Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment.

Objective: To evaluate the degree of E-2 deficiency in male congenital hypogonadotropic hypogonadism (CHH), and its response to different hormonal treatments.Design: Retrospective and prospective studies.Setting: Academic institution.Patient(s): Untreated or treated CHH, healthy men, untreated men with Klinefelter syndrome (KS). Intervention(s): Serum sex hormone-binding globulin (SHBG) and total E-2 (TE2) as well as bioavailable (BE2) and free (FE2) levels were measured and determined.Main Outcome Measure(s): Total, bioavailable, and free testosterone, TE2, BE2, FE2 were compared in normal men, untreated and treated CHH and in untreated KS.Result(s): TE2, BE2, and FE2 levels were very significantly lower in untreated patients with CHH (n = 91) than in controls (n = 63) and in patients with KS (n = 45). The TE2 correlated positively with serum total T in patients with CHH. The TE2 also correlated very positively with serum LH in the combined population of patients with CHH and healthy men, suggesting that low E-2 levels in CHH are due to severe LH-driven T deficiency. All fractions of circulating E-2 were very significantly higher in patients with CHH receiving T enanthate (n = 101) or the FSH-hCG combination (n = 88) than in untreated patients with CHH. Contrary to dihydrotestosterone (DHT), both T enanthate and combined FSH-hCGtherapy significantly and prospectively increased TE2 levels in patients with CHH.Conclusion(s): Contrary to KS, the male hypogonadism observed in CHH is associated with profound E-2 deficiency, which can be overcome by aromatizable androgen or combined gonadotropin therapy. (Fertil Steril (R) 2011; 95: 2324-29. (C) 2011 by American Society for Reproductive Medicine.)

Hypothalamic-pituitary-gonadal function in men with liver cirrhosis before and after liver transplantation

Objective: To evaluate the influence of end-stage liver disease and orthotopic liver transplantation in the pituitary function and hormone metabolism before and after liver transplantation.Methods: In a prospective study, serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and prolactin (PRL) of 30 male patients with cirrhosis were determined two to four hours before and six months after liver transplantation. The results were compared according to the Model for End-stage Liver Disease (MELD).Results: male patients with liver cirrhosis have hypogonadism. FSH was normal, but inappropriately low due to androgen failure; E2 and PRL, on their turn, were high. After liver transplantation, FSH and LH levels increased (p < 0.05), whereas E2 and PRL normalized (p < 0.05). The MELD score did not influence changes in FSH, PRL and LH, however, the more severe the cirrhosis was, the more significant was the normalization of E2 (p = 0.01).Conclusion: Patients with cirrhosis and male hypogonadism have inappropriately normal levels of FSH and LH, associated with an increase in E2 and LRP. After liver transplantation, FSH and LH increased, while E2 and PRL returned to normal. Changes in E2 levels were most pronounced in patients with MELD > 18. The severity of cirrhosis had no influence on FSH, PRL and LH.

Inactivating Mutations of the Human Luteinizing Hormone Receptor in Both Sexes

The human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) plays a fundamental role in male and female reproductive physiology. Over the past 15 years, several homozygous or compound heterozygous loss-of-function mutations in the LHCGR gene have been described in males and females. In genetic males, mutations in LHCGR were associated with distinct degrees of impairment in pre- and postnatal testosterone secretion resulting in a phenotypic spectrum. Patients with the severe form of LH resistance have predominantly female external genitalia and absence of secondary sex differentiation at puberty. Patients with milder forms have predominantly male external genitalia with micropenis and/or hypospadias or only infertility without ambiguity. The undermasculization is associated with low basal, as well as human CG-stimulated, testosterone levels and elevated LH levels after pubertal age, without abnormal step-up in testosterone biosynthesis precursors. The testes have only slightly reduced size but mature Leydig cells are absent or scarce (Leydig cell hypoplasia). Genetic females with inactivating LHCGR mutations have female external genitalia, spontaneous breast and pubic hair development at puberty, and normal or late menarche followed by oligoamenorrhea and infertility. Estradiol and progesterone levels are normal for the early to midfollicular phase, but do not reach ovulatory or luteal phase levels. Serum LH levels are high whereas follicle-stimulating hormone levels are normal or only slightly increased. Pelvic ultrasound has demonstrated a small or normal uterus and normal or enlarged ovaries with cysts. The inactivating mutations of the LHCGR have provided important insights into distinct physiological roles of LH in reproduction of both sexes.

Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort

BACKGROUND & AIMS Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

[Klinik und Diagnose von Hypogonadismus und Andropause]

Diagnosis and therapy of male hypogonadism is still a challenge because of the unspecific clinical signs and symptoms. The clinical presentation of a androgen deficiency is age-related. In the adult men, one can often observe fatigue, decrease in physical capacity, loss of libido and erectile dysfunction. At the physical examination, genitalia have always to be assessed in search of a testes/penis atrophy. Two fasting measurements of total testosterone concentrations by a reliable assay are needed to confirm the diagnosis. By assessing gonadotropines the origin of hypogonadism can be determined (central/secondary or peripheral/primary). Exogenous administration of androgens should be considered in young, sportive, healthy and muscular males. Patients with metabolic syndrome should only be screened for hypogonadism in the presence of suggestive symptoms. Prostate disease, hematocrit higher than 50 %, uncontrolled heart failure and severe obstructive sleep apnea are contraindications of a testosterone replacement therapy. Patients with metabolic-syndrome-associated low testosterone levels should firstly benefit from a lifestyle intervention that can normalize clinical and biochemical hypogonadism. So far, there is no clear evidence for a possible benefit of testosterone therapy in patients with the metabolic syndrome. Similarly, in patients with PADAM (partial androgen deficiency of the aging male) testosterone therapy is not established or recommended.

Hipogonadismo : revisão a propósito de 3 casos clínicos

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Hypogonadism in male cancer patients: A cross-sectional study

Introduction. Cancer is the second most common cause of death in the USA (2). Studies have shown a coexistence of cancer and hypogonadism (9,31,13). The majority of patients with cancer develop cachexia, which cannot be solely explained by anorexia seen in these patients. Testosterone is a male sex hormone which is known to increase muscle mass and strength, maintain cancellous bone mass, and increase cortical bone mass, in addition to improving libido, sexual desire, and fantasy (14). If a high prevalence of hypogonadism is detected in male cancer patients, and a significant difference exists in testosterone levels in cancer patients with cachexia versus those without cachexia, testosterone may be administered in future randomized trials to help alleviate cachexia. Study group and design The study group consisted of male cancer patients and non-cancer controls aged between 40 and 70 years. The primary study design was cross-sectional with a sample size of 135. The present data analysis is done on a subset convenience sample of 72 patients recruited between November 2006 and January 2010. ^ Methods. Patients aged 40-70 years with or without a diagnosis of cancer were recruited into the study. All patients with a BMI over 35, significant edema, non-melanomatous skin cancer, current alcohol or illicit drug abuse, concomitant usage of medications interfering with gonadal axis, and anabolic agents, patients on tube feeds or parenteral nutrition within 3 months prior to enrollment were excluded from the study. The study was approved by the Institutional Review Board of Baylor College of Medicine and is being conducted at the Michael E. DeBakey Veterans Affairs Medical Center at Houston. My thesis is a pilot data analysis that employs a smaller subset convenience sample of 72 patients determined by using the data available for the 72 patients (of the intended sample of 135 patients) recruited between November 2006 and January 2010. The primary aim of this analysis is to compare the proportion of patients with hypogonadism in the male cancer and non-cancer control groups, and to evaluate if a significant difference exists with respect to testosterone levels in male cancer patients with cachexia versus those without cachexia. The procedures of the study relevant to the current data analysis included blood collection to measure levels of testosterone and measurement of body weight to categorize cancer patients into cancer cachexia and cancer non-cachexia sub-groups. ^ Results. After logarithmic transformation of data of cancer and control groups, the unpaired t test with unequal variances was done. The proportion of patients with hypogonadism in the male cancer and non-cancer control groups was 47.5% and 22.7% with a Pearson chi2 statistic of 1.6036 and a p value of 0.205. Comparing the mean calculated Bioavailable testosterone in male cancer patients and non-cancer controls resulted in a t statistic of 21.83 and a p value less than 0.001. When the cancer group alone was taken, the mean free testosterone, calculated bioavailable testosterone and total testosterone levels in the cancer non-cachexia sub-group were 3.93, 5.09, 103.51 respectively and in the cancer cachexia sub-group were 3.58, 4.17, 84.08 respectively. The unpaired t test with equal variances showed that the two sub-groups had p values of 0.2015, 0.1842, and 0.4894 with respect to calculated bioavailable testosterone, free testosterone, and total testosterone respectively. ^ Conclusions. The small sample size of this exploratory study, resulting in a small power, does not allow us to draw definitive conclusions. For the given sub-sample, the proportion of patients with hypogonadism in the cancer group was not significantly different from that of patients with hypogonadism in the control group. Inferences on prevalence of hypogonadism in male cancer patients could not be made in this paper as the sub-sample is small and therefore not representative of the general population. However, there was a statistically significant difference in calculated Bioavailable testosterone levels in male cancer patients versus non-cancer controls. Analysis of cachectic and non-cachectic patients within the male cancer group showed no significant difference in testosterone levels (total, free, and calculated bioavailable testosterone) between both sub-groups. However, to re-iterate, this study is exploratory and the results may change once the complete dataset is obtained and analyzed. It however serves as a good template to guide further research and analysis.^

Mutational analysis of the necdin gene in patients with congenital isolated hypogonadotropic hypogonadism

Context: Necdin activates GNRH gene expression and is fundamental for the development, migration, and axonal extension of murine GNRH neurons. In humans, necdin plays a potential role in the hypogonadotropic hypogonadism phenotype in patients with Prader-Willi syndrome. Aim: To investigate necdin gene (NDN) variants in patients with isolated hypogonadotropic hypogonadism (IHH). Patients and methods: We studied 160 Brazilian patients with IHH, which includes 92 with Kallmann syndrome and 68 with normosmic IHH. Genomic DNA was extracted and the single NDN exon was amplified and sequenced. To measure GNRH transcriptional activity, luciferase reporter plasmids containing GNRH regulatory regions were transiently transfected into GT1-7 cells in the presence and absence of overexpressed wild-type or mutant necdin. Results: A heterozygous variant of necdin, p.V318A, was identified in a 23-year-old male with Kallmann syndrome. The p.V318A was also present in affected aunt and his father and was absent in 100 Brazilian control subjects. Previous FGFR1 gene analysis revealed a missense mutation (p.P366L) in this family. Functional studies revealed a minor difference in the activation of GNRH transcription by mutant protein compared with wild type in that a significant impairment of the necdin protein activity threshold was observed. Conclusion: A rare variant of necdin (p.V318A) was described in a family with Kallmann syndrome associated with a FGFR1 mutation. Familial segregation and in vitro analysis suggested that this non-synonymous variant did not have a direct causative role in the hypogonadism phenotype. NDN mutations are not a frequent cause of congenital IHH.

Early onset of primary hypogonadism revealed by serum anti-Mullerian hormone determination during infancy and childhood in trisomy 21

Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2 months-20 year). To compare with an adequate control population, we established reference levels for serum anti-Mullerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6 months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6 months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.

A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism

Context: Loss-of-function mutations of the kisspeptin-1 receptor gene, KISS1R, have been identified in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH). Objective: To investigate KISS1R defects in patients with absent or delayed puberty. Patients: We investigated KISS1R gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP). Methods: The entire coding region of KISS1R was amplified by PCR followed by automatic sequencing. In addition, screening for KISS1R exonic deletions was performed by multiplex ligation-dependent probe amplification. Results: One novel homozygous KISS1R mutation was identified in two siblings with nIHH. This variant was an insertion/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position -2 to -4, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 30 splice acceptor site of intron 2 of KISS1R. The brothers who carried this KISS1R mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous KISS1R variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, in vitro studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP. Conclusion: Loss-of-function mutations of KISS1R represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel KISS1R homozygous splice acceptor site mutation in the familial form of nIHH.

Testosterone Deficiency Increases Hospital Readmission and Mortality Rates in Male Patients with Heart Failure

Background:Testosterone deficiency in patients with heart failure (HF) is associated with decreased exercise capacity and mortality; however, its impact on hospital readmission rate is uncertain. Furthermore, the relationship between testosterone deficiency and sympathetic activation is unknown.Objective:We investigated the role of testosterone level on hospital readmission and mortality rates as well as sympathetic nerve activity in patients with HF.Methods:Total testosterone (TT) and free testosterone (FT) were measured in 110 hospitalized male patients with a left ventricular ejection fraction < 45% and New York Heart Association classification IV. The patients were placed into low testosterone (LT; n = 66) and normal testosterone (NT; n = 44) groups. Hypogonadism was defined as TT < 300 ng/dL and FT < 131 pmol/L. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography in a subpopulation of 27 patients.Results:Length of hospital stay was longer in the LT group compared to in the NT group (37 ± 4 vs. 25 ± 4 days; p = 0.008). Similarly, the cumulative hazard of readmission within 1 year was greater in the LT group compared to in the NT group (44% vs. 22%, p = 0.001). In the single-predictor analysis, TT (hazard ratio [HR], 2.77; 95% confidence interval [CI], 1.58–4.85; p = 0.02) predicted hospital readmission within 90 days. In addition, TT (HR, 4.65; 95% CI, 2.67–8.10; p = 0.009) and readmission within 90 days (HR, 3.27; 95% CI, 1.23–8.69; p = 0.02) predicted increased mortality. Neurohumoral activation, as estimated by MSNA, was significantly higher in the LT group compared to in the NT group (65 ± 3 vs. 51 ± 4 bursts/100 heart beats; p < 0.001).Conclusion:These results support the concept that LT is an independent risk factor for hospital readmission within 90 days and increased mortality in patients with HF. Furthermore, increased MSNA was observed in patients with LT.

Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor.

In this study, we describe a patient with a phenotype of complete hypogonadotropic hypogonadism who presented primary failure of pulsatile GnRH therapy, but responded to exogenous gonadotropin administration. This patient bore a novel point mutation (T for A) at codon 168 of the gene encoding the GnRH receptor (GnRH-R), resulting in a serine to arginine change in the fourth transmembrane domain of the receptor. This novel mutation was present in the homozygous state in the patient, whereas it was in the heterozygous state in both phenotypically normal parents. When introduced into the complementary DNA coding for the GnRH-R, this mutation resulted in the complete loss of the receptor-mediated signaling response to GnRH. In conclusion, we report the first mutation of the GnRH-R gene that can induce a total loss of function of this receptor and is associated with a phenotype of complete hypogonadotropic hypogonadism.

Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.

Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin-releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner.