Anticancer Drugs-Related Hypogonadism in Male Patients with Advanced Cancers on Active Treatment: A Systematic Review.

BACKGROUND: In male patients with cancer treated with antineoplastic drug, hypogonadism is a neglected cause of diminished quality of life. This condition may be cancer related as well as toxicity related. The role of antineoplastic drug in causing hypogonadism is poorly understood. The aim of this systematic review was to establish the prevalence, nature (primary/secondary), and impact of hypogonadism on quality of life in male patients with cancer on antineoplastic therapy. METHODS: The search strategy used PubMed, Embase, and Cochrane databases to select articles in English language that described hypogonadism in male patients with cancer. The search period was from January 1, 1945 to February 28, 2023. We included observational studies, case reports or case series and excluded studies concerning hematological malignancies, prostate cancer, female patients, and survivors. FINDINGS: Of 4488 records identified, 28 studies met inclusion criteria (17 observational studies, 11 case reports or case series). Anti-angiogenic drugs and crizotinib were found to have a role in the development of hypogonadism. Patients treated with immune checkpoint-inhibitors developed secondary hypogonadism due to immune-related hypophysitis or orchitis. As for active chemotherapy, platinum salts were often associated with hypogonadism, followed by antimetabolites and taxanes. Selected studies were heterogeneous for populations, interventions, and outcomes assessments. Thus, a generalization is difficult. Moreover, the role of concurrent etiologies cannot be excluded in most studies. CONCLUSION: Our research emphasizes the importance of evaluating the gonadal axis before treatment in patients considered at risk and testing it at regular intervals or in case of clinical suspicion.

Novel perspectives of testosterone therapy in men with functional hypogonadism: traversing the gaps of knowledge.

INTRODUCTION: In the past decade, there has been a significant augmentation in the corpus of evidence pertaining to functional hypogonadism. Despite this, prevailing clinical guidelines continue to advise against the universal screening for hypogonadism in middle-aged and elderly males. FINDINGS: Numerous randomized controlled trials have scrutinized the effects of testosterone therapy in males afflicted with type 2 diabetes and/or obesity. However, these guidelines uniformly assert that lifestyle modifications and weight reduction should be the primary intervention strategies in overweight and obese males, relegating testosterone therapy to a secondary, selective option. It is extensively documented that testosterone therapy can yield substantial improvements in various metabolic parameters as well as ameliorate symptoms of erectile dysfunction. Moreover, recent studies have demonstrated the potential of testosterone therapy in reversing type 2 diabetes in males with low-normal testosterone levels who are at elevated risk for this condition, in comparison to the outcomes achievable through lifestyle modifications alone. CONCLUSION: This focused review article aims to present a comprehensive update on the latest data concerning the innovative aspects of testosterone therapy in males with functional hypogonadism, particularly in the context of type 2 diabetes and/or obesity. Additionally, it will delve into the cardiovascular safety of such interventions within this high-risk demographic, with a special emphasis on insights gleaned from the TRAVERSE trial.

Epigenome editing based on CRISPR/dCas9p300 facilitates transdifferentiation of human fibroblasts into Leydig-like cells.

Recently, Leydig cell (LCs) transplantation has a promising potential to treat male hypogonadism. However, the scarcity of seed cells is the actual barrier impeding the application of LCs transplantation. Utilizing the cutting-edge CRISPR/dCas9VP64 technology, human foreskin fibroblasts (HFFs) were transdifferentiated into Leydig-like cells（iLCs） in previous study, but the efficiency of transdifferentiation is not very satisfactory. Therefore, this study was conducted to further optimize the CRISPR/dCas9 system for obtaining sufficient iLCs. First, the stable CYP11A1-Promoter-GFP-HFFs cell line was established by infecting HFFs with CYP11A1-Promoter-GFP lentiviral vectors, and then co-infected with dCas9p300 and the combination of sgRNAs targeted to NR5A1, GATA4 and DMRT1. Next, this study adopted quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence to determine the efficiency of transdifferentiation, the generation of testosterone, the expression levels of steroidogenic biomarkers. Moreover, we utilized chromatin immuno-precipitation (ChIP) followed by quantitative polymerase chain reaction (ChIP-qPCR) to measure the levels of acetylation of targeted H3K27. The results revealed that advanced dCas9p300 facilitated generation of iLCs. Moreover, the dCas9p300-mediated iLCs significantly expressed the steroidogenic biomarkers and produced more testosterone with or without LH treatment than the dCas9VP64-mediated. Additionally, preferred enrichment in H3K27ac at the promoters was detected only with dCas9p300 treatment. The data provided here imply that the improved version of dCas9 can aid in the harvesting of iLCs, and will provide sufficient seed cells for cell transplantation treatment of androgen deficiency in the future.

Standardising the biochemical confirmation of adult male hypogonadism: A joint position statement by the Society for Endocrinology and Association of Clinical Biochemistry and Laboratory Medicine.

BACKGROUND: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilise assay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain. DESIGN: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. RESULTS: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. CONCLUSIONS: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems.

Hypergonadotropic hypogonadism and chromosomal aberrations: clinical heterogeneity and implications on the health of elderly men, case series.

BACKGROUND: Hypogonadism in older men is often considered as late onset hypogonadism. However, this clinical condition results from primary testicular failure which could be of genetic origin with Klinefelter syndrome being the most common chromosomal abnormality associated with it. CASE PRESENTATION: We report a heterogeneous group of cases who were diagnosed with hypergonadotropic hypogonadism in their adulthood and were found to have rare chromosomal aberrations. All were elderly men (in their 70 s and 80 s) for whom the diagnosis was made during the evaluation of incidental symptoms suggestive of endocrinopathy. The first had hyponatremia; the other two had gynaecomastia and features of hypogonadism noted during admission for various acute medical problems. With respect to their genetic results; the first had a male karyotype with balanced reciprocal translocation between the long arm of chromosome 4 and the short arm of chromosome 7. The second case had a male karotype with one normal X chromosome and an isochrome for the short arm of the Y chromosome. The third case was an XX male with unbalanced translocation between the X & Y chromosomes with retention of the SRY locus. CONCLUSION: Hypergonadotrophic hypogonadism in the elderly, may be due to chromosomal aberrations, resulting in heterogeneous and diverse clinical phenotypes. Vigilance must be exercised when seeing cases with subtle clinical findings. This report suggests that in selected cases of adult hypergonadotropic hypogonadism, chromosomal analysis may be indicated.

Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology.

According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations. A crucial element in this theory is the presence of binding proteins, which function as gatekeepers for steroid action. For testosterone, tissue exposure is governed by a delicate equilibrium between free and total testosterone which is determined through interaction with the binding proteins sex hormone-binding globulin and albumin. Ageing, genetics and various pathological conditions influence this equilibrium, hereby possibly modulating hormonal exposure to the target tissues. Despite ongoing controversy on the subject, strong evidence from recent in vitro, in vivo and human experiments emphasizes the relevance of free testosterone. Currently, however, clinical possibilities for free hormone diagnostics are limited. Direct immunoassays are inaccurate, while gold standard liquid chromatography with tandem mass spectrometry (LC-MS/MS) coupled equilibrium dialysis is not available for clinical routine. Calculation models for free testosterone, despite intrinsic limitations, provide a suitable alternative, of which the Vermeulen calculator is currently the preferred method. Calculated free testosterone is indeed associated with bone health, frailty and other clinical endpoints. Moreover, the added value of free testosterone in the clinical diagnosis of male hypogonadism is clearly evident. In suspected hypogonadal men in whom borderline low total testosterone and/or altered sex hormone-binding globulin levels are detected, the determination of free testosterone avoids under- and overdiagnosis, facilitating adequate prescription of hormonal replacement therapy. As such, free testosterone should be integrated as a standard biochemical parameter, on top of total testosterone, in the diagnostic workflow of male hypogonadism.

Cardiometabolic indices predict hypogonadism in male patients with type 2 diabetes.

PURPOSE: To evaluate in men with type 2 diabetes the association of cardiometabolic indices [Visceral Adiposity Index (VAI), Triglyceride Glucose Index (TyG), and lipid accumulation product (LAP)] with total testosterone (TT) levels, and their predictive cut-off values in identifying hypogonadism. METHODS: 265 consecutive men aged 40-70 years with type 2 diabetes performed an andrological evaluation; metabolic parameters and TT were determined. Receiver operating characteristic (ROC) curves were used to identify cut-off values of cardiometabolic indices in predicting low testosterone (TT < 12 nmol/l). RESULTS: VAI, TyG, and LAP were negatively associated with TT levels. The prevalence of hypogonadism in men in the fourth quartiles of VAI, TyG, and LAP was ~ 70.0-75.0% compared to ~ 10.0-17.0% in men in the first quartiles (p < 0.001). The sensitivity and specificity of the three cardiometabolic indices in predicting TT < 12 nmol/l were significantly higher concerning BMI, waist circumference, lipid profile and HbA1c. Cut off values of VAI ≥ 3.985, TyG ≥ 4.925, and LAP ≥ 51.645 predict hypogonadism with good sensitivity and specificity. CONCLUSION: This is the first study evaluating the association of VAI, TyG, and LAP with hypogonadism in men with type 2 diabetes. Alterations in these indices should direct the patients to andrological evaluation.

Hypothalamic-Pituitary-Gonadal Axis Disorders Impacting Fertility in Both Sexes and the Potential of Kisspeptin-Based Therapies to Treat Them.

Impaired function of the hypothalamic-pituitary-gonadal (HPG) axis can lead to a vast array of reproductive disorders some of which are inherited or acquired, but many are of unknown etiology. Among the clinical consequences of HPG impairment, infertility is quite common. According to the latest report from the World Health Organization, the global prevalence of infertility during a person's lifetime is a staggering 17.5% which translate into 1 out of every 6 people experiencing it. In both sexes, infertility is associated with adverse health events, and if unresolved, infertility can cause substantial psychological stress, social stigmatization, and economic strain. Even though significant advances have been made in the management and treatment of infertility, low or variable efficacy of treatments and medication adverse effects still pose a significant problem. However, the discovery that in humans inactivating mutations in the gene encoding the kisspeptin receptor (Kiss1R) results in pubertal failure and infertility has expanded our understanding of the mechanisms underlying the neuroendocrine control of reproduction, opening up potential new therapies for the treatment of infertility disorders. In this chapter we provide an overview of common infertility disorders affecting men and women, their recommended treatments, and the potential of kisspeptin-based pharmacotherapies to treat them.

Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism.

Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in its diagnosis and management exist. There are several current guidelines on testosterone replacement therapy that have been driven predominantly by single disciplines. The Society for Endocrinology commissioned this new guideline to provide all care providers with a multidisciplinary approach to treating patients with MH. This guideline has been compiled using expertise from endocrine (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices. These guidelines also provide a patient perspective to help clinicians best manage MH.

Reproductive axis ageing and fertility in men.

Compared to women, increasing male age is not accompanied by such marked changes in reproductive function but changes certainly do happen. These include alterations to the hypothalamo-pituitary-testicular axis, with resultant implications for testosterone production and bioavailability as well as spermatogenesis. There is a decline in sexual function as men age, with a dramatic increase in the prevalence of erectile dysfunction after the age of 40, which is a marker for both clinically evident as well as covert coronary artery disease. Despite a quantitative decline in spermatogenesis and reduced fecundability, the male potential for fertility persists throughout adult life, however there are also increasingly recognised alterations in sperm quality and function with significant implications for offspring health. These changes are relevant to both natural and medically assisted conception.

Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety.

BACKGROUND: Long-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT). AIM: To determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning. METHODS: Hypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12-month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12-month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy. OUTCOMES: The efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured. RESULTS: Over 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300-1,000 ng/dL [10-35 nmol/L]; mean ± SD: 617 ± 427 ng/dL [21 ± 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical T-induced safety changes were observed, including a 3-6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 ± 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests. CLINICAL IMPLICATIONS: Over 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT. STRENGTHS & LIMITATIONS: These are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations. CONCLUSION: Oral TU offers a safe and effective long-term treatment option for men with hypogonadism. Honig S, Gittelman M, Kaminetsky J, et al. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022;19:1750-1758.

Serum concentrations of dihydrotestosterone are associated with symptoms of hypogonadism in biochemically eugonadal men.

PURPOSE: Symptoms of hypogonadism are often reported by subjects with normal serum testosterone (T) levels. We aimed to assess the association between clinical symptoms in andrological outpatients and sex steroids levels. METHODS: This is a retrospective cross-sectional cohort study in an Academic clinic and research unit. International Index of Erectile Function (IIEF, EF domain) and Aging Males Symptoms scale (AMS) questionnaires were completed by 635 and 574 men, respectively (mean age: 47.3 ± 13.9 and 47.4 ± 13.8 years, p = 0.829), free of interfering medications with complaints possibly related to hypogonadism. RESULTS: Serum total/free T as well as dihydro-T (DHT) was associated with IIEF-EF and AMS scores in the overall population using univariate analyses. Multivariate approaches revealed DHT concentrations in subjects with normal T levels (n = 416, Total T > 12 nmol/L) to be significant predictors of AMS scores. A 0.1 nmol/l serum DHT increase within the eugonadal range was associated with a 4.67% decrease in odds of having worse symptoms (p = 0.011). In men with biochemical hypogonadism (Total T < 12 nmol/L), total and free T rather than DHT were associated with AMS results. This association was not found for IIEF-EF scores. Indirect effects of age and BMI were seen for relations with hormone concentrations but not questionnaire scores. CONCLUSION: DHT can be associated with symptoms of hypogonadism in biochemically eugonadal men. Serum DHT measurement might be helpful once the diagnosis of hypogonadism has been ruled out but should not be routinely included in the primary diagnostic process.

Addressing male sexual and reproductive health in the wake of COVID-19 outbreak.

PURPOSE: The COVID-19 pandemic, caused by the SARS-CoV-2, represents an unprecedented challenge for healthcare. COVID-19 features a state of hyperinflammation resulting in a "cytokine storm", which leads to severe complications, such as the development of micro-thrombosis and disseminated intravascular coagulation (DIC). Despite isolation measures, the number of affected patients is growing daily: as of June 12th, over 7.5 million cases have been confirmed worldwide, with more than 420,000 global deaths. Over 3.5 million patients have recovered from COVID-19; although this number is increasing by the day, great attention should be directed towards the possible long-term outcomes of the disease. Despite being a trivial matter for patients in intensive care units (ICUs), erectile dysfunction (ED) is a likely consequence of COVID-19 for survivors, and considering the high transmissibility of the infection and the higher contagion rates among elderly men, a worrying phenomenon for a large part of affected patients. METHODS: A literature research on the possible mechanisms involved in the development of ED in COVID-19 survivors was performed. RESULTS: Endothelial dysfunction, subclinical hypogonadism, psychological distress and impaired pulmonary hemodynamics all contribute to the potential onset of ED. Additionally, COVID-19 might exacerbate cardiovascular conditions; therefore, further increasing the risk of ED. Testicular function in COVID-19 patients requires careful investigation for the unclear association with testosterone deficiency and the possible consequences for reproductive health. Treatment with phosphodiesterase-5 (PDE5) inhibitors might be beneficial for both COVID-19 and ED. CONCLUSION: COVID-19 survivors might develop sexual and reproductive health issues. Andrological assessment and tailored treatments should be considered in the follow-up.

A Review of Nonpharmacological Strategies in the Treatment of Relative Energy Deficiency in Sport.

Relative energy deficiency in sport (RED-S) can result in negative health and performance outcomes in both male and female athletes. The underlying etiology of RED-S is low energy availability (LEA), which occurs when there is insufficient dietary energy intake to meet exercise energy expenditure, corrected for fat-free mass, leaving inadequate energy available to ensure homeostasis and adequate energy turnover (optimize normal bodily functions to positively impact health), but also optimizing recovery, training adaptations, and performance. As such, treatment of RED-S involves increasing energy intake and/or decreasing exercise energy expenditure to address the underlying LEA. Clinically, however, the time burden and methodological errors associated with the quantification of energy intake, exercise energy expenditure, and fat-free mass to assess energy availability in free-living conditions make it difficult for the practitioner to implement in everyday practice. Furthermore, interpretation is complicated by the lack of validated energy availability thresholds, which can result in compromised health and performance outcomes in male and female athletes across various stages of maturation, ethnic races, and different types of sports. This narrative review focuses on pragmatic nonpharmacological strategies in the treatment of RED-S, featuring factors such as low carbohydrate availability, within-day prolonged periods of LEA, insufficient intake of bone-building nutrients, lack of mechanical bone stress, and/or psychogenic stress. This includes the implementation of strategies that address exacerbating factors of LEA, as well as novel treatment methods and underlying mechanisms of action, while highlighting areas of further research.

Leydig-like cells derived from reprogrammed human foreskin fibroblasts by CRISPR/dCas9 increase the level of serum testosterone in castrated male rats.

In the past few years, Leydig cell (LC) transplantation has been regarded as an effective strategy for providing physiological patterns of testosterone in vivo. Recently, we have successfully converted human foreskin fibroblasts (HFFs) into functional Leydig-like cells (iLCs) in vitro by using the CRISPR/dCas9 system, which shows promising potential for seed cells. However, it is not known whether the reprogrammed iLCs can survive or restore serum testosterone levels in vivo. Therefore, in this study, we evaluate whether reprogrammed iLCs can restore the serum testosterone levels of castrated rats when they are transplanted into the fibrous capsule. We first developed the castrated Sprague Dawley rat model through bilateral orchiectomy and subsequently injected extracellular matrix gel containing transplanted cells into the fibrous capsule of castrated rats. Finally, we evaluated dynamic serum levels of testosterone and luteinizing hormone (LH) in castrated rats, the survival of implanted iLCs, and the expression levels of Leydig steroidogenic enzymes by immunofluorescence staining and Western blotting. Our results demonstrated that implanted iLCs could partially restore the serum testosterone level of castrated rats, weakly mimic the role of adult Leydig cells in the hypothalamic-pituitary-gonadal axis for a short period, and survive and secrete testosterone, through 6 weeks after transplantation. Therefore, this study may be valuable for treating male hypogonadism in the future.

Endosialin defines human stem Leydig cells with regenerative potential.

STUDY QUESTION: Is endosialin a specific marker of human stem Leydig cells (SLCs) with the ability to differentiate into testosterone-producing Leydig cells (LCs) in vitro and in vivo? SUMMARY ANSWER: Endosialin is a specific marker of human SLCs which differentiate into testosterone-producing LCs in vitro and in vivo. WHAT IS KNOWN ALREADY: Human SLCs have been identified and isolated using the marker platelet-derived growth factor receptor α (PDGFRα) or nerve growth factor receptor (NGFR). However, the specificity was not high; thus, LCs and germ cells could be mistakenly sorted as SLCs if PDGFRα or NGFR was used as a marker for human SLCs isolation. STUDY DESIGN, SIZE, DURATION: Firstly, we re-evaluated the specificity of PDGFRα and NGFR for SLCs in adult human testes. Then we analysed the previously published single-cell sequencing data and found that endosialin may identify human SLCs. Subsequently, we sorted endosialin+ cells from four human donors and characterized their self-renewal and multipotent properties. To assess whether endosialin+ cells have the potential to differentiate into functional LCs in vitro, these cells were stimulated by differentiation-inducing medium. We next assessed the in vivo regenerative potential of human endosialin+ cells after xenotransplantation into the testes of immunodeficient mice. PARTICIPANTS/MATERIALS, SETTING, METHODS: Single-cell sequencing analysis, immunofluorescence and flow cytometry were used to characterize human testis tissues. In vitro colony formation, multipotent differentiation (adipogenic, osteogenic and chondrogenic) and Leydig cell-lineage induction were used to assess stem cell activity. Xenotransplantation into 3-week-old immunodeficient mice was used to determine in vivo regenerative potential. Endpoint measures included testosterone measurements, cell proliferation, immunofluorescence, flow cytometry and quantitative RT-PCR. MAIN RESULTS AND THE ROLE OF CHANCE: The results indicate that endosialin is a specific marker of SLCs compared with PDGFRα and NGFR. Additionally, endosialin+ cells isolated from human testes show extensive proliferation and differentiation potential in vitro: their self-renewal ability was inferred by the formation of spherical clones derived from a single cell. Moreover, these cells could differentiate into functional LCs that secreted testosterone in response to LH in a concentration-dependent manner in vitro. These self-renewal and differentiation properties reinforce the proposal that human testicular endosialin+ cells are SLCs. Furthermore, transplanted human endosialin+ cells appear to colonize the murine host testes, localize to peritubular and perivascular regions, proliferate measurably and differentiate partially into testosterone-producing LCs in vivo. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: Owing to the difficulty in collecting human testis tissue, the sample size was limited. The functions of endosialin on SLCs need to be elucidated in future studies. WIDER IMPLICATIONS OF THE FINDINGS: A discriminatory marker, endosialin, for human SLCs purification is a prerequisite to advance research in SLCs and logically promote further clinical translation of SLCs-based therapies for male hypogonadism. STUDY FUNDING/COMPETING INTEREST(S): A.P.X. was supported by the National Key Research and Development Program of China (2017YFA0103802 and 2018YFA0107200). C.D. was supported by the National Natural Science Foundation of China (81971314) and the Natural Science Foundation of Guangdong Province, China (2018B030311039). The authors declare no conflict of interest.

Hypertension and Reproduction.

PURPOSE OF REVIEW: Many aspects of reproduction have been associated with increased blood pressure and impaired glucose metabolism that reveals a subsequent increased risk of cardiovascular disease. The aim of this review is to assess reproductive life factors associated with an increased risk of hypertension and cardiovascular disease, e.g., early life programming, sexual, and reproductive health in men and women. RECENT FINDINGS: Impaired fetal growth, with low birth weight adjusted for gestational age, has been found associated with hypertension in adulthood. Erectile dysfunction, currently considered an early diagnostic marker of cardiovascular disease preceding the manifestation of coronary artery disease by several years, frequently coexisting with hypertension, could also be exacerbated by some antihypertensive drugs. Male hypogonadism or subfertility are associated with increased cardiovascular risk. Hypertensive disorders in pregnancy including preeclampsia represent a major cause of maternal, fetal and neonatal morbidity, and mortality. The risk of developing preeclampsia can be substantially reduced in women at its high or moderate risk with a low dose of acetylsalicylic acid initiated from 12 weeks of gestation. An increased risk of hypertension in women following invasive-assisted reproductive technologies has been newly observed. Blood pressure elevation has been noticed following contraceptive pill use, around the menopause and in postmenopausal age. Furthermore, drug treatment of hypertension has to be considered as a factor with a potential impact on reproduction (e.g., due to teratogenic drug effects). In summary, a deeper understanding of reproductive life effects on hypertension and metabolic abnormalities may improve prediction of future cardiovascular disease.

Short-term effects of surgical weight loss after sleeve gastrectomy on sex steroids plasma levels and PSA concentration in men with severe obesity.

Male obesity is known to be associated with hypogonadism, which can be reverted after surgical weight reduction. However, the evidence about how rapidly this effect rises after surgery and what consequences each procedure have on prostate function and prostatic-specific antigen (PSA) concentration is scarce. So, we evaluated total testosterone, estradiol, luteinizing hormone, follicle-stimulating hormone and PSA plasma levels in a group of 29 Caucasian obese men (BMI - 43.4 ± 8.5 kg/m2) before and one month after sleeve gastrectomy. 19 lean healthy male subjects were considered as controls. As expected, obese patients showed a high prevalence of hypogonadism (51.6%) at baseline, with reduced total testosterone compared to lean controls (10.8 ± 3.5 vs 15.7 ± 4.2 nmol/l, p < .01), higher estradiol (124.4 ± 46.5 vs 78.7 ± 39.6 pmol/l, p < .01), lower luteinizing hormone and follicle stimulating hormone (3.6 ± 1.3 and 2.5 ± 0.9 vs 5.2 ± 2.4 and 5.9 ± 3.8 U/L, respectively, p < .05) plasma levels. One month after surgery, patients showed a significant body weight reduction (-17.2 ± 6.7 kg) with increased total testosterone (from 10.8 ± 3.5 to 18.9 ± 4.9 nmol/l, p < .001), reduced estradiol (from 124.4 ± 46.5 to 96.1 ± 34.3 pmol/l, p < .05) and increased PSA (from 0.74 ± 0.38 to 1.0 ± 0.51 µg/l, p < .001). These results confirm that hypogonadism is highly prevalent in obese males, but they also show that it can be early reversed after sleeve gastrectomy, further confirming the strong indication to surgery of hypogonadal patients with severely reduced quality of life. Higher testosterone levels may be responsible for the increase of PSA observed after surgery; however, PSA concentration has to be monitored over time to avoid underrating of potential severe prostate diseases.

Testosterone treatment longer than 1 year shows more effects on functional hypogonadism and related metabolic, vascular, diabetic and obesity parameters (results of the 2-year clinical trial).

OBJECTIVE: We evaluated long-term effects of testosterone undecanoate on glycemic control, metabolic syndrome, vascular function and morphology in obese men with functional hypogonadism (FH) and type 2 diabetes (T2D) in a 2-year prospective clinical trial. METHODS: A total of 55 participants were enrolled in this study; group P (n = 27) received placebo during first and testosterone therapy (TTh) during second year, group T (n = 28) received TTh both years. We pooled results after 1 year of TTh to obtain more statistical power. Results for group T after 2 years of TTh are also presented. We evaluated wide assortment of biochemical (fasting plasma glucose-FPG, glycated hemoglobin-HbA1c and lipid profile), hormonal, vascular (flow-mediated dilatation-FMD and intima-media thickness-IMT), anthropometrical and derived parameters (BMI, HOMA-IR, non-HDL cholesterol, bioavailable and calculated free testosterone). Quality of life was assessed using Aging Males' Symptoms (AMS) questionnaire. RESULTS: FPG, HbA1c, HOMA-IR and IMT decreased, FMD increased, lipid profile and AMS sexual sub-score improved, and testosterone levels fully normalized after 2 years of TTh. CONCLUSIONS: Two-year of TTh resulted in normalized serum testosterone levels, improved glycemia, endothelial function, lipids and insulin sensitivity, and quelled the symptoms of hypogonadism, potentially reducing cardiovascular risk in obese men with FH and T2D.

Correlation of anti-Mullerian hormone with humanchorionic gonadotropin test in the evaluation of testicular function of children with 46 XY male hypogonadism: Use of anti-Mullerian hormone as abiomarker.

AIM: It is challenging to evaluate reproductive potential during childhood. These challenges necessitate the use of invasive dynamic tests. Although the anti-Mullerian hormone (AMH) is a reliable biomarker in evaluating testicular function, especially in the pre-pubertal period, there are uncertainties concerning its use in a clinical setting. This study is focused on comparing the AMH and human chorionic gonadotropin (hCG) test in boys with hypogonadism. METHODS: A total of 160 boys aged between 0 and 18 years who presented with complaints associated with hypogonadism were prospectively enrolled in the study. All children were assigned to the following five groups: gonadal disorders (n = 34), androgen synthesis and end organ effect disorder (n = 48), isolated genital malformation disorders (n = 57), hypogonadotropic hypogonadism (n = 15) and constitutional delayed puberty (n = 6). All children underwent a short 3-day hCG test (1500 U/m2 /day). The concordance and correlation were evaluated between the hCG test and AMH. RESULTS: All groups exhibited a strong correlation (r160 = 0.689) and strong concordance (Kappa coefficient160 = 0.7) between the AMH and hCG test. Values of AMH higher than 32.7 pmol/L and hCG responses higher than 86 pmol/L were significant as indicative markers of functional testicular tissue presence. CONCLUSIONS: This study has shown that there is a strong correlation between the AMH and short-term hCG test and that values of AMH higher than 32.7 pmol/L and stimulated testosterone higher than 86 pmol/L can be used as indicators of functionally sufficient testicular tissue. These results indicate that AMH value can be used as a reliable and useful biomarker in the evaluation of the testicular function in 46 XY hypogonadism.