Hypogonadism in Children with a Previous History of Cancer: Endocrine Management and Follow-Up.

Hypogonadism after treatment for childhood cancer is a recognized complication and its cause may be subdivided into primary gonadal failure and central hypogonadism. Here, we provide an overview of the risk factors for the development of hypogonadism, assessment and potential interventions and give a summary of the current recommendations for management and follow-up of hypogonadism in childhood cancer survivors.

Association between serum levels of testosterone and biomarkers of subclinical atherosclerosis.

OBJECTIVE: To investigate the association between serum levels of testosterone and biomarkers of subclinical atherosclerosis based on data from 119 middle-aged men of the general population. METHODS: Testosterone, Apolipoprotein A-1 (ApoA-1), Apolipoprotein B (ApoB), Apolipoprotein B-to-Apolipoprotein A-1 ratio (ApoB-to-ApoA-1), high-sensitive C-reactive protein (hsCRP), and fibrinogen levels were measured. Data were also gathered based on age, BMI, waist circumference, smoking, alcohol consumption, and family history of cardiovascular diseases. Men were classified into two groups based on testosterone levels: hypogonadal (testosterone ≤12 nmol/L) and eugonadal men (testosterone >12 nmol/L). RESULTS: When compared to eugonadal, the hypogonadal men were significantly older (56 years vs. 55 years, p = .03), had greater BMI (28 kg/cm2 vs. 26 kg/cm2, p = .01), and higher waist circumference (104 cm vs. 100 cm, p = .01). Moreover, ApoB, ApoB-to-ApoA-1 ratio, and hsCRP were significantly higher in hypogonadal men compared to eugonadal men (1.1 g/L vs. 1.0 g/L, p = .03), (0.8 vs. 0.7, p = .03), (3.3 mg/L vs. 2.0 mg/L, p = .01), respectively. On the other hand, ApoA-1 and fibrinogen levels did not differ significantly between groups (p > .05). In an adjusted multivariate regression analysis model, only ApoB showed a significant negative association with testosterone levels (ß = -0.01; 95% CI = -0.02, -1.50; p = .04). CONCLUSION: Testosterone levels showed an inverse relation to ApoB, a biomarker implicated in subclinical atherosclerosis. These findings support the hypothesis that low testosterone levels play a role in atherosclerosis.

Medical management of non-obstructive azoospermia.

Non-obstructive azoospermia is diagnosed in approximately 10% of infertile men. It represents a failure of spermatogenesis within the testis and, from a management standpoint, is due to either a lack of appropriate stimulation by gonadotropins or an intrinsic testicular impairment. The former category of patients has hypogonadotropic hypogonadism and benefits from specific hormonal therapy. These men show a remarkable recovery of spermatogenic function with exogenously administered gonadotropins or gonadotropin-releasing hormone. This category of patients also includes some individuals whose spermatogenic potential has been suppressed by excess androgens or steroids, and they also benefit from medical management. The other, larger category of non-obstructive azoospermia consists of men with an intrinsic testicular impairment where empirical medical therapy yields little benefit. The primary role of medical management in these men is to improve the quantity and quality of sperm retrieved from their testis for in vitro fertilization. Gonadotropins and aromatase inhibitors show promise in achieving this end point.

Medical management of non-obstructive azoospermia

Non-obstructive azoospermia is diagnosed in approximately 10% of infertile men. It represents a failure of spermatogenesis within the testis and, from a management standpoint, is due to either a lack of appropriate stimulation by gonadotropins or an intrinsic testicular impairment. The former category of patients has hypogonadotropic hypogonadism and benefits from specific hormonal therapy. These men show a remarkable recovery of spermatogenic function with exogenously administered gonadotropins or gonadotropin-releasing hormone. This category of patients also includes some individuals whose spermatogenic potential has been suppressed by excess androgens or steroids, and they also benefit from medical management. The other, larger category of non-obstructive azoospermia consists of men with an intrinsic testicular impairment where empirical medical therapy yields little benefit. The primary role of medical management in these men is to improve the quantity and quality of sperm retrieved from their testis for in vitro fertilization. Gonadotropins and aromatase inhibitors show promise in achieving this end point.

Molecular defects of the GnRH-receptor gene in Chinese patients with idiopathic hypogonadotropic hypogonadism and the severity of hypogonadism.

BACKGROUND: Human mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene cause normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein-coupled receptor, which consist mostly of missense mutations. OBJECTIVES: To identify and determine the frequency of mutations in the coding region of the gonadotropin-releasing hormone receptor (GnRHR) gene in forty Chinese patients with normosmic idiopathic hypogonadotropic hypogonadism (IHH) and establish genotype/phenotype correlations where possible. METHODS: The diagnosis of HH was based on absent or incomplete sexual development after 17 years of age in girls and 18 years in boys associated with low or normal levels of LH in both sexes and low levels of testosterone in males and of estradiol in females. All patients presented with a normal sense of smell in an olfactory specific test. Forty IHH patients and 40 controls were screened for mutations in the coding sequence of the GnRHR gene. The coding region of the GnRHR gene was amplified by PCR and directly sequenced. RESULTS: A missense mutation, serine 168 arginine (S168R), located in the fourth transmembrane domain of the GnRHR gene, was identified as being in a homozygous state in one male with complete HH. The S168R mutation has been previously shown to be a cause in the complete loss of receptor function because hormone binding to the receptor is completely impaired. In another patient, a compound heterozygous mutation (Gln106Arg and Arg262Gln) was identified in a male with partial HH. The Gln106Arg mutation is located in the first extracellular loop of GnRH-R, this mutation decreases but not does eliminate GnRH binding; while Arg262Gln mutation is located in the third extracellular loop of GnRH-R and only decreases signal transduction. A good correlation between genotype and phenotype was found in our patients. The patient, who was homozygous for the completely inactivating S168R mutation, had complete HH. In addition, the affected patient who was compound heterozygous for the Glnl06Arg--Arg262Gln mutations - has partial HH. CONCLUSIONS: GnRHR mutations can be classified into partial or complete loss of function mutations. Partially inactivating substitutions of the GnRHR frequently found in familial hypogonadotrophic hypogonadism are Q106R and R262Q. Comparison of compound heterozygous with homozygous patients suggests that their phenotype and the response to GnRH is determined by the GnRHR variant with the less severe loss of function.

How to recognize late-onset hypogonadism in men with sexual dysfunction.

Late-onset hypogonadism (LOH) has been considered the most common form of male hypogonadism with a prevalence of approximately 1 in 100 men. Diagnosis of LOH should be made in symptomatic men with unequivocally low serum testosterone (T) levels. However, its clinical presentation is often insidious and difficult to recognize because it is characterized by nonspecific symptoms that make differential diagnosis with physiological ageing problematic. Sexual dysfunction is the most important determinant for medical consultation and the most specific symptom associated with low T. We therefore analysed a consecutive series of 1734 subjects who attended our unit for sexual dysfunction to investigate the associations between low T (different thresholds), sexual parameters, medical history data (delayed puberty, pituitary disease or cryptorchidism) and their physical exam results. Metabolic parameters, in particular waist circumference, display the greatest accuracy in detecting low T. We found that only the association of several symptoms and signs could significantly raise the clinical suspicion of low T. Structured inventories, which cluster together symptoms and signs of hypogonadism, can help clinicians suspect androgen deficiency. In particular, structured interviews, such as ANDROTEST, have been demonstrated to have a greater accuracy when compared to self reported questionnaires in detecting low T levels.

Terapia de privación de andrógenos y obesidad mórbida: ¿tienen en común el riesgo cardiovascular por síndrome metabólico? / Androgen Deprivation Therapy And Morbid Obesity: Do They Share Cardiovascular Risk Through Metabolic Syndrome?

Antecedentes: A pesar de que el uso de la terapia de privación de andrógenos (TPA) ha producido una mejora en la supervivencia de hombres con cáncer de próstata avanzado, el hipogonadismo resultante se asocia con efectos negativos acusados, comparables a los que se observan en la obesidad mórbida, estando el riesgo cardiovascular entre los más letales. Objetivos: Evaluar el síndrome metabólico, las anomalías metabólicas y el riesgo cardiovascular en pacientes con cáncer de próstata sometidos a TPA, sin TPA y con obesidad mórbida. Métodos: Se trata de un estudio transversal que incluye a 79 hombres con cáncer de próstata, de los cuales 54 están sometidos a TPA y en 25 está ausente esta terapia, incluyéndose también a 91 pacientes con obesidad mórbida agrupados por sexo y edad. Para definir el síndrome metabólico empleamos los criterios de la Federación Internacional de Diabetes (FID). Se compararonl as anomalías metabólicas, los marcadores metabólicos y la puntuación Framingham entre los pacientes en terapia TPA, sin terapia TPA y con obesidad mórbida con el fin de predecir el riesgo de enfermedad coronaria a 10 años. Resultados: Los pacientes en terapia TPA presentaron una incidencia mucho mayor de diabetes y obesidad centralizada, así como mayores niveles de colesterol total y lipoproteínas de baja densidad (LBD), en comparación con los varones eugonadales. El riesgo cardiovascular medio fue significativamente superior en pacientes sometidos a TPA (39,97±12,53% vs. 26,09±14,80%; p = 0,021). Los sujetos con obesidad mórbida tenían un mayor riesgo de enfermedad coronaria a 10 años, comparable a la de los pacientes sometidos a TPA (p = 0,054). Conclusión: Este estudio apunta a que en los pacientes sometidos a TPA la preponderancia de anomalías metabólicas y riesgos cardiovasculares es mayor, siendo similar a la observada en sujetos con obesidad mórbida. Es posible que ambos procesos tengan en común el riesgo cardiovascular por vía de síndrome metabólico (AU)

Background: Although the use of androgen deprivation therapy (ADT) has resulted in improved survival in men with advanced prostate cancer, the resulting hypogonadism is associated with profound adverse effects comparable to those found in morbid obesity, being cardiovascular risk among the most lethal. Objectives: Evaluate metabolic syndrome, metabolic abnormalities and cardiovascular risk in patients with prostate cancer under ADT, not under ADT and morbid obese men. Methods: This is a cross-sectional study that involves 79 men presenting prostate cancer, of whom 54 under ADT and 25 not under ADT and 91 morbidly obese patients paired by sex and age. To define metabolic syndrome, we used the International Diabetes Federation (IDF) criteria. Metabolic abnormalities, metabolic markers and Framingham score to predict the ten year coronary heart disease risk were compared among patients under ADT, not under ADT and morbid obese. Results: Patients under ADT presented significantly greater occurrence of diabetes and central obesity and higher levels of total cholesterol and low density lipoprotein (LDL) compared to eugonadal men. The mean cardiovascular risk was significantly higher in patients under ADT (39.97±12.53% vs. 26.09±14.80%; p = 0.021). Morbidly obese subjects had increased ten year coronary heart disease risk; comparable to patients under ADT (p = 0.054). Conclusion: This study suggests that patients under ADT show higher prevalence of metabolic abnormalities and cardiovascular risk similar to those found in morbidly obese subjects. It is possible that both processes share cardiovascular risk through metabolic syndrome (AU)

Epidemiology, diagnosis, and treatment of male hypogonadotropic hypogonadism.

Hypogonadotropic hypogonadism (HH), or secondary hypogonadism, is a clinical condition due to an impairment of the pituitary function, characterized by low testosterone plasma levels associated with normal or low FSH and LH plasma levels. An impairment of gonadotropin secretion and, therefore, a reduced efficiency of spermatogenesis was reported to be frequently associated to conditions different from the classical causes of secondary hypogonadism. These conditions (metabolic, endocrine and eating disorders, physical exercise etc.) have been associated with a non-classical form of HH that could be called "functional" HH (FHH). FHH differs from the classical one by the evidence that gonadotropin levels are in the low-normal range, but are inadequate for the testosterone levels, that often are also in the low-normal range. This commentary aims at reviewing knowledge on the forms of male HH in order to indicate and discuss clinical context, diagnostic and therapeutic approach in the less known non-classical form, i.e. FHH.

Is intracytoplasmic sperm injection essential for the treatment of hypogonadotrophic hypogonadism? A comparison between idiopathic and secondary hypogonadotrophic hypogonadism.

Although infertility of hypogonadotrophic aetiology is uncommon (0.5-1%), it is important as a potentially treatable cause of male infertility. Broadly, hypogonadotrophic hypogonadism (HH) is divided into two categories, idiopathic and secondary postpubertal. In order to determine whether gonadotrophin replacement is sufficient to treat hypo gonadotrophic infertile men or there is a substantial need for intracytoplasmic sperm injection to increase chances of pregnancy, we performed a retrospective clinical analysis of seventeen hypogonadotrophic adult men (aged 25-38). Five patients had orchiopexy for cryptorchidism; three prepubertal and two postpubertal. All had non-obstructive azoospermia and received a combination of human chorionic gonadotrophin (hCG) and follicle stimulating hormone (FSH) for 4-24 months. Viable sperms started to appear in the ejaculate 3 months after treatment. Natural conception was achieved in six men with secondary HH (developed after head trauma, infection and surgery). By contrast, intracytoplasmic sperm injection (ICSI) was needed to produce successful fertilisation in the eleven men with idiopathic HH after failed gonadotrophin treatment. In conclusion, we recommend that ICSI should be considered, in addition to gonadotrophins to enhance the fertility of men with IHH, once oligospermic.

Hipogonadismo masculino / Male hypogonadism

El hipogonadismo masculino es un síndrome que involucra la falla testicular en cuanto a la producción de andrógenos y de una espermatogénesis adecuada. En este Consenso se discutirán, exclusivamente, los aspectos vinculados al déficit de andrógenos. La deficiencia androgénica es una situación clínica frecuente. El síndrome de Klinefelter tiene una prevalencia de 1 en 500 recién nacidos vivos y si se suman otras causas congénitas o adquiridas de lesiones testiculares e hipotálamo-hipofisarias, se estima que alrededor de 1 en 200 hombres presentan reducción de los niveles circulantes de testosterona (T). Si, además, se considera la deficiencia androgénica asociada al envejecimiento, esta prevalencia aumenta significativamente. El hipogonadismo en su presentación clínica clásica es de fácil diagnóstico, pero las formas menos severas presentan dificultades para su reconocimiento. Sin embargo, es de fundamental importancia establecer con certeza la deficiencia androgénica antes de iniciar cualquier terapia de sustitución debido a los riesgos potenciales

NCEP-ATPIII-defined metabolic syndrome, type 2 diabetes mellitus, and prevalence of hypogonadism in male patients with sexual dysfunction.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are characterized by insulin resistance and often associated with male hypogonadism. AIM: To discriminate the specific contribution of T2DM and MetS to male hypogonadism. METHODS: A consecutive series of 1,134 (mean age 52.1 +/- 13 years) male patients with sexual dysfunction was studied. MAIN OUTCOME MEASURES: Several hormonal and biochemical parameters were studied along with ANDROTEST, a 12-item validated structured interview, specifically designed for the screening of hypogonadism (total testosterone [TT] <10.4 nmol/L or free testosterone [FT] <37 pmol/L) in a male population with sexual dysfunction. RESULTS: Irrespective of the criteria used to define hypogonadism, MetS was associated with a significantly higher prevalence of the condition, both in subjects with and without T2DM (41% and 29% vs. 13.2% and 77.1% and 58% vs. 40.6%, respectively, for TT and FT in patients with MetS and with or without T2DM, when compared with subjects without MetS and T2DM; both P < 0.0001). Conversely, T2DM was associated with a higher prevalence of hypogonadism in subjects with MetS but not in those without MetS. Patients with MetS, with or without T2DM, also showed a higher ANDROTEST score when compared with patients without MetS. Logistic multivariate regression analysis, incorporating the five components of MetS, identified a significant association of elevated waist circumference and hypertriglyceridemia with hypogonadism both in patients, with or without T2DM. CONCLUSIONS: Our study demonstrated that MetS, and in particular visceral adiposity (as assessed by increased waistline and hypertriglyceridemia), is specifically associated with hypogonadism in subjects consulting for sexual dysfunction.

[Partial androgen deficiency in aging male (Padam syndrome): terminology and current approaches to choice of replacement hormonal therapy].

The authors propose a novel approach to treatment of PADAM syndrome based on stimulation of synthesis of endogenic testosterone. A total of 150 patients with PADAM were examined in the Endocrinological Research Center. The examination included physical and andrological examinations with digital rectal investigation of the prostate, filling-in questionnaires, hormonal and biochemical tests. In view of positive test with chorionic gonadotropin (CG), therapy of choice was stimulating therapy with CG. The dose was adjusted individually - from 1000 to 3000 units once in 4 days (1000 units dose was given to 20% patients, 2000 - to 70% and 3000 - to 10% patients). Efficacy did not reduce in long-term treatment. The authors make the following conclusion: choice of PADAM therapy should be individual and based on the age of the patient, body mass index, the necessity to retain spermatogenesis, packed cell volume, associated diseases. Secondary nature of PADAM and positive test for CG allows usage of CG as a perspective therapy in prevention and treatment of age-related lowering of testosterone.

[The genetics of hypogonadotropic hypogonadism in the male]. / Hypogonadotroper Hypogonadismus beim Mann. Abklärungskaskade vom Hirn bis ins Genom.

Underlying causes of hypogonadotropic hypogonadism are acquired or congenital disorders of the hypothalamus or pituitary (e.g. pituitary adenoma, craniopharyngioma, prior radiotherapy, trauma, severe general diseases, extreme stress, genetic mutations). In addition to a comprehensive history and physical examination, the diagnostic work-up includes measurement of testosterone, LH and FSH, with the aim of differentiating between primary and secondary hypogonadism. Where indicated, investigation of pituitary function, the use of imaging procedures, possibly an olfactory test, a GnRH stimulation test or genetic analyses may be added. Depending upon the indication, treatment is effected with testosterone, GnRH or gonadotropines.

Delta-4-androstene-3,17-dione binds androgen receptor, promotes myogenesis in vitro, and increases serum testosterone levels, fat-free mass, and muscle strength in hypogonadal men.

Previous studies of Delta 4-androstene-3,17-dione (4-androstenedione) administration in men have not demonstrated sustained increments in testosterone levels, fat-free mass (FFM), and muscle strength, and failure to demonstrate androstenedione's androgenic/anabolic effects has stifled efforts to regulate its sales. To determine whether 4-androstenedione has androgenic/anabolic properties, we evaluated its association with androgen receptor (AR) and its effects on myogenesis in vitro. Additionally, we studied the effects of a high dose of 4-androstenedione on testosterone levels, FFM, and muscle strength in hypogonadal men. We determined the dissociation constant (K(d)) for 4-androstenedione using fluorescence anisotropy measurement of competitive displacement of fluorescent androgen from AR ligand-binding domain. AR nuclear translocation and myogenic activity of androstenedione were evaluated in mesenchymal, pluripotent C3H10T1/2 cells, in which androgens stimulate myogenesis through an AR pathway. We determined effects of a high dose of androstenedione (500 mg thrice daily) given for 12 wk on FFM, muscle strength, and hormone levels in nine healthy, hypogonadal men. 4-Androstenedione competitively displaced fluorescent androgen from AR ligand-binding domain with a lower affinity than dihydrotestosterone (K(d), 648 +/- 21 and 10 +/- 0.4 nm, respectively). In C3H10T1/2 cells, 4-androstenedione caused nuclear translocation of AR and stimulated myogenesis, as indicated by a dose-dependent increase in myosin heavy chain II+ myotube area and up-regulation of MyoD protein. Stimulatory effects of 4-androstenedione on myosin heavy chain II+ myotubes and myogenic determination factor expression were attenuated by bicalutamide, an AR antagonist. Administration of 1500 mg 4-androstenedione daily to hypogonadal men significantly increased serum androstenedione, total and free testosterone, estradiol, and estrone levels and suppressed SHBG and high-density lipoprotein cholesterol levels. 4-androstenedione administration was associated with significant gains in FFM (+1.7 +/- 0.5 kg; P = 0.012) and muscle strength in bench press (+4.3 +/- 3.1 kg; P = 0.006) and leg press exercises (+18.8 +/- 17.3 kg; P = 0.045). 4-androstenedione is an androgen that binds AR, induces AR nuclear translocation, and promotes myogenesis in vitro, with substantially lower potency than dihydrotestosterone. 4-androstenedione administration in high doses to hypogonadal men increases testosterone levels, FFM, and muscle strength, although at the dose tested, the anabolic effects in hypogonadal men are likely because of its conversion to testosterone.

[Testosterone deficiency and the problem of normal values]. / Testosteronmangel und die Problematik der Normwerte.

If a testosterone deficiency is demonstrated, the exact cause of the endocrine hypogonadism should be determined by appropriate endocrinological, imaging and other andrological diagnostic techniques, as such a deficiency can be the result of various illnesses. At present there are no satisfactory evidence based, generally accepted norms for testosterone levels recognised for the aging male. Laboratory analysis of testosterone must be carried out taking into consideration the physiological variability using methods validated in house, with strict internal and external quality control. For the diagnosis of reduced testosterone levels, satisfactorily established own normal values for the technique used are recommended.

[Diagnosis and therapy of hypogonadism in adult males]. / Diagnostik und Therapie des Hypogonadismus bei erwachsenen Männern.

Hypogonadism in men is defined as endocrine dysfunction of the testes, and due to reduced serum testosterone levels leads to symptoms of testosterone deficiency. Depending on the location of disruption in the endocrinological cycle, hypogonadism is classified as primary, secondary, or tertiary. In primary hypogonadism, the production of testosterone in the Leydig's cells of the testes does not function properly. Serum LH concentrations are elevated in the sense of counterregulation (hypogonadotropic hypogonadism). In secondary hypogonadism, LH secretion (and usually also FSH) from the hypophysis is impaired so that Leydig's cells are not stimulated, while in tertiary hypogonadism the hypothalamus is damaged. The clinical course in cases of reduced serum testosterone levels is determined essentially by the point in time when hypogonadism becomes manifest. Delayed puberty, eunuchoid stature, and underdeveloped secondary sex characteristics suggest prepubertal onset of hypogonadism.

Andrógenos y hueso en la mujer / Androgens and bone in women

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