Woodhouse-Sakati syndrome in an Indian patient with a novel pathogenic variant.

Woodhouse-Sakati syndrome consists of hypogonadism, diabetes mellitus, alopecia, ECG abnormalities, and dystonia. This condition is caused by the loss of function of the DCAF17 gene. Most of the patients have been reported from Greater Middle Eastern countries. We report a 38 male from southern India who presented with syncope and massive hemoptysis due to ruptured bronchopulmonary collaterals. He also had alopecia, cataracts, recently diagnosed diabetes and hypogonadism. Whole exome sequencing showed a novel homozygous truncating variant in the DCAF17 gene. Despite embolization of the aortopulmonary collaterals, the patient died of recurrent hemoptysis.

Serum gonadal hormones levels and hypogonadism in ART naïve newly diagnosed HIV infected adult males in Mwanza, Tanzania.

BACKGROUND: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is an endemic chronic disease which is characterized with progressive depletion of CD4 T cells and increased susceptibility to opportunistic infections. Previous studies have associated HIV infection with increased hypogonadism. However, the prevalence of hypogonadism remained poorly defined and widely ranging in various studies. This study aims to evaluate the serum gonadal hormonal levels and hypogonadism in antiretroviral therapy (ART) naïve newly diagnosed HIV infected-males in Mwanza, Tanzania. METHODS: This was a comparison study involving 81 ART naïve newly diagnosed HIV-infected adult males as study group and 81 apparently healthy HIV-negative males as comparison group. The participants in the study group and comparison group were matched by body mass index and age. Serum hormones [Total testosterone (TT), follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E) were estimated. Serum testosterone < 300 ng/dl, or testosterone > 300 ng/dl with high LH and FSH (compensatory hypogonadism) were taken as markers of hypogonadism. Data were analyzed using STATA version 15. RESULTS: The median serum testosterone level among ART naïve newly diagnosed HIV-infected adult males was significantly lower as compared to their comparison group (447 [259-534] versus 517 [396-605]; p = 0.0074) and shown to decrease with decreasing CD4 level. The median [IQR] serum FSH level among ART naïve newly diagnosed HIV-infected adult males was significantly higher than among their comparison group (3.8 [2.1-6.5] versus 2.6 [1.8-4.2]; p = 0.0086). The differences in serum LH and Estradiol were not statistically significant. Furthermore, the proportion of hypogonadism was significantly higher among ART naïve newly diagnosed HIV-infected adult males than in their comparison group (37.0% [30/81] versus 14.8% [12/81]; p = 0.0006). Out of these 30, 24 HIV-infected males had secondary hypogonadism, one had primary, and the remaining five had compensatory hypogonadism. CONCLUSION: Serum testosterone was lower and follicle stimulating hormone was higher among ART naïve HIV-infected males as compared to the HIV negative controls. Hypogonadism, mainly secondary, is common endocrine abnormality among ART naïve HIV-infected male patients in this study. HIV is associated with variations in gonadal hormones which may lead to sexual dysfunction in infected individuals.

Androgen Deficiency in Aging Males (ADAM) Score as a Predictor of Total Testosterone Levels in Type 2 Diabetes Mellitus: A Prospective, Cross-sectional Study.

OBJECTIVE: Assessment of Androgen Deficiency in Aging Males (ADAM) questionnaire in predicting serum testosterone levels in type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A single centre, prospective, cross-sectional epidemiological study in 250 male individuals with T2DM. ADAM questionnaire and serum total testosterone (TT) levels were analyzed for correlation using a Chi-squared test. Jaccard analysis to evaluate the concordance and dissimilarity between ADAM score and TT levels, providing insights into ADAM's predictive ability for testosterone levels. RESULTS: The mean age of the study population was 49.1 ± 7.8 years. The mean duration of diabetes was 6.2 ± 5.1 years. 27.6% were diagnosed with hypogonadism, while 72.4% were eugonadal. The mean age was 51.1 and 48.4 years in the hypogonadal and eugonadal cohorts, respectively (p < 0.02). The mean TT in the hypogonadal cohort was 220.6 ± 61.3 ng/dL, and in the eugonadal cohort was 475.4 ± 152.9 ng/dL (p < 0.001). The mean body mass index (BMI) in the hypogonadal cohort was 26.5 ± 4.0 kg/m2, and in the eugonadal group was 25.2 ± 3.6 kg/m2 (p < 0.02). Chi-square analysis established a strong positive correlation between the positive ADAM score and hypogonadism (p < 0.011). Of the 69 hypogonadal subjects, 84.05% had a positive ADAM score, yielding a sensitivity of 84.05% in detecting hypogonadism with a specificity of 32.04%. CONCLUSION: The ADAM questionnaire is a practical and cost-effective initial screening tool for identifying symptoms suggestive of testosterone deficiency. It has high sensitivity in identifying men with hypogonadism, while caution must be in place as it has a very low specificity. In resource-poor settings, ADAM score could be a clinical marker of hypogonadism.

Hypogonadism is frequent in very old men with multimorbidity and is associated with anemia and sarcopenia.

BACKGROUND: Clinical data regarding hypogonadism in very old men with multimorbidity are rare. Hypogonadism can contribute to osteoporosis, anemia and sarcopenia and is therefore a relevant problem for geriatric patients. METHODS: A total of 167 men aged 65-96 years (mean 81 ± 7 years) admitted to an acute geriatric ward were included in a cross-sectional study. Body composition derived from dual-energy X­ray absorptiometry, bone mineral density, handgrip strength, multimorbidity, polypharmacy and laboratory values were obtained from the routine electronic clinical patient file. RESULTS: Hypogonadism was present in 62% (n = 104) of the study participants, of whom 83% showed clinical manifestation of hypogonadism (hypogonadism in combination with anemia, sarcopenia and/or low T­score). The subgroups showed a distribution of 52% primary and 48% secondary hypogonadism. Compared to the eugonadal patients, hypogonadal patients had reduced handgrip strength (p = 0.031) and lower hemoglobin levels (p = 0.043), even after adjustment for age, body mass index and glomerular filtration rate. CONCLUSION: Hypogonadism is common in geriatric patients. If chronic anemia, sarcopenia, or osteoporosis are diagnosed, testosterone levels should be determined in geriatric settings.

Challenges in Diagnosis and Treatment of Male Hypogonadism.

Hypogonadism is a condition characterized by diminished or absent production of sex hormones by the testicles in men and the ovaries in women. Hypogonadism is classified into primary and secondary hypogonadism. Each type of hypogonadism can be caused by congenital and acquired factors. There are many factors that contribute to the occurrence of hypogonadism, including genetic and developmental disorders, infection, kidney disease, liver disease, autoimmune disorders, chemotherapy, radiation, surgery, and trauma. This represents the considerable challenge in diagnosing hypogonadism.The goals of treatment include restore sexual functionality and well-being, initiating and sustaining virilization, osteoporosis prevention, normalize growth hormone levels in elderly men if possible, and restoring fertility in instances of hypogonadotropic hypogonadism. The main approach to treating hypogonadism is hormone replacement therapy. Male with prostate cancer, breast cancer, and untreated prolactinoma are contraindicated for hormone replacement therapy. When selecting a type of testosterone therapy for male with hypogonadism, several factors need to be considered, such as the diversity of treatment response and the  type of testosterone formulation. The duration of therapy depends on individual response, therapeutic goals, signs and symptoms, and hormonal levels. The response to testosterone therapy is evaluated based on symptoms and signs as well as improvements in hormone profiles in the blood. Endocrine Society Clinical Practice Guideline recommend therapeutic goals based on the alleviation of symptoms and signs, as well as reaching testosterone levels between 400 - 700 ng/dL (one week after administering testosterone enanthate or cypionate) and maintaining baseline hematocrit.Hormone therapy is the primary modality in the management of hypogonadism. The variety of signs and symptoms makes early diagnosis of this condition challenging. Moreover, administering hypogonadism therapy involves numerous considerations influenced by various patient factors and the potential for adverse effects. This poses a challenge for physicians to provide targeted hypogonadism therapy with minimal complications.

[Hypogonadism in men with inflammatory joint diseases: Frequency and clinical characteristics].

AIM: To study the frequency of hypogonadism (HG) in men with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) and to evaluate the impact of HG on the course of RA and and concomitant diseases. MATERIALS AND METHODS: A single-stage continuous study included 170 men with RA, 57 men with AS and 85 men with PsA, who were hospitalized at the Nasonova Research Institute of Rheumatology. Patients were assessed for total testosterone (ТS) levels and subsequently divided into subgroups with normal (>12 nmol/l) and reduced levels. An intergroup comparison was carried out on the main indicators used in clinical rheumatological practice to assess the stage, activity and other medical and demographic characteristics of rheumatic disease, as well as on concomitant conditions. The second stage of the study involved a pairwise intergroup comparison among patients with HG with RA, AS and PsA. RESULTS: The incidence of ТS deficiency among patients with RA was 24.1%, among patients with AS - 17.5%, and with PsA - 31.8%. In patients with RA, HG was associated with a significantly higher mean body mass index, higher fasting blood glucose and uric acid, higher erythrocyte sedimentation rate and anemia. Patients with AS with HG had significantly lower hemoglobin levels and more frequent anemia, as well as higher levels of C-reactive protein and erythrocyte sedimentation rate. In PsA, older age was observed in the androgen deficiency group, as well as higher body mass index and fasting glucose levels; obesity was more common. An intergroup comparison of quantitative and qualitative indicators between patients with androgen deficiency in all three rheumatic diseases (RDs) did not reveal significant differences in the average concentrations of ТS, luteinizing hormone, sex hormone binding globulin, experience of RD, laboratory markers of inflammatory activity, as well as glucose and uric acid. A similar incidence of diabetes mellitus, obesity and anemia was noted for all three nosologies. CONCLUSION: ТS levels and the presence of HG were not associated with the stage and activity of RD, but ТS deficiency was accompanied by higher laboratory indicators of inflammatory activity, lower hemoglobin values, and metabolic disorders. Patients with HG, regardless of nosology, had similar levels of sex hormones and indicators reflecting RD and concomitant conditions.

Reconsidering the olfactory and brain structures in Kallmann's syndrome: New findings in the analysis of volumetry.

OBJECTIVE: Kallmann's syndrome (KS) is characterized by hypogonadotropic hypogonadism and olfactory disorders. The complementary exams for evaluating of patients with hypogonadotrophic hypogonadism are important for the diagnosis and management of these patients. PATIENTS: We performed a well-established olfactory Sniffin' Stick test (SST) on 17 adult patients with KS and brain magnetic resonance imaging (MRI) to evaluate olfactory structures and further analysis by Freesurfer, a software for segmentation and volumetric evaluation of brain structures. We compared the Freesurfer results with 34 healthy patients matched for age and sex and performed correlations between the data studied. RESULTS: More than half of the patients with KS reported preserved smell but had olfactory disorders in the SST. In the MRI, 16 patients showed changes in the olfactory groove, the olfactory bulb-tract complex was altered in all of them and 52% had symmetrical structural changes. Interestingly, the pituitary gland was normal in only 29%. Regarding correlations, symmetrical changes in the olfactory structures were related to anosmia in 100%, while asymmetric changes induced anosmia in only 50% (p = .0294). In Freesurfer's assessment, patients with KS, compared to controls, had lower brainstem volume. In those with aplastic anterior olfactory sulcus, the brainstem volume was lower than in hypoplasia (p = .0333). CONCLUSIONS: Olfactory assessment and MRI proved to be important auxiliary tools for the diagnosis and management of patients with KS. New studies are needed to confirm the decrease in brainstem volume found by the Freesurfer software in patients with KS. Further studies are needed to confirm the decrease in brainstem volume found by the Freesurfer software in patients with KS.

Assessing hypothalamic pituitary gonadal function in reproductive disorders.

Reproductive conditions secondary to disorders of the hypothalamic-pituitary-gonadal (HPG) axis are common and are associated with important health implications and considerable psychosocial impact. Basal and dynamic tests enable interrogation of individual components of the HPG axis, facilitating diagnosis and understanding of the pathophysiology of reproductive disorders. Onset of puberty is controlled by hypothalamic gonadotrophin-releasing hormone (GnRH) neuronal function. To date, a dynamic test of hypothalamic function is not yet available. Therefore, accurate differentiation of pubertal disorders such as constitutional delay of growth and puberty (CDGP) and congenital hypogonadotrophic hypogonadism (CHH) as causes of delayed puberty is challenging due to similar clinical presentations and hormonal profiles. Likewise, although the two commonest reproductive disorders in women, polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhoea (FHA) have disparate hypothalamic function, oligo/amenorrhoea frequently poses a diagnostic conundrum owing to the overlap in the criteria used to define both conditions. This review aims to describe pubertal and reproductive disorders secondary to pathologies affecting the HPG axis. Challenges encountered in clinical practice in differentiating pubertal and reproductive conditions are reviewed in conjunction with the utility of baseline and dynamic endocrine tests to interrogate specific components of the HPG axis. We also highlight putative hypothalamic, pituitary, and gonadal markers in development that could improve the diagnosis of patients presenting with disorders of puberty or reproduction.

A de novo hexokinase 1 (HK1) variant presenting as Boucher-Neuhäuser syndrome.

Boucher-Neuhäuser syndrome (BNHS) is characterized by chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar dysfunction and atrophy. The disorder has been associated with biallelic pathogenic variants in the patatin-like phospholipase domain-containing protein 6 (PNPLA6) gene. We present an individual with a clinical diagnosis consistent with BNHS who lacked any PNPLA6 variants but on quartet family exome sequencing had a de novo variant in the hexokinase 1 (HK1) gene (NM_000188.2 [GRCh37/hg19]: g.71139826G>A, c.1240G>A, p.Gly414Arg), suggesting genetic heterogeneity for BNHS. Longitudinal follow-up indicated neurological deterioration, neuropsychiatric symptoms, and progressive cerebellar atrophy. The BNHS phenotype overlaps and expands the known HK1 genotypic and phenotypic spectrum. Individuals with variants in HK1 should undergo evaluation for hypogonadotropic hypogonadism, potentially amenable to treatment.

Testosterone and aging male, a perspective from a developing country.

PURPOSE: Hypogonadism is associated with a wide range of physical and psychological symptoms that can affect the overall health of men. However, in a developing country, there are several imposing challenges in the diagnosis and treatment of hypogonadism, including a lack of awareness and understanding of the condition among healthcare providers and patients, limited resources and the high cost of treatment. This review aimed to examine the potential benefits and risks of testosterone replacement therapy (TRT) and provides a perspective of a developing country on the topic. MATERIALS AND METHODS: A comprehensive literature review was conducted to gather relevant information on the impact of testosterone deficiency on ageing males and the effectiveness of TRT for treating hypogonadism. Published peer-reviewed articles were analyzed to evaluate the benefits and risks of TRT. Additionally, the unique challenges faced in the diagnosis and treatment of hypogonadism in a developing country were considered. RESULTS: Testosterone replacement therapy has been shown to be an effective treatment for hypogonadism, particularly in symptomatic men with low testosterone levels. It offers potential benefits such as improvements in symptoms and overall quality of life. However, there are associated risks and side effects that need to be considered. In a developing country, challenges such as limited awareness and understanding of hypogonadism, resource constraints, and high treatment costs pose additional barriers to accessing TRT and comprehensive care. CONCLUSION: In conclusion, TRT holds promise as a treatment for hypogonadism, but its implementation and accessibility face significant challenges in a developing country. Addressing these challenges, including raising awareness, allocating resources, and finding cost-effective solutions, is crucial for ensuring that men with hypogonadism in such settings receive appropriate diagnosis and treatment. Further research and efforts are needed to improve the management of hypogonadism in developing countries and optimize the potential benefits of TRT for affected individuals.

Hypergonadotropic hypogonadism and chromosomal aberrations: clinical heterogeneity and implications on the health of elderly men, case series.

BACKGROUND: Hypogonadism in older men is often considered as late onset hypogonadism. However, this clinical condition results from primary testicular failure which could be of genetic origin with Klinefelter syndrome being the most common chromosomal abnormality associated with it. CASE PRESENTATION: We report a heterogeneous group of cases who were diagnosed with hypergonadotropic hypogonadism in their adulthood and were found to have rare chromosomal aberrations. All were elderly men (in their 70 s and 80 s) for whom the diagnosis was made during the evaluation of incidental symptoms suggestive of endocrinopathy. The first had hyponatremia; the other two had gynaecomastia and features of hypogonadism noted during admission for various acute medical problems. With respect to their genetic results; the first had a male karyotype with balanced reciprocal translocation between the long arm of chromosome 4 and the short arm of chromosome 7. The second case had a male karotype with one normal X chromosome and an isochrome for the short arm of the Y chromosome. The third case was an XX male with unbalanced translocation between the X & Y chromosomes with retention of the SRY locus. CONCLUSION: Hypergonadotrophic hypogonadism in the elderly, may be due to chromosomal aberrations, resulting in heterogeneous and diverse clinical phenotypes. Vigilance must be exercised when seeing cases with subtle clinical findings. This report suggests that in selected cases of adult hypergonadotropic hypogonadism, chromosomal analysis may be indicated.

Hyperglycemia with hypogonadism and growth hormone deficiency in a 17-year-old male with H syndrome: the first case report from Syria.

BACKGROUND: The nucleoside transport capabilities of the human equilibrative nucleoside transporter-3 (hENT3) are disrupted by mutations in SLC29A3 (10q22.2), which are genes for the nucleoside transporter and are the cause of the unusual autosomal recessive disease known as H syndrome. As a result, histiocytic cells invade a number of organs. CASE PRESENTATION: A 17-year-old Syrian male was admitted to the internal medicine department with a one-month history of polyuria, polydipsia, general weakness, and pallor. He had a history of progressive bilateral sensorineural hearing loss and failure to gain weight for three years. Physical examination revealed various abnormalities, including scrotal mass, small penis and testicles, absence of pubic and axillary hair, joint abnormalities, short stature, hallux valgus, fibrous protrusion near the navel, and hyperpigmented non-itchy painful skin plaques. Clinical signs along with laboratory test results confirmed hyperglycemia, primary hypogonadism, osteopenia, and growth hormone deficiency. After a review of the relevant medical literature, this patient's presentation of hyperglycemia with hypogonadism, hyperpigmentation, hallux valgus, hearing loss, hematological abnormalities, and short stature suggested the diagnosis of H syndrome. The patient received treatment with insulin and testosterone, leading to a significant improvement in his presenting symptoms. CONCLUSIONS: H syndrome is a very rare condition, and the fact that the first case has only recently been reported in Syria serves to emphasize how rare it is. H Syndrome should be suspected if a patient has short stature with signs of hyperglycemia and other endocrine and cutaneous abnormalities. We are reporting this case to increase physicians' awareness of this exceedingly rare and unique syndrome.

Idiopathic hypogonadotropic hypogonadism caused by compound heterozygosity for two novel mutations in the GNRH1 gene: a case report.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism (IHH) is a rare congenital or acquired genetic disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. IHH patients are divided into two major groups, hyposmic or anosmic IHH (Kallmann syndrome) and normosmic IHH (nIHH), according to whether their sense of smell is intact. Here we report a case of novel compound heterozygous mutations in the GNRH1 gene in a 15-year-old male with nIHH. CASE PRESENTATION: The patient presented typical clinical symptoms of delayed testicular development, with testosterone < 3.5 mmol/L and reduced gonadotropin (follicle-stimulating hormone, luteinizing hormone) levels. Two heterozygous variants of the GNRH1 gene were detected, nonsense variant 1: c.85G > T:p.G29* and variant 2: c.1A > G:p.M1V, which disrupted the start codon. CONCLUSIONS: Two GNRH1 mutations responsible for nIHH are identified in this study. Our findings extend the mutational spectrum of GNRH1 by revealing novel causative mutations of nIHH.

Cardiometabolic indices predict hypogonadism in male patients with type 2 diabetes.

PURPOSE: To evaluate in men with type 2 diabetes the association of cardiometabolic indices [Visceral Adiposity Index (VAI), Triglyceride Glucose Index (TyG), and lipid accumulation product (LAP)] with total testosterone (TT) levels, and their predictive cut-off values in identifying hypogonadism. METHODS: 265 consecutive men aged 40-70 years with type 2 diabetes performed an andrological evaluation; metabolic parameters and TT were determined. Receiver operating characteristic (ROC) curves were used to identify cut-off values of cardiometabolic indices in predicting low testosterone (TT < 12 nmol/l). RESULTS: VAI, TyG, and LAP were negatively associated with TT levels. The prevalence of hypogonadism in men in the fourth quartiles of VAI, TyG, and LAP was ~ 70.0-75.0% compared to ~ 10.0-17.0% in men in the first quartiles (p < 0.001). The sensitivity and specificity of the three cardiometabolic indices in predicting TT < 12 nmol/l were significantly higher concerning BMI, waist circumference, lipid profile and HbA1c. Cut off values of VAI ≥ 3.985, TyG ≥ 4.925, and LAP ≥ 51.645 predict hypogonadism with good sensitivity and specificity. CONCLUSION: This is the first study evaluating the association of VAI, TyG, and LAP with hypogonadism in men with type 2 diabetes. Alterations in these indices should direct the patients to andrological evaluation.

Exogenous Testosterone Replacement Therapy Is Associated with Increased Risk for Vascular Graft Infections Among Hypogonadal Men.

BACKGROUND: Vascular graft infections (VGIs) are a major source of morbidity following vascular bypass surgery. Hypogonadal men may be at increased risk for impaired wound healing and infections, but it is unclear if testosterone replacement therapy (TRT) mitigates this risk. We designed this study to evaluate the relationship between hypogonadism and the use of testosterone replacement therapy (TRT) with subsequent risk for developing a VGI. METHODS: We performed a retrospective analysis of claims in the MarketScan database identifying men greater than 18 years of age who underwent placement of a prosthetic graft in the peripheral arterial circulation from January 2009 to December 2020. Patients were stratified based on diagnosis of hypogonadism and use of TRT within 180 days before surgery. The primary outcome was VGI and the need for surgical excision. The association between hypogonadism and TRT use on risk of VGI was analyzed using Kaplan-Meier plots and multivariate Cox proportional hazards models. RESULTS: We identified 18,312 men who underwent a prosthetic bypass graft procedure in the upper and lower extremity during the study period, of which 802 (5%) had diagnosis of hypogonadism. Among men with hypogonadism, 251 (31%) were receiving TRT. Patients on TRT were younger, more likely to be diabetic, and more likely develop a VGI during follow-up (14% vs. 8%; P < 0.001) that was in the lower extremity. At 5 years, freedom from VGI was significantly lower for hypogonadal men on TRT than patients not on TRT or without hypogonadism (Log rank P < 0.001). In Cox regression models adjusted for age, diabetes, obesity, smoking, corticosteroid use, and procedure type, hypogonadal men on TRT were at a significantly increased risk of graft infection (hazard ratio (HR):1.94, 95% confidence interval (CI):1.4-2.7; P < 0.001) compared to controls. CONCLUSIONS: This study demonstrates TRT among hypogonadal men is associated with an increased risk of prosthetic VGIs. Temporary cessation of TRT should be considered for men undergoing prosthetic graft implants, particularly those in the lower extremity.

Summary of the clinical practice manual for late-onset hypogonadism.

Testosterone plays an important role in maintaining both physical and mental function. Age-related testosterone depletion contributes to the development of angina, arteriosclerosis, obesity, metabolic syndrome, dementia, frailty, and a range of other conditions. A condition involving age-related testosterone depletion and the associated clinical symptoms is defined as late-onset hypogonadism (LOH). LOH is treated by testosterone replacement therapy. Indications for testosterone replacement therapy are determined by evaluating symptoms and signs.

Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series.

Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5-15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype-phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the CHD7 gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in IL17RD (c.960G>A, p.Met320Ile), FGF17 (c.208G>A, p.Gly70Arg), and DUSP6 (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the PROK2 (c.163del, p.Ile55*), CHD7 (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), FLRT3 (c.1106C>T, p.Ala369Val), and CCDC103 (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, FGF17 (p.Gly70Arg), DUSP6 (p.Leu145Arg), and CHD7 p.(Thr917Met). Except for DUSP6, where the L145R variant was shown to disrupt the interaction between ß6 and ß3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the CHD7 gene. The molecular modeling results suggest that the VUS of the DUSP6 (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the IL17RD (c.960G>A, p.Met320Ile) and FGF17 (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.

[Assessment of the man in the infertile couple]. / Évaluation de l'homme du couple infertile.

BACKGROUND: Among couples consulting for infertility, there is a male component, either alone or associated with a female aetiology in around one in 2 cases. MATERIAL AND METHODS: Bibliographic search in PubMed using the keywords "male infertility", "diagnosis", "management" and "evaluation" limited to clinical articles in English and French prior to 1/01/2023. RESULTS: The AFU recommends: (1) a complete medical history including: family history, patient history affecting fertility, lifestyle habits (toxicity), treatments, symptoms, sexual dysfunctions; (2) a physical examination including: BMI, signs of hypogonadism, secondary sexual characteristics, scrotal examination (volume and consistency of testes, vas deferens, epididymal or testicular nodules, presence of varicocele); (3) two spermograms, if abnormal on the first; (4) a systematic scrotal ultrasound,± an endorectal ultrasound depending on the clinic; (5) a hormonal work-up (testosterone, FSH; if testosterone is low: LH assay to differentiate between central or peripheral hypogonadism); (6) karyotype if sperm concentration≤10 million/mL; (7) evaluation of Y chromosome microdeletions if concentration≤1 million/mL; (8) evaluation of the CFTR gene in cases of suspected bilateral or unilateral agenesis of the vas deferens and seminal vesicles. The role and usefulness of direct and indirect tests to assess the effects of oxidative stress on sperm DNA will also be explained. CONCLUSION: This review complements and updates the AFU/SALF 2021 recommendations.

Cases of hypogonadotropic hypogonadism: A single-center experience.

Background: Delayed puberty (DP) affects approximately 2% of adolescents. In most patients of both genders, delayed puberty is due to constitutional delay in growth and puberty (CDGP); it is a self-limiting condition starting later than usual during puberty but progressing normally. Other causes of DP include permanent hypogonadotropic hypogonadism, functional hypogonadotropic hypogonadism, and gonadal insufficiency. Methods: Nine patients admitted to the Ankara Atatürk Sanatoryum Training and Research Hospital Pediatric Endocrinology Department with hypogonadotropic hypogonadism between January 2012 and December 2022 were analyzed. Results: Nine patients who applied to our pediatric endocrinology clinic with delayed puberty were analyzed. These nine patients were diagnosed and reported as hypogonadotropic hypogonadism with molecular methods. We aimed to determine the status of these cases from a molecular point of view, to emphasize the importance of hypogonadotropic hypogonadism in patients with delayed puberty, and to reveal the rarely encountered delayed puberty together with the clinical and laboratory data set of the patients. Conclusions: To emphasize the importance of hypogonadotropic hypogonadism, which is a rare cause of delayed puberty, the molecular predispositions of our patients followed in our clinic are reviewed, and the data we have provided will contribute to the accumulation of data in this area.

Diagnosis of hypogonadism in ageing men.

To make the diagnosis of hypogonadism in an ageing man, in absence of rare organic cause often referred to as functional or late onset hypogonadism (LOH), he should present with a clinical syndrome suggestive of androgen deficiency and have consistently low serum testosterone (T) levels. This does not differ from the diagnosis of any other form of hypogonadism. Particular to LOH diagnostic are uncertainties surrounding this entity: signs and symptoms of androgen deficiency (including sexual symptoms) are nonspecific in older men; clinical significance of only moderately low T levels is uncertain; comorbidity plays a substantial role with potential for reversibility; the place of T therapy in these men is debatable. This context demands for a pragmatic, but appropriately conservative approach to diagnosis. Evaluation should be stepwise with clinical evaluation, if suggestive for androgen deficiency, followed by measurement of a fasting morning serum T, if unequivocally low to be confirmed in a separate morning sample by a second low T or, if initial T borderline low or in presence of factors known to affect SHBG, by a low calculated free T level. All other (free) T results make hypogonadism an unlikely cause of the patient's symptoms. In the absence of consensus cut-off levels for total and free T in the published clinical guidelines for diagnosis of hypogonadism, it seems appropriate in the context of LOH to use stringent criteria indicating a convincingly low serum T. The approach to the diagnosis of LOH is not fundamentally different from that of other forms of hypogonadism but should put extra weight on prioritizing the shunning of overdiagnosis above the risk of underdiagnosis.