Partial Hypogonadotropic Hypogonadism Research Articles

Long Term Growth Hormone Therapy in a Patient with IGF1R Deletion Accompanied by Delayed Puberty and Central Hypothyroidism.

Insulin-like growth factor-1 (IGF-1) is the main driver of growth during prenatal life and acts through insulin-like growth factor 1 receptor (IGF1R). Patients with IGF1R defects exhibit variable phenotypic features. A 10.9-year-old boy presented with severe short stature, microcephaly, minor dysmorphic features and mild mental retardation. Genetic analysis for IGF1R revealed heterozygous deletion of the complete IGF1R. At the age of 12.3 years, daily subcutaneous rhGH was started and continued for a total of 5.7 years in two courses with improvement of height velocity as well as final height. Puberty was delayed and eventually he could not develop full puberty suggesting partial hypogonadotropic hypogonadism. Hypothyroidism initially developed during rhGH therapy. However, low T4 levels sustained after cessation of rhGH therapy thus central hypothyroidism is a likely diagnosis. rhGH has partial effect for induction of growth in cases with IGF1R defects. However, long-term treatment with an early onset may have more beneficial effects. In addition, patients with IGF1R defects should be followed for delayed puberty-hypogonadism, and hypothyroidism.

Evaluating the Combination of Human Chorionic Gonadotropin and Clomiphene Citrate in Treatment of Male Hypogonadotropic Hypogonadism: A Prospective Study.

BackgroundIn this study, we evaluated MHH patients who wished to preserve fertility, assessing the efficacy of a short course (12 months) of a combined hCG +clomiphene citrate.Materials and MethodsThe cross-sectional study included 19 patients with hypogonadotropic hypogonadism who were admitted to the Andrology and Fertility Hospital of Hanoi between March 2016 and March 2018. Using hCG every three days in combination with clomiphene citrate 25mg per day until normal testosterone levels are reached, maintain the dose until spermatozoa are present.ResultsThe mean age was 30.2 ± 5.6. Differences in penis length between the time before and after treatment were significant (p=0.005). The average dose of hCG using in our study was 5579 ± 1773.7 IU. After treatment 6 months and 12 months, the changes in clinical features in all patients and the total hypogonadotropic hypogonadism group were statistically significant (p<0.001). In particular, the differences in testosterone hormone levels in the partial hypogonadotropic hypogonadism group were also statistically significant (p=0.03). No adverse event was observed in our study. The number of patients appearing sperm in the semen is 9 patients (47.4%) after 12 months, but most of the sperm were completely deformed (<1%), and the average motility in the progressive motility group was below 8%.ConclusionIn conclusion, a combination of hCG and clomiphene citrate may be an option for MHH patients who desired fertility. After 12 months, 47.4% of patients have sperm in semen but almost all of them were deformity. Hormone profile and secondary sexual characteristics improved significantly. There was no adverse event in our study that considered it as safe therapy.

Puberty and Inhibin B in 35 Adolescents With Pituitary Stalk Interruption Syndrome.

Background: In patients with pituitary stalk interruption syndrome (PSIS), long-term follow-up is necessary to address their gonadotrophic status. The objectives of this study were (1) to describe pubertal features of and (2) to assess the ability of serum inhibin B concentration to predict hypogonadotropic hypogonadism (HH) in patients with PSIS.Methods: This retrospective single-center study included 35 patients with PSIS and known gonadotrophic status for whom a serum sample preserved at −22°C (collected at initial evaluation or later) was available for measuring inhibin B by the same hormonal immunoassay method.Results: Among the 21 boys, 15 had normal puberty (early in two), and six had partial (n = 2) or complete (n = 4) HH. Among the 14 girls, five had normal puberty (early in one)—four with regular menses and one in the process of puberty—, four had complete HH, and five had amenorrhea (primary in three and secondary in two) after normal pubertal development, despite a normal pubertal gonadotropin response to gonadotropin-releasing hormone test. These were considered as having partial HH. Only three boys had values over the normal lower range for serum inhibin B concentrations despite partial (n = 2) or complete (n = 1) HH. Inhibin B concentrations were low in all girls with complete HH, normal in all those with partial HH except in one and in those with normal puberty except in two. Considering boys and girls together, the occurrence of under-range inhibin B was significantly higher in those with HH than in those without (47 vs. 10%, p = 0.02). All 15 patients with HH had associated thyroid-stimulating hormone and adrenocorticotropic hormone deficiency except for 3 girls with partial HH.Conclusions: Under-range inhibin B concentrations in patients with PSIS might be suggestive of HH. These concentrations provide a simple first-line predictive test, especially in boys.

SAT-227 Long-Term Outcomes of Two Siblings with X-Linked Congenital Adrenal Hypoplasia Due to a Mutation in NR0B1 (DAX1) Gene: Reproductive and Neuropsychiatric Aspects

Background: X-linked congenital adrenal hypoplasia (CAH) is a rare disease caused by mutations in the NR0B1 (DAX-1) gene. Non-classical manifestations have been described, including late-onset adrenal insufficiency (AI) and gonadotropin-independent precocious puberty (GIPP). We report long-term endocrine and neuropsychiatric outcomes of two siblings with CAH due to mutation in NR0B1.Case report: A 2-yr-old boy was referred due to progressive clinical signs of puberty since 6 months of age. At the age of 3 yr, AI was diagnosed, and the molecular analysis revealed a mutation in the NR0B1 (p.Cys65Leufs*6). Glucocorticoid replacement resulted in reduced testicular volume and decreased testosterone levels. At 11 yr, cyproterone acetate was indicated due to pubertal progression and bone age advancement. At 17 yr the patient had incomplete sexual development and no pubarche. Testosterone levels declined, despite pubertal levels of basal and GnRH-stimulated gonadotropin levels, indicating partial hypogonadotropic hypogonadism. Adult height was 156 cm (SDS: -2.7) within his target height of 161 cm (SDS: -2.1). This patient also presented a psychiatric diagnosis of mood disorder and attention-deficit/hyperactivity disorder (ADHD), and was under methylphenidate, topiramate and sertraline. Both the patient and his mother had SNP array performed, which excluded contiguous gene syndrome. His younger brother also harbored the same mutation in the NR0B1, confirmed shortly after birth. AI was diagnosed with 1 month of age. Cortisone acetate and fludrocortisone were initiated. At 11 months of age, he presented signs of pubertal development with an elevated ACTH and testosterone levels with suppressed gonadotropins, confirming the diagnosis of GIPP. He was treated with cyproterone acetate. At 8 yr, a pubertal response to the GnRH test was detected, and leuprorelin was added. At 9 yr, due to the low growth velocity and advanced bone age, rhGH was started. However, this patient presented a poor compliance and severe obesity (BMI 33 kg/m2). Treatment for GIPP and secondary CPP was stopped at 10 yr, with bone age of 13.5 yr and height of 151 cm (SDS: - 2.3). The diagnosis of ADHD and autism spectrum disorder was made after neuropsychiatric assessment and the patient received treatment with methylphenidate and sertraline. Conclusion: Pubertal development of patients with CAH due to NR0B1 mutations can be heterogeneous. However, the intriguing neuropsychiatric features in two siblings may suggest a role of NR0B1 in neuropsychological development or other still unknown underlying genetic defect.

Hypogonadism and Anemia in an Athlete

We report the case of a highly trained endurance athlete (22-year-old) who developed anemia (Hb 9.5 mg/dl) over a period of 6 months. Iron deficient or haemolytic anemia, as well as chronic loss of blood, were excluded. Further, laboratory analyses revealed that this athlete exhibited very low levels of testosterone due to a partial hypogonadotropic hypogonadism. Following testosterone supplementation, red blood cell indices improved. Although hypogonadotropic hypogonadism is well known to be associated with reduced hematopoesis, it rarely causes anemia in athletes. This should be considered as a possible cause for anemia. Extreme training, unbalanced nutrition or the combination of both, have been shown to be causally involved in the development of secondary hypogonadotropic hypogonadism.

Basal Follicle-Stimulating Hormone and Peak Gonadotropin Levels after Gonadotropin-Releasing Hormone Infusion Show High Diagnostic Accuracy in Boys with Suspicion of Hypogonadotropic Hypogonadism

Differential diagnosis between hypogonadotropic hypogonadism (HH) and constitutional delay of puberty in boys is challenging. Most tests use an acute GnRH stimulus, allowing only the release of previously synthesized gonadotropins. A constant GnRH infusion, inducing de novo gonadotropin synthesis, may allow a better discrimination. We evaluated the diagnostic accuracy of basal and peak gonadotropins after GnRH infusion, measured by ultrasensitive assays, to confirm the diagnosis in boys with suspected HH. We conducted a validation study following Standards for Reporting of Diagnostic Accuracy criteria at a tertiary public hospital. A GnRH i.v. infusion test was performed in 32 boys. LH and FSH were determined by immunofluorometric assay at 0-120 min. DIAGNOSIS ASCERTAINMENT: The following diagnoses were ascertained: complete HH (n = 19; testes < 4 ml at 18 yr), partial HH (n = 6; testes enlargement remained arrested for > or = 1 yr or did not reach 15 ml), and constitutional delay of puberty (n = 7; testes > or = 15 ml at 18 yr). Sensitivity, specificity, positive and negative predictive values, and diagnostic efficiency were assessed. Basal FSH less than 1.2 IU/liter confirmed HH with specificity of 1.00 (95% confidence interval = 0.59-1.00), rendering GnRH infusion unnecessary. In patients with basal FSH of at least 1.2 IU/liter, the coexistence of peak FSH less than 4.6 IU/liter and peak LH less than 5.8 IU/liter after GnRH infusion had high specificity (1.00; 95% confidence interval = 0.59-1.00) and diagnostic efficiency (76.9%) for HH. Basal FSH less than 1.2 IU/liter confirms HH, which precludes from further testing, reducing patient discomfort and healthcare system costs. In patients with basal FSH of at least 1.2 IU/liter, a GnRH infusion test has a high diagnostic efficiency.

A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism

Genetic studies in patients with severe early-onset obesity have provided insights into the molecular and physiological pathways that regulate body weight in humans. We report a 19-year-old male with hyperphagia and severe obesity, mild learning difficulties and hypogonadism, in whom diagnostic tests for Prader-Willi syndrome (PWS) had been negative. We carried out detailed clinical and metabolic phenotyping of this patient and investigated the genetic basis of this obesity syndrome using Agilent 185 k array comparative genomic hybridization (aCGH) and Affymetrix 6.0 genotyping arrays. The identified deletion was validated using multiplex ligation-dependent probe amplification and long-range PCR, followed by breakpoint sequencing which enabled precise localization of the deletion. We identified a approximately 187 kb microdeletion at chromosome 15q11-13 that encompasses non-coding small nucleolar RNAs (including HBII-85 snoRNAs) which were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism and growth failure. We have identified a novel deletion on chromosome 15q11-13 in an individual with hyperphagia, obesity, hypogonadism and other features associated with PWS, which is normally caused by deficiency of several paternally expressed imprinted transcripts within chromosome 15q11-13, a region that includes multiple protein-coding genes as well as several non-coding snoRNAs. These findings provide direct evidence for the role of a particular family of non-coding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth and reproduction.

Association d’un hypogonadisme hypogonadotrope et d’une ataxie cérébelleuse chez un homme : à propos d’un cas

We present the case of a male patient who presented progressive cerebellar ataxia since childhood who developed partial hypogonadotropic hypogonadism discovered when searching for a cause of low fecundity. The association of these two entities has been described in several rare syndromes: Homes ataxia, Boucher-Neuhauser syndrome and Richards-Rundle syndrome. The genetic background of these three syndromic associations defined solely on the basis of clinical manifestations remains to be elucidated, leading to uncertain diagnosis. The present case suggests the syndromic entity could be associated with autosomal recessive spinocerebellar ataxia with hypogonadotropic hypogonadism which includes several genotypic entities.

Characteristics of infertile men with intermittent non-obstructive complete asthenospermia

Objective: Male factor patients with a history of low sperm counts often exhibit low or absent motility. This variability in semen quality presents a clinical challenge during ART cycles as “back up” plans and procedures are necessary at the time of egg retrieval to ensure that viable sperm are available for ICSI. We present the clinical features, natural history and a management strategy, including the use of FNA mapping, in a cohort of intermittent nonobstructive asthenospermic patients. Design: Case controlled, retrospective review of a consecutive patients at a single institution. Materials and Methods: Over 2 years, 15 men presented with infertility characterized by intermittent complete asthenospermia, defined as at least 1 documented semen analysis showing motile sperm and another without. All patients underwent formal evaluation with history, physical exam, semen with centrifuged pellet analysis, and hormones. In addition, patients were offered fine needle aspiration (FNA) mapping to localize testis sperm prior to IVF-ICSI. Semen quality at ICSI and the need for “back up” TESA/TESE procedures were assessed. Results: Prior paternity was documented in 3/15 (20%) patients. Medical diagnoses included varicocele (5/15, 33%), idiopathic (4/15, 27%), diabetes (2/15, 13%), DES exposure (2/15, 13%), partial hypogonadotropic hypogonadism (1/15), and balanced translocation (1/15). Mean testis volumes were 15.6 mL on right and 14mL on left. Mean testosterone and FSH levels were 305 (normal 260–1000) and 9.7 (normal 1–8), respectively. Range of semen volume was 2–4.5mL, total sperm count was 10 sperm to 3 million sperm, and motility ranged from 0–50%. On pre-ICSI, FNA mapping (n=15 patients), mature sperm were found in 14/15 (93%) patients; 1 patient had elongated spermatids. Roughly half of testis maps showed an “even” sperm distribution in the testis and the other half showed “pockets” of sperm. The mean interval from FNA mapping to ICSI was 4.7 months (range 1–23 months). At ICSI (n=13 patients), sufficient motile ejaculated sperm were obtained in 5/13 (39%) patients (motile sperm count range: 20–400,000) and “back up” procedures were needed in 8/13 (61%) patients due to lack of motile sperm. ICSI “back up” procedures included unilateral TESA (n=3), bilateral TESA (n=2), bilateral TESE (n=1) and unilateral Micro-TESE (n=2) at which time sufficient sperm were found in 6/8 patients. Conclusion: Successful management of male infertility due to severe oligoasthenospermia is a complex challenge for ICSI programs. Among these patients, systemic medical diagnoses are likely present, and “back up” plans and procedures are likely to be employed at ICSI.

Basal ultrasensitive LH assay: a useful tool in the early diagnosis of male pubertal delay?

The aim of this study was to evaluate the usefulness of basal measurements of gonadotropins in distinguishing between constitutionally delayed puberty (DP) and hypogonadotropic hypogonadism (HH), comparing its diagnostic efficiency with that of the dynamic GnRH infusion test (0.83 microg/min during 120 min). We studied 20 males, chronological age (CA) 14-18 years, with a final diagnosis of DP (n = 8), partial HH (n = 5) and complete HH (n = 7), confirmed by follow-up. We also evaluated basal samples of ultrasensitive LH and FSH in 117 healthy control males (CA 2-19 yr), classified according to Tanner stage. In the control group, ROC plot analysis showed a cutoff to differentiate prepuberty from puberty of 0.65 IU/l for LH (sensitivity: 91%, specificity: 98%). Differences were found (p < 0.05) in basal LH and in maximal responses to GnRH in complete HH in relation to DP and partial HH. The diagnostic efficiency of the GnRH infusion test was 85%. For basal LH, a cut-off limit of 0.65 IU/l showed a diagnostic efficiency of 85% for complete HH and 100% for partial HH and DP. We conclude that, in our experience, basal LH levels above 0.65 IU/l measured by ultrasensitive assay would rule out a complete deficiency. It was not possible to differentiate DP from partial HH, either in basal samples or with the infusion test.

Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction.

Several point mutations in the GnRH receptor gene have been described in an autosomal recessive form of congenital isolated hypogonadotropic hypogonadism (HH). We investigated 17 Brazilian patients (10 males and 7 females) from 14 different families, with HH and normal olfaction. The diagnosis of HH was based on absent or incomplete sexual development after 17 yr of age 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. The coding region of the GnRH receptor gene was amplified by PCR and directly sequenced. A novel missense mutation, Arg(139)His, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified in the homozygous state in one female with complete HH. The Arg(139)His mutation completely eliminated detectable GnRH-binding activity and prevented GnRH-induced stimulation of inositol phosphate accumulation in vitro. In another family, a new compound heterozygous mutation (Asn(10)Lys and Gln(106)Arg) was identified in four siblings (two males and two females) with partial HH. The Gln(106)Arg mutation, located in the first extracellular loop, has been previously described, and in vitro analysis indicated that the mutant receptor was able to bind GnRH, but with a reduced affinity. The Asn(10)Lys mutation in the extracellular amino-terminal domain of the receptor also reduced the affinity for GnRH in vitro. In this family we also identified a previously described silent polymorphism at amino acid residue 151 in the second intracellular loop that segregated with the two inactivating mutations of the GnRH receptor. This polymorphism was also found in two unrelated patients with sporadic HH without GnRH receptor loss of function mutations. No mutations were identified in the remaining cases. A good correlation between genotype and phenotype was found in our patients. The woman, who is homozygous for the completely inactivating Arg(139)His mutation, has complete HH with undetectable serum basal LH and FSH levels that failed to respond to GnRH stimulation. In addition, the affected patients who are compound heterozygotes for the Asn(10)Lys/Gln(106)Arg mutations, have partial HH with low serum basal LH levels that were responsive to GnRH stimulation. No clinical or hormonal differences were found between HH patients with and without mutations in the GnRH receptor gene, indicating that these data do not contribute to the identification of HH patients with GnRH receptor mutations. In conclusion, we report the first naturally occurring mutation within the conserved DRS motif of the GnRH receptor in a female with complete HH and a novel compound heterozygous mutation (Asn(10)Lys and Gln(106)Arg) in a family with partial HH, increasing the repertoire of the inactivating mutations of the GnRH receptor.

X-linked hypogonadism, gynecomastia, mental retardation, short stature, and obesity—a new syndrome

Five male members in four generations of the same family had hypogonadism, gynecomastia, mental retardation, obesity, and short stature. The X-linked mode of inheritance, the distinctive facies, the normal size of the hands and feet, and the true gynecomastia are the main characteristics. Endocrine evaluation and histologic studies of the testes suggest partial hypogonadotropic hypogonadism. This disorder represents a new syndrome distinct from others previously described.

928 X-LINKED HYPOGONADISM, GYNECOMASTIA, MENTAL RETARDATION, SHORT STATURE AND OBESITY. A NEW SYNDROME

Five male members in four generations of the same family presented with hypogonadism, micropenis, mental retardation and short stature. The adults had gynecomastia, obesity and normal size hands and feet. Four had small head, with narrow forehead in two. History of neonatal hypotonia with difficulty in feedings was obtained in two. A variety of structural abnormalities of the hand and other skeletal defects were observed in some. Chromosomal studies including banding were normal. Serum LH and FSH were normal in three adults (12.3 and 4.5 mIU/ml; 9.0 and 7.0 mIU/ml and 22.5 and 18.1 mIU/m1). Serum testosterone levels were low (90 ng/d1; 54 ng/d1 and 75 ng/d1) and responded to hCG with at least doubling of the initial value. Testicular biopsies in two adults showed patchy involvement with tubular shrinkage, folding of the basement membrane, thickening of the tunica propria and loss of germinal epithelium in some areas. Other tubules were less affected and showed spermatogenesis. Leydig cells were present. The findings suggest partial hypogonadotropic hypogonadism. Their phenotype and the abnormalities in their sexual development are most likely the result of a developmental anomaly of the CNS. The mode of inheritance, gynecomastia and absence of small hands and feet suggest that this disorder represents a new syndrome resembling but distinct from that described by Prader and Willi.Supported in part by John W. Champion Center.