Hypogonadotropic hypogonadism in women

This article presents the role of the hypothalamus in reproduction, the definition of hypogonadotropic hypogonadism (HH), and the causes of acquired and syndromic HH and idiopathic HH (IHH). The authors present a short review of major causes of acquired HH, but most of the causes of IHH will not be discussed because they do not fall within the scope of the article. More attention is devoted to idiopathic HH, especially the genetic basis of IHH. Also presented in the article are clinical criteria of CHARGE syndrome. Later, the article discusses the clinical presentation, establishing the diagnosis, and management of IHH. The article ends with a brief overview of nutritional hypothalamic dysfunction and athletic amenorrhea.     

Congenital hypogonadotropic hypogonadism due to GnRH receptor mutations in three brothers reveal sites affecting conformation and coupling

Congenital hypogonadotropic hypogonadism (CHH) is characterized by low gonadotropins and failure to progress normally through puberty. Mutations in the gene encoding the GnRH receptor (GNRHR1) result in CHH when present as compound heterozygous or homozygous inactivating mutations. This study identifies and characterizes the properties of two novel GNRHR1 mutations in a family in which three brothers display normosmic CHH while their sister was unaffected. Molecular analysis in the proband and the affected brothers revealed two novel non-synonymous missense GNRHR1 mutations, present in a compound heterozygous state, whereas their unaffected parents possessed only one inactivating mutation, demonstrating the autosomal recessive transmission in this kindred and excluding X-linked inheritance equivocally suggested by the initial pedigree analysis. The first mutation at c.845 C>G introduces an Arg substitution for the conserved Pro 282 in transmembrane domain (TMD) 6. The Pro282Arg mutant is unable to bind radiolabeled GnRH analogue. As this conserved residue is important in receptor conformation, it is likely that the mutation perturbs the binding pocket and affects trafficking to the cell surface. The second mutation at c.968 A>G introduces a Cys substitution for Tyr 323 in the functionally crucial N/DPxxY motif in TMD 7. The Tyr323Cys mutant has an increased GnRH binding affinity but reduced receptor expression at the plasma membrane and impaired G protein-coupling. Inositol phosphate accumulation assays demonstrated absent and impaired Gα(q/11) signal transduction by Pro282Arg and Tyr323Cys mutants, respectively. Pretreatment with the membrane permeant GnRHR antagonist NBI-42902, which rescues cell surface expression of many GNRHR1 mutants, significantly increased the levels of radioligand binding and intracellular signaling of the Tyr323Cys mutant but not Pro282Arg. Immunocytochemistry confirmed that both mutants are present on the cell membrane albeit at low levels. Together these molecular deficiencies of the two novel GNRHR1 mutations lead to the CHH phenotype when present as a compound heterozygote.     

Hypogonadotropic hypogonadism in men with hereditary hemochromatosis

Hereditary hemochromatosis is a genetic disease that progresses silently. This disease is often diagnosed late when complications appear. Hypogonadotropic hypogonadism (HH) is one of the classical complications of hemochromatosis. Its frequency is declining probably because of earlier diagnosis and better informed physicians. Certain symptoms linked to HH can have an impact on a patient’s sexuality, such as decreased libido, erectile dysfunction, and impairment of ejaculation, as well as on his reproductive capacities.This review is based on an online search in English, French and German language publications found in PubMed/Medline, up to 23 September 2016 using the following key word: Male infertility, Hypogonadotropic Hypogonadism, Hereditary Hemochromatosis.Thirty-four papers met these inclusion criteria. This review describes the impact of iron overload on male fertility, resulting in hypogonadotropic hypogonadism and proposes treatment modalities.     

Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism

GnRH is the central regulator of reproductive function responding to central nervous system cues to control gonadotropin synthesis and secretion. GnRH neurons originate in the olfactory placode and migrate to the forebrain, in which they are found in a scattered distribution. Congenital idiopathic hypogonadotropic hypogonadism (CIHH) has been associated with mutations or deletions in a number of genes that participate in the development of GnRH neurons and expression of GnRH. Despite the critical role of GnRH in mammalian reproduction, a comprehensive understanding of the developmental factors that are responsible for regulating the establishment of mature GnRH neurons and the expression of GnRH is lacking. orthodenticle homeobox 2 (OTX2), a homeodomain protein required for the formation of the forebrain, has been shown to be expressed in GnRH neurons, up-regulated during GnRH neuronal development, and responsible for increased GnRH promoter activity in GnRH neuronal cell lines. Interestingly, mutations in Otx2 have been associated with human hypogonadotropic hypogonadism, but the mechanism by which Otx2 mutations cause CIHH is unknown. Here we show that deletion of Otx2 in GnRH neurons results in a significant decrease in GnRH neurons in the hypothalamus, a delay in pubertal onset, abnormal estrous cyclicity, and infertility. Taken together, these data provide in vivo evidence that Otx2 is critical for GnRH expression and reproductive competence.     

Loss of rapid transferrin receptor recycling due to a mutation in Sec15l1 in hbd mice

The hbd (hemoglobin deficit) mutation affects iron trafficking in murine reticulocytes. It is due to a deletion that eliminates exon 8 of Sec15l1, the homolog of a gene that encodes an exocyst component in yeast. We tested the hypothesis that the mutation causes defective slow or rapid receptor recycling by measuring endocytosis and exocytosis of transferrin by hbd reticulocytes. Endocytosis and initial iron incorporation were relatively unaffected, but exocytosis was unexpectedly slowed. These data indicate that rapid transferrin recycling is defective after pSec15l1 has mutated.     

Progressive ataxia due to a missense mutation in a calcium-channel gene.

We describe a family with severe progressive cerebellar ataxia involving the trunk, the extremities, and speech. The proband, who has prominent atrophy of the cerebellum, shown by magnetic resonance imaging, was confined to a wheelchair at the age of 44 years. Two sons have episodes of vertigo and ataxia that are not responsive to acetazolamide. Quantitative eye-movement testing showed a consistent pattern of abnormalities localizing to the cerebellum. Genotyping suggested linkage to chromosome 19p, and SSCP showed an aberrant migrating fragment in exon 6 of the calcium-channel gene CACNA1A, which cosegregated with the disease. Sequencing of exon 6 identified a G-->A transposition in one allele, at nucleotide 1152, resulting in a predicted glycine-to-arginine substitution at codon 293. The CAG-repeat expansion associated with spinocerebellar ataxia 6 was not present in any family members. This family is unique in having a non-CAG-repeat mutation that leads to severe progressive ataxia. Since a great deal is known about the function of calcium channels, we speculate on how this missense mutation leads to the combination of clinical symptoms and signs.     

Beta-thalassemia due to a T----A mutation within the ATA box

Sequence analyses of amplified DNA from a Yugoslavian patient with Hb Lepore-beta-thalassemia and from his father with a simple beta-thalassemia trait have revealed a T----A mutation within the ATA box at a position 30 base pairs upstream from the Cap site. The nucleotide substitution was confirmed through dot-blot analysis of amplified DNA with specific 32P-labeled synthetic oligonucleotide probes. The patient had a clinically severe condition; his Hb Lepore-beta-thalassemia was of the beta + type, as about 8-10% of the non-alpha chain was normal beta A. The same T----A mutation at nucleotide -30 was present on both chromosomes of a young Turkish patient who suffered from a thalassemia intermedia with a low level of Hb F (13.1%) and a relatively high beta A chain synthesis. These data are similar to those obtained for other types of beta +-thalassemia caused by comparable substitutions at positions 31, 29, and 28 base pairs upstream from the Cap site of the beta-globin gene.     

A Turkish family with Nance-Horan syndrome due to a novel mutation

Nance-Horan Syndrome (NHS) is a rare X-linked syndrome characterized by congenital cataract which leads to profound vision loss, characteristic dysmorphic features and specific dental anomalies. Microcornea, microphthalmia and mild or moderate mental retardation may accompany these features. Heterozygous females often manifest similarly but with less severe features than affected males. We describe two brothers who have the NHS phenotype and their carrier mother who had microcornea but not cataract. We identified a previously unreported frameshift mutation (c.558insA) in exon 1 of the NHS gene in these patients and their mother which is predicted to result in the incorporation of 11 aberrant amino acids prior to a stop codon (p.E186Efs11X). We also discussed genotype–phenotype correlation according to relevant literature.     

Induction of puberty in a patient with hypogonadotropic hypogonadism: effect of sequentially applied hCG and pulsatile GnRH administration

Pulsatile substitution with GnRH appears to be the therapy of choice in patients with Kallmann's syndrome, a well defined type of hypogonadotropic hypogonadism. We tried to simplify the treatment and to limit the subcutaneous GnRH therapy to the period absolutely necessary to induce spermatogenesis. Therefore we applied in sequence first hCG to stimulate testicular growth and second pulsatile GnRH application to induce spermatogenesis. We herein report that with this mode of therapy testicular growth from infantile to adult size and normal spermatogenesis could be achieved. We conclude that pulsatile GnRH application is a new effective therapy of hypogonadotropic hypogonadism which can be simplified considerably by pretreatment with hCG.     

Spectinomycin resistance due to a mutation in an rRNA operon of Escherichia coli

A spectinomycin resistance mutation was isolated in an Escherichia coli rRNA operon (rrnH) located on a multicopy plasmid. Cell-free protein-synthesizing extracts made from cells containing the plasmid were partially resistant to spectinomycin. Although spectinomycin is an aminoglycoside antibiotic, the mutation did not confer resistance to any other aminoglycoside antibiotic tested.     

Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain.

An infant with a neurodegenerative disorder accompanied by lactic acidemia is described. In muscle homogenate, the activity of lipoamide dehydrogenase (LAD), the third catalytic subunit of pyruvate dehydrogenase complex (PDHc), alpha-ketoglutarate dehydrogenase complex (KGDHc), and branched-chain keto acid dehydrogenase complex was reduced to 15% of the control. The activity of PDHc was undetectable and the activity of KGDHc was 2% of the control mean. The immunoreactive LAD protein was reduced to about 10% of the control. Direct sequencing of LAD cDNA revealed only one mutation, substituting Asp for Val at position 479 of the precursor form. The mutation resides within the interface domain and likely perturbs stable dimerization. The phenotypic heterogeneity in LAD deficiency is not directly correlated with the residual LAD activity but rather with its impact on the multienzymatic complex activity.     

FGFR3 dimer stabilization due to a single amino acid pathogenic mutation

Mutations in the transmembrane (TM) domains of receptor tyrosine kinases (RTKs) have been implicated in the induction of pathological phenotypes. These mutations are believed to stabilize the RTK dimers, and thus promote unregulated signaling. However, the energetics behind the pathology induction has not been determined. An example of a TM domain pathogenic mutation is the Ala391-->Glu mutation in fibroblast growth factor receptor 3 (FGFR3), linked to Crouzon syndrome with acanthosis nigricans, as well as to bladder cancer. Here, we determine the free energy of dimerization of wild-type and mutant FGFR3 TM domain in lipid bilayers using F?rster resonance energy transfer, and we show that hydrogen bonding between Glu391 and the adjacent helix in the dimer is a feasible mechanism for dimer stabilization. The measured change in the free energy of dimerization due to the Ala391-->Glu pathogenic mutation is -1.3 kcal/mol, consistent with previous reports of hydrogen bond strengths in proteins. This is the first quantitative measurement of mutant RTK stabilization in a membrane environment. We show that this seemingly modest value can lead to a large increase in dimer fraction and thus profoundly affect RTK-mediated signal transduction.     

Long-term carbimazole treatment of neonatal nonautoimmune hyperthyroidism due to a new activating TSH receptor gene mutation (Ala428Val)

BACKGROUND: Hereditary nonautoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin receptor gene. Antithyroid treatment failed to control hyperthyroidism in most cases, so that primary thyroid ablation or 131I therapy is advocated as the preferred treatment of choice. PATIENT/METHODS: We describe a case of neonatal nonautoimmune hyperthyroidism treated with carbimazole. Molecular analysis revealed a new heterozygous point mutation (A428V) in the TSH receptor (TSHR) gene. RESULT: Antithyroid treatment was successful in controlling hyperthyroidism for the first 5.9 years of age. CONCLUSION: We conclude that carbimazole therapy is effective in treating nonautoimmune hyperthyroidism. It may be an alternative to thyroidectomy or radioiodine treatment.     

Alterations in the production of hemocytes due to a neoplastic mutation of Drosophila melanogaster

The hemocytes of a genetically induced, temperature-sensitive lethal mutation of Drosophila, Tum¹, were examined both quantitatively and qualitatively during the third larval instar. At the tumor-permissive temperature, 29°C, there was a fourfold increase in the concentration of circulating hemocytes in mutant larvae as compared to control. Additionally, the relative frequency of lamellocytes was 30 times greater in Tum¹ larvae than Basc in the early third instar. However, the severity of this abnormality gradually diminished as Tum¹ approached pupariation; though high frequencies of lamellocytes were always present. At the tumor-restrictive temperature (15°C) the concentration of circulating hemocytes was over twice that found at 29°C for Tum¹ larvae, and did not change during the course of third instar. However, in contrast to 29°C there was no abnormal increase in the frequency of lamellocytes at the tumor-restrictive temperature. Control larvae had equivalent concentrations of hemocytes at both temperatures. In one of two temperature shift experiments, Tum¹ larvae shifted from 15° to 29°C at the beginning of third instar expressed the abnormal hemocyte concentration and differentiation associated with larvae raised continuously at 29°C. In addition, Tum¹ larvae shifted from 29° to 15°C expressed reduced abnormalities of hemocyte differentiation, e.g., with fewer lamellocytes in circulation. The possibility of a temperature-sensitive period for the activation of the Tum¹ gene is discussed.