No approved-drug candidate for hypogonadotropic hypogonadism 23 with or without anosmia is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
A 2003 study of a large consanguineous family with five siblings affected by isolated hypogonadotropic hypogonadism (IHH) and a normal gonadotropin-releasing hormone receptor coding sequence found a homozygous 155-nucleotide deletion in the GPR54 gene in all affected siblings. The deletion covered the splicing acceptor site of the intron 4–exon 5 junction and part of exon 5, and was absent or present on only one allele in unaffected family members. GPR54 had been identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors, and a 54-amino-acid peptide derived from the KiSS1 protein was later identified as its ligand. The study concluded that loss of function of GPR54 is a cause of IHH, and that GPR54 and possibly the KiSS1-derived peptide play a previously unsuspected major role in the gonadotropic axis.
A 1997 paper noted that hypogonadotropic hypogonadism with anosmia is known as Kallmann syndrome, and the gene for the X-linked form had been mapped to chromosome Xp22.3 with several mutations described. In idiopathic hypogonadotropic hypogonadism without anosmia, the involved genes had not been characterised. The gonadotropin-releasing hormone (GnRH) receptor gene was considered a candidate, but no abnormality of the GnRH gene itself had been found in several patients.
A 2018 study of 100 HIV-infected men in India found an overall prevalence of hypogonadism of 66%, with 30–35% of patients reporting symptoms of hypoandrogenemia. Hypogonadotropic hypogonadism was present in 42% of patients. A significant association was found between hypogonadism prevalence and the level of immunodeficiency, with prevalence increasing as CD4 counts decreased. Lower free testosterone and dehydroepiandrosterone sulfate levels were found in cases of severe immunosuppression, with a statistically significant correlation with CD4 counts. Mean free testosterone and follicle-stimulating hormone were significantly higher in patients on antiretroviral therapy than in those not on therapy, but no specific antiretroviral drug or combination correlated significantly with any sex hormone level.
What is still missing is a clear understanding of the full genetic architecture of hypogonadotropic hypogonadism beyond GPR54 and GnRH receptor mutations, and how these mutations translate into clinical management. The HIV-associated data come from a single-centre study with 100 men and no randomised treatment comparison. No trial has tested whether restoring GPR54 signalling or targeting the KiSS1 pathway can reverse the condition in humans, and no stratified approach based on genotype or immune status has been validated.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Proceedings of the National Academy of Sciences · 2003 · 2417 citations · open access
Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
AbstractHypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.
https://doi.org/10.1073/pnas.1834399100New England Journal of Medicine · 1997 · 529 citations · open access
A Family with Hypogonadotropic Hypogonadism and Mutations in the Gonadotropin-Releasing Hormone Receptor
AbstractHypogonadotropic hypogonadism is often associated with anosmia in a condition known as Kallmann's syndrome. The gene for the X-linked form of Kallmann's syndrome has been mapped to chromosome Xp22.3,1 and several mutations have been described.2–4 In idiopathic hypogonadotropic hypogonadism there is no anosmia, and the involved genes have not been characterized. One possible candidate is the gene for gonadotropin-releasing hormone (GnRH), especially since hypogonadal mice with the deletion of this gene have been identified.5 However, no abnormality of the gene for GnRH has been found in several patients with idiopathic hypogonadotropic hypogonadism.6–9 The gene for the GnRH receptor . . .
https://doi.org/10.1056/nejm199711273372205Expert Opinion on Pharmacotherapy · 2024 · 16 citations
Testosterone replacement therapy: clinical considerations
AbstractINTRODUCTION: As an increasingly popular therapeutic option, testosterone replacement therapy (TRT) has gained significant notoriety for its health benefits in indicated populations, such as those suffering from hypogonadism. AREAS COVERED: Benefits such as improved libido, muscle mass, cognition, and quality of life have led to widened public interest in testosterone as a health supplement. No therapy exists without side effects; testosterone replacement therapy has been associated with side effects such as an increased risk of polycythemia, benign prostate hypertrophy (BPH), prostate cancer, gynecomastia, testicular atrophy, and infertility. Testosterone replacement therapy is often accompanied by several prophylactic co-therapies aimed at reducing the prevalence of these side effects. Literature searches for sections on the clinical benefits and risks associated with TRT were performed to include clinical trials, meta-analyses, and systematic reviews from the last 10 years. EXPERT OPINION: Data from clinical studies over the last decade suggest that the benefits of this therapy outweigh the risks and result in overall increased quality of life and remission of symptoms related to hypogonadism. With this in mind, the authors of this review suggest that carefully designed clinical trials are warranted for the investigation of TRT in symptomatic age-related hypogonadism.
https://doi.org/10.1080/14656566.2024.2306832Postgraduate Medical Journal · 1966 · 14 citations · open access
Hypogonadism and life-long anosmia
AbstractJournal Article Hypogonadism and life-long anosmia Get access T D R Hockaday, MA, BM, BSc (Oxon), MRCP (Lond) T D R Hockaday, MA, BM, BSc (Oxon), MRCP (Lond) Lecturer in Medicine Department of the Regius Professor of Medicine, Radcliffe Infirmary, Oxford Search for other works by this author on: Oxford Academic Google Scholar Postgraduate Medical Journal, Volume 42, Issue 491, September 1966, Pages 572–574, https://doi.org/10.1136/pgmj.42.491.572 Published: 01 September 1966
https://doi.org/10.1136/pgmj.42.491.572Indian Journal of Endocrinology and Metabolism · 2018 · 12 citations · open access
Sex hormone profile in human immunodeficiency virus-infected men and it's correlation with CD4 cell counts
AbstractBackground: In human immunodeficiency virus (HIV)-infected men, hypogonadism is the most common endocrinological disorder, and most cases of hypogonadism are secondary. The aim of this study was to find out the hormonal abnormalities in HIV-infected males and it's correlation with CD4 cell counts. Materials and Methods: One hundred HIV-infected male patients were evaluated in the Department of Medicine, Postgraduate Institute of Medical Education and Research and Dr. Ram Manohar Lohia Hospital, New Delhi, India, over a period of 12 months from September 2014 to August 2015 using history, physical examination, routine baseline investigations, and CD4 counts. Free testosterone, dehydroepiandrosterone sulfate (DHEAS), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin were measured using an overnight fasting sample. Patients were divided into three groups on the basis of CD4 counts (Group A: CD4 counts ≥350/mm3, Group B: CD4 counts between 200 and 349/mm3, and Group C: CD4 counts <200/mm3). Data were analyzed using Student's t-test, ANOVA test, Chi-square test, and Pearson's test and P ≤ 0.05 was considered statistically significant. Results: In 100 HIV-infected males, overall prevalence of hypogonadism was found to be 66%, and 30%–35% patients had symptoms of hypoandrogenemia. Hypogonadotropic hypogonadism was found in 42% of patients. A significant association (P = 0.027) was found between prevalence of hypogonadism and the level of immunodeficiency with an increase in the prevalence of hypogonadism as CD4 counts decreased. Lower levels of free testosterone and DHEAS were found in cases of severe immunosuppression with a statistically significant correlation with CD4 counts. Correlation of other sex hormones (LH, FSH, and prolactin) with CD4 counts not statistically significant. Mean free testosterone and FSH were found to be significantly higher in patients on antiretroviral therapy (ART) than in those not on ART (P = 0.028 and P = 0.045, respectively), but no specific ART drug or their drug combination was found to have a significant correlation with levels of any sex hormone. Conclusion: Hypogonadism (hypogonadotropic hypogonadism) was found to be a common endocrinological disorder in HIV-infected male population, seen more commonly in association with low CD4 counts.
https://doi.org/10.4103/ijem.ijem_694_17Asian Journal of Andrology · 2014 · 4 citations · open access
An idiopathic hypogonadotropic hypogonadism patient with metabolic disorder and diabetes: case report
AbstractDear Editor, Congenital idiopathic hypogonadotropic hypogonadism (CIHH) is a rare congenital disorder characterized by delayed or absent sexual maturation and infertility associated with inappropriately low gonadotropin and sex steroid levels. We report a 34-year-old patient with CIHH accompanying with metabolic syndrome (MS) and diabetes. The patient was admitted to our center for the evaluation of high-blood sugar in July 26, 2013. He presented with polyuria, polydipsia and lost 5 kg of his body weight over the past 6 months. He developed blurred vision for 2 weeks before admission. His casual plasma glucose was 26 mmol l−1 and ketone bodies were normal. The patient was diagnosed with cryptorchidism at 6 years old without any therapy. He has poor secondary sex characteristics after puberty, and no further evaluation was conducted. He is the only child of the nonconsanguineous parents and had no history of hyposmia or anosmia, hearing loss. On physical examination, he had normal blood pressure and his height was 171 cm, weight 64 kg, body mass index 21.9 kg m−2, waist circumference 103 cm, hip circumference 89 cm. He has high pitched voice, absent beard, sparse pubic hair (Tanner stage 2), bilateral testes cannot be palpable in the scrotum, and microphallus with penis length was 3.0 cm. Results of the biochemical analysis are listed in Table 1, serum total cholesterol 7.17 mmol l−1, triglyceride 2.47 mmol l−1, high density lipoprotein-cholesterol 1.4 mmol l−1, low density lipoprotein-cholesterol 4.48 mmol l−1. Urine microalbuminuria was 529.7 mg l−1. The oral glucose tolerance test (75 g glucose) showed that peak insulin and c-peptide were 64.63 mmol l−1 and 5.46 ng ml−1 respectively at 180 min. glycosylated hemoglobin was 11.1%. Islet cell autoantibodies (ICA), insulin autoantibody (IAA) and glutamic acid decarboxylase antibody (GADA) were all negative. Serum concentrations of luteinizing hormone (LH) (0.1 IU l−1) and follicule-stimulating hormone (0.39 IU l−1) and testosterone (0.4 nmol l−1) were significantly lower than the normal range. The gonadotropin-releasing hormone stimulation test (100 μg intravenous) results showed that the peak of LH was 1.41 IU l−1 at 45 min, while the stimulation test with human chorionic gonadotrophin (2000 IU i.m. for 3 days) revealed that 72 h testosterone levels was at the lower limit of the normal range (2.0 nmol l−1). The laboratory data presented normal basal levels of thyroid hormones, thyroid stimulating hormone, growth hormone, prolactin, adrenocorticotropic hormone and cortisol (Table 1). The karyotype is 46, XY. A magnetic resonance imaging (MRI) of the testis showed bilateral testis was located at the level of the femoral head, but an MRI of the pituitary was normal. Ophthalmological findings showed the right eye was intraretinal hemorrhage, and the left eye was proliferative retinopathy. Bone mineral density showed osteoporosis. Electromyography showed severe diabetic neuropathy.Table 1: Laboratory findings on admissionBoth cross-sectional and longitudinal epidemiological studies have reported that testosterone is inversely related to the different components of MS in men.12 And hypogonadotropic hypogonadism occurs commonly in patients with Type 2 diabetes,3 but the majority data were investigated in study groups confounded with aging, obesity or chronic metabolic disorders. Recently, some disorder of sex development were reported to be associated with increased risks of diabetes and the MS as well.456 However, abnormal glucose metabolism in young men with CIHH were only reported in two small studies,78 and there was few data on the components of MS in young men with CIHH. The present patient was diagnosed as CIHH, due to absent sexual maturation, bilateral cryptorchidism and selectively low gonadotropin, low testosterone, normal karyotype and pituitary image. Until now, he had never received hormone replacement therapy, and with low testosterone during puberty and postpuberty. At the age of 34-year-old, the patient was diagnosed as MS according to 2005 International Diabetes Federation criteria. Moreover, the patient had severe complications of diabetes, including diabetic nephropathy, retinopathy, and neuropathy. His diabetes was characterized by no ketoacidosis, negative antibodies for IAA, ICA and GADA. His blood glucose levels gradually decreased after a daily dose of insulin of 0.7 U kg−1, suggesting insulin resistance. All above points supported the diagnosis of Type 2 diabetes mellitus. Although the specific pathway of the development of diabetes and MS in testosterone deficiency are still not fully clear, it was reported that testosterone could up-regulate the expression of glucose transporter 4 (GLUT4) and insulin receptor substrate 1 to stimulate glucose uptake into muscle and adipose,9 and deficiency of androgen action could decrease lipolysis and affect the expression of several key enzymes involved in lipogenesis.10 In conclusion, we report a 34-year-old patient with CIHH accompanying with MS and diabetes, the change of the patient's metabolic parameters after testosterone therapy need further follow-up. AUTHOR CONTRIBUTIONS MNZ and BS conceived of the study, drafted and revised the manuscript. CHQ and LB participated in the design of the study. XYC and WJL assisted with the revising of the manuscript. SQ participated in its design and coordination and revision of the manuscript. All authors read and approved the final manuscript. COMPETING INTERESTS The authors declare no competing interests. ACKNOWLEDGMENTS The data collection was funded by the Excellent Young Teachers Program of Tongji University, Shanghai, China (No. 1501219070).
https://doi.org/10.4103/1008-682x.137885学術講演梗概集. B-1, 構造I, 荷重・信頼性,応用力学・構造解析,基礎構造,シェル・立体構造・膜構造 · 2002 · 0 citations
20191 締固め砂杭工法による改良地盤の S 波速度の評価
AbstractHypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.
https://doi.org/10.1073/pnas.1834399100Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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