Male Hypogonadism: Basic, Clinical and Therapeutic Principles
Abstract
Now in a revised second edition, this comprehensive text covers all aspects of male hypogonadism from the basic science to clinical management, comprehensively explaining and applying new insights to the treatment of hypogonadal men. Chapters covering neuroendocrine control of testicular function, Leydig cell function, spermatogenesis, and normal and delayed puberty open the book. The focus then turns to the pathophysiology and treatment of hypogonadism and other forms of testicular dysfunction, such as Klinefelter syndrome, cryptorchidism, and disorders of the pituitary, as well as reproductive and endocrine consequences of cancer treatment, environmental factors, obesity and aging. Next are chapters that describe the available options for androgen replacement therapy, and the outcomes when men with hypogonadism of various causes are treated with testosterone, as well as a chapter devoted to current approaches to stimulating spermatogenesis in gonadotropin-deficient men.
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Highly practical and updated with the latest available data, this second edition of Male Hypogonadism: Basic, Clinical and Therapeutic Principles cogently presents a large body of scientific information on male reproductive endocrinology to provide a thorough understanding of the pathophysiology, clinical characteristics, and treatments for disorders that adversely affect testicular function.
Chapters (20)
The proximate regulator of testicular function is gonadotropin-releasing hormone (GnRH) produced in neurons scattered throughout the anterior hypothalamus. When it reaches the anterior pituitary, GnRH stimulates the synthesis and secretion of the pituitary gonadotropic hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH are released into the circulation in bursts and activate G-protein coupled receptors on Leydig and Sertoli cells, respectively, that stimulate testosterone production and spermatogenesis. The system is tightly regulated and is maintained at a proper set-point by the negative feedback effects of testicular steroids and inhibin-B. Testicular function is also influenced by multiple internal (paracrine and autocrine) and external (endocrine) environmental factors.
The Leydig cells are found in the interstitial compartment of the testis and are the major source of androgens in males. At least two populations of Leydig cells differentiate sequentially as the testis develops—a fetal population which regulates masculinization in utero and an adult population which develops before puberty and regulates adult fertility and sex drive. A third, neonatal population is also observed in the human which may represent re-activation of the fetal Leydig cells. The fetal Leydig cells in the human depend upon stimulation by chorionic gonadotropin and produce androgens through the canonical steroidogenic pathway and also, possibly, through an alternative “backdoor” pathway; both pathways apparently being required for normal fetal masculinization. Fetal Leydig cells also secrete insulin-like factor 3 (INSL3) which, along with androgen, induces testicular descent. The fetal Leydig cell population persists into adulthood in mice but becomes secondary to the adult population. Development of the adult Leydig cell population is dependent on the Sertoli cells and on luteinizing hormone (LH) from the pituitary. The adult cells in humans secrete mainly testosterone synthesized through the Δ5 canonical pathway, and cell activity is dependent on LH and the bone-derived hormone osteocalcin while the Sertoli cells, through unknown factors, act to maintain Leydig cell numbers. During aging in humans, there is a reduction in Leydig cell activity and, possibly, Leydig cell numbers. Leydig cell tumors are rare but will lead to precocious puberty when they occur in prepubertal boys. In about half of cases these tumors are associated with activating mutations in the steroidogenic machinery [e.g., the luteinizing hormone/choriogonadotropin receptor (LHCGR)].
![Fig. 3.2 Cell-cell interaction within the testis and its functional relationship to the hypothalamic-pituitarytesticular axis. The classic hormonal regulatory axis that exerts its regulatory effects on the testis through the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn regulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. Testosterone produced by interstitial Leydig cells provides the feedback loop to modulate the production of GnRH from the hypothalamus and thereby LH and FSH from the pituitary gland. In humans and primates in contrast to rodents, testosterone has no direct feedback effect on the pituitary [240]. Inhibin produced by Sertoli cells provides selective feedback to the production of FSH. There is cross talk among germ cells (including spermatogonial stem cells) and Sertoli cells in the seminiferous epithelium, as well as Leydig cells and peritubular myoid cells in the interstitium. Studies have shown an array of growth factors, genes and hormones are involved. Abbreviations: CSF1, colony stimulating factor 1; BMP4, bone morphogenetic protein 4; GDF9, growth differentiation factor-9; GnRH, gonadotropin-releasing hormone; P-Mod-S, peritubular myoid cell modulates Sertoli cell factor; TGF-b1, transforming growth factor-1; Wt1, Wilms' tumor 1](https://www.researchgate.net/profile/Haiqi-Chen/publication/316465852/figure/fig1/AS:763589572956160@1559065349031/Cell-cell-interaction-within-the-testis-and-its-functional-relationship-to-the_Q320.jpg)
Spermatogenesis in humans is comprised of a series of highly complicated cellular events, necessary to support the production of an upward of 200 million sperm daily from puberty through the entire adulthood of a healthy man. Recent advances in the field using the techniques of cell and molecular biology, genetics, and biochemistry have unraveled many of the mysteries in spermatogenesis. In this Chapter, we highlight some recent advances in the field regarding the biology of human spermatogenesis. We also summarize and discuss recent advances regarding the regulation of spermatogenesis in humans. Due to rapid advances in our understanding of spermatogenesis and the large number of published reports in the literature in the last 2–3 decades, we focus on rapidly developing areas to stimulate the interest of our readers, in particular in areas that offer advances for the treatment of infertility in men.
Puberty is the developmental stage of physical and psychological maturation in which reproductive capacity is attained. The onset of puberty is driven by the activation of the hypothalamic–pituitary–gonadal axis after the break that restrains this axis during the majority of childhood is released. This review will cover the clinical assessment of puberty, variation in the timing of puberty, and the complex factors that regulate the onset and timing of puberty. In addition, the presentation, diagnosis, and differential diagnosis of male delayed puberty will be discussed. Male delayed puberty is common, affecting up to three percent of the population. The main differential diagnoses of delayed puberty in males include self-limited delayed puberty (DP), idiopathic hypogonadotropic hypogonadism (IHH), and hypergonadotropic hypogonadism. Treatment of isolated CDGP involves expectant observation or short courses of low-dose sex steroid supplementation. More complex and involved management is required in males with hypogonadism to achieve both the development of secondary sexual characteristics and to maximize the potential for fertility.
Ever since the first detailed clinical description by Franz Kallmann, congenital hypogonadotropic hypogonadism has been recognized both clinically and genetically as a heterogeneous disease. There are two broadly recognized clinical forms of CHH: Kallmann syndrome (KS), characterized by CHH and anosmia, represents a syndromic phenotype resulting from joint developmental failure of the GnRH and olfactory systems whereas normosmic CHH (nCHH), i.e., those with a normal sense of smell, indict processes that impair GnRH secretion and/or action without discernible GnRH migratory defects. Reproductive features of CHH depend on the timing of the defect in GnRH deficiency and its severity. In addition, several non-reproductive features are also evident in some patients and relate to the developmental etiology of the condition and the genetic and cellular pathways that are defective. There is considerable phenotypic heterogeneity in the clinical presentation of CHH, and, in addition to the typical KS and nCHH presentations, several variant forms of CHH are recognized including fertile eunuch variant, adult-onset CHH, and, more recently, reversible forms of CHH, wherein CHH recovers in adulthood with the resumption of spontaneous hypothalamo-pituitary gonadal activity. The pathophysiology of CHH, the varied genetic causes of CHH, syndromic forms of CHH, and the clinical evaluation of CHH humans are extensively described in this chapter. Quite remarkably, despite the rarity of CHH, physiologic and genetic studies in CHH patients have begun to reveal several key insights into the regulation of GnRH neurons in humans. First, in keeping with the critical evolutionary role of the reproductive system in species survival, genetic studies of humans with CHH have revealed mutations in several novel genes that represent multi-tiered, overlapping genetic and cellular pathways that govern GnRH neuronal ontogeny. Moreover, in some cases, KS and nCHH occur within a single family sharing a similar genetic milieu suggesting that both variants of CHH represent part of a continuous spectrum of GnRH deficiency. In addition, there is an emerging evidence of oligogenicity, thus explaining the variable expressivity and incomplete penetrance seen within CHH families. Collectively, the phenotypic and genetic features of CHH patients represent a remarkable advancement of our collective understanding of the hypothalamic control of reproduction. However, despite this remarkable progress, the genetic basis of CHH is only known in ~40% of cases and it is clear that several key genes remain to be discovered. With the accelerating advances in next-generation sequencing and reducing costs, further novel genes will be discovered and this chapter will require additional updates.
Mutations in the genes of gonadotropin subunits (CGA, LHB, FSHB, and CGB) and receptors (LHCGR and FSHR) are extremely rare causes of male hypogonadism. No germ line mutations of CGA have been reported, apparently because of the incompatibility of pregnancy maintenance in the absence of hGG. Five inactivating LHB mutations have been described in men with normal prenatal masculinization but arrested pubertal development. The three men so far described with FSHB mutation were azoospermic. Constitutively activating mutations of the LHCGR gene give rise to very early onset familial male-limited precocious puberty (FMPP) also termed testotoxicosis. Inactivating LHCGR mutation results in an array of male phenotypes ranging from micropenis and hypospadias to complete sex reversal (XY, disorder of sexual development), depending on the completeness of receptor inactivation. Inactivating FSHR mutations in men cause a decrease in testicular size and suppressed quality and quantity of spermatogenesis but not azoospermia, and some affected men may be fertile. Only two cases of activating FSHR mutations have been detected, and they suggest that the mutation does not have phenotype in men with otherwise normal endocrine function. The discrepancy between the phenotypes of men with inactivating FSHB (azoospermia) and FSHR (no azoospermia) mutations must be clarified with additional subjects. Information about the genotypic effects of common polymorphisms in gonadotropin and gonadotropin receptor genes is gradually mounting. A common polymorphism in LHB affects bioactivity of the hormone and has multiple mild phenotypic effects, including slow tempo of puberty in boys and is enriched in post-term boys with cryptorchidism. Some FSHB and FSHR polymorphisms have been shown to affect spermatogenesis and the response of oligozoospermic men to FSH therapy. Such polymorphisms may represent important targets for the pharmacogenetic evaluation of gonadotropin treatment in infertility.
Fertility in men with congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be impaired. Testicular adrenal rest tumors are the most frequent cause of impaired fertility. Their location adjacent to the testicular mediastinum, and their steroid-producing properties, may interfere with spermatogenesis and Leydig cell function. It is sometimes accompanied by hypergonadotropic hypogonadism. Hypogonadotropic hypogonadotropism is a second major cause of impaired fertility, resulting from suppression of the hypothalamic–pituitary–gonadal axis by adrenal androgen excess. Other testicular abnormalities and psychological factors, such as poor adherence, compliance, and transition problems, may also contribute to impaired fertility. Treatment consists of intensification of glucocorticoid treatment and assisted reproduction techniques. Genetic testing of the asymptomatic female partner is recommended for couples planning to have children.
Male hypogonadism is a clinical condition in which there is insufficient testosterone production, and/or hypospermatogenesis. Testicular testosterone production is regulated by hypothalamic–pituitary–gonadal axis in which GnRH stimulates gonadotrophs of the anterior pituitary to produce and secrete the gonadotropins FSH and LH. LH stimulates Leydig cells to produce testosterone, and FSH stimulates receptors on Sertoli cells. Pathological conditions affecting the pituitary or suprasellar region can cause hypogonadism characterized by low testosterone and low/low-normal LH levels as well as deficiency of other pituitary hormones. A thorough pituitary evaluation (hormonal investigation and MR/TC) is therefore mandatory when there is evidence for central hypogonadism. This chapter describes the disorders of the pituitary and suprasellar region that produce male hypogonadism, including functional and non-functional pituitary adenomas, non-pituitary and parasellar tumors, and non-neoplastic causes of hypogonadotropic hypogonadism, with respect to prevalence, diagnosis, clinical presentation and therapy.
Klinefelter syndrome (KS) is the most common sex chromosome disorder in men affecting 1 in 400–600 males across all ethnic groups. Men with KS have at least one supernumerary X chromosome resulting in a 47, XXY genotype. KS can present in childhood, adolescence or adulthood with varying degrees of hypogonadism, gynecomastia, very small testes and azoospermia. In adults, FSH and LH levels are elevated, and testosterone levels are low or low normal. The diagnosis is confirmed by tissue karyotyping which usually reveals a 47, XXY genotype, although about 10% of men with KS phenotype are mosaic (47, XXY/46, XY), and infrequently additional X chromosomes are present. Treatment consists of testosterone replacement, and in the subset of patients in whom sperm are present on testicular biopsy, infertility can be treated by in vitro fertilization using intracytoplasmic sperm injection.
Cryptorchidism, the condition in which one or both testes are not descended fully into the scrotum, is one of the most frequent developmental anomalies of the human male. Although there is spontaneous descent in the first few months of life in many males born with this condition, the prevalence thereafter is about 1%. The genetic direction of testicular descent is only partially understood. There are multiple etiologies of cryptorchidism, both anatomic and hormonal, with many testes having the potential for normal function. Germ cells in the undescended testis fail to undergo normal differentiation from early infancy, hence the recommendation for treatment between 6 and 12 months of age. Men with undescended testes frequently have impaired sperm production and decreased inhibin B and elevated FSH levels. Only a small portion of men who had unilateral cryptorchidism are infertile based upon paternity; however, in contrast nearly half of men with previous bilateral cryptorchidism are infertile. The risk of developing a testicular tumor, primarily of germ cell origin, is increased substantially, particularly among the bilateral group and those not corrected before puberty.
Chronic liver disease and cirrhosis are common causes of morbidity and mortality. However, the relationship between sex hormones, most notably testosterone, and liver disease has been examined only in limited studies. Liver disease is generally associated with central hypogonadism, except in the setting of alcoholic liver disease in which ethanol results in testicular damage. There are limited data on the efficacy and safety of treatment of hypogonadism in the setting of liver disease. Data are mixed on improvements in morbidity and mortality with testosterone treatment with improvement in gynecomastia appearing to be the most consistently reported benefit. Although not powered to examine safety outcomes, studies have not demonstrated a clear increase in associated adverse events with testosterone therapy. Liver transplantation is also associated with improvement in testosterone levels in the majority of individuals. However, this finding is not uniform, likely related in part to pre-existing metabolic damage, immunosuppression, graft function, and potentially other comorbidities. Further research is needed on the efficacy and safety of testosterone treatment in liver disease.
Survival rates after cancer treatment have increased dramatically in recent decades, resulting in an increasing focus on the harmful effects of cancer treatment for these patients. One of the major long-term effects of cancer and its treatment is compromised reproductive function in both males and females. These effects may occur as a result of direct effects on the gonad or indirect effects via damage to the hypothalamus or pituitary. In males, there may be impairment of testicular function prior to the commencement of treatment while the direct effects of exposure to cytotoxic therapies may also damage the seminiferous epithelium leading to oligo- or azoospermia. In addition to effects on the germ cells, Leydig cell dysfunction may occur, resulting in impaired testosterone production. This chapter describes the effects of cancer and its treatment on male reproductive function in terms of damage to the seminiferous epithelium and testosterone production. We also discuss the options, both established and experimental, for fertility preservation in these patients.
The large improvement in sporting performances in recent decades is partly due to the volume of training that athletes are undertaking. In response to exercise training, testosterone will acutely increase, decrease or have no change in concentration, depending on many factors including exercise modality, intensity, and duration. Exercise training places a tremendous amount of stress on the body, and if excessive or not managed appropriately, it can compromise an athlete’s health and performance. As a result, the endocrine system can become disrupted, Male athletes with chronic training overload may develop the exercise-hypogonadal male condition with a corresponding reduction in resting testosterone levels, possibly due to both central and peripheral regulatory compromises. In addition to low testosterone, these males also exhibit a lack of corresponding luteinizing hormone secretion. Moreover and regrettably, athletes at all levels of competition have been recorded as using exogenous anabolic-androgenic steroids, leading to a pseudo-hypogonadism state. Although rare, some athletes are candidates for testosterone replacement therapy for medical conditions, however physicians should be aware of the sanctioned and permitted use of exogenous hormones by athletes as dictated by the World Anti-Doping Agency.
Male reproductive disorders are remarkably common, and there is growing, if inconclusive, evidence that these may be caused by altered diet, lifestyle (smoking, alcohol, sedentation, recreational drugs, pharmaceutical drugs) or chemical exposures (e.g., pesticides and other endocrine-disrupting compounds). Such factors may cause their impact via effects during fetal development (i.e., maternal pregnancy effects) or in adulthood, or via a combination of the two. There is now strong evidence that a proportion of male reproductive disorders originate as a consequence of ‘testicular dysgenesis syndrome (TDS)’ which is thought to involve subtle deficiencies in fetal androgen production/action. However, what may cause TDS remains unclear. Although there is a widely held perception that environmental chemical exposures are an important cause of male reproductive disorders, evidence to this effect is equivocal, and it is argued that dietary and lifestyle changes are more likely to be important. There are considerable difficulties in studying how environmental effects can impact male reproductive health, especially where fetal origins are suspected, but readers are reminded to remain open to accepting such effects, bearing in mind that our reproductive processes have evolved so as to be in tune with (i.e., to reflect) our environment.
Sex steroids are implicated in the etiology of the metabolic syndrome (MetS) with different effects in men and women that likely reflect the sex dimorphic balance between circulating testosterone and estradiol levels. In men, low testosterone levels are a major risk factor for the MetS, and testosterone replacement therapy has been proposed as treatment option for associated conditions, i.e., type 2 diabetes and cardiovascular disease. The plasma levels and tissue availability of androgens and estrogens are regulated by sex hormone-binding globulin (SHBG), reduced plasma levels of which are a risk factor for the development of MetS. This chapter reviews the biochemical and molecular properties of SHBG and its role in the regulation of androgen and estrogen action; the molecular mechanisms that control the hepatic production of plasma SHBG, and how these are dysregulated in MetS patients. New information linking genetic mutations that may influence SHBG production or function with the etiology of MS-associated diseases are discussed. The utility of plasma SHBG and free testosterone measurements as biomarkers of MetS risk is also reviewed.
Aging is associated with changes in pituitary testicular function in men which are partly explained by changes in the testis and by comorbidities, body weight, nutrition, and the presence of diabetes mellitus. The 0.8–1.3% annual fall in nonSHBG bound “bioavailable” testosterone levels results in a reduction of 30–50% by the sixth to eighth decades of life. Low testosterone concentrations are associated with relative sarcopenia, osteopenia, visceral fat accumulation, reduced sexual function, detectable cognitive impairment, and variable depression of mood. Accordingly, the mechanisms driving the progressive decline in androgens are important to understand. To this end, we highlight age-associated alterations in three dominant sites of physiological control; viz., the hypothalamus, pituitary gland, and testis. The cognate signals are gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and testosterone, which jointly determine androgen availability via feedback and feedforward adaptations. According to this emergent notion, no single gland acts in isolation to maintain homeostasis. We underscore an integrative concept by highlighting how aging-related testosterone depletion is an ensemble outcome of deterioration of interlinked control.
Testosterone (T) declines with increasing age due to depletion of Leydig cells and an impaired testicular response to LH, and changes in hypothalamic–pituitary function which are aggravated by changes due to aging-related chronic illnesses. Obesity, independent of age, is also associated with low T from low SHBG and down-regulation of hypothalamic–pituitary gonadotropin secretion, the mechanisms for which may involve adipokines, pro-inflammatory cytokines and central insulin resistance. In contrast to classical pathological male hypogonadism, the T decline with aging/obesity (so-called late-onset hypogonadism or LOH) is relatively modest, often in the borderline rather than pathological range, and its clinical consequences remain uncertain. According to current practice guidelines, LOH can be recognized when low T is accompanied by cognate symptoms of androgen deficiency. However, the threshold(s) for subnormal T (total or free) and the nature or severity of symptoms are not well defined. Among the common symptoms in aging men that potentially may arise from low T, sexual dysfunction is considered the most specific for hypogonadism. There is also mounting evidence from recent randomized placebo-controlled trials that T replacement in older men with LOH can improve sexual function. Although LOH is often associated with higher central fat mass and insulin resistance, particularly in type 2 diabetics, there is so far insufficient evidence that T treatment results in clinically significant improvement in glucose homeostasis or glycemic control. Low T, independent of obesity, is a predictor of increased overall and cardiovascular mortality. It is likely that low T represents a marker of poor health and obesity, rather than an actual path variable leading to adverse clinical outcomes. This is an important caveat when rationalizing T replacement as symptomatic treatment in older men, in whom the underlying cause of low T should always be sought and managed.
Androgen replacement therapy should be considered for all hypogonadal men with persistent low serum testosterone levels and symptoms of testosterone deficiency. Before commencement of replacement, contraindications to androgen treatment should be identified. In hypogonadal men, androgens improve sexual function, energy and mood, increase muscle mass and strength, as well as bone mineral density. Androgen therapy can be tailored to each patient’s needs and preferences. There are many new androgen delivery systems introduced in the past few years and many more are in development. Selective androgen receptor modulators may have the potential of optimizing beneficial effects while minimizing potential adverse effects. In older men, monitoring of prostate dysfunction and red cell indexes is necessary and important. With care, androgens can be used efficaciously and with minimal potential side effects.
Mild androgen deficiency and inflammation are common features of many systemic chronic illnesses. Nonspecific complaints such as fatigue, reduced energy, and poor sleep in conjunction with observable sarcopenia and osteopenia, are prominent in many of these chronic disorders, and are reminiscent of symptomatic hypogonadism. Unequivocally androgen-responsive organs include bone, striated muscle, cardiac muscle, vascular smooth muscle, brain and adipose tissues. Androgen therapy, by targeting these tissues, could plausibly ameliorate those features of specific chronic illnesses which arise from dysfunction of these organs. However randomized placebo-controlled trials are still required to establish efficacy. This chapter summarizes and tabulates these pivotal randomized placebo-controlled studies, and makes recommendations regarding potential uses and further research.
New knowledge of genetic causes for congenital hypogonadotropic hypogonadism and an expanded understanding of the physiologic principles of male reproductive health enable physicians to better classify and treat hypospermatogenesis in hypogonadotropic men. Nowadays, men with hypothalamic or pituitary disorders have an excellent prognosis for fertility restoration and for paternity by natural intercourse or using assisted reproductive techniques. Effective regimens of subcutaneous injections of hCG and FSH have been developed, and some men can be treated with GnRH using an infusion pump. Gonadotropin treatment is generally initiated by administering hCG for 3–6 months, and if men remain azoospermic, FSH is added. On the other hand, there is some evidence supporting beginning with hFSH. Testosterone or anabolic steroid use often causes azoospermia, and cessation of treatment results in spontaneous recovery of normal spermatogenesis.
... It is released into circulation as a homodimer of identical subunits, containing a single steroid-binding site for active androgens. 7 When discussing testosterone level in elderly, it is important to mention and discuss the free testosterone. As the smallest fraction of testosterone found in circulation, it is not routinely checked in Indonesia. ...
... 13 Winters and Huhtaniemi in his book "Male Hypogonadism: Basic, Clinical and Therapeutic Principles" stated that TRT should be initiated if the repeat morning total testosterone level <350 ng/dL and/or the serum free of bioavailable testosterone are below the normal laboratory reference. 7 In Indonesia or Asia, there is still no specific cutoff values of low total testosterone. One study assessing the level and total free testosterone when the signs and symptoms of andropause appeared. ...
Background: Late Onset Hypogonadism (LOH) is a disease associated with advancing age, characterized by symptoms and a deficiency in serum testosterone. It is important to choose which patient suitable for testosterone replacement therapy (TRT), but there is no one consensus that fits for all. After treating patients with testosterone replacement therapy (TRT), several parameters need to be evaluated. Case: A 74-years old male came with chief complaint of difficulty to maintain erection since 2 years ago.. PADAM questionnaire was positive and IIEF-5 score was 6. Physical examination showed an underweight condition. Total testosterone level was 3,65ng/mL, and patient chose to be given TRT instead of evaluating his free testosterone. PDE-5 inhibitor and non-pharmacologic treatment was also given. Follow-up showed that his erection was improved. Discussions: At which level should testosterone be substituted is still debatable. Several consensuses issued by several organization still cannot be used universally. Study in Indonesia showed that symptoms of LOH had been occur when the testosterone level still in normal range. After giving TRT to our patients, routine follow up is needed. Non pharmacologic treatment also needs to be addressed to improve the outcome. Conclusions: Symptoms of LOH had been occurred even though testosterone level is still in normal range. The consideration made by clinician is the most important thing to be evaluated, whether to give TRT or not. Somatic and laboratory parameters mentioned in this study is important to be evaluated.
... (2) Medical secretion in the seminal fluid after which the pharmaceutical products either become absorbed across the vaginal epithelium into the maternal systemic circulation; migrates through the cervical canal; are carried by the fertilizing spermatozoon into the oocyte; or are transported from the vaginal venous or lymphatic drainage to the uterine artery known as the counter-current mechanism. (3) The presence of the drug in the tissue of the testis as well as the seminal fluid causing cytotoxic and genotoxic damage to the different stages of spermatogenesis. the secretion of immunosuppressive cytokines, lipids and peptides by the Sertoli cells. ...
... the secretion of immunosuppressive cytokines, lipids and peptides by the Sertoli cells. 3 Toxicants change the homeostasis inside the Sertoli cells, causing destabilization of the blood-testis barrier. This process potentially causes medications to pass freely into the adluminal compartment and changes the complex microenvironment, and is thought to increase the oxidative stress inside sperm cells. ...
Introduction:
Immunosuppressant drugs are increasingly used in the reproductive years. Theoretically, such medications could affect fetal health either through changes in the sperm DNA or through fetal exposure caused by a presence in the seminal fluid. This systematic overview summarizes existing literature on the spermatotoxic and genotoxic potentials of methotrexate (MTX), a drug widely used to treat rheumatic and dermatologic diseases, and mycophenolate mofetil (MMF), which alone or supplemented with ganciclovir (GCV) may be crucial for the survival of organ transplants.
Material and methods:
The systematic overview was performed in accordance with the PRISMA guidelines: A systematic literature search of the MEDLINE and EMBASE databases was done using a combination of relevant terms to search for studies on spermatotoxic or genotoxic changes related to treatment with either MTX, GCV or MMF. The search was restricted to English language literature, and to in-vivo animal studies (mammalian species) and clinical human studies.
Results:
A total of 102 studies were identified, hereof 25 human and 77 animal studies. For MTX, human studies of immunosuppressive dosages show transient effect on sperm quality parameters, which return to reference values within 3 months. No human studies have investigated the sperm DNA damaging effect of MTX, but in other organs the genotoxic effects of immunosuppressive doses of MTX are fluctuating. In animals, immunosuppressive and cytotoxic doses of MTX adversely affects sperm quality parameters and show widespread genotoxic damages in various organs. Cytotoxic doses transiently change the DNA-material in all cell stages of spermatogenesis in rodents. For GCV and MMF, data are limited and the results are indeterminate, for which reason spermatotoxic and genotoxic potentials cannot be excluded.
Conclusions:
Data from human and animal studies indicate transient spermatotoxic and genotoxic potentials of immunosuppressive and cytotoxic doses of MTX. Studies investigating GCV and MMF are limited.
... One of its functions is anabolic effects on stimulating tissue growth and development. Testosterone stimulates nitrogen retention and protein synthesis, and is required in order to maintain the structural protein anabolism [7]. By contrast, cortisol is a catabolic hormone. ...
... By contrast, cortisol is a catabolic hormone. Cortisol is a glucocorticoid that is secreted by the adrenal cortex of the adrenal glands [8] and one of its functions is protein degradation [7]. It is also indicated that this hormone is able to prevent protein synthesis and increase muscle mass [8]. ...
Purpose
Different types of physical activity can induce different hormonal and physiological responses. In this study, we examined the testosterone, cortisol, creatine kinase (CK) and lactate dehydrogenase (LDH) response to acute intermittent (IE) and continuous (CE) aerobic exercise in sedentary men.
Methods
In this single-blinded randomised crossover study, eleven sedentary healthy males completed protocols (CE and IE) on two different days separated by a 1-week washout period. CE comprised 40 min of running on a treadmill at 60% of reserve heart rate. IE consisted of 40 min of running on a treadmill with intensity alternating between 50% (2 min) and 80% (1 min) of reserve heart rate. Blood samples were taken before and immediately after each exercise session.
Results
Serum testosterone concentrations increased significantly after IE (+8.0%, P = 0.021) and decreased non-significantly after CE (−5.8%, P = 0.409). The IE response was greater than the CE response (P = 0.01). Cortisol concentration decreased in both IE and CE exercise (P = 0.001 and P = 0.016, respectively), by −33.6 and −34.6%, respectively. The testosterone to cortisol ratio increased significantly after both forms of exercise (IE: P = 0.003; CE: P = 0.041). CK concentrations significantly increased from PRE to POST (IE: +20.6%, P = 0.001; CE: +26.5%, P = 0.046). Despite the increase in concentrations of LDH, the changes were not significant (F(3, 30) = 1.01, P = 0.402; IE: +11.4% and CE: +23.1%).
Conclusions
In summary, it seems that intermittent exercise can be more useful in the development of body anabolic processes in sedentary men due to pronounced increases in testosterone.
... The duration of one spermatogenic cycle (period until the same tubular stage appears again at the same place) is approximately 8.6 days in mice, and approximately 35 days are required for a spermatogonium to develop into a haploid spermatozoon (Oakberg, 1956;Griswold, 2016). In humans, the duration of one spermatogenic cycle is 16 days and the time required for a spermatogonium to develop into a haploid spermatozooñ 68 days, divided into six stages (Amann, 2008;Huhtaniemi and Winters, 2017). ...
Normal function of the C-terminal Eps15 homology domain-containing protein 1 (EHD1) has previously been associated with endocytic vesicle trafficking, shaping of intracellular membranes, and ciliogenesis. We recently identified an autosomal recessive missense mutation c.1192C>T (p.R398W) of EHD1 in patients who had low molecular weight proteinuria (0.7–2.1 g/d) and high-frequency hearing loss. It was already known from Ehd1 knockout mice that inactivation of Ehd1 can lead to male infertility. However, the exact role of the EHD1 protein and its p.R398W mutant during spermatogenesis remained still unclear. Here, we report the testicular phenotype of a knockin mouse model carrying the p.R398W mutation in the EHD1 protein. Male homozygous knockin mice were infertile, whereas the mutation had no effect on female fertility. Testes and epididymes were significantly reduced in size and weight. The testicular epithelium appeared profoundly damaged and had a disorganized architecture. The composition of developing cell types was altered. Malformed acrosomes covered underdeveloped and misshaped sperm heads. In the sperm tail, midpieces were largely missing indicating disturbed assembly of the sperm tail. Defective structures, i.e., nuclei, acrosomes, and sperm tail midpieces, were observed in large vacuoles scattered throughout the epithelium. Interestingly, cilia formation itself did not appear to be affected, as the axoneme and other parts of the sperm tails except the midpieces appeared to be intact. In wildtype mice, EHD1 co-localized with acrosomal granules on round spermatids, suggesting a role of the EHD1 protein during acrosomal development. Wildtype EHD1 also co-localized with the VPS35 component of the retromer complex, whereas the p.R398W mutant did not. The testicular pathologies appeared very early during the first spermatogenic wave in young mice (starting at 14 dpp) and tubular destruction worsened with age. Taken together, EHD1 plays an important and probably multifaceted role in spermatogenesis in mice. Therefore, EHD1 may also be a hitherto underestimated infertility gene in humans.
... Banaszewska et al. did not find significant differences between LH/FSH ratio means between women with and without PCOS [18]. In our study, we found it to be significantly lower in infertile PCOS than fertile PCOS group and control; a comparative study disagrees with our results regarding the non-fertile group only and states that LH and LH/FSH ratio showed insignificant results in the PCOS group [19,20], this discrepancy in LH and the ratio possibly can be justified by the BMI of the participants as the means of our sample were in the overweight range for all groups and this tends to lower the LH value in the current study [21]. ...
... Sex hormone-binding globulin (SHBG) is a crucial biomarker for the prediction of GDM in the first trimester of pregnancy. Increased SHBG biosynthesis is activated by high oestrogen levels in pregnancy (Winters 2004); however, decreased serum levels are associated with insulin resistance and type 2 diabetes mellitus (Ding et al. 2009;Le et al. 2012). This inverse relationship between SHBG and insulin resistance forms the basis of our hypothesis that first trimester SHBG levels would serve as a reliable predictor of GDM development in the study population. ...
There has been a steady rise in the disease burden of Gestational Diabetes Mellitus (GDM) in the sub-Saharan African region over time. Diagnostic testing for GDM is currently recommended at 24 − 28 weeks of gestation, leaving a narrow window for intervention before delivery. Hence the need for early prediction and preventive intervention. The performance of first trimester serum sex hormone-binding globulin (SHBG) assay as a predictor of GDM was determined by binary logistic regression. Women with GDM (n = 49) had a significantly lower mean first trimester SHBG level (104.7 ± 61.6 nmol/L) than did those without GDM (n = 180; 265.2 ± 141.5 nmol/L; p
... While [16] indicated that the thickening of the sperm tubing walls may be due to the secretion of Sertoli cells Collagen Fibers IV, thus causing poor spermatogenesis development, While the researchers reported [17] that the weak relationship between the epithelium Spermatogonic and interstitial tissue may be due to the increase in the thickness of the wall Seminiferous tubule and with this increase shows a lot of changes within the testicle, especially in Sertoli cells that directly affect the differentiation and The development of germ cells. The results of present study also showed the emergence of Vaculation and in some sections of the sperm tubules Seminiferous tubule as well as the widening of the distance between the germ cells, and ecdysis of the epithelial tissue and aggregation in the cavity of some Seminiferous tubule as well as the occurrence of degeneration and increase the distance between neighboring Sertoli cells as shown in the Figures (1, 2, 3). ...
... Alternatively, the diagnosis of LOH (characterized by consistently low testosterone levels and combinations of symptoms related to androgen deficiency but without identifiable mechanisms other than those related to aging or lifestyle) [13,16,17] is prevalent among western men [1,23]. While diagnostic criteria for classical hypogonadism seem clear [13,36], diagnosis of LOH varies by specialist, lab, medical society, and region [13,16,17,24,35,37]. Furthermore, much of the expansion of U.S. PT sales has been driven by off-label indications such as LOH or treatment of androgen levels without a reported diagnosis [7,31]. ...
Prescription testosterone sales in the United States have skyrocketed in the last two decades due to an aging population, direct-to-consumer advertising, and prescriber views of the benefits and risks to testosterone, among other factors. However, few studies have attempted to directly examine patient experiences on prescription testosterone therapy. The present exploratory study involved an online self-report survey of U.S. testosterone patients who were at least 21 years of age. The primary focus was on patient perspectives concerning motivations leading to the initiation of testosterone therapy and the perceived effects of treatment. Responses to open-ended questions drew upon a coding scheme incorporating both inductive and deductive approaches, influenced by the clinical, male life history theory, and behavioral endocrinology literature. Results indicated that the most frequent reasons men gave for taking prescription testosterone were low testosterone (37.1%), well-being (35.2%), energy (28.7%), libido (21.9%), and social energy (19.4%); older men claimed libido as a motivation for testosterone initiation more frequently than younger men (p < 0.001). Men most frequently claimed testosterone improved their energy (52.3%), libido (41.9%), and muscle (28.5%). Results are interpreted in the context of medical, life history theoretical and behavioral endocrinology approaches, including an emphasis on sex and energy.
... As a novel tool in this population, we will also implement the assessment of autonomous nervous function by means of heart rate variability, throughout the exercise protocol as well as the consecutive nights. Furthermore, measures of hormone concentrations will provide an objective measure to determine the anabolic or catabolic state, acutely induced by a single exercise session and chronically after 4 weeks of training [36]. ...
Exercise has been well demonstrated to potentially reduce chemotherapy-induced side effects and possibly aid slowing down tumor growth in cancer patients but exercise training adherence is typically low. Thus, training regimens which are perceived less strenuous but do not compromise the training-induced beneficial adaptations will help to increase adherence to exercise and reduce attrition.
This 4-armed study aims to investigate the effects of high intensity interval training (HIIT) in hyperoxia versus intermittent hyperoxia and hypoxia in cancer patients undergoing chemotherapy. Forty-eight cancer patients will be randomized into either of three intervention groups or a no-training control group. Patients in the intervention groups will perform twice weekly HIIT on a cycle ergometer in hyperoxia, intermittent hyperoxia and hypoxia or normoxia. Study outcomes will be assessed before and after 4 weeks of training, while selected measures will also be performed pre- and post the first and last training session. The primary aim of this study is to investigate the feasibility, compliance, tolerance and safety of the training. Secondary endpoints will include measures of quality of life, aerobic capacity, transcutaneous oxygen saturation, red blood cell deformability, as well as the assessment of anabolic and catabolic hormone concentrations, reactive oxygen species, cytokine profiles and NK-cell cytotoxicity.
To the best of our knowledge, this is the first study investigating the combined effects of exercise with modified fraction of inspired O2 in cancer patients. As such, we provide a novel approach for exercise as an adjuvant therapy in cancer patients undergoing chemotherapy.
Epidemiological studies suggest an association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). This study aimed to investigate the pathophysiological markers of AD vs. T2DM for each sex separately and propose models that would distinguish control, AD, T2DM, and AD-T2DM comorbidity groups. AD and T2DM differed in levels of some circulating steroids (measured mostly by GC-MS) and in other observed characteristics, such as markers of obesity, glucose metabolism, and liver function tests. Regarding steroid metabolism, AD patients (both sexes) had significantly higher sex hormone binding globulin (SHBG), cortisol, and 17-hydroxy progesterone, and lower estradiol and 5α-androstane-3α,17β-diol, compared to T2DM patients. However, compared to healthy controls, changes in the steroid spectrum (especially increases in levels of steroids from the C21 group, including their 5α/β-reduced forms, androstenedione, etc.) were similar in patients with AD and patients with T2DM, though more expressed in diabetics. It can be assumed that many of these steroids are involved in counter-regulatory protective mechanisms that mitigate the development and progression of AD and T2DM. In conclusion, our results demonstrated the ability to effectively differentiate AD, T2DM, and controls in both men and women, distinguish the two pathologies from each other, and differentiate patients with AD and T2DM comorbidities.
This review presents a comprehensive discussion of the clinical condition of delayed puberty, a common presentation to the paediatric endocrinologist, which may present both diagnostic and prognostic challenges. Our understanding of the genetic control of pubertal timing has advanced thanks to active investigation in this field over the last two decades, but remains in large part a fascinating and mysterious conundrum. The phenotype of delayed puberty is associated with adult health risks and common etiologies, and there is evidence for polygenic control of pubertal timing in the general population, sex-specificity and epigenetic modulation. Moreover, much has been learned from comprehension of mono- and di-genic etiologies of pubertal delay and associated disorders and, in recent years, knowledge of oligo-genic inheritance in conditions of GnRH deficiency. Recently there have been several novel discoveries in the field of self-limited delayed puberty, encompassing exciting developments linking this condition to both GnRH neuronal biology and metabolism and body mass. These data together highlight the fascinating heterogeneity of disorders underlying this phenotype and point to areas of future research where impactful developments can be made.
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