Hypothalamic-pituitary-testicular Research Articles

Testosterone therapy for functional hypogonadism in middle-aged and elderly males: current evidence and future perspectives.

Population aging is a global phenomenon driving research focus toward preventing and managing age-related disorders. Functional hypogonadism (FH) has been defined as the combination of low testosterone levels, typically serum total testosterone below 300-350 ng/dL, together with manifestations of hypogonadism, in the absence of an intrinsic pathology of the hypothalamic-pituitary-testicular (HPT) axis. It is usually seen in middle-aged or elderly males as a product of aging and multimorbidity. This age-related decline in testosterone levels has been associated with numerous adverse outcomes. Testosterone therapy (TTh) is the mainstay of treatment for organic hypogonadism with an identifiable intrinsic pathology of the HPT axis. Current guidelines generally make weak recommendations for TTh in patients with FH, mostly in the presence of sexual dysfunction. Concerns about long-term safety have historically limited TTh use in middle-aged and elderly males with FH. However, recent randomized controlled trials and meta-analyses have demonstrated safe long-term outcomes regarding prostatic and cardiovascular health, together with decreases in all-cause mortality and improvements in various domains, including sexual function, body composition, physical strength, bone density, and hematopoiesis. Furthermore, there are numerous insightful studies suggesting additional benefits of TTh, for instance in cardio-renal-metabolic conditions. Specifically, future trials should investigate the role of TTh in improving symptoms and prognosis in various clinical contexts, including sarcopenia, frailty, dyslipidemia, arterial hypertension, diabetes mellitus, fracture risk, heart failure, stable angina, chronic kidney disease, mood disorders, and cognitive dysfunction.

Testosterone therapy in older men: clinical implications of recent landmark trials.

Testosterone therapy for men with hypogonadism due to identifiable hypothalamic-pituitary-testicular (HPT) pathology is uncontroversial. However, the risks and benefits of testosterone for men with clinical features of hypogonadism in the absence of identifiable HPT axis pathology have been uncertain. Recent landmark placebo-controlled trials assessed the benefits and risks of testosterone therapy (≤ 3 years) for middle aged and older men with symptoms and possible signs of hypogonadism or end-organ androgen deficiency, low or low-normal serum testosterone concentrations, but no HPT pathology: testosterone therapy 1) had modest-but clinically significant-benefits on average self-reported energy and mood, sexual function and satisfaction; 2) in conjunction with a lifestyle program, reversed or reduced incident diabetes mellitus type 2 (T2D) in men at high risk of or newly diagnosed with T2D; 3) modestly improved objectively assessed muscle strength and timed walking distance; 4) increased bone density and strength, but did not reduce falls or typical osteoporotic fractures and surprisingly increased the risk of fractures typically attributable to trauma; and 5) did not significantly increase the risk of myocardial infarction, stroke or prostate cancer. These landmark trials help to inform clinical decision-making about testosterone therapy for men.

Exploring the dynamics of exercise intensity on male fertility and reproductive health: advancements and implications for fertility research.

On a global scale, 15% of couples experience infertility. Approximately 50% of these cases refer to male infertility. This literature review investigated the effects of exercise activities on male fertility and reproductive health. This subject was explored using studies conducted on human and animal models. Physical activity is widely recognized to improve overall well-being, but engaging in excessive exercise might potentially lead to male infertility due to the negative impact on hypothalamic-pituitary-testicular (HPT) function, increased oxidative stress, and the presence of chronic inflammation. Infertility might result from the fundamental factors that induce a decline in testosterone production and semen quality. Physical activity has the potential strategy to enhance male fertility in cases of infertility caused by obesity and diabetes. Exercise enhances spermatogenesis and semen quality in lifestyle-induced infertility by increasing testicular antioxidant defense, reducing pro-inflammatory cytokines, and promoting steroidogenesis.

Di-(2-ethylhexyl) phthalate exacerbates abnormalities of testicular development in F1 males via inhibition the Wnt/β-catenin signaling pathway

The theory of “Developmental Origins of Health and Disease (DOHaD)” espouses that environmental exposures to toxicants during critical developmental stages can affect health outcomes in adulthood. Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that can be transferred to developing organisms via the placenta and breast milk as an environmental endocrine disruptor. We herein implemented a cross-fostering model to decipher the contributions of prenatal vs. postnatal exposure to low or high dose DEHP (30 or 500 mg/kg-bw•d) on reproductive outcomes in male offspring and the underlying mechanism of action. Unexpectedly, we observed that postnatal DEHP exposure programmed weight gain in a dose-dependent manner, in-utero exposure to high dose DEHP appeared to constitute a significant factor in the weight loss of male offspring. Moreover, in the low dose group, offspring of control that were suckled by DEHP dams (CC-DE) generated a considerable number of adverse reproductive outcomes compared with the offspring of DEHP that were suckled by control dams (DE-CC), based on histopathologic alterations in the testis, blockage of sex hormone secretion, and transcriptional inhibition of steroid-hormone-related factors in the hypothalamic-pituitary-testicular (HPT) axis. However, DE-CC group affected reproductive dysfunction in male offspring more so than CC-DE in the high dose group. Mechanistically, DEHP contributed to the inhibition of steroidogenesis by perturbing the Wnt/β-catenin-signaling pathway. These studies confirm the sensitivity window in which future reproductive outcomes in offspring are influenced following developmental exposure to DEHP at two different dosages, and reveals a critical role for the Wnt/β-catenin signaling pathway in DEHP-induced male reproductive disorders.

Male obesity secondary hypogonadism: effectiveness of ketogenic diet on testicular function

Epidemiological studies have reported an association between obesity/metabolic syndrome (MetS) and male reproductive disorders. Endocrine dysfunctions, direct testicular damage, chronic low-grade inflammation, and insulin resistance (IR) are involved in the occurrence of male obesity secondary hypogonadism (MOSH) which in turn alters the metabolic imbalance, creating a sort of vicious circle. Since IR and chronic inflammation state play a pivotal role in MOSH, low-calorie and low-carbohydrate diet protocols may be administered in obese men to improve their metabolic and hormonal profile. The ketogenic diet (KD) has been reported to determine positive effects on body weight, IR, cardio-metabolic risk, hypothalamic-pituitary-testicular (HPT) axis, and prostate with possible improvement of plasma androgens levels, sexual function (SF), and male fertility. This review aims to evaluate the effectiveness of KD on testicular function. Emerging evidence reports that very low-calorie KD (VLCKD) may revert MOSH by restoring HPT axis function and testosterone (T) levels. Moreover, VLCKD could improve SF, prostate health and lower urinary tract symptoms (LUTSs) in overweight/obese male patients. VLCKD may also positively impact spermatogenesis although evidence is still poor. Future studies are warranted to clarify the effectiveness of KD on testicular and prostate gland function

OR25-01 Longitudinal Changes in the Hypothalamic-Pituitary-Testicular (HPT) Axis in Men with Longevity

Abstract Disclosure: D. He: None. T. Gao: None. N. Barzilai: None. S. Milman: None. S. Aleksic: None. Background: Aging in men is associated with a reduction in testosterone (T) levels. In men aged 50 - 80, the decline in T mainly occurs due to hypothalamic-pituitary dysfunction, which results from unhealthy aging characterized by obesity and metabolic disorders. The changes in the HPT axis in men with longevity are less understood. Our recent cross-sectional study in men aged 90 and older showed high prevalence of testicular dysfunction which was not associated with metabolic health. We now explore the longitudinal changes in the HPT axis in men with longevity to better understand their relationship with metabolic health and survival. Methods: In an observational study of community-dwelling Ashkenazi Jewish men (n = 68, mean age (SD) at baseline sample 84 ± 4 years), levels of total T (TT, LC/MS), LH, and SHBG were measured in longitudinal serum samples (a median of 3 measures per subject, age at final sample 89 ± 3 years). Men were followed for survival after the final sample. Free T (FT) was calculated per Vermeulen et al. Men treated with T or GnRH agonists were excluded. Metabolic measures included BMI, A1c, and serum lipids. Individual longitudinal trajectories of TT, FT, LH, and SHBG were estimated with linear regression. Biochemical gonadal phenotypes were determined based on the levels of TT and LH. Results: Baseline and final levels of TT, FT, LH, and SHBG were, respectively: 417 ± 173 and 346 ± 187 ng/dL (TT), 6.0 ± 2.4 and 4.7 ± 2.5 ng/dL (FT), 8.0 [5.1, 14.4] and 10.0 [5.9, 20.4] mIU/mL (LH), and 58 ± 20 and 63 ± 23 nmol/L (SHBG), with average change rate/year of −17 ± 47 ng/dL (TT), −0.3 ± 0.5 ng/dL (FT), 0.7 ± 2.2 mIU/mL (LH) and 0.9 ± 4.1 nmol/L (SHBG). At baseline, the most prevalent biochemical gonadal phenotype was eugonadism (54%), followed by compensated testicular dysfunction (24%), testicular dysfunction (10%), and hypothalamic-pituitary dysfunction (12%), while respective prevalence rates at the final sample were 40%, 24%, 29%, and 7%. Baseline TT (p=0.002), age (p=0.02), and history of cancer (p=0.01) predicted more negative trajectory, while the history of cardiovascular disease (p=0.02) predicted more positive trajectory of TT. Neither TT, FT, LH nor SHBG trajectories were significant predictors of final BMI, A1c, or serum lipid levels. Positive TT trajectory was associated with shorter survival, after adjustment for SHBG, age, and comorbidities (HR 6.61 [1.46, 29.8], p=0.01). Conclusions: This is one of the first longitudinal studies of the HPT axis in community-dwelling men with longevity. As men survive into the late 80s, they increasingly develop testicular dysfunction while hypothalamic-pituitary dysfunction is rare. Changes in testosterone levels do not seem to predict metabolic dysfunction; however, an increase in total testosterone with aging may be associated with reduced survival. These findings need to be explored further in larger and ethnically diverse cohorts. Presentation Date: Saturday, June 17, 2023

Testicular dysfunction at diagnosis in children and teenagers with haematopoietic malignancies improves after initial chemotherapy.

Hematopoietic malignancies are the most frequent type of cancer in childhood. Recent advances in cancer treatment have significantly improved survival until adulthood. There is an extensive literature on the effects of cancer treatment on the gonadal axis in adult survivors of childhood cancer mainly focused on sperm production, but scarce information exists on the immediate impact of cancer and its treatment in boys. In this work, we determined the status of the hypothalamic-pituitary-testicular (HPT) axis function at diagnosis and the immediate impact of chemotherapy at the start of treatment in children and adolescents with hematopoietic malignancies. In a prospective study of 94 boys and adolescents with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or non-Hodgkin lymphoma (NHL), we determined serum AMH, inhibin B and FSH to assess the gonadotrophin-Sertoli cell component of the HPT axis, and testosterone and LH to evaluate the gonadotrophin-Leydig cell component, at diagnosis and after 3 months of chemotherapy. Secondarily, the general health state was evaluated. In prepubertal boys, at diagnosis, AMH, inhibin B and FSH were lower compared to the reference population, reflecting an FSH-Sertoli cell axis dysfunction. After 3 months of chemotherapy, all hormone concentrations increased. At pubertal age, at diagnosis, AMH and inhibin B were lower compared to the reference population for Tanner stage, with inappropriately normal FSH, suggesting a primary Sertoli cell dysfunction with insufficient gonadotrophin compensation. The LH-Leydig cell axis was mildly disrupted. After 3 months of chemotherapy, inhibin B and AMH were unchanged while median FSH levels rose to values that exceeded the reference range, indicating a significant impairment of Sertoli cell function. Testosterone normalized concomitantly with an abnormal LH elevation reflecting a compensated Leydig cell impairment. General health biomarkers were impaired at diagnosis and improved after 3 months. The HPT axis function is impaired in boys with hematopoietic malignancies before the initiation of chemotherapy. There is a primary testicular dysfunction and a concomitant functional central hypogonadism that could be due to an impaired overall health. The HPT axis function improves during the initial 3 months of chemotherapy concomitantly with the general health state. However, in pubertal boys the dysfunction persists as shown by elevated gonadotropin levels after 3 months.

Susceptibility of male reproductive system to bisphenol A, an endocrine disruptor: Updates from epidemiological and experimental evidence.

Bisphenol A (BPA) is an omnipresent environmental pollutant. Despite being restrictions in-force for its utilization, it is widely being used in the production of polycarbonate plastics and epoxy resins. Direct, low-dose, and long-term exposure to BPA is expected when they are used in the packaging of food products and are used as containers for food consumption. Occupationally, workers are typically exposed to BPA at higher levels and for longer periods during the manufacturing process. BPA is a known endocrine disruptor chemical (EDC), that causes male infertility, which has a negative impact on human life from emotional, physical, and societal standpoints. To minimize the use of BPA in numerous consumer products, efforts and regulations are being made. Despite legislative limits in numerous nations, BPA is still found in consumer products. This paper examines BPA's overall male reproductive toxicity, including its impact on the hypothalamic-pituitary-testicular (HPT) axis, hormonal homeostasis, testicular steroidogenesis, sperm parameters, reproductive organs, and antioxidant defense system. Furthermore, this paper highlighted the role of non-monotonic dose-response (NMDR) in BPA exposure, which will help to improve the overall understanding of the harmful effects of BPA on the male reproductive system.

Consumption of soy isoflavones during the prepubertal phase delays puberty and causes hypergonadotropic hypogonadism with disruption of hypothalamic-pituitary gonadotropins regulation in male rats

Isoflavones are phytoestrogens with recognized estrogenic activity but may also affect testosterone, corticosterone and thyroid hormone levels in experimental models. However, the molecular mechanisms involved in these alterations are still unclear. Isoflavones are present in soy-based infant formula, in breast milk after the consumption of soy by the mother and are widely used for the preparation of beverages consumed by toddlers and teenagers. In this sense, we proposed to investigate the effects of soy isoflavone exposure during the prepubertal period, a recognized window of sensitivity for endocrine disruption, over the hypothalamic-pituitary-testicular (HPT) axis. For this, 42 3-week-old male Wistar rats were exposed to 0.5, 5 or 50 mg of soy isoflavones/kg from postnatal day (PND) 23 to PND60. We evaluated body growth, age at puberty, serum concentrations of LH, FSH, testosterone and estradiol, and the expression of the transcripts (mRNA) of genes encoding key genes controlling the hypothalamic-pituitary-testicular (HPT) axis. In the hypothalamus, we observed an increase in Esr1 mRNA expression (0.5 and 5 mg). In the pituitary, we observed an increase in Gnrhr mRNA expression (50 mg), a reduction in Lhb mRNA expression (0.5 mg), and a reduction in Ar mRNA expression. In the testis, we observed an increase in Lhcgr mRNA expression (50 mg) and a reduction in Star mRNA expression (0.5 and 5 mg). The serum levels of LH (5 and 50 mg) and FSH (0.5 mg) were increased, while testosterone and estradiol were reduced. Puberty was delayed in all groups. Taken together, these results suggest that prepubertal consumption of relevant levels of soy isoflavones disrupts the HPT axis, causing hypergonadotropic hypogonadism and altered expression levels of key genes regulating the axis.

Copper deposition in Wilson's disease causes male fertility decline by impairing reproductive hormone release through inducing apoptosis and inhibiting ERK signal in hypothalamic-pituitary of mice.

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism characterized by liver and central nervous system dysfunction. Considerable evidence suggests that infertility is also very common in male patients with WD, but the exact molecular mechanisms involved remain unknown. In order to further investigate the pathological changes in the hypothalamic-pituitary-testicular (HPT) axis and its mechanisms, mice were divided into the normal control group (NC), WD model TX mice group (WD), dimercaptosuccinic acid–treated TX mice group (DMSA), and pregnant horse serum gonadotropin–treated TX mice group (PMSG). The copper content and morphology of hypothalamus and pituitary tissues, the ultrastructure and apoptosis of hypothalamus neurons and pituitary gonadotropin cells, the serum levels of reproductive hormones, and the pregnancy rate and litter size of the female mice were studied. The expression of apoptosis-related proteins and the phosphorylation of extracellular regulatory protein kinase (ERK) 1/2 in the hypothalamus and pituitary were detected. The results showed that the copper content was significantly increased in the WD group, and the histopathological morphology and ultrastructure of the hypothalamus and pituitary were damaged. The levels of the gonadotropin-releasing hormone, the follicle-stimulating hormone, the luteinizing hormone, and testosterone were significantly decreased. The apoptosis rate in the hypothalamus and pituitary was significantly increased. The expressions of proapoptotic proteins Bax and Caspase-3 were significantly increased, the expression of the anti-apoptotic protein Bcl-2 was significantly decreased, and the phosphorylation level of ERK1/2 was significantly decreased. Fertility is significantly reduced. After DMSA intervention, the hypothalamus tissue copper content decreased, the hypothalamus and pituitary tissue morphology and ultrastructure were improved, cell apoptosis was alleviated, the expression of Bax and Caspase-3 was significantly decreased, the expression of Bcl-2 was significantly increased, and the reproductive hormone level, phosphorylation level, and fertility were increased. Fertility was preserved after treatment with PMSG in male TX mice. These results suggest that copper deposition in WD causes male fertility decline by impairing reproductive neuroendocrine hormone release through inducing apoptosis and inhibiting the ERK signal in the hypothalamic–pituitary region. This study can also provide reference for the damage of copper pollution to the male reproductive system.

Integrity of hypothalamic-pituitary-testicular axis in exceptional longevity.

Hypothalamic integrity increasingly is being recognized as a marker of healthy longevity in rodent models. Insight into hypothalamic function in humans with exceptional longevity can be gained via investigation of the hypothalamic–pituitary‐testicular (HPT) axis in men with exceptional longevity. This study aimed to characterize the HPT axis function, defined by levels of testosterone (T) and luteinizing hormone (LH), in 84 Ashkenazi Jewish men aged 90–106 years. We found that 94% of men exhibited preserved hypothalamic–pituitary function, as evidenced by either normal testosterone and LH levels (25%) or an appropriate rise in LH in response to aging‐related primary testicular dysfunction (69%), a hormone pattern mirroring female menopause. Total T level was not associated with metabolic parameters or survival. These results demonstrate a high prevalence of testicular dysfunction with preserved hypothalamic–pituitary function in men with exceptional longevity. Thus, the role of hypothalamic integrity and HPT axis in healthy aging warrants further investigation.

Gene co-expression networks contributing to reproductive development in Holstein-Friesian bull calves

Enhanced early life nutrition stimulates the functionality of the hypothalamic-pituitary–testicular (HPT) biochemical signalling axis, resulting in precocious reproductive development in bull calves. Additionally, there is evidence that peptides and hormones produced within adipose tissue depots are also central in mediating the effect of metabolic status with reproductive development. The objective of this study was to undertake gene co-expression analyses on transcriptional data of the HPT and adipose tissues derived from bull calves fed contrasting planes of nutrition up to 18 weeks of life. The relationship between networks of co-expressed genes in each tissue dataset with calf phenotypic data was also assessed using a Pearson correlation analysis. Phenotypic data were related to metabolic status (systemic concentrations of insulin, leptin, adiponectin and IGF-1) reproductive development (systemic concentrations of testosterone, FSH and LH) and markers of testicular development (seminiferous tubule diameter, seminiferous tubule lumen score, spermatogenic cells and Sertoli cells). In the hypothalamus, gene co-expression networks involved in biochemical signalling processes related to gonadotropin-releasing hormone (GnRH) secretion were positively associated (P < 0.05) with systemic concentrations of IGF-1 and insulin. Similarly, a network of gene transcripts involved in GnRH signalling in the anterior pituitary was positively associated (P < 0.05) with systemic concentrations of LH. In the testes and adipose tissues, networks of co-expressed genes implicated in cholesterol and fatty acid biosynthesis were positively associated (P < 0.05) with lumen score, Sertoli cell number, and stage of spermatogenesis. Additionally, gene co-expression networks significantly associated (P < 0.05) with both metabolic and reproductive trait data were found to be enriched (P < 0.05) for biological pathways related to energy production, cellular growth and proliferation, GnRH signalling and cholesterol biosynthesis across multiple tissues examined. Results from this study highlight networks of co-expressed genes directly associated with markers of enhanced metabolic status and subsequent earlier reproductive development. Furthermore, genes involved in biological processes mentioned above may hold potential for informing genomic selection breeding programmes for the selection of calves capable of displaying earlier reproductive development as a consequence of enhanced dietary intake.

Pathogenesis of Viral Infections and Male Reproductive Health: An Evidence-Based Study.

Viruses, being intracellular obligate parasites, can cause several congenital and sexually transmitted diseases. Depending on the site of infection, viruses can adopt various pathogenic mechanisms for their survival and to escape the host immune response. The male reproductive system is one of the attainable targets of many viruses including immunodeficiency virus (HIV), Zika virus (ZIKV), adenovirus, cytomegalovirus (CMV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and infection with such viruses may cause serious health issues. Leydig cells and seminiferous tubules are the prime sites of mammalian testis for viral infection. The azoospermic condition is a common symptom of viral infection, wherein the hypothalamic-pituitary-testicular (HPT) axis can be disrupted, leading to decreased levels of luteinizing hormone (LH). Furthermore, oxidative stress (OS) is a major contributing factor to viral infection-associated male infertility. The likelihood of direct and indirect infection, as well as sex-based variability in the vulnerability pattern to viral infections, has been observed. However, there appears to be a long-term impact of viral infection on male reproductive performance due to testicular tissue pathogenicity - a process that requires thorough investigation. The present study aimed to explore how the viruses affect the male reproductive system, including their distribution in tissues and body fluids, possible targets as well as the effects on the endocrine system. We used the major electronic databases such as MEDLINE and SCOPUS. Google Scholar was also consulted for additional literature search related to the topic. Obtained literatures were sorted based on the content. The articles that reported the pathogenesis of viruses on male reproductive health and were published in the English language were included in the present study.

The relation between obesity, kisspeptin, leptin, and male fertility.

Over the past decades, obesity and infertility in men increased in parallel, and the association between both phenomena have been examined by several researchers. despite the fact that there is no agreement, obesity appears to affect the reproductive potential of men through various mechanisms, such as changes in the hypothalamic-pituitary-testicular (HPT) axis, spermatogenesis, sperm quality and/or alteration of sexual health. Leptin is a hormone produced by the adipose tissue, and its production elevates with increasing body fat. Many studies have supported the relationship between raised leptin production and reproductive function regulation. In fact, Leptin acts on the HPT axis in men at all levels. However, most obese men are insensitive to increased production of endogenous leptin and functional leptin resistance development. Recently, it has been recommended that Kisspeptin neurons mediate the leptin's effects on the reproductive system. Kisspeptin binding to its receptor on gonadotropin-releasing hormone (GnRH) neurons, activates the mammal's reproductive axis and stimulates GnRH release. Increasing infertility associated with obesity is probably mediated by the Kisspeptin-GnRH pathway. In this review, the link between obesity, kisspeptin, leptin, and male fertility will be discussed.

Intracerebroventricular asprosin administration strongly stimulates hypothalamic-pituitary-testicular axis in rats

Asprosin, a protein-based secretary product of white adipose tissue, stimulates appetite hepatic glucose production. It crosses blood-brain barrier and stimulates appetite center and causes sperm chemotaxis but exact role of this endogenous agent is not completely known. This study was conducted to investigate possible effects of central asprosin infusion on the hormones involved in the hypothalamic-pituitary-testicular (HPT) axis and sperm cells.Spraque Dawley male rats were divided into four groups; control, sham, low asprosin (34) and high asprosin (68 nM) groups, (n = 10 for each group). Control group remain intact while a brain infusion kit was placed in the lateral ventricles of the rats in the sham group (artificial cerebrospinal fluid) and asprosin (34 and 68 nM) was infused for 14 days. At the end of the experiment, the hypothalamus, blood, and epididymis tissues of the rats were collected. Gonadotropin-releasing hormone (GnRH) mRNA and tissue protein levels were determined in the hypothalamus tissue by RT-PCR and Western Blot methods. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were examined using the ELISA method from blood samples and sperm cells were examined in the epididymis tissue. GnRH mRNA and protein expressions of asprosin administered groups were higher than control and sham groups (p < 0.05). Asprosin infusion was also found to increase serum FSH, LH, and testosterone levels (p < 0.05). In addition, sperm density, motility, and progressive movement were observed to increase in asprosin administered groups (p < 0.05).This study suggests that central asprosin stimulate the HPT axis and also epididymis tissue. Our results implicates potential role for asprosin in male infertility.

Impacts of Immunometabolism on Male Reproduction.

The physiological process of male reproduction relies on the orchestration of neuroendocrine, immune, and energy metabolism. Spermatogenesis is controlled by the hypothalamic-pituitary-testicular (HPT) axis, which modulates the production of gonadal steroid hormones in the testes. The immune cells and cytokines in testes provide a protective microenvironment for the development and maturation of germ cells. The metabolic cellular responses and processes in testes provide energy production and biosynthetic precursors to regulate germ cell development and control testicular immunity and inflammation. The metabolism of immune cells is crucial for both inflammatory and anti-inflammatory responses, which supposes to affect the spermatogenesis in testes. In this review, the role of immunometabolism in male reproduction will be highlighted. Obesity, metabolic dysfunction, such as type 2 diabetes mellitus, are well documented to impact male fertility; thus, their impacts on the immune cells distributed in testes will also be discussed. Finally, the potential significance of the medicine targeting the specific metabolic intermediates or immune metabolism checkpoints to improve male reproduction will also be reassessed.

Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit.

Although gonadal axis dysregulation from energy deficit is well recognized in women, the effects of energy deficit on the male gonadal axis have received much less attention. To identify relevant articles, we conducted PubMed searches from inception to May 2021. Case series and mechanistic studies demonstrate that energy deficit (both acutely over days or chronically over months) either from inadequate energy intake and/or excessive energy expenditure can lower serum testosterone concentration as a result of hypothalamic-pituitary-testicular (HPT) axis dysregulation in men. The extent to which this has clinical consequences that can be disentangled from the effects of nutritional insufficiency, concomitant endocrine dysregulation (eg, adrenal and thyroid axis), and coexisting comorbidities (eg, depression and substance abuse) is uncertain. HPT axis dysfunction is primarily the result of loss of GnRH pulsatility resulting from a failure of leptin to induce kisspeptin signaling. The roles of neuroendocrine consequences of depression, hypothalamic-pituitary-adrenal axis activation, proinflammatory cytokines, Ghrelin, and genetic susceptibility remain unclear. In contrast to hypogonadism from organic pathology of the HPT axis, energy deficit-associated HPT dysregulation is functional, and generally reversible by restoring energy balance. The clinical management of such men should aim to restore adequate nutrition and achieve and maintain a healthy body weight. Psychosocial comorbidities must be identified and addressed. There is no evidence that testosterone treatment is beneficial. Many knowledge gaps regarding epidemiology, pathophysiology, and treatment remain and we highlight several areas that require future research.

COVID-19 and male reproductive system: pathogenic features and possible mechanisms.

Multiorgan dysfunction is the main characteristic of severe COVID-19 patients and the involvement of male reproductive system may occur among these patients. Although there is a limited evidence to confirm the orchitis and virus presence in the semen of patients, there are concerns about the transmission of virus through the semen. In addition, reduced fertility or infertility can be seen as consequences of severe COVID-19 in recovered subjects. In this study, we aimed to review articles related to COVID-19 and male reproductive system to find the possible underlying mechanisms of SARS-CoV-2 in affecting male fertility. The following keywords of SARS-CoV-2, COVID-19, testis, orchitis, semen, angiotensin-converting enzyme 2 (ACE2), hypothalamic–pituitary–testicular (HPT) axis, Hypothalamus, etc., were defined to find the related publications from standard search engines, e.g., PUBMED, SCOPUS, Google Scholar. According to studies, COVID-19 occurs in severe patients as respiratory disease, along with multi-organ failure. The most important mechanisms are classified as direct and indirect pathogenesis of SARS-CoV-2. The presence of ACE2 on the cell surface of various cells in testis increases the risk of direct infection by this virus. SARS-CoV-2 also affects the testis through the cytokine storm. In addition, the important role of HPT axis dysregulation through impaired Leydig cells and hypothalamus should be considered. Using antiviral and immunomodulatory therapy can be harmful for testis function. Further investigations are required to investigate potential mechanisms of male infertility in survivals of COVID-19. Since involvement of testis is essential for fertility, increasing the knowledge of health system may improve the outcomes.

The Hypothalamic-Pituitary-Testicular Axis in Exceptionally Old Men

Introduction: As life expectancy continues to increase and more men reach the extremes of age, it is important to understand the physiology of the aging hypothalamic-pituitary-testicular (HPT) axis and its role in health. While prior studies primarily focused on men younger than age ninety, we studied a unique cohort enriched for men with exceptional longevity to characterize the age-related trends in male sex-hormones, the etiology of the observed changes in the HPT axis, and its relationship with metabolic dysfunction and survival at the extremes of age. Methods: This is a cross-sectional study of community-dwelling Ashkenazi Jewish men (n = 427), age range 50-106 years. Longitudinal follow-up for vital status was conducted for men age ≥ 88 at enrollment (n = 86). Measurements included serum total testosterone (TT) by LC/MS, LH, SHBG, lipids, glucose and BMI. Free testosterone (FT) was calculated according to Vermeulen et. al. A change-point linear regression model was applied to describe the age trend of TT. Multivariable linear regression adjusted for comorbidities tested the associations between metabolic parameters and TT. The association between survival and TT was evaluated with the age-adjusted Cox proportional hazards model. Age-specific cutoffs for TT and LH were used to define primary and secondary hypogonadism. Results: The change point model was a significantly better fit for the data compared to the straight-line model (p = 0.004), indicating that TT significantly declines after age 88 years. Men age < 88 years had higher average TT (401 ± 162 vs. 278 ± 178 ng/dL, p < 0.001), FT (6.3 ± 2.0 vs. 3.3± 2.1 pg/mL, p < 0.001), and lower LH (4.3 [3.0 - 6.1] vs. 14.6 [7.2 - 25.5] mIU/mL, p < 0.001), compared to men age ≥ 88 years. The prevalence of primary and secondary hypogonadism was 2% and 11%, respectively, in men age < 88 years, and 30% and 11%, among men age ≥ 88 years (p < 0.001). A multivariable linear regression analysis revealed interactions between age, dichotomized at the change-point of 88 years, and metabolic parameters. Models stratified at age 88 demonstrated an inverse association between TT and BMI (p = 0.02), serum triglycerides (p = 0.007), and random glucose levels (p = 0.02) among men age < 88; whereas a positive association was noted between TT and HDL cholesterol (p = 0.009) in this group. In men age ≥ 88 years, TT was not associated with any of the metabolic parameters or overall survival. Conclusions: Low testosterone in men with exceptional longevity is largely a result of primary testicular failure that occurs around age 88 and is accompanied by preserved hypothalamic-pituitary response with no associated metabolic dysfunction or effect on survival. This is in contrast to younger men, whose low T typically results from hypothalamic-pituitary dysfunction and is associated with metabolic derangements.

PSIX-26 Effect of enhanced nutrition during early life on the transcriptional profile of the arcuate nucleus region of the hypothalamus in Holstein Friesian bull calves

Abstract Improved nutrition and metabolic status during early life are known to advance sexual development in the bull calf. This is mediated through complex neuroendocrine signaling at the level of the hypothalamic-pituitary-testicular (HPT) axis resulting in precocious testicular development and spermatogenesis. The arcuate nucleus region (ARC) of the hypothalamus is centrally involved in the integration of peripheral metabolic cues with GnRH neuronal function and gonadotropin pulsatility which in turn stimulate testicular development. However, the precise molecular mechanisms regulating the influence of prevailing nutritional status on hypothalamic function are yet to be fully elucidated. The objective of this study was to evaluate differentially expressed genes (DEG) within the ARC of bull calves offered contrasting planes of nutrition during the first 12 weeks of life, to coincide with the characteristic transient gonadotropin rise. Holstein-Friesian bull calves with a mean (+SD) bodyweight and age of 48.8(5.3) kg and 17.5(2.8) days, respectively, were assigned to either a high energy (H; n = 15) or moderate energy (M; n = 15) plane of nutrition designed for growth rates of 1.0 and 0.5 kg/day, respectively. At 12 weeks of age all calves were euthanized and the ARC harvested. RNA was isolated from all ARC samples and RNAseq analysis conducted. As expected, H calves were heavier at euthanasia (H=112 kg; M=88 kg, P &amp;lt; 0.001). RNAseq analysis resulted in the identification of 83 DEG (P.adj&amp;lt; 0.1; fold change &amp;gt;1.5), all of which were down-regulated in H compared to M calves. DEG were enriched for biological pathways associated with immune function including complement system and acute phase response signaling (P.adj&amp;lt; 0.01). However, no DEG identified were directly involved in reproductive developmental processes. Results from this study suggest that the typically positive effect of enhanced nutrition on reproductive development may not be apparent within the ARC at 12 weeks of age.