Idiopathic Hypogonadotropic Hypogonadism Research Articles

SAT-295 Low Dose rFSH Prior to HCG-rFSH Therapy in Kallmann Syndrome

[Background] Kallmann syndrome (KS) is known as a disorder characterized by hypogonadotropic hypogonadism and anosmia. Sato et al. reported that approximately 60% of Congenital male hypogonadotropic hypogonadism (CMHH) could not achieve sufficient spermatogenesis with the current hCG-rFSH combination therapy. [Objective] With the aim of improving gonadal function of KS, we treat KS patient with new methods proposed by Sato et al. and the effectiveness of low dose of rFSH mono-therapy followed by hCG-rFSH in an adolescent patient is discussed.[Case report] At the age of 14 years, he was diagnosed as KS because of cryptorchidism and micropenis in infancy and delayed puberty and hyposmia in adolescence, and identified with KAL1 mutation. The responses of LHRH stimulation were low levels (peak LH 0.85 mIU/mL, peak FSH 2.05 mIU/mL). The levels of testosterone responded for HCG stimulation test were 0.29 ng/mL before stimulation and 0.81 ng/mL after stimulation.From the age of 15 years, low dose rFSH (75 IU) was administered daily for 10 weeks, then switched to hCG-rFSH. Every six months, replacement doses of hCG and rFSH were increased. His height gain was 10.8 cm after treatment. Testicular volume was 2 mL when treatment began and increased to 6 mL in two years.Then, testosterone reached adult level. [Conclusion] Low dose rFSH therapy prior to hCG-rFSH to treat adolescent patients with KS seems to gain pubertal development slowly but improve testosterone secretion sufficiently.

SAT-212 62-Year-Old Woman with Undiagnosed Kallman Syndrome: A Case of Missed Opportunities

Background: Kallman Syndrome (Isolated gonadotropin-releasing hormone (GnRH) deficiency with anosmia/hyposmia) affects both sexes but has male preponderance. The sex difference likely relates to genetics and possible early diagnosis in males because of microphallus and cryptorchidism. The presentation of Kallman syndrome in females may be very subtle and may lead to a delay in the diagnosis and management. Clinical Case A 62-year-old Caucasian female with a history of hypertension, hyperlipidemia, seizure disorder, COPD, multiple fractures and peripheral vascular disease was referred for evaluation of chronic hyponatremia that was diagnosed 6 years ago. The patient was euvolemic on the exam, and laboratory evaluation was consistent with SIADH. Labs showed Na 122-130 mmol/L, normal thyroid function and cortisol levels, serum Osm 259 mOsm/kg (Normal 280-300 mOsm/kg), urine Osm 565mOsm/kg (Normal 50-1200 mOsm/kg). Hyponatremia had been managed with fluid restriction and salt tablets. Other work-up was negative for malignancy. Unrelated to hyponatremia, the patient had striking virilization and hirsutism. On further history, she reported primary amenorrhea, infertility, lack of secondary sexual characteristics and anosmia. Physical exam was notable for absent secondary female sexual characteristics. Additional family history revealed a brother with anosmia and incomplete secondary sexual development and multiple females who never achieved puberty or fertility. Further workup included a normal pituitary MRI, and inappropriately low FSH of 1.0mIU/ml and LH of 0.3 m IU/ml (expected post-menopausal levels > 51 and 14, respectively). Other pituitary axis evaluation was normal. The patient also had a history of low trauma fractures of the hip and forearm. Bone density scan showed severe osteoporosis with a T-Score of -4.80 at the right femoral neck and -4.90 at the spine. Secondary osteoporosis work-up was negative. She was started on anabolic therapy with Teriparatide with plans to follow with antiresorptive therapy. Conclusion: This patient was diagnosed with hypogonadotropic hypogonadism due to Kallman Syndrome with severe osteoporosis. This case illustrates the value of physical exam and considering diagnoses and work up beyond the initial reason for consultation. A timely diagnosis in her case could have improved her quality of life, helped her achieve fertility and possibly may have prevented severe osteoporosis. The literature review also suggests a significant percentage of patients do not receive treatment for osteoporosis after hip fracture. (1) References 1-Solomon DH, Johnston SS, Boytsov NN, McMorrow D, Lane JM, Krohn KD. Osteoporosis Medication Use After Hip Fracture in U.S. Patients Between 2002 and 2011, J Bone Miner Res. 2014 Sep;29(9):1929-37.

MON-224 Congenital Hypogonadotropic Hypogonadism: Features and Genetics of 60 Females Patients

Context Congenital hypogonadotropic hypogonadism (CHH) in females is a rare reproductive disorder about five times less prevalent than in males. Its diagnosis is often difficult to make due to the genetic and phenotypic heterogeneities. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH. However, a genetic mutation is only found in 30% cases and genetic approach concerns mostly male patients. Materials and Methods This retrospective, single-center study included 60 female patients with CHH; they underwent a genetic analysis of 16 genes: (ANOS1, GNRH1, GNRHR, FGFR1, FGF8, TAC3, TACR3, PROK2, PROKR2, CHD7, WDR11, SEMA3A, HS6ST1, KISS1, KISS1R, SOX10) using the next generation sequencing. Each variant was classified known as damaging the protein function or not by the literature. The population was retrospectively divided into four groups based on genetic analysis. Patients with a complete genotype confirming CHH phenotype were named the « CG group »; with a partial genotype, « PG group », women with 2 different gene defects supposing digenic mutations were « DG group » and patients without mutation found were « NM group ». Results 48 variants were identified in 36 patients, 45 of them were known for damaging the protein function with 17 nonsense, frameshift or splice site mutations. The phenotype was fully explained by the genetic anomalies in 20 patients, it seems partial in 8, a digenic cause is supposed in 5 cases and polymorphism in 3 patients. The most frequently mutated gene was GNRHR in 18,75%, followed by FGFR1 and PROKR2 in 16,7%, SEMA3A 12,5%, PROK2 and TAC3 in 6,25%, SOX10, KISS1R, FGF8 and CHD7 in 4% and TAC3, GNRH1 and SOX2 in 2%. The age at the diagnosis was statistically earlier in « CG group », p= 0,018. Additional symptoms such as middle line defects, tooth agenesis and hearing loss were statistically more important in « CG group » (30%) and « PG group » (37,50%) than in « DG group » (0%) and « NM group » (7,41%) p=0,05. 61,7% patients underwent trials stopped their treatment. Reversal was identified in 8% (3 patients) by spontaneous menstrual cycling for at least 1 month. Conclusion Recent findings on the reversibility, phenotypic variability and oligogenicity of CHH have challenged the conventional beliefs and current dogma associated with congenital defect and explain the difficulty to predict genotype-phenotype correlations. CHH patients with a complete genotype seems generally to have a more severe disease with an early age at diagnosis and additional symptoms.

Delayed Puberty-Phenotypic Diversity, Molecular Genetic Mechanisms, and Recent Discoveries.

This review presents a comprehensive discussion of the clinical condition of delayed puberty, a common presentation to the pediatric endocrinologist, which may present both diagnostic and prognostic challenges. Our understanding of the genetic control of pubertal timing has advanced thanks to active investigation in this field over the last two decades, but it remains in large part a fascinating and mysterious conundrum. The phenotype of delayed puberty is associated with adult health risks and common etiologies, and there is evidence for polygenic control of pubertal timing in the general population, sex-specificity, and epigenetic modulation. Moreover, much has been learned from comprehension of monogenic and digenic etiologies of pubertal delay and associated disorders and, in recent years, knowledge of oligogenic inheritance in conditions of GnRH deficiency. Recently there have been several novel discoveries in the field of self-limited delayed puberty, encompassing exciting developments linking this condition to both GnRH neuronal biology and metabolism and body mass. These data together highlight the fascinating heterogeneity of disorders underlying this phenotype and point to areas of future research where impactful developments can be made.

Whole Exome Sequencing Revealed a Novel Nonsense Variant in the GNRHR Gene Causing Normosmic Hypogonadotropic Hypogonadism in a Pakistani Family

Background: Congenital hypogonadotropic hypogonadism (CHH) is a heterogeneous disorder characterized by delayed or loss of puberty and infertility due to functional deficiency in the hypothalamic gonadotropin-releasing hormone (GnRH). CHH can be classified into 2 subtypes on the basis of olfaction: Kallmann syndrome and normosmic CHH (nCHH). The spectrum of genetic variants causing CHH is continually expanding. Here, we recruited a consanguineous Pakistani family having 2 male and 2 female infertile patients diagnosed with idiopathic nCHH. Aims: The aim of this study was to investigate the genetic cause of nCHH in the family. Methods: Clinical and physical analyses were performed for the patients. Genetic analysis was carried out using whole exome and Sanger sequencing. Results: Clinical and physical investigations confirmed low levels of gonadotropins and failure of secondary sexual development in the patients. Genetic analysis identified a novel nonsense mutation (chr4: g.68619942G>A, c.112C>T, p.Arg38*) in the gonadotropin-releasing hormone receptor gene (GNRHR) recessively co-segregating with nCHH in this family. All the patients are homozygous and their parents are heterozygous carriers, while normal siblings are heterozygous carriers or wild-type for this mutation, indicating that the identified mutation is pathogenic for nCHH in the family. Conclusion: We report the first homozygous nonsense mutation in the GNRHR gene (chr4: g. 68619942G>A, c.112C>T, p. Arg38*) that is associated with familial nCHH. Hence, our study displayed a good correlation of the genotype and phenotype of nCHH patients.

Screening for mutations in selected miRNA genes in hypogonadotropic hypogonadism patients.

In approximately half of congenital hypogonadotropic hypogonadism (cHH) patients, the genetic cause remains unidentified. Since the lack of certain miRNAs in animal models has led to cHH, we sequenced human miRNAs predicted to regulate cHH-related genes (MIR7-3, MIR141, MIR429 and MIR200A-C) in 24 cHH patients with Sanger sequencing. A heterozygous variant in MIR200A (rs202051309; general population frequency of 0.02) was found in one patient. Our results suggest that mutations in the studied miRNAs are unlikely causes of cHH. However, the complex interplay between miRNAs and their target genes in these diseases requires further investigations.

Next-generation sequencing refines the genetic architecture of Greek GnRH-deficient patients.

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a rare disease with a wide spectrum of reproductive and non-reproductive clinical characteristics. Apart from the phenotypic heterogeneity, IGD is also highly genetically heterogeneous with >35 genes implicated in the disease. Despite this genetic heterogeneity, genetic enrichment in specific subpopulations has been described. We have previously described low prevalence of genetic variation in the Greek IGD cohort discovered with utilization of Sanger sequencing in 14 known IGD genes. Here, we describe the expansion of genetic screening in the largest IGD Greek cohort that has ever been studied with the usage of whole-exome sequencing, searching for rare sequencing variants (RSVs) in 37 known IGD genes. Even though Sanger sequencing detected genetic variation in 21/81 IGD patients in 7/14 IGD genes without any evidence of oligogenicity, whole exome sequencing (WES) revealed that 27/87 IGD patients carried a rare genetic change in a total of 15 genes with 4 IGD cases being oligogenic. Our findings suggest that next-generation sequencing (NGS) techniques can discover previously undetected variation, making them the standardized method for screening patients with rare and/or more common disorders.

Thyroid function in Klinefelter syndrome: a multicentre study from KING group.

The prevalence and the etiopathogenesis of thyroid dysfunctions in Klinefelter syndrome (KS) are still unclear. The primary aim of this study was to evaluate the pathogenetic role of hypogonadism in the thyroid disorders described in KS, with the scope to distinguish between patients with KS and hypogonadism due to other causes (Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, iatrogenic hypogonadism and acquired hypogonadotropic hypogonadism after surgical removal of pituitary adenomas) called non-KS. Therefore, we evaluated thyroid function in KS and in non-KS hypogonadal patients. This is a case-control multicentre study from KING group: Endocrinology clinics in university-affiliated medical centres. One hundred and seventy four KS, and sixty-two non-KS hypogonadal men were enrolled. The primary outcome was the prevalence of thyroid diseases in KS and in non-KS. Changes in hormonal parameters were evaluated. Exclusion criterion was secondary hypothyroidism. Analyses were performed using Student's t test. Mann-Whitney test and Chi-square test. FT4 was significantly lower in KS vs non-KS. KS and non-KS presented similar TSH and testosterone levels. Hashimoto's thyroiditis (HT) was diagnosed in 7% of KS. Five KS developed hypothyroidism. The ratio FT3/FT4 was similar in both groups. TSH index was 1.9 in KS and 2.3 in non-KS. Adjustment for differences in age, sample size and concomitant disease in multivariate models did not alter the results. We demonstrated in KS no etiopathogenic link to hypogonadism or change in the set point of thyrotrophic control in the altered FT4 production. The prevalence of HT in KS was similar to normal male population, showing absence of increased risk of HT associated with the XXY karyotype.

An Update on Aetiopathology, Various Genetic Causes and Management of Delayed Puberty-A Minireview

Delayed Puberty (DP), especially in boys, is a common presentation in paediatrics. By definition DP is defined as the presentation of clinical signs of puberty 2-2.5SD later than in the normal population. With the recent advances in understanding of the neuroendocrine, genetic and environmental factors controlling pubertal development it has become easier to understand the pathophysiology of DP. The discovery of kisspeptin signaling through its receptor identified neuroendocrine mechanisms controlling the gonadotropin releasing hormone (GnRH) pulse generator at the onset of puberty. Genetic mechanisms from single gene mutations to single nucleotide polymorphisms associated with DP are being identified. Environmental factors, including nutritional factors, besides endocrine disruptors, have been associated with the secular trends and abnormal timing of puberty. Inspite of these advances, the main question remains how to differentiate DP associated with underlying pathology of hypogonadism from constitutional delay in growth and puberty (CDP) that remains challenging as biochemical tests do not always discriminate the 2.The diagnostic accuracies of newer investigations which include the 36-hour luteininzing hormone releasing hormone(LHRH) tests, GnRH agonist tests, antimullerian hormone and inhibin B, need further evaluation. Sex hormone replacement remains the main therapy that is available for DP, whose choice is based on clinical practice and the availability of the various sex steroid preparations. Spontaneous reversal of hypogonadism has been reported in boys having idiopathic hypogonadotropic hypogonadism following sex steroid treatment, which highlights the importance of reassessment at the end of pubertal induction .Novel therapies having a more physiological bases like gonadotropins or kisspeptin agonists are getting investigated for the management of hypogonadotropic hypogonadism. A careful assessment and knowledge of the normal physiology remains the mainstay of managing patients with DP.

Modulation of proteostasis and protein trafficking: a therapeutic avenue for misfolded G protein-coupled receptors causing disease in humans.

Proteostasis refers to the process whereby the cell maintains in equilibrium the protein content of different compartments. This system consists of a highly interconnected network intended to efficiently regulate the synthesis, folding, trafficking, and degradation of newly synthesized proteins. Molecular chaperones are key players of the proteostasis network. These proteins assist in the assembly and folding processes of newly synthesized proteins in a concerted manner to achieve a three-dimensional structure compatible with export from the endoplasmic reticulum to other cell compartments. Pharmacologic interventions intended to modulate the proteostasis network and tackle the devastating effects of conformational diseases caused by protein misfolding are under development. These include small molecules called pharmacoperones, which are highly specific toward the target protein serving as a molecular framework to cause misfolded mutant proteins to fold and adopt a stable conformation suitable for passing the scrutiny of the quality control system and reach its correct location within the cell. Here, we review the main components of the proteostasis network and how pharmacoperones may be employed to correct misfolding of two G protein-coupled receptors, the vasopressin 2 receptor and the gonadotropin-releasing hormone receptor, whose mutations lead to X-linked nephrogenic diabetes insipidus and congenital hypogonadotropic hypogonadism in humans respectively.

Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History.

After completion of puberty a subset of men experience functional hypogonadotropic hypogonadism (FHH) secondary to excessive exercise or weight loss. This phenomenon is akin to hypothalamic amenorrhea (HA) in women, yet little is known about FHH in men. To investigate the neuroendocrine mechanisms, genetics, and natural history underlying FHH. Retrospective study in an academic medical center. Healthy postpubertal men presenting with symptoms of hypogonadism in the setting of excessive exercise (>10 hours/week) or weight loss (>10% of body weight). Healthy age-matched men served as controls. Clinical assessment, biochemical and neuroendocrine profiling, body composition, semen analysis, and genetic evaluation of genes known to cause isolated GnRH deficiency. Reproductive hormone levels, endogenous GnRH-induced LH pulse patterns, and rare genetic variants. Ten men with FHH were compared with 18 age-matched controls. Patients had significantly lower body mass index, testosterone, LH, and mean LH pulse amplitudes yet normal LH pulse frequency, serum FSH, and sperm counts. Some patients exhibited nocturnal, sleep-entrained LH pulses characteristic of early puberty, and one FHH subject showed a completely apulsatile LH secretion. After decreased exercise and weight gain, five men with men had normalized serum testosterone levels, and symptoms resolved. Rare missense variants in NSMF (n = 1) and CHD7 (n = 1) were identified in two men with FHH. FHH is a rare, reversible form of male GnRH deficiency. LH pulse patterns in male FHH are similar to those observed in women with HA. This study expands the spectrum of GnRH deficiency disorders in men.

Testosterone replacement in congenital hypogonadotropic hypogonadism maintains bone density but has only limited osteoanabolic effects.

Congenital hypogonadotropic hypogonadism (CHH) is a rare condition characterized by complete sex steroid deficiency. Therefore, CHH is a unique human model to study the impact of long-term testosterone replacement therapy (TRT) on bone. In this single-center retrospective observational study, we assessed the long-term impact of TRT on femoral and lumbar bone mineral density (BMD) in adult CHH men. A total of 25 patients with CHH were included. Femoral and lumbar BMD was assessed by dual-energy X-ray absorptiometry (DEXA) and reported as T-scores. In six patients (treatment-naive group), BMD was measured before start of TRT. The other 19 (pre-treated group) had received TRT for a median duration of 7years (range 1-41years) before first BMD measurement. Age at which TRT was started ranged from 12 to 57years old. Median time between first and last DEXA scan was 11years (range 2-28). At the first DEXA scan, 83% and 61% of CHH patients had lumbar and femoral osteopenia/osteoporosis, respectively. In the treatment-naive group, the increase in lumbar T-score was 2.19±0.13 (mean ± SEM, p<0.01 between first and last DEXA scan) and 1.47±0.29 at femoral level (p<0.001). For the pre-treated group, the increase in lumbar and femoral T-score was 0.77±0.17 (p<0.001) and 0.19±0.12 (p=0.13), respectively. However, lumbar and femoral osteopenia/osteoporosis persisted in 61% and 48% of CHH patients even after several years of continuous TRT. Additionally, BMD clearly decreased in patients who interrupted TRT. Despite modest improvement after starting TRT, BMD remains in the osteopenic/osteoporotic range in most patients with CHH. However, prolonged TRT prevents further bone loss, both at lumbar and femoral level.

932 - Loss-of-function mutation in FGFR1 gene as a cause of idiopathic hypogonadotropic hypogonadism

932 - Loss-of-function mutation in FGFR1 gene as a cause of idiopathic hypogonadotropic hypogonadism

Congenital Hypogonadotrophic Hypogonadism: Minipuberty and the Case for Neonatal Diagnosis.

Congenital hypogonadotrophic hypogonadism (CHH) is a rare but important etiology of pubertal failure and infertility, resulting from impaired gonadotrophin-releasing hormone secretion or action. Despite the availability of effective hormonal therapies, the majority of men with CHH experience unsatisfactory outcomes, including chronic psychosocial and reproductive sequelae. Early detection and timely interventions are crucial to address the gaps in medical care and improve the outlook for these patients. In this paper, we review the clinical implications of missing minipuberty in CHH and therapeutic strategies that can modify the course of disease, as well as explore a targeted approach to identifying affected male infants by integrating clinical and biochemical data in the early postnatal months.

High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of normal pubertal development due to deficient gonadotropin-releasing hormone (GnRH) secretion or action, and is caused by genetic defects in several genes. Mutations in the CHD7 gene cause CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital hypoplasia and Ear abnormalities), but have also been found in patients with isolated CHH. The aim of this study was to identify CHD7 mutations in patients with CHH. Fifty Portuguese patients with CHH were screened for mutations in the CHD7 gene by DNA sequencing. Eight (16%) patients had CHD7 rare sequence variants that consisted of six missense (p.Gly388Glu, p.His903Pro, p.Thr1082Ile, p.Val1452Leu, p.Asp1854Gly, and p.Arg2065His) and two synonymous (p.Ser559Ser, and p.Ala2785Ala) mutations. Five of these mutations have never been reported before. Three CHD7 mutations occurred in patients that had mutations in additional CHH-genes. This study uncovered novel genetic variants that expand the known spectrum of mutations associated with CHH. The frequency of CHD7 mutations in this cohort was higher than that of other major CHH-genes and confirms the importance of including CHD7 in the genetic testing of CHH, even in the absence of additional CHARGE features.

Clinical Management of Congenital Hypogonadotropic Hypogonadism.

The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (∼10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development.

Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism.

Multiple metabolic and inflammatory mechanisms are considered the determinants of acquired functional isolated hypogonadotropic hypogonadism (IHH) in males, whereas classic IHH is a rare congenital condition with a strong genetic background. Since we recently uncovered a frequent familiarity for classic IHH among patients with mild adult-onset hypogonadism (AO-IHH), here we performed a genetic characterization by next generation sequencing of 160 males with classic or “functional” forms. The prevalence of rare variants in 28 candidate genes was significantly higher than in controls in all IHH patients, independently of the age of IHH onset, degree of hypogonadism or presence of obesity. In fact, it did not differ among patients with classic or milder forms of IHH, however particular genes appear to be more specifically associated with one or the other category of IHH. ROC curves showed that Total Testosterone <6.05 nmol/L and an age of onset <41 years are sensitive cutoffs to identify patients with significantly higher chances of harboring rare IHH gene variants. In conclusion, rare IHH genes variants can frequently predispose to AO-IHH with acquired mild hormonal deficiencies. The identification of a genetic predisposition can improve the familial and individual management of AO-IHH and explain the heritability of congenital IHH.

Correlation of Olfactory Phenotype by Indian Smell Identification Test and Quantitative MRI of Olfactory Apparatus in Idiopathic Hypogonadotropic Hypogonadism.

Objectives:Idiopathic hypogonadotropic hypogonadism (IHH) can be associated with anosmia/hyposmia. The objective of this study is to evaluate olfaction by Indian smell identification test (INSIT) and measure olfactory bulbs (OBs) and sulci using dedicated magnetic resonance imaging (MRI) in patients with IHH and correlate MRI findings with INSIT.Methods:Forty patients with IHH underwent (a) brief smell identification test (INSIT) and (b) MRI of the olfactory apparatus. The size of olfactory sulcus and bulb was quantified and compared with the normative data obtained in 22 controls. The agreement between INSIT and MRI was assessed using Kappa index.Results:Of the 40 patients, 8 patients who reported abnormal smell sensation and 12 of the remaining 32 patients who reported normal smell sensation historically had a low score on INSIT. Thus, there were 20 patients with Kallmann syndrome (KS) and the rest 20 were normosmic IHH (nIHH). Of 40 patients with IHH, MRI finding was suggestive of normal (n = 16), hypoplastic (n = 12), and aplastic (n = 12) olfactory apparatus. All 20 patients with KS have olfactory abnormalities (n = 12 aplastic, n = 8 hypoplastic), and 4 of 20 nIHH have olfactory abnormalities (hypoplastic only) on MRI. There is (a) significant positive correlation (r = 0.54, P = 0.013) between the OB volume (MRI) and smell test scores and (b) moderate agreement (Kappa index: 0.49) between smell defect (INSIT score ≤ 4) and aplastic olfactory apparatus.Conclusion:Self-reporting of smell significantly underestimates olfactory phenotype, and hence we recommend an objective smell test to differentiate KS from nIHH. Olfactory phenotype significantly correlates with MRI quantification of olfactory apparatus in IHH.

Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males.

Hormonal induction of spermatogenesis offers men with azoospermia due to hypogonadotrophic hypogonadism (HH) the promising prospect of fertility restoration. However, an important exception is the subset of individuals affected by congenital hypogonadotrophic hypogonadism (CHH), also known as Kallmann syndrome if associated with anosmia, who often display dismal responses to fertility induction, despite prolonged therapy. This primarily stems from the loss of minipuberty, which is a crucial phase of testicular maturation in early life that has a far-reaching impact on eventual spermatogenic capacity. Further exacerbating the compromised reproductive health is the failure to initiate timely pubertal induction in many CHH patients, resulting in suboptimal genital and psychosexual development. In this paper, the clinical implications and management of male HH across the lifespan is comprehensively reviewed, with a special focus on novel strategies that have the potential to modify disease severity and maximize fertility potential in CHH by addressing the inadequacies of conventional approaches.

The clinical and psychological profiles of patients with hypogonadism, followed in 3 reference hospitals of Cameroon: an observational study.

IntroductionHypogonadism refers to a syndrome that results from failure of gonads to function properly. The main concern is considerable rise in morbidity, as shown by increased cardiovascular risk, infertility, osteoporosis and above all, the psychological impact on the life of the patients with hypogonadism. Judicious steroid replacement and culturally-sensitive psychological support before and during steroid therapy remains the key tool in the management of this condition. The present study aimed at filling the knowledge gap on hypogonadism in Cameroon.MethodsWe conducted a cross-sectional study over a period of 12 months, in 3 reference hospitals of Cameroon. We included males and females diagnosed with hypogonadism, aged 16 to 50 years and 16 to 45 years respectively. After a complete clinical examination, patients were invited to fill the modified middlesex hospital questionnaire for psychoneurotic evaluation.ResultsWe recruited 59 patients with a sex ratio of 1:1. The mean age of the females and males were 27.7 ± 9.1years and 30.8 ± 11.7 years respectively. Normosmic Idiopathic Hypogonadotropic Hypogonadism (NIHH) was the most common presentation. Compulsive obsessive traits, phobic anxiety and hysterical trait, were most pronounced in these patients. Testosterone titers significantly correlated positively with testicular size and negatively with body mass index (BMI). A significant positive correlation was found between the testicular volumes measured with ultrasound (US) and with the orchidometer.ConclusionNormosmic idiopathic hypogonadotropic hypogonadism is the most common presentation of hypogonadism in the study population. There is a significant psychosocial impact requiring further investigation and attention.