wishing to conceive. For patients who wish to remain fertile, nasal TRT, clomiphene citrate, exogenous gonadotropins, gonadotropin releasing hormone and aromatase inhibitors have been used as alternative treatment options with different degrees of success. A review of the literature was performed to identify the safety and efficacy of alternative treatment options. Gonadotropin releasing hormone can successfully induce spermatogenesis but is impractical to administer. Likewise, aromatase inhibitors have limited use due to inducing osteopenia. Nasal TRT may be a good treatment option for these patients, but its efficacy has so far only been demonstrated in small sample sizes. However, clomiphene citrate and exogenous gonadotropins are safe, offer good symptom control and can successfully induce fertility in hypogonadism patients.

Kallmann syndrome is a genetic disorder characterized by delayed or absence of puberty and a reduced or absent sense of smell (anosmia). Kallmann syndrome is a form of hypogonadotropic hypogonadism due to lack of the production of sex hormones which is associated with development of secondary sexual characteristics. Kallmann Syndrome is a genetically heterogeneous disorder, characterized by the combination of hypogonadotropic hypogonadism (a deficiency in sex hormone production) and anosmia. Germline mutations in KAL1 gene causes deficiency in GnRH hormone followed by low level of circulating gonadotropin and testosterone which finally leads to the failure of puberty (development of secondary sexual characters). Kallmann Syndrome can be inherited in several manners including X-linked recessive (e.g., mutations within KAL1) and autosomal dominant and recessive forms. Germline mutation in KAL1 gene was identified among 8% of patients with Kallmann Syndrome. A review of the recent literature done reveals numerous clinical manifestations in Kallmann Syndrome patients with the KAL1 mutation, including microgenitalia, impotence, reduced libido, infertility, unilateral renal agenesis, and synkinesia. Genetic molecular diagnostics through prenatal diagnosis and preimplantation genetic testing are most significant way to reduce the risk of Kallmann syndrome in next generation. Complication associated with Kallmann syndrome can be prevented by early diagnosis, diet supplementation and medical therapy. Goal of therapeutic intervention is to the development of secondary sexual characteristics, build and sustain bone density as well as muscle mass and restore fertility. This review aims to explore the genetic diagnosis and management strategies for Kallmann Syndrome, particularly focusing on KAL1 gene mutations.

Background: Male patients with congenital hypogonadotropic hypogonadism (CHH) have impaired postnatal activation of the hypothalamic-pituitary-gonadal axis that occurs during mini-puberty. The aim of this study was to report our experience using gonadotropin replacement therapy for mini-puberty in male infants with CHH and to establish treatment recommendations. Methods: The patients included in this retrospective case series (n = 9) were diagnosed in the postnatal period due to micropenis, with two being accompanied by cryptorchidism and four with other associated hormonal deficits. All patients started treatment with gonadotropins early after diagnosis, between 2 weeks and 5 months of age, with a schedule of discontinuous injections with subcutaneous human chorionic gonadotropin (62.5-500 IU) two times per week and recombinant follicle-stimulating hormone-alpha (37.5-75 IU) three times per week. Results: The data from our study show an early response, ranging from almost undetectable levels of testosterone at diagnosis to elevated levels after starting treatment, as well as a positive clinical response with increases in testicular volume and penis size in all cases without requiring complementary treatment with testosterone esters and without adverse effects. Conclusions: Our results show that gonadotropin replacement therapy is a well-tolerated and effective treatment for testicular and penile problems in male patients with CHH.

Several studies have reported an increasing occurrence of poly- and perfluorinated alkyl substances (PFASs) in Arctic wildlife tissues, raising concerns due to their resistance to degradation. While some research has explored PFAS's physiological effects on birds, their impact on reproductive functions, particularly sperm quality, remains underexplored. This study aims to assess (1) potential association between PFAS concentrations in blood and sperm quality in black-legged kittiwakes (Rissa tridactyla), focusing on the percentage of abnormal spermatozoa, sperm velocity, percentage of sperm motility, and morphology; and (2) examine the association of plasma levels of testosterone, corticosterone, and luteinizing hormone with both PFAS concentrations and sperm quality parameters to assess possible endocrine disrupting pathways. Our findings reveal a positive correlation between the concentration of longer-chain perfluoroalkyl carboxylates (PFCA; C11-C14) in blood and the percentage of abnormal sperm in kittiwakes. Additionally, we observed that two other PFAS (i.e., PFOSlin and PFNA), distinct from those associated with sperm abnormalities, were positively correlated with the stress hormone corticosterone. These findings emphasize the potentially harmful substance-specific effects of long-chain PFCAs on seabirds and the need for further research into the impact of pollutants on sperm quality as a potential additional detrimental effect on birds.

Teleost testis development during the annual cycle involves dramatic changes in cellular compositions and molecular events. In this study, the testicular cells derived from adult black rockfish at distinct stages - regressed, regenerating and differentiating - were meticulously dissected via single-cell transcriptome sequencing. A continuous developmental trajectory of spermatogenic cells, from spermatogonia to spermatids, was delineated, elucidating the molecular events involved in spermatogenesis. Subsequently, the dynamic regulation of gene expression associated with spermatogonia proliferation and differentiation was observed across spermatogonia subgroups and developmental stages. A bioenergetic transition from glycolysis to mitochondrial respiration of spermatogonia during the annual developmental cycle was demonstrated, and a deeper level of heterogeneity and molecular characteristics was revealed by re-clustering analysis. Additionally, the developmental trajectory of Sertoli cells was delineated, alongside the divergence of Leydig cells and macrophages. Moreover, the interaction network between testicular micro-environment somatic cells and spermatogenic cells was established. Overall, our study provides detailed information on both germ and somatic cells within teleost testes during the annual reproductive cycle, which lays the foundation for spermatogenesis regulation and germplasm preservation of endangered species.

There is a lack of pooled data exploring the time and rates for human chorionic gonadotropin (hCG) monotherapy vs. combination therapies (hCG+human menopausal gonadotropin or recombinant human follicle-stimulating hormone) to restore spermatogenesis in azoospermic men with congenital hypogonadotropic hypogonadism (CHH). We aimed to investigate the time and rates to recover spermatogenesis among azoospermic CHH men receiving monotherapy vs. combination therapy.

We conducted a systematic review and meta-analysis following the PRISMA guidelines. The search was performed on PubMed, EMBASE, Web of Science, and Scopus databases up to November 2023. Forrest plots were generated to visually present the pooled effect sizes for time to recover spermatogenesis, specifically employing the standardized mean difference (SMD). Publication bias was assessed utilizing funnel plots. PROSPERO ID: CRD42023473615.

The search identified 720 studies meeting inclusion criteria. Our meta-analysis of 1,240 men with CHH revealed significant differences in the time to recover spermatogenesis between combination therapies and monotherapy. The weighted mean recovery time was significantly shorter for combination therapies (10 months) compared to monotherapy (33 months). The SMD under the common effect model was 8.8 for combination therapies and 24.98 for monotherapy, indicating a more rapid recovery with combination therapies, p<0.01. The rates of sperm recovery were 66.76% for combination therapies and 51.9% for monotherapy, p=0.03. Significant heterogeneity was observed in both groups (I²=86% for combination therapies and I²=68% for monotherapy), suggesting considerable variation in individual responses.

The present meta-analysis reveals that in men with CHH, combination therapies expedite spermatogenesis recovery more than monotherapy. Additionally, combination therapies yield a higher rate of sperm appearing in the ejaculate as compared to hCG monotherapy. The significant heterogeneity observed in both groups underscores the variability in individual responses, warranting further investigation and caution in interpreting these results.

In male congenital hypogonadotropic hypogonadism (CHH), it was observed that lower dose human gonadotropic hormone (hCG) can maintain normal intratesticular testosterone levels. We propose this study to compare the low-dose hCG, follicle stimulating hormone (FSH), and Testosterone (T) [LFT Regimen] to conventional treatment to induce virilization and fertility.

This open-label randomized pilot study was conducted from June 2020 to December 2021.

CHH were randomly assigned to either the LFT regimen (Group A)-low-dose hCG (500U thrice per week), FSH (150U thrice per week), and T(100 mg biweekly) or conventional therapy(GroupB) with high hCG dose(2000U thrice per week) and the same FSH dose. The hCG dosage was titrated to reduce anti-mullerian hormone (AMH) by 50% and normalization of plasma T in groups A and B, respectively. The primary objective was to compare the percentage of individuals who achieved spermatogenesis between the two groups.

Out of 30 patients, 23 (76·7%) subjects achieved spermatogenesis, and the median time was 12 (9-14·9) months. There was no difference in achieving spermatogenesis between the two groups (64·3% vs 7·5%,P = 0·204), and even the median time for spermatogenesis was similar (15months vs 12months,P = 0·248). Both groups had nonsignificant median plasma AMH at spermatogenesis, [6·6 ng/ml (3·3-9·76) vs4·41 ng/ml (2·3-6·47), P = 0·298]. Similarly, the median plasma Inhibin B at spermatogenesis between groups were comparable [152·4 pg/ml (101·7-198·0) vs49·1 pg/ml (128·7-237·3), P = 0·488].

A reasonable approach to induce fertility in male CHH is to initiate combination therapy using FSH, low-dose hCG targeting AMH <6·9 ng/ml, along with T to achieve normal range. Monitoring AMH could serve as a proxy indicator of spermatogenesis.

Hypogonadotropic hypogonadism can be caused by brain tumors. For a malignancy such as a germ cell tumor, chemotherapy combined with radiation is administered. In patients who wish for children, the inability to undergo sperm cryopreservation before treatment because of impaired spermatogenesis and/or ejaculation dysfunction can be problematic. We herein present two cases involving a 26-year-old man and a 30-year-old man with hypogonadotropic hypogonadism due to an intracranial germinoma and both wished to have children. Gonadotropin replacement therapy prior to anticancer chemotherapy resulted in subsequent spontaneous pregnancy or assisted reproductive therapy. Subsequent treatment of the tumor resulted in no recurrence for 9 and 2 years, respectively. Close consultation with an oncologist is mandatory in such cases. Depending on the tumor prognosis, however, it may be possible to delay tumor treatment and prioritize fertility because there is a possibility of impaired spermatogenesis due to additional chemotherapy.

Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive disorder caused by deficient secretion or action of gonadotropin-releasing hormone (GnRH) and is a hormonally treatable form of male infertility. Both pulsatile GnRH treatment and combined gonadotropin therapy effectively induce spermatogenesis in 75%-80% of males with CHH, albeit the ejaculate does not usually approach normal semen parameters by WHO criteria. This is in some contrast to the cumulative fertility outcomes in females with CHH on gonadotropin treatment that are indistinguishable from those of reproductively normal females. Emerging data provide insights into early life determinants of male fertility (i.e., minipuberty), and research has identified key predictors of outcomes for fertility-inducing treatment in men with CHH. Such developments provide mounting evidence for tailoring approaches to maximize fertility potential in CHH, although there is no clear consensus to date on the optimal approach to fertility-inducing treatment. This review provides an up-to-date review on the current evidence underpinning therapeutic approaches for inducing spermatogenesis in males with CHH. In the absence of evidence-based clinical guidelines, this synthesis of current evidence provides guidance for clinicians working with males with CHH seeking fertility.

Male infertility is a prevalent issue impacting numerous couples worldwide. This review aims to evaluate the effectiveness of empirical therapies for male infertility, focusing on both lifestyle modifications and medical treatments. This study provides a comprehensive overview of interventions aimed at improving male fertility outcomes.

A thorough review of the existing literature was conducted, encompassing studies on lifestyle changes such as dietary changes, smoking cessation, alcohol moderation, and exercise. Additionally, medical treatments including selective estrogen receptor modulators, gonadotropins, aromatase inhibitors, phosphodiesterase-5 inhibitors, antioxidants, dopamine agonists, kallikrein, indomethacin, low-dose corticosteroids, alpha-blockers, and nitric oxide donors were evaluated. The study population included males diagnosed with infertility, focusing on various underlying causes.

Lifestyle modifications were found to have a positive impact on sperm quality. Evidence shows that a healthy diet, smoking cessation, moderate alcohol consumption, and regular exercise improve fertility outcomes. Medical treatments demonstrated significant improvements in sperm production and quality. Selective estrogen receptor modulators and gonadotropins enhanced sperm parameters. Aromatase inhibitors and phosphodiesterase-5 inhibitors specifically improved sperm motility and increased pregnancy rates. Antioxidants, such as vitamins E and C and coenzyme Q10, reduced oxidative stress and enhanced sperm counts, motility, and morphology. Dopamine agonists, particularly cabergoline, normalized prolactin levels and improved fertility outcomes. Kallikrein therapy improved sperm parameters and increased pregnancy rates. Indomethacin treatment was associated with increased sperm concentrations and motility. Low-dose corticosteroids and alpha-blockers showed variable results, and nitric oxide donors like L-arginine enhanced sperm counts and motility.

Empirical therapies, including lifestyle modifications and medical treatments, significantly enhance sperm quality and reproductive potential. These integrated approaches are essential in improving fertility outcomes in males. However, further extensive randomized trials are necessary to definitively establish the most effective treatments.

There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.

Pituitary deficiency, or hypopituitarism, is a rare chronic disease. It is defined by insufficient synthesis of one or more pituitary hormones (growth hormone, TSH, ACTH, LH-FSH, prolactin), whether or not associated with arginine vasopressin deficiency (formerly known as diabetes insipidus). In adult patients, it is usually acquired (notably during childhood), but can also be congenital, due to abnormal pituitary development. The present study focuses on congenital pituitary deficiency in adults, from diagnosis to follow-up, including special situations such as pregnancy or the elderly. The clinical presentation is highly variable, ranging from isolated deficit to multiple deficits, which may be part of a syndromic form or not. Diagnosis is based on a combination of clinical, biological (assessment of all hormonal axes), radiological (brain and hypothalamic-pituitary MRI) and genetic factors. Treatment consists in hormonal replacement therapy, adapted according to the period of life and the deficits, which may be progressive. Comorbidities, risk of complications and acute decompensation, and the impact on fertility and quality of life all require adaptative multidisciplinary care and long-term monitoring.

Fibroblast growth factor receptor 1 ( FGFR1 ) mutations are associated with congenital hypogonadotropic hypogonadism (CHH) through inheritance or spontaneous occurrence. We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital (Beijing, China) using next-generation and Sanger sequencing. We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups. Among 19 patients with FGFR1 mutations, three were recurrent, and 16 were novel variants. Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with the prevalent P366L variant. The majority of FGFR1 mutations was inherited (57.9%), with frameshift mutations exclusive to the de novo mutation group. The inherited mutation group had a lower incidence of cryptorchidism, short stature, and skeletal deformities. In the inherited mutation group, luteinizing hormone (LH) levels were 0.5 IU l -1 , follicle-stimulating hormone (FSH) levels were 1.0 IU l -1 , and testosterone levels were 1.3 nmol l -1 . In contrast, the de novo group had LH levels of 0.2 IU l -1 , FSH levels of 0.5 IU l -1 , and testosterone levels of 0.9 nmol l -1 , indicating milder hypothalamus-pituitary-gonadal axis (HPGA) functional deficiency in the inherited group. The inherited mutation group showed a tendency toward higher spermatogenesis rates. In conclusion, this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations, contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations.

Hemochromatosis (HC) is characterized by the progressive accumulation of iron in the body, resulting in organ damage. Endocrine complications are particularly common, especially when the condition manifests in childhood or adolescence, when HC can adversely affect linear growth or pubertal development, with significant repercussions on quality of life even into adulthood. Therefore, a timely and accurate diagnosis of these disorders is mandatory, but sometimes complex for hematologists without endocrinological support. This is a narrative review focused on puberty and growth disorders during infancy and adolescence aiming to offer guidance for diagnosis, treatment, and proper follow-up. Additionally, it aims to highlight gaps in the existing literature and emphasizes the importance of collaboration among specialists, which is essential in the era of precision medicine.

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism (MOSH) with emerging evidence on the role of testosterone therapy. We aim to provide an updated and practical approach towards its management. We did a comprehensive literature search across MEDLINE (via PubMed), Scopus, and Google Scholar databases using the keywords "MOSH" OR "Obesity-related hypogonadism" OR "Testosterone replacement therapy" OR "Selective estrogen receptor modulator" OR "SERM" OR "Guidelines on male hypogonadism" as well as a manual search of references within the articles. A narrative review based on available evidence, recommendations and their practical implications was done. Although weight loss is the ideal therapeutic strategy for patients with MOSH, achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice. Therefore, androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity. However, there is conflicting evidence for the appropriate use of testosterone replacement therapy (TRT), and it can also be associated with complications. This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH. Before starting testosterone replacement in functional hypogonadism of obesity, it would be desirable to initiate lifestyle modification to ensure weight reduction. TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients. Balancing the risks and benefits of TRT should be considered in every patient before and during long-term management.

Managing patients unable to produce sex steroids using gonadotropins to mimic minipuberty in hypogonadotropic hypogonadism, or sex steroids in patients with Klinefelter or Turner syndrome, is promising. There is a need to pursue research in this area, with large prospective cohorts and long-term data before these treatments can be routinely considered.

Both pulsatile gonadotropin-releasing hormone (GnRH) and combined gonadotropin therapy are effective to induce spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). This study aimed to evaluate the effect of pulsatile GnRH therapy on spermatogenesis in male patients with CHH who had poor response to combined gonadotropin therapy.

Patients who had poor response to combined gonadotropin therapy ≥ 6 months were recruited and shifted to pulsatile GnRH therapy. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, testosterone, and testicular volume were used for data analysis.

A total of 28 CHH patients who had poor response to combined gonadotropin (HCG/HMG) therapy for 12.5 (6.0, 17.75) months were recruited and switched to pulsatile GnRH therapy for 10.0 (7.25, 16.0) months. Sperm was detected in 17/28 patients (60.7%). The mean time for the appearance of sperm in semen was 12.0 (7.5, 17.5) months. Compared to those who could not achieve spermatogenesis during pulsatile GnRH therapy, the successful group had a higher level of LH60min (4.32 vs. 1.10 IU/L, P = 0.043) and FSH60min (4.28 vs. 1.90 IU/L, P = 0.021). Testicular size increased during pulsatile GnRH therapy, compared to previous HCG/ HMG therapy (P < 0.05).

For CHH patients with prior poor response to one year of HCG/ HMG therapy, switching to pulsatile GnRH therapy may induce spermatogenesis.

To evaluate total testosterone distribution in male idiopathic infertility.

A retrospective, real-world case-control clinical study was conducted. Cases consisted of men evaluated for couple infertility, specifically those with alterations in semen parameters and normal gonadotropin levels, and after excluding all known causes of male infertility. Controls were male subjects who underwent semen analysis for screening purposes, without any abnormality detected. The total testosterone distribution was evaluated in cases and controls. Further analyses were performed subgrouping cases according to total testosterone reference threshold suggested by scientific societies (i.e., 3.5 ng/mL).

Cases included 214 idiopathic infertile men (mean age 38.2 ± 6.2 years) and controls 224 subjects with normozoospermia (mean age 33.7 ± 7.5 years). Total testosterone was not-normally distributed in both cases and controls, with positive asymmetric distribution slightly shifted on the left in cases. The rate of subjects with testosterone lower than 3.5 ng/mL was higher in cases (23.8%) than controls (4.5%) (p < 0.001). In cases with testosterone lower than 3.5 ng/mL, a significant direct correlation between testosterone and the percentage of normal morphology sperms was highlighted, also applying multivariate stepwise linear regression analysis (R = 0.430, standard error = 0.3, p = 0.020).

Although idiopathic infertile men show by definition altered semen analysis and gonadotropins within reference ranges, testosterone serum levels are widely variable in this population. Approximately a quarter of these patients present some sort of functional hypogonadism. Our data support the need to better classify idiopathic male infertility and total testosterone serum levels could be a supportive parameter in tracing the patient's therapeutic profile.

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.

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.

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).

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.

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.

For the Italian translation of the abstract see Supplementary Materials section.

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?

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.

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.

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.

Selective oestrogen receptor modulators and aromatase inhibitors stimulate endogenous gonadotrophins and testosterone in men with hypogonadism. There are no systematic reviews/meta-analyses assessing the effects of selective oestrogen receptor modulators/aromatase inhibitors on semen parameters in men with secondary hypogonadism.

To assess the effect of monotherapy or a combination of selective oestrogen receptor modulators/aromatase inhibitors on sperm parameters and/or fertility in men with secondary hypogonadism.

A systematic search was conducted in PubMed, MEDLINE, Cochrane Library and ClinicalTrials.gov. Study selection and data extraction were performed by two reviewers independently. Randomised controlled trials and non-randomised studies of interventions reporting effects of selective oestrogen receptor modulators and/or aromatase inhibitors on semen parameters or fertility in men with low testosterone with low/normal gonadotrophins were selected. The risk of bias was assessed using ROB-2 and ROBINS-I tools. The results of randomised controlled trials were summarised using vote counting while summarising effect estimates where available. Non-randomised studies of intervention meta-analysis were conducted using the random-effect model. The certainty of evidence was assessed using GRADE.

Five non-randomised studies of interventions (n = 105) of selective oestrogen receptor modulators showed an increase in sperm concentration (pooled mean difference 6.64 million/mL; 95% confidence interval 1.54, 11.74, I2  = 0%) and three non-randomised studies of interventions (n = 83) of selective oestrogen receptor modulators showed an increase in total motile sperm count (pooled mean difference 10.52; 95% confidence interval 1.46-19.59, I2  = 0%), with very low certainty of evidence. The mean body mass index of participants was >30 kg/m2 . Four randomised controlled trials (n = 591) comparing selective oestrogen receptor modulators to placebo showed a heterogeneous effect on sperm concentration. Three included men with overweight or obesity. The results were of very low certainty of evidence. Limited pregnancy or live birth data were available. No studies comparing aromatase inhibitors with placebo or testosterone were found.

Current studies are of limited size and quality but suggest that selective oestrogen receptor modulators may improve semen parameters in those patients, particularly when associated with obesity.

To compare the effects of combined gonadotropin and pulsatile gonadotropin-releasing hormone (GnRH) therapy on spermatogenesis in patients with pituitary stalk interruption syndrome (PSIS).

Male patients with PSIS (N = 119) were retrospectively studied. Patients received pulsatile GnRH therapy (N = 59) were divided into response and poor-response groups based on luteinizing hormone (LH) levels after 1-month treatment with a cutoff value of 1 or 2 IU/L. Participants with gonadotropin therapy were divided into human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) group (N = 60), and patients with pulsatile GnRH therapy were classified into GnRH group (N = 28) with treatment duration ≥6 months.

The overall success rates of spermatogenesis for hMG/hCG and GnRH therapy were 51.67% (31/60) vs 33.90% (20/59), respectively. GnRH group required a shorter period to induce spermatogenesis (8 vs 15 months, P = .019). hMG/hCG group had higher median total testosterone than GnRH group [2.16, interquartile range(IQR) 1.06-4.89 vs 1.31, IQR 0.21-2.26 ng/mL, P = .004]. GnRH therapy had a beneficial effect on spermatogenesis compared to hMG/hCG therapy (hazard ratio 1.97, 95% confidence interval 1.08-3.57, P = .026). In patients with pulsatile GnRH therapy, compared with the poor-response group, the response group had a higher successful spermatogenesis rate (5.00% vs 48.72%, P = .002) and higher median basal total testosterone (0.00, IQR 0.00-0.03 vs 0.04, IQR 0.00-0.16 ng/mL, P = .026) with LH = 1 IU/L as the cutoff value after 1-month pulsatile GnRH therapy.

Pulsatile GnRH therapy was superior to hMG/hCG therapy for spermatogenesis in patients with PSIS. Earlier spermatogenesis and higher concentrations of sperm could be obtained in the GnRH group if patients received therapy over 6 months.

Currently, most men with infertility cannot be given an aetiology, which reflects a lack of knowledge around gamete production and how it is affected by genetics and the environment. A failure to recognize the burden of male infertility and its potential as a biomarker for systemic illness exists. The absence of such knowledge results in patients generally being treated as a uniform group, for whom the strategy is to bypass the causality using medically assisted reproduction (MAR) techniques. In doing so, opportunities to prevent co-morbidity are missed and the burden of MAR is shifted to the woman. To advance understanding of men's reproductive health, longitudinal and multi-national centres for data and sample collection are essential. Such programmes must enable an integrated view of the consequences of genetics, epigenetics and environmental factors on fertility and offspring health. Definition and possible amelioration of the consequences of MAR for conceived children are needed. Inherent in this statement is the necessity to promote fertility restoration and/or use the least invasive MAR strategy available. To achieve this aim, protocols must be rigorously tested and the move towards personalized medicine encouraged. Equally, education of the public, governments and clinicians on the frequency and consequences of infertility is needed. Health options, including male contraceptives, must be expanded, and the opportunities encompassed in such investment understood. The pressing questions related to male reproductive health, spanning the spectrum of andrology are identified in the Expert Recommendation.

Hypogonadotropic hypogonadism is characterized by inadequate secretion of pituitary gonadotropins, leading to absent, partial, or arrested puberty. In males, classical treatment with testosterone promotes virilization but not testicular growth or spermatogenesis. To quantify treatment practices and efficacy, we systematically reviewed all studies investigating gonadotropins for the achievement of pubertal outcomes in males with hypogonadotropic hypogonadism.

Systematic review and meta-analysis.

A systematic review of Medline, Embase, Global Health, and PsycINFO databases in December 2022. Risk of Bias 2.0/Risk Of Bias In Non-randomized Studies of Interventions/National Heart, Lung, and Blood Institute tools for quality appraisal. Protocol registered on PROSPERO (CRD42022381713).

After screening 3925 abstracts, 103 studies were identified including 5328 patients from 21 countries. The average age of participants was <25 years in 45.6% (n = 47) of studies. Studies utilized human chorionic gonadotropin (hCG) (n = 93, 90.3% of studies), human menopausal gonadotropin (n = 42, 40.8%), follicle-stimulating hormone (FSH) (n = 37, 35.9%), and gonadotropin-releasing hormone (28.2% n = 29). The median reported duration of treatment/follow-up was 18 months (interquartile range 10.5-24 months). Gonadotropins induced significant increases in testicular volume, penile size, and testosterone in over 98% of analyses. Spermatogenesis rates were higher with hCG + FSH (86%, 95% confidence interval [CI] 82%-91%) as compared with hCG alone (40%, 95% CI 25%-56%). However, study heterogeneity and treatment variability were high.

This systematic review provides convincing evidence of the efficacy of gonadotropins for pubertal induction. However, there remains substantial heterogeneity in treatment choice, dose, duration, and outcomes assessed. Formal guidelines and randomized studies are needed.

Treatments to stimulate spermatogenesis and antioxidant food supplements are often offered to infertile patients either before sperm extraction surgery to improve results, or as part of medically assisted reproduction or spontaneous fertility to increase the likelihood of a live birth.

A bibliographic search limited to English-language literature on men published before 5/2023 was carried out, including clinical trials, literature reviews and meta-analyses on spermatogenesis-stimulating molecules and antioxidant treatments.

Several medical treatments seem capable of improving male fertility: they act mainly by stimulating spermatogenesis through hormones, or by reducing the effects of oxidative stress. With regard to oligoasthenozoospermia, the literature shows that certain hormonal treatments stimulating spermatogenesis are useful. In the case of non-obstructive azoospermia, the value of treatment depends on the patient's FSH and testosterone levels. AOX supplementation appears to improve certain spermogram parameters and have an impact on pregnancy and live birth rates.

This review should help urologists gain a better understanding of the various medical treatments and enable them to define an appropriate therapeutic strategy, tailored to the patient and the couple, in order to obtain the best results.

Although epidemiology shows that both men and woman can experience infertility, the female partner usually experiences most of the diagnostic and therapeutic burden. Thus, management of couple infertility is a unique example of gender inequality. The use of exogenous gonadotropins in assisted reproductive technology (ART) to induce multifollicular growth is well consolidated in women, but the same is not done with the same level of confidence and purpose in infertile men. Indeed, the treatment of idiopathic male infertility is based on an empirical approach that involves administration of the follicle-stimulating hormone (FSH) in dosages within the replacement therapy range. This treatment has so far been attempted when the endogenous FSH serum levels are within the reference ranges. According to the most recent evidence, a "substitutive" FSH administration may not be effective enough, while a stimulatory approach could boost spermatogenesis over its basal levels without adverse extragonadal effects. This article aims to describe the rationale behind the empirical application of gonadotropins in couple infertility, highlighting the need for a change in the therapeutic approach, especially for the male partner.

Oligoasthenozoospermia is becoming a serious problem, but effective prevention or treatment is lacking. Hyperoside, one of the main active ingredients in traditional Chinese medicine, may be effective in the treatment of oligoasthenozoospermia. In this study, we used cyclophosphamide (CTX: 50 mg/kg) to establish a mouse model of Oligoasthenozoospermia to investigate the therapeutic effect of hyperoside (30 mg/kg) on CTX-induced oligoasthenozoospermia. All mice were divided into four groups: blank control group (Control), treatment control group (Hyp), disease group (CTX) and treatment group (CTX + H). Mice body weight, testicular weight, sperm parameters and testicular histology were used to assess the reproductive capacity of mice and to explore the underlying mechanism of hyperoside in the treatment of oligoasthenozoospermia by assessing hormone levels, protein levels of molecules related to hormone synthesis and transcript levels of important genes related to spermatogenesis. Treatment with hyperoside significantly improved sperm density, sperm viability and testicular function compared to untreated oligoasthenozoospermia mice. In mechanism, treatment with hyperoside resulted in significant improvement in pathological changes in spermatogenic tubules, with an increase in testosterone production, and upregulations of Protein Kinase CAMP-Activated Catalytic Subunit Beta (PRKACB), Steroidogenic Acute Regulatory Protein (STAR), and Cytochrome P450 Family 17 Subfamily A Member 1 (CYP17A1) for testosterone production. Hyperoside also promoted the cell cycle of germ cells and up-regulated meiosis and spermatogenesis-related genes, including DNA Meiotic Recombinase 1 (Dmc1), Ataxia telangiectasia mutated (Atm) and RAD21 Cohesin Complex Component (Rad21). In conclusion, hyperoside exerted protective effects on oligoasthenozoospermia mice by regulating testosterone production, meiosis and sperm maturation of germ cells.