Cases Of Hypogonadotropic Hypogonadism Research Articles

7802 A Review of 21 Cases of Kallmann Syndrome

Abstract Disclosure: T. Kashima: None. M. Ishimaru: None. E. Tanimoto: None. S. Fukui: None. C. Nakamura: None. N. Ujita: None. H. Miyagi: None. M. Igarashi: None. H. Doi: None. K. Yoshii: None. Y. Naiki: None. R. Horikawa: None. Kallmann syndrome is the most common form of hypogonadotropic hypogonadism. The incidence is estimated to be 1 in 10,000 birth boys and 1 in 50,000 birth girls. The goals of treatment for childhood puberty are to induce the progression of secondary sexual characteristics close to physiological sexual maturity, to improve psychosocial problems caused by delayed puberty, and to achieve fertility. Methods.Twenty-one patients (fifteen males and six females) with a diagnosis of Kallmann syndrome who visited our Department between August 2004 and November 2023 were included in the study. The electronic medical records were reviewed retrospectively. Results.The median age at first visit was 15 years and 11 months (13 years and 3 months to 17 years and 7 months). The chief complained were secondary sexual characteristics not yet developed, olfactory disturbance, amenorrhea, decreased growth rate, and micropenis. Three adults had symptoms of Kallmann's syndrome and were seen for close examination. 6 had a history of hearing loss. Family history included 2 cases of hypogonadotropic hypogonadism and a sibling with Sjogren-Larsson syndrome. 9 cases had genetic testing, including KAL1, KAL2, FGF8, IL17D, 1 case each, and 2 gene variants of CHD2.At the time of initial examination, the median testicular volume in males was 1.0 mL (1.0-3.0 ml). Five of the six female patients had no breast enlargement.Endocrine examination revealed that the mean basic LH and LHRH test peak values were 0.25 and 3.40 mIU/mL, respectively; the mean basic FSH and peak FSH values were 0.91 and 4.47 mIU/m, respectively; the mean testosterone level in males was 0.09 ng/mL; and the mean estradiol level in females was 5.58 pg/mL.For the 20 patients, excluding children, gonadotropins (HCG+rFSH) for men and estrogen patches for women were both started at low doses and titrated up to Kaufman therapy in women. Median age at initiation of treatment was 16 years and 5 months (14 years and 1 month to 18 years and 6 months). Bone density increased after the start of treatment. One patient diagnosed with micropenis in infancy was treated with testosterone for micropenis at 2 years and 5 months. Two male patients had a baby with their partners. Discussion.The age of diagnosis (age of first examination) is considerably older than the average age of onset of secondary sexual characteristics, so it is necessary to educate the public so that patients can be examined earlier. The patient's fertility was partially confirmed, and a smooth transition to adult/reproductive medical care can be expected through earlier intervention. Presentation: 6/1/2024

A case of hypogonadotropic hypogonadism (HH) due to CHARGE syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A case of idiopathic hypogonadotropic hypogonadism with dental and orofacial defects

Isolated deficiency of gonadotropin-releasing hormone is a heterogeneous disorder with wide genetic and clinical overlap. It mainly presents as hypogonadotropic hypogonadism (HH). HH associated with anosmia is known as Kallmann syndrome (KS), while its normosmic variant is called normosmic idiopathic HH. However, it is associated with several nonreproductive features including dental defects. Fibroblast growth factor receptor 1 gene mutation, which is seen in the autosomal dominant form of idiopathic HH (HH 2), has often been linked to the associated dental abnormalities and orofacial defects; however, no literature exists for its association with anosmin-1 (ANOS1) gene mutation which is found in the X-linked form of HH (KS). ANOS1 gene was earlier known as KAL1 (Kallmann syndrome 1) gene, and encodes for the extracellular matrix protein called anosmin. Hence, we report a case of idiopathic HH (KS) so as to delineate the possible role of ANOS1 gene in dental/orofacial development. This can help prioritize gene screening and also provide scope for further genetic studies required to prove such association.

Anti-Müllerian hormone, an ovarian reserve marker in hypogonadotropic hypogonadism

ObjectiveTo determine the usefulness of Anti-Müllerian Hormone (AMH) and antral follicle count (AFC) as an ovarian reserve marker in hypogonadotropic hypogonadism (HH) patients and to find a limit value for the gonadotropin levels in the diagnosis of HH patients. Study designIt is a retrospective cross-sectional single-center study. One hundred ninety-nine women with HH and 171 healthy controls with no cycle disorders were included into this study. Continuous variables were expressed as mean ± standard deviation. Statistical comparisons were carried out according to the intention to treat by Student’s t-test, Mann-Whitney U test, where appropriate. Receiver operating characteristic curve-ROC was used to represent the sensitivity and specificity pair corresponding to decision threshold of FSH and LH levels in HH diagnosis. P < 0.05 was accepted to be statistically significant. ResultsThere was not any statistically significant difference between HH and control group regarding the age (23.94 ± 6.56 vs. 23.92 ± 3.01, respectively; p = 0.09). Serum AMH levels didn’t show statistically significant difference between HH and control group (3.26 ± 2.61 ng/mL vs. 3.15 ± 1.46 ng/mL, respectively; p = 0.11). The difference of AFC between HH and control group was statistically significant (6.67 ± 6.33 vs. 10.91 ± 2.92, respectively; p < 0.001). Follicle-stimulating hormone (FSH), Luteinizing-hormone (LH) and Estradiol (E2) levels between the groups were found to be significantly different. Area under the receiver operating characteristic curve-ROC for FSH was 0.98 and for LH was 0.96. For the diagnosis of HH, FSH levels lower than 3.05 IU/L (with a sensitivity of 92% and specificity of 94%) and LH levels lower than 1.55 IU/L (with a sensitivity of 91% and specificity of 92%) can be used. ConclusionIn conclusion, serum AMH levels reflect the follicle cohort in HH cases validly with negligible underestimation of ovarian reserve. FSH < 3.05 IU/L and LH < 1.55 IU/L could be used with high sensitivity and specificity for the diagnosis of HH.

Abstract 45: The clinical and etiological profile of primary amenorrhea: A single centre experience from South Tamil Nadu

Introduction: Primary amenorrhea, the absence of menstrual cycles by 16years of age, or by 13 years with associated short stature or lack of secondary sexual characters, is most commonly due to gonadal dysgenesis and Mullerian agenesis worldwide and in previous Indian studies.Aims and Objectives: To study the clinal and etiological profile of primary amenorrhea patients presenting to our center.Methods: All cases of primary amenorrhea attending Endocrinology OP from October 2019 to October 2021 were included. Detailed history and physical examination, routine investigations, LH, FSH, TSH, testosterone and estradiol by Roche Cobase e411 and ultrasound abdomen and pelvis were done in all cases, followed by MRI pelvis or MRI brain. Serum cortisol, 11-deoxycorticosterone, 21deoxycortisol, DHEAS, dihydrotestosterone, androstenedione and 17αhydroxyprogesterone, karyotyping, laparoscopy, and gonadal biopsy were done in appropriate cases.Results: 30 patients with primary amenorrhea were included, of which nine were Turner syndrome, seven Mullerian abnormalities, six hypogonadotropic hypogonadism, three CDGP, two CAH-17 alfa hydroxylase deficiency, one case each of 17 beta hydroxysteroid deficiency CAH and Swyer syndrome. Mean age was 20.2years, oldest 33years. All Turner syndrome and 3 hypogonadotropic hypogonadism cases were short in stature. Secondary sexual characters were normal in Mullerian agenesis. Bony deformities were present in two Turner cases and one Mullerian agenesis, renal anomalies in five Mullerian agenesis and two Turner syndrome, and cardiac anomalies in three Turner cases. Hormonal profile, imaging/ karyotype confirmed the diagnosis. Mosaicism was present in 2 cases of Turner syndrome.Conclusion: Primary amenorrhea is quite common in South Indian population and clinical features correlate well with etiology, Turner syndrome being the most common etiology, followed by Mullerian agenesis and hypogonadotropic hypogonadism. Delayed age of diagnosis reflects need for increasing awareness and removing social stigma.

Reproductive prognosis of patients with hypogonadotropic hypogonadism: Retrospective review of 16 cases with amenorrhea.

The aim of this study was to evaluate the general characteristics, menstruation status, and fertility outcomes of patients with hypogonadotropic hypogonadism (HH). We evaluated 16 patients with HH who visited our institution between April 2012 and March 2016 with a complaint of amenorrhea. Four (25%) patients had primary amenorrhea and the remaining 12 (75%) cases had secondary amenorrhea. Among the patients with primary amenorrhea, weight loss was considered to be the underlying cause in one (25%) patient, whereas the remaining three (75%) cases were idiopathic HH. Among HH cases with secondary amenorrhea, six (50%) developed amenorrhea following weight loss, whereas the remaining six cases were of unknown etiology. Among the 16 patients with HH, we observed the sporadic restart of the menstrual cycle in four (25%) women during follow-up. Infertility treatment was administered to nine patients with HH who wished to become pregnant. Clomiphene citrate was effective in four patients with secondary amenorrhea and induced follicular development. Seven of nine patients with HH (77.8%) became pregnant following infertility treatment. In some cases of HH, the serum levels of gonadotropin increased sporadically during follow-up, regardless of the recovery of menstruation. We followed one patient with HH for more than 20 years. Although her gonadotropin levels were generally low and sometimes fluctuated without spontaneous menstruation, they increased dramatically to menopausal levels at 50 years of age. However, they again decreased to hypogonadotropic levels. As the pathophysiology varied widely among patients, the etiologic factors underlying HH might also vary.

Clinical characteristics and molecular genetic analysis of a cohort with idiopathic congenital hypogonadism.

Hypogonadism is defined as inadequate sex hormone production due to defects in the hypothalamic-pituitary-gonadal axis. In recent years, rare single gene defects have been identified in both hypergonadotropic hypogonadism (Hh), and hypogonadotropic hypogonadism (HH) cases with no chromosomal anomalies. The aim of the present study is to investigate the underlying molecular genetic etiology and the genotype-phenotype relationship of a series of patients with Hh and HH. In total, 27 HH and six Hh cases were evaluated. Clinical and laboratory features are extracted from patients' hospital files. Whole exome sequencing (WES) analysis was performed. A total of 27 HH cases (15 female) (mean age: 15.8±2.7 years) and six Hh patients (six females) (mean age: 14.9±1.2 years) were included. In molecular genetic analysis, a pathogenic/likely pathogenic variant was identified in five (two patients from the same family) of 27 HH cases (two novel) and three of the six Hh. In HH group variants (pathogenic, likely pathogenic and variant of uncertain significance) were identified in KISS1R (n=2), PROK2 (n=1), FGFR1 (n=1), HS6ST1 (n=1), GNRH1 (n=1) genes. In the Hh group, splice-site mutations were detected in DCAF17 (n=1) and MCM9 (n=2) genes. HH and Hh cases are genetically heterogeneous diseases due to oligogenic inheritance, incomplete penetrance, and variable expressivity. We found rare variants in CHH related genes in half of our HH cases, whereas they classified as pathogenic/likely pathogenic according to ACMG criteria in only about 15% of HH cases. Using advanced genetic analysis methods such as whole-genome sequencing and long-read sequencing may increase the mutation detection rate, which should always be associated with and expert genetic counseling to interpret the data.

Case of Hypogonadotropic Hypogonadism (HH), Obesity, Diabetes Type 2, Hyperlipidemia Associated with BBS Genes

While the surgical stages of single ventricle (SV) palliation serve to separate pulmonary venous and systemic venous return, and to volume-unload the SV, staged palliation also results in transition from parallel to series circulation, increasing total vascular resistance. How this transition affects pressure loading of the SV is as yet unreported.We performed a retrospective chart review of Stage I, II, and III cardiac catheterization (CC) and echocardiographic data from 2001-2017 in all SV pts, with focus on systemic, pulmonary, and total vascular resistance (SVR, PVR, TVR respectively). Longitudinal analyses were performed with log-transformed variables. Effects of SVR-lowering medications were analyzed using Wilcoxon rank-sum testing.There were 372 total patients who underwent CC at a Stage I (median age of 4.4 months, n=310), Stage II (median age 2.7 years, n = 244), and Stage III (median age 7.3 years, n = 113). Total volume loading decreases with progression to Stage III (P< 0.001). While PVR gradually increases from Stage II to Stage III, and SVR increases from Stage I to Stage III, TVR dramatically increases with progress towards series circulation. TVR was not affected by use of systemic vasodilator therapy. TVR, PVR, SVR, and CI did not correlate with indices of SV function at Stage III.TVR steadily increases with an increasing contribution from SVR over progressive stages. TVR was not affected by systemic vasodilator agents. TVR did not correlate with echo-based indices of SV function. Further studies are needed to see if modulating TVR can improve exercise tolerance and outcomes.

Endocrine and Cytogenetic Profile of Variations in Genital Development: Series of 9 Cases at the Mali Hospital

We carried out a retrospective and descriptive study in the Medicine and Endocrinology service of the Mali Hospital from January 2015 to December 2018. Nine cases of anomalies in sexual differentiation were referred for pubertal delay, growth retardation, gynecomastia, micropenis or infertility. Outcomes: The average age was 14 years; 5 patients were declared female at birth; 2 were married without children; 7 patients came from the region of Kayes; 8 patients consulted for pubertal delay; 1 patient presented with association of a blind vagina and 2 bilateral inguinal gonads. 3 of 4 patients declared male at birth had a micropenis; 2 patients had gynecomastia with a history of hypospadias. Ultrasound and biological data showed a clinical-hormonal picture of hypergonadotropic hypogonadism in 6 patients, 1 case of hypogonadotropic hypogonadism with hypercorticism and 2 cases with normal gonadotropic axis; two cases of azoospermia. Karyotypic analysis showed: 3 cases of SK, 2 cases of Klinefelter Syndrome, 2 cases of Androgen Insensitivity Syndrome and 2 cases of male 46 XX syndrome including one with sry negative. Conclusion: The precise diagnosis of anomalies in sexual differentiation remains complicated in Mali, due to the inadequacy of the technical platform. Diagnosis must be made at an early stage to allow normal growth, puberty and satisfactory fertility. Taking charge of the medical treatment possibly associated with plastic surgery could give good results.

The Epidemiology and Hormonal Assessment of Patients with Empty Sella on Pituitary Magnetic Resonance: A Retrospective Single Centre Study in Saudi Community Based Hospital

Background: No large enough series have been reported to allow a detailed definition of the epidemiology of primary empty sella (PES) and diagnostic anterior pituitary hormones abnormalities in Saudi Arabia. Objective: To evaluate the epidemiological and hormonal profile of patients with PES. Design: Retrospective analysis of pituitary Magnetic Resonance Image (MRI) and hormonal data of patients with PES between January 2008 and December 2017. Settings: Departments of Endocrinology and Radiology at King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia. Patients: 537 patients with clinical, hormonal and radiological data. Main outcome measures: The frequency of PES in patients and associated abnormal pituitary hormones. Results: Over the 9-year period, Out of 537 patients; 161 (30 %) were male and 376 (70 %) were female with mean age 35.4 ± 13.7. Among them we found 50 (9.3%) cases with PES on MRI. 11 (22 %) cases were male and 39 (78 %) were female with female to male ratio of 3.5 to 1. Cases with PES were significantly older than cases with pituitary adenoma and normal MRI, 45.3 ± 19.6 vs. 35.3 ± 13.9, p value &lt;0.0001. PES occurred with the greatest frequency at the fourth decade. During the hormonal assessment, 34 (68%) cases of PES were found to have some degree of anterior pituitary hormones abnormailities. No anterior pituitary hormones abnormalities were found in 16 (32%) of cases. Hyperprolactinemia was found in 26 (52%) of cases. Cases of hypogonadotropic hypogonadism and central hypothyroidism were equally distributed, 4 cases ( 8% ). Female predominance was found. Conclusion: In our study, PES was more common in middle aged female. The high incidence of endocrine abnormalities in patients with PES mandates that these patients should routinely be subjected to endocrine evaluation to detect these deficiencies early. Limitations: Question of clustering of cases within the study region and limited study sample size.

Diagnostic dilemmas in the management of a case of azoospermia due to adult onset hypogonadotropic hypogonadism along with posttubercular epididymal obstruction

Adult-onset idiopathic hypogonadotropic hypogonadism (HH) is one of the rare but reversible cause of male infertility. It is one of the few causes of non-obstructive azoospermia (OA). In very rare situations, obstructive azoosperima is also seen along with non-OA. We report our experience with the management of such a case of male infertility − a case of adult-onset HH with posttubercular epididymal obstruction. Index case was a 33-year-old male diagnosed with adult-onset HH. He had persistent azoospermia after 6 months of gonadotropins therapy. On further evaluation, he was also found to have OA (posttubercular epididymal obstruction). The in vitro fertilization (IVF)-Embryo Transfer (ET) with percutaneous epididymal sperm aspiration was successful in achieving a pregnancy.

Genetics of Hypogonadotropic Hypogonadism.

Hypogonadotropic hypogonadism (HH) often manifests as pubertal delay. A considerable proportion of cases of HH is due to genetic mutations. Recognizing those mutated genes and associated phenotypes may improve our diagnostic capabilities. GNRHR and TACR3 should be the first two genes to be screened in a clinical setting for equivocal cases such as constitutional delay in puberty versus idiopathic HH. In Kallmann syndrome (KS), according to the presence of certain accompanying clinical features, genetic screening for particular gene(s) may be prioritized: synkinesia (KAL1), dental agenesis (FGF8/FGFR1), bony anomalies (FGF8/FGFR1), and hearing loss (CHD7, SOX10). FEZF1 has recently been added to the growing list of KS genes. Also, discovery of mutations in KISS1/KISS1R and TAC3/TACR3 in kisspeptin and neurokinin B signaling, respectively, has provided major advancements in our understanding of the biology of the gonadotropin-releasing hormone pulse generator. Identification of further causative mutations accounting for the HH phenotype, which is now more feasible with the increasing popularity of whole exome sequencing, may provide deeper insight into the biology of the hypothalamic-pituitary-gonadal axis.

A Case of Hypogonadotropic Hypogonadism Caused by Opioid Treatment for Nonmalignant Chronic Pain

We report a case of 42-year-old male patient with hypogonadotropic hypogonadism. He suffered from general fatigue and erectile dysfunction after the treatment with transdermal fentanyl for chronic pain by traffic injury. Endocrine examinations and hormone stimulating tests showed that he had hypogonadotropic hypogonadism. Brain magnetic resonance imaging (MRI) showed no abnormal findings, and he had no past history of accounting for acquired hypogonadotropic hypogonadism. Therefore, his hypogonadism was diagnosed to be caused by opioid treatment. Although opioid-induced endocrine dysfunctions are not widely recognized, this case suggests that we should consider the possibility of endocrine dysfunctions in patients with opioid treatment.

Pituitary Iron and Volume Predicts Hypogonadal Hypogonadism in Transfusional Iron Overload

Abstract 1094 Introduction:Hypogonadotropic Hypogonadism (HH) is one of the most common morbidities in patients with transfusion-dependent anemias such as thalassemia major. Unfortunately, pituitary dysfunction is difficult to detect prior to puberty because of immaturity of the hypothalamic-pituitary-gonadal axis. We used MRI to measure pituitary R2 and volume to determine at what age these patients develop pituitary iron overload and volume loss. Additionally, we aimed to stratify the risk of clinical HH based on pituitary R2 and pituitary volume, and determine predictors of pituitary iron deposition and volume loss. Methods:We recruited 56 patients (52 with thalassemia major and 4 with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Diagnosis of HH was determined by either lack of secondary pubertal characteristics by age 13 for females or age 14 for males, by primary or secondary amenorrhea in females ages 16 or older, or by the need for testosterone administration in males. Patients also had pancreas R2*, heart R2*, and liver iron concentration measured by MRI. Normative pituitary R2 and volume trends were determined by a cohort of 100 control patients. Results:Patients were 20.4 ± 12.1 years old and well distributed by sex (31 males, 25 females). All subjects received blood transfusions every 2–4 weeks and were on appropriate chelation therapy as indicated by their physician. Mean pituitary R2 Z-score was 4.5 and mean anterior pituitary volume Z-score was −0.9. Figure 1 shows pituitary R2 values as a function of age, superimposed on normal trends from the control population. Patients with transfusional iron overload began to develop pituitary iron overload in the first decade of life; however, significant iron deposition were observed beginning in the second decade. Heavy pituitary iron deposition (Z-score > 5) and volume loss (Z-score < −2.5) were predictive of HH (Figure 2). Volume loss was highly specific (87%) but identified only half of HH cases. The remaining HH patients had heavy pituitary iron (Z-score > 5), but preserved pituitary volume. Pituitary R2 correlated significantly with serum ferritin as well as liver iron concentration, pancreatic R2*, and cardiac R2* by MRI. [Display omitted] [Display omitted] Discussion:Pituitary iron loading begins as early as the first decade of life in chronically transfused patients, meriting a pituitary MRI in children under 10 years old. Severe pituitary iron loading as well as volume loss throughout the second decade of life, and are predictive of HH, warranting more intensive screening in this age group. However, many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. This may also be explained by improvements in gland function observed following intensive chelation therapy. Serial tracking of pituitary iron and volume trends on age-appropriate nomograms should improve diagnostic accuracy and toxicity prophylaxis. Disclosures:Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Hypogonadisme hypogonadotrope : notions récentes sur la régulation de l’axe hypothalamo-hypophyso-gonadique

Hypogonadotropic hypogonadism (HH) is defined by the absence of sex steroid synthesis associated with the lack of appropriate gonadotrophin secretion. This leads to a variable degree of impuberism, often diagnosed during childhood or adolescence. Genetics of HH involve many genes. However, molecular defects have been identified in only 30 % of patients. Kallmann syndrome (KS) is defined by the association of HH and anosmia. Six genes are involved in KS ( KAL1, FGFR1, FGF8, PROK2, PROKR2 and CHD7). However, genetics of KS is complex, because of the variability of the phenotype for a similar molecular defect. Otherwise, heterozygous anomalies are frequently described. Identification in the same patient of several mutations in some of these genes (digenism) could account for this variability. Autosomal recessive transmission is frequently observed in familial cases of HH without anosmia. Molecular alterations have been identified for several neuropeptides or their corresponding receptors, which are involved in the physiology of the gonadotropic axis : GNRHR, KISS1R/ GPR54, neurokinin B ( TAC3), TACR3 and GNRH1 (and PROK2, PROKR2 and CHD7). Anomalies of leptin or its receptor are also involved in HH cases. A new negative regulating element has been recently identified in humans : RFRP3, which is ortholog of the avian GnIH (gonadotrophin inhibitory hormone). Recent progress about these neuropeptides leads to a new model of comprehension of the gonadotropic axis physiology, from a linear model to a network model, which regulates the central element of regulation of the gonadotropic axis, represented by the GnRH neurons.

Antipituitary Antibodies against Gonadotropin-Secreting Cells in Adult Male Patients with Apparently Idiopathic Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism (HH) can occur at any stage of life as an isolated congenital or acquired abnormality or within a more generalized pituitary or hypothalamic impairment. However, the defect in patients with idiopathic HH is still unknown. The aim of this study was to investigate the prevalence of antipituitary antibodies (APA) in a group of HH patients with or without Kallmann's syndrome and to characterize their pituitary target. We conducted a cross-sectional cohort study. The study was performed at the Endocrinology Unit of the Second University of Naples. Twenty-one HH patients with normal sense of smell (group 1), 10 patients with Kallmann's syndrome (group 2), 13 patients with HH associated with other pituitary hormone deficiencies (group 3), and 50 normal controls were studied. APA were evaluated in patients and in controls by indirect immunofluorescence. Moreover, a magnetic resonance imaging (MRI) of the hypothalamic-pituitary region was performed in all three groups of patients. APA were detected at high titer in eight out of 21 patients in group 1 (38%) and in five of 13 in group 3 (38.4%), and at low titers in two out of 10 in group 2 (20%) and in three of 50 controls (6%). In patients of group 1, APA immunostained selectively gonadotropin-secreting cells, whereas in those of group 3, they immunostained other pituitary hormone-secreting cells also. None of patients in group 1 showed alterations on MRI, whereas all patients in group 2 showed aplasia/hypoplasia of the olfactory bulbs/tracts and/or of olfactory sulci. Among the five APA-positive patients in group 3, three had normal MRI, one had findings of empty sella, and one had findings of autoimmune hypophysitis. Our results suggest that some apparently idiopathic cases of HH, both isolated and associated with other pituitary impairment, can be caused by an early autoimmune process involving the gonadotrophs at pituitary level. Future longitudinal studies are needed to clarify the natural history of this process and the possible effect of early corticosteroid therapy.

Hypogonadotropic hypogonadism in a female with the Johnson-McMillin syndrome

A case of hypogonadotropic hypogonadism associated with the Johnson-McMillin syndrome is presented. This is a rare, autosomal dominant disorder, characterized by variable degrees of alopecia and anosmia, conductive hearing loss, and increased dental caries. Until now hypogonadotropic hypogonadism has only been observed in affected men. Ovulation can be induced with gonadotropins and conception can be obtained, but because prenatal diagnosis is not as yet possible, oocyte donation should be offered as an alternative for procreation.

A case of complete hypogonadotropic hypogonadism with a mutation in the gonadotropin-releasing hormone receptor gene

ObjectiveTo screen for mutations in the GnRH receptor gene in a case of complete hypogonadotropic hypogonadism (HH) with GnRH resistance. DesignCase report. SettingA university hospital. Patient(s)A male patient with the complete form of HH without anosmia. Intervention(s)Physical examination and laboratory and genetic studies. Main outcome measure(s)Gonadotropins at the basal state and after GnRH administration and GnRH receptor DNA sequencing. Result(s)A novel missense mutation, localized in the first amino acid of the extracellular loop found in the heterozygous state, and another mutation, Arg139His (R139H), located in the conserved aspartate-arginine-serine motif at the junction of the third transmembrane and second intracellular loop of the GnRH receptor, were identified in the homozygous state. Pedigree studies reveal that both parents were heterozygous for R139H, while the mother carried the missense mutation at codon 1(M1T). Conclusion(s)GnRH receptor mutations may account for a larger proportion of cases of HH than previously thought. The phenotypic spectrum of HH seems to vary, and this heterogeneity may be related, at least in part, to the degree of impaired biological activity of the mutated GnRH receptor caused by the allelic type of mutations.

Misrouted cell surface receptors as a novel disease aetiology and potential therapeutic target: the case of hypogonadotropic hypogonadism due to gonadotropin-releasing hormone resistance

Misrouted cell surface receptors as a novel disease aetiology and potential therapeutic target: the case of hypogonadotropic hypogonadism due to gonadotropin-releasing hormone resistance

The Molecular Basis of Human Hypogonadotropic Hypogonadism

Patients with hypogonadotropic hypogonadism (HH) present with delayed puberty, infertility, and low serum gonadotropins. The molecular basis for most cases of HH is unknown, but single gene mutations have been described for some hypothalamic and pituitary genes. Kallmann syndrome due to KAL gene mutations and adrenal hypoplasia congenita/HH caused by AHC gene mutations are both X-linked recessive disorders. Mutations in the gonadotropin releasing hormone receptor, leptin, and the leptin receptor cause autosomal recessive HH. In addition, isolated deficiencies of follicle stimulating hormone and luteinizing hormone in the corresponding specific β-subunit genes and PROP1 gene mutations represent pituitary deficiency states, resulting in a phenotype of HH. Despite these remarkable advances in our understanding of human HH, the cause of approximately 90% remains unknown.