Male hypogonadism

The hypothalamic–pituitary–gonadal (HPG) axis regulates the development, endocrine and reproductive function of the gonads throughout all phases of life. Male hypogonadism is defined an inadequate gonadal function, as manifested by deficiency in gametogenesis and/or secretion of gonadal hormones. In most cases, male hypogonadism is diagnosed through detailed history, physical examination and a few basic hormonal evaluations. In selected cases, however, additional tests are needed to define the aetiology and the extent of HPG axis dysfunction. These include semen analysis, pituitary imaging studies, genetic studies, bone densitometry, testicular ultrasonography, testicular biopsy and hormonal dynamic testing. The stimulation tests of the HPG are of particular importance in the differential diagnosis of congenital delayed puberty versus pre-pubertal hypogonadism in children. This review will focus on the methods, indications and limitations of endocrine testing in the characterisation and differential diagnosis of male hypogonadism at various ages. A practical hands-on guide on how to perform these tests is also provided.     

Diabetes mellitus and the impairment of male reproductive function: Possible signaling pathways

Background and aimsToday, it has been shown that diabetes mellitus (DM) can affect male fertility. Glucose metabolism is a vital process in spermatogenesis that is impacted by diabetes condition. But the mechanisms by which DM causes male infertility are not wholly clarified. The aim of this review is to provide brief information about the influence of hyperglycemia on male fertility and specific emphasis on the molecular signaling pathway that is involved.MethodsBroad literature search in the electronic database “Pubmed”, “Google Scholar”, the website of “World Health Organization” (WHO) and Control Disease and Prevention (CDC) took place. There was no time restriction. A key criterion for the selection of articles was English and language. Finally, one hundred thirty seven articles were included in the review.ResultsDiabetes mellitus affects many signaling pathways that involved in the spermatogenesis. It seems that increased ROS and oxidative stress in the diabetes is the beginning of all fertility problems and affects all of involved signaling pathways in the spermatogenesis.ConclusionsIt seems that there was strong interconnected between oxidative stress and all of involved signaling pathways in the reproductive problems in diabetes. So, approaches that diminish oxidative stress in the testis can be effective in improving diabetes related infertility complications.     

Contemporary concepts in the evaluation and management of male infertility

Infertility in men is a common condition. At the core of the medical evaluation of the male partner in a couple who are unable to conceive is the history and physical examination. Special attention should be directed to the patient's developmental history and any use of testosterone products. The physical examination focuses on the genitals, and includes assessments of the size and consistency of the testicles, epididymis, vas deferens, and presence of varicoceles. Although many sophisticated tests are available, semen analysis is still the most important diagnostic tool used to assess fertility, and includes parameters such as sperm count, motility and viability. Treatment of male factor infertility can involve targeted agents, in the case of specific conditions such as hypogonadotropic hypogonadism, or it can be empirical-using medical therapy or assisted conception techniques-for patients in whom no underlying cause has been identified. Although an all-encompassing treatment for male factor infertility has not yet been developed, the field offers many promising avenues of research.     

Female hypogonadism: evaluation of the hypothalamic–pituitary–ovarian axis

Female hypogonadism refers to deficient or abnormal function of the hypothalamic–pituitary–ovarian axis that clinically presents with menstrual cycle disturbances. Female hypogonadism can be due to a congenital or acquired cause, and the defect can be at the level of the hypothalamus, pituitary or ovary. A careful history, physical exam and selected laboratory testing can often determine the locus of the defect and whether it results from a structural or hormonal problem. Laboratory testing generally relies on basal hormone levels; however, timing of blood sampling in relation to menses is important to interpretation of the data.     

Male gonadal function in coeliac disease: 1. Sexual dysfunction, infertility, and semen quality

The prevalence of hypogonadism, sexual dysfunction and abnormalities of semen quality was determined in 28 consecutive males with coeliac disease. These observations were related to jejunal morphology and nutritional status, and were compared with findings in 19 men with Crohn's disease of similar age and nutritional status. Two of the 28 coeliacs (7%) had clinical evidence of hypogonadism but impotence and decreased sexual activity occurred more commonly, the latter apparently improving after gluten withdrawal. Of the married coeliacs, 19% had infertile marriages, a value greater than expected in the general population. Hypogonadism and sexual dysfunction were not detected in our patients with Crohn's disease. Seminal analysis in coeliacs revealed marked abnormalities of sperm morphology and motility, but only the former appeared to improve after gluten withdrawal. Similar abnormalities, however, were also detected in patients with Crohn's disease, although, unlike the coeliacs, 46% also had reduced concentrations of spermatozoa. Semen quality in coeliac disease could not be clearly related to general or specific (serum vitamin B₁₂ and red cell folate) nutritional deficiencies or to fertility, although sperm motility was markedly reduced in two of the three coeliacs with infertile marriages. The presence of antisperm antibodies did not appear to be an important aetiological factor in male infertility in coeliac disease. The pathogenesis of infertility and sexual dysfunction in coeliac disease remains unclear, suggesting that factors such as endocrine dysfunction or other specific nutritional deficiency may be involved.     

Assessment of hypogonadism and its determinants among adult men with type 2 diabetes mellitus

Background and aimsThe impact of utilizing both symptoms as well as biochemically confirmed androgen deficiency in diagnosis of hypogonadism among type 2 diabetic men is relatively less studied. Furthermore, various determinants of hypogonadism in these men especially the role of insulin resistance and hypogonadism were studied.MethodsThis is a cross sectional study of 353 T2DM men aged 20–70 years of age. Hypogonadism was defined by taking both symptoms as well as calculated testosterone levels. Symptoms were defined using androgen deficiency in ageing male (ADAM) criteria. Various metabolic and clinical parameters were assessed and evaluated with regards to presence or absence of hypogonadism.ResultsAmong 353 patients, 60 had both symptoms as well as biochemical evidence of hypogonadism. Assessment of calculated free testosterone but not total testosterone identified all such patients. Body mass index, HbA1c, fasting triglyceride level and HOMA IR inversely correlated with calculated free testosterone. We found that insulin resistance (HOMA IR) was independently associated with hypogonadism (odds ratio=1.108).ConclusionAssessment of both symptoms of hypogonadism and calculated free testosterone represents a better way for correct identification of hypogonadal diabetic men. Insulin resistance has a strong association with hypogonadism independent of obesity and complication status of diabetes.     

Role of cytokines in testicular function

Inflammatory disease has been established to affect male reproductive function and fertility. Relevant inflammatory diseases include general and chronic infectious diseases as well as localized acute or chronic infections of the male genitourinary tract. Male accessory gland infections account for almost 15% of all cases of male infertility seen in infertility clinics while fertility usually is not a clinical objective among patients with acute systemic infections such as Gramnegatives sepsis. Infections of the male accessory glands frequently are associated with increased counts of white blood cells in semen and elevated levels of proinflammatory cytokines in semen and the testis. There is a mounting body of evidence that demonstrates the importance of cytokines and chemokines in the regulation of testicular and glandular function during pathophysiological states as well as under normal physiological conditions when cytokines act as growth and differentiation factors. The purpose of this review is to examine the role of cytokines in the regulation of steroidogenesis and spermatogenesis in the testis under physiological and pathophysiological conditions and considers clinical investigations that help to improve the evaluation and treatment of male infertility.     

The complex association between metabolic syndrome and male hypogonadism

BackgroundThe complex association between metabolic syndrome (MetS) and male hypogonadism is well established. A number of observational studies show that low testosterone is associated with insulin resistance and an increased risk for diabetes mellitus and MetS in men.AimsTo elucidate the association between MetS and male hypogonadism, present epidemiological data on the co-existence of the two comorbidities, enlighten the underlying pathophysiology and appraise the effects of testosterone supplementation therapy (TTh) and lifestyle modifications on MetS and body composition in men.Materials and MethodsSystematic search to PubMed and Medline databases for publications reporting data on association between MetS and male hypogonadism.ResultsBoth MetS and male hypogonadism have a high prevalence in the general population and are frequently co-existing e.g. in males with diabetes. Accumulating evidence from animal and human studies suggests that MetS is involved in the pathogenesis of hypogonadism in males as well as the other way around. On the other hand, there is evidence for a favorable effect of testosterone supplementation in testosterone deficient men with MetS and/or diabetes mellitus.ConclusionsStudies with superior methodological characteristics are needed in order to establish a role for testosterone supplementation in men with MetS and/or diabetes mellitus.     

The endocrine control of spermatogenesis.

The hormonal regulation of spermatogenesis involves a complex interplay within the hypothalamo-pituitary-testicular axis, which commences before birth with male sexual development and continues through puberty and into adulthood. Hypothalamic gonadotrophin-releasing hormone drives these events by inducing pituitary gonadotrophin secretion, thereby stimulating testicular androgen secretion (providing virility) and spermatogenesis (providing fertility). Evidence from both animal models and man supports a need for both follicle-stimulating hormone and testosterone in achieving full spermatogenic potential, but a species difference in their relative roles exists. Clinical endocrine disorders can arise from a deficiency of hypothalamic gonadotrophin-releasing hormone and/or pituitary gonadotrophins, which results in hypogonadotrophic hypogonadism, featuring delayed/absent puberty and infertility. Physiologically-based and effective treatment with pulsatile gonadotrophin-releasing hormone or gonadotrophins can often restore fertility. Clinical conditions can also be caused by rare genetic disorders of the gonadotrophin molecules or the receptors for androgens and gonadotrophins, which result in a range of phenotypes (from male pseudohermaphroditism through to infertility); these disorders provide a unique insight into the physiology of sexual development and spermatogenesis.     

Effectiveness of acupuncture for asthenozoospermia: A protocol for systematic review and meta-analysis

Background:According to the World Health Organization, the global incidence of infertility is about 15%, and more than 50% of infertility cases are caused by male infertility. Asthenozoospermia is caused by male fertility decline and male infertility. Due to work pressure, environmental pollution, sexual diseases, and other factors, the number of patients with asthenozoospermia has increased in recent years. It has been confirmed that acupuncture has a certain effect on patients with asthenozoospermia. Acupuncture and moxibustion can be an adjuvant treatment plan for the treatment of asthenozoospermia in addition to drug treatment.Methods:Randomized controlled trials of acupuncture for asthenozoospermia will be searched in the relevant database, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), and Chinese Scientific Journal Database (VIP database). The studies of electronic searches will be exported to EndNote V.9.1 software. We will run meta-analyses using the Review Manager (RevMan) V.5.3 software. Any disagreements will be solved in consultation with a third reviewer.Results:Our study aims to explore the efficacy of acupuncture for asthenozoospermia and to provide up-to-date evidence for clinical of asthenozoospermia.Conclusion:This study will perform a comprehensive systematic review and meta-analysis on the efficacy of acupuncture for asthenozoospermia, making up for the lack of relevant evidence of the clinical use of acupuncture.INPLASY registration number:INPLASY 202140032.     

Androgens and spermatogenesis

Male infertility contributes to 50% of all cases of infertility. The main cause is low quality and quantity of sperm. In humans, spermatogenesis starts at the beginning of puberty and lasts lifelong. It is under the control of FSH and testicular androgens, and mainly testosterone (T), and therefore requires a normal gonadotroph axis, intratesticular T production by Leydig cells and functional androgen receptors (ARs) within testicular Sertoli cells. Various clinical cases illustrate the roles of T in human spermatogenesis. Men with complete congenital hypogonadotropic hypogonadism (HH) are usually azoospermic. Treatment by exogenous testosterone injection and FSH is not able to produce sperm. However, combined treatment with FSH and hCG is effective. This example shows that intratesticular T plays a major role in spermatogenesis. Furthermore, testicular histology of men with LH receptor mutations shows Leydig cell hypoplasia/agenesis/dysplasia with conserved Sertoli cell count. The sperm count is reduced, as in males with partial inactivating mutation of the androgen receptor. Some protocols of hormonal male contraception or exogenous androgen abuse induce negative feedback in the hypothalamic pituitary axis, decreasing FSH, LH and T levels and inducing sperm defects and testicular atrophy. The time to recovery after cessation of drug abuse is around 14 months for sperm output and 38 months for sperm motility. In summary, abnormal androgen production and/or AR signaling impairs spermatogenesis in humans. The minimal level of intratesticular T for normal sperm production is a matter of debate. Interestingly, some animal models showed that completely T-independent spermatogenesis is possible, potentially through strong FSH activation. Finally, recent data suggest important roles of prenatal life and minipuberty in adult spermatogenesis.     

Gonadal function in young adult males with metabolic syndrome

AimsAim of the study was to assess the gonadal function of young adult males with metabolic syndrome and to compare them with healthy age matched controls.MethodsForty young male subjects of age group 20–40 years who fulfilled the IDF criteria (2005) for diagnosis of metabolic syndrome were included in the study. Thorough evaluation of the subjects was done and history of sexual dysfunction if any was noted. Pooled blood samples were collected from each subject in fasting state for total testosterone, SHBG, FSH, LH, prolactin and insulin levels. All hormonal analyses were done by radio immune assay (RIA). Hypogonadism was defined as total testosterone less than 3 ng/ml. Eighteen healthy age matched controls were also taken for the study.ResultsTwenty percent of subjects with metabolic syndrome had eugonadotropic hypogonadism compared to 5.5% controls. Subjects with metabolic syndrome also had significantly lower SHBG level compared to the controls.ConclusionFrom this study it has been observed that eugonadotropic hypogonadism with low total testosterone and normal or low normal gonadotropin levels may be a feature of the metabolic syndrome in young adult males. Significant low SHBG levels as compared to controls could be one of the factors responsible for various biochemical alteration seen in these cases. This study highlights the importance of evaluating gonadal function in young adult males with the metabolic syndrome and has therapeutic implications in the management of such subjects with gonadal dysfunction.     

Efficacy of electroacupuncture for the treatment of asthenozoospermia: A protocol for systematic review and meta-analysis

Introduction:Infertility has affected millions of couples aged 15 to 44 years worldwide. Recently, some studies suggest that abnormal semen quality is the main cause of male infertility and asthenozoospermia accounts for 19% of the infertility of men. The situation has brought a huge burden to the patient with asthenozoospermia and society. Acupuncture is a part of traditional Chinese medicine. Electroacupuncture (EA) has gained in popularity. Although a positive effect of manual acupuncture and EA on sperm parameters has been documented in several studies, there still a lack of more solid evidence. We hope to provide a convincing study for EA.Methods and analysis:The electronic databases of MEDLINE, PubMed, Web of Science, EMBASE, Cochrane Library, Clinicaltrials. org, China National Knowledge Infrastructure Database (CNKI), Wan fang Database, China Biology Medicine Database (CBM), VIP Science Technology Periodical Database, Chinese Clinical Trial Registry will be retrieved. All the randomized controlled trials of rESWT for patients with CP/CPPS will be included. We will evaluate the outcomes including NIH-CPSI, VAS, IPSS, IIEF-5, and conduct this study strictly according to the Cochrane Handbook for Systematic Reviews of Interventions.Results:The present study is a protocol for systematic review and meta-analysis without results, and data analysis will be carried out after the protocol. We will share our findings on October 31st, 2021.Conclusions:EA for asthenospermia is a microtrauma surgery with less pain. EA can effectively improve sperm motility; however, its efficacy has not been assessed scientifically and systematically. To address this limitation, this study will inspect the efficacy and safety of the EA in patients with asthenospermia.Ethics and dissemination:Formal ethical approval is not required in this protocol. We will collect and analyze data based on published studies, and since there are no patients involved in this study, individual privacy will not be under concerns. The results of this review will be disseminated to peer-reviewed journals or submit to related conferences.Protocol registration number:INPLASY2020100071     

Hyperostosis frontalis interna: An Egyptian case referred to the second dynasty (2890–2650 BC) from Tarkhan-Egypt

Aim of the work and case presentationThis article is to present the evidence of hyperostosis frontalis interna (HFI) in a young adult male, approximately (25–26) years old, recovered from a second dynasty site (2890–2650 BC) at Tarkhan in the south of Dahshur-Egypt.HFI is rare in historic populations. It is most commonly found among females with prolonged estrogen stimulation. Males with hormonal disturbances like primary hypogonadism were found to manifest with HFI.ConclusionThis study is a further contribution to the case history of HFI in osteoarcheological studies. Further researches are recommended to have an overview on such an old disease in Egypt.     

Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) causes pubertal failure and infertility in both women and men due to partial or total secretory failure of the two pituitary gonadotropins lutropin (LH) and follitropin (FSH) during periods of physiological activation of the gonadotropic axis. Men and women with CHH frequently seek treatment for infertility after hypogonadism therapy. Some etiologies, such as autosomal dominant or X-linked Kallmann syndrome, raise the question of hereditary transmission, leading to increasing demands for genetic counseling and monitoring of medically assisted pregnancies. Diagnosis and treatment of newborn boys is, therefore, becoming an increasingly important issue. In male individuals with complete forms of CHH, the antenatal and neonatal gonadotropin deficit leads to formation of a micropenis and cryptorchidism, which could undermine future sexual and reproductive functions. Standard treatments, usually started after the age of puberty, often only partially correct the genital abnormalities and spermatogenesis. The aim of this Review is to examine the possible additional benefits of neonatal gonadotropin therapy in male patients with CHH. Encouraging results of neonatal therapy, together with a few reports of prepubertal treatment, support the use of this novel therapeutic strategy aimed at improving sexual and reproductive functions in adulthood.     

Gonadotrophin resistance

Gonadotrophin resistance is caused by inactivating mutations in receptors (Rs) of the two gonadotrophins, i.e. luteinizing hormone (LH) and follicle-stimulating hormone (FSH), presenting as hypergonadotrophic hypogonadism and infertility/subfertility in both sexes. These conditions are extremely rare, but must be kept in mind upon differential diagnosis of disorders of sexual maturation, hypogonadism and infertility. In 46,XY individuals inactivation of LHR causes a disturbance in male-type sexual differentiation that ranges from male pseudohermaphroditism (complete lack of genital masculinization) to mild conditions such as cryptorchidism and hypospadias, depending on completeness of the receptor inactivation. In women, the phenotype is milder, presenting mainly as anovulatory amenorrhoea and hypo-oestrogenization. Inactivation of FSHR causes in otherwise normally masculinized men small testis size and variably reduced spermatogenesis, but not azoospermia or absolute infertility. In women the phenotype is more severe, with primary or early secondary amenorrhoea, arrested follicular maturation and anovulatory infertility. Incomplete forms with milder phenotype and partial responsiveness to FSH have also been described. Although gonadotrophin resistance is a very rare condition, its correct diagnosis is important for the selection of adequate treatment.     

Hypogonadisme hypogonadotrope congénital

Congenital hypogonadotropic hypogonadism is defined by reduced steroid hormone synthesis and secretion due to low LH and FSH secretion. It is a rare disease with an unknown prevalence (about 1/5000). It results from a fetal defect in GnRH neuron migration, a defect of pituitary development or from a functional defect of the hypothalamopituitary axis between GnRH neurons and gonadotropic cells. The diagnosis should be considered at birth in males with micropenis, during adolescence in case of delayed puberty or absent puberty, and during adulthood in case of infertility. It may be restricted to the gonadotropic axis, combined with other endocrine system defects or be part of a complex syndrome. Several gene defects have now been described. Molecular studies should be performed to confirm the diagnosis and to help provide apropriate genetic counseling. Treatment to induce puberty should be provided at adolescence, followed by hormonal substitution treatment during adulthood. Specific infertility treatment may also be proposed but patients with the dominant form of gonadotropic deficiency should be informed of the risk of transmission.     

Obesity and male hypogonadism: Tales of a vicious cycle

Obesity prevalence, particularly in children and young adults, is perilously increasing worldwide foreseeing serious negative health impacts in the future to come. Obesity is linked to impaired male gonadal function and is currently a major cause of hypogonadism. Besides signs and symptoms directly derived from decreased circulating testosterone levels, males with obesity also present poor fertility outcomes, further evidencing the parallelism between obesity and male reproductive function. In addition, males with androgen deficiency also exhibit increased fat accumulation and reduced muscle and mineral bone mass. Thus, compelling evidence highlights a vicious cycle where male hypogonadism can lead to increased adiposity, while obesity can be a cause for male hypogonadism. On the opposite direction, sustained weight loss can attain amelioration of male gonadal function. In this scenario, a thorough evaluation of gonadal function in men with obesity is crucial to dissect the causes from the consequences in order to target clinical interventions towards maximized improvement of reproductive health. This review will address the causes and consequences of the bidirectional relationship between obesity and hypogonadism, highlighting the implicit male reproductive repercussions.     

RESTORATION OF SPERMATOGENESIS WITH PULSATILE GONADOTROPHIN RELEASING HORMONE THERAPY IN HYPOGONADOTROPHIC HYPOGONADISM OF TRAUMATIC ETIOLOGY

Head trauma is one of the rarest reported causes of hypogonadotrophic hypogonadism and treatment of this condition with pulsatile gonadotrophin releasing hormone (GnRH) has not been previously described. A 36-year-old man with azoospermia from hypogonadotrophic hypogonadism following head trauma was given pulsatile GnRH therapy. 10 μg of GnRH was administered every 90 minutes through a subcutaneous catheter in the abdominal wall. After 15 months, the ejaculate contained 34 × 10⁶ spermatozoa/ml of semen. Prolonged pulsatile GnRH therapy can restore gonadal function in males with hypogonadotrophic hypogonadism of traumatic etiology. Our experience adds to the growing spectrum of hypothalamic disorders causing hypogonadism that is amenable to treatment by this method.     

Reversible male infertility in late onset congenital adrenal hyperplasia.

We have studied a male patient who presented with secondary infertility. His eldest daughter suffers from late onset congenital adrenal hyperplasia. Based on his hormonal profile, adrenal and gonadal stimulation tests, semen analyses and testicular biopsy he was diagnosed as suffering from the same disease as his daughter. Steroid treatment yielded improvement in all the parameters mentioned above. Four months later his wife became pregnant and he fathered a child. Suppression of gonadotropin secretion due to overproduction of adrenal androgens would appear to be the reason for the failure of testicular maturation and spermatogenesis in this patient. We conclude: 1) glucocorticoid treatment is indicated in infertile males suffering from nonclassical 21-hydroxylase deficiency; 2) Late onset congenital adrenal hyperplasia should be suspected in any male infertility of unknown origin.