Prevalence of hypogonadism in transfusion-dependent ß-thalassemia patients of Bangladesh: investigating the role of serum ferritin level as a diagnostic tool

ABSTRACT Introduction: Hypogonadism is one of the most frequent complications in transfusion-dependent thalassemia patients and early recognition and treatment is the core element in restoring impaired gonadal function. Despite the high burden of disease, relevant studies are scarcely addressing the gonadal function of such patients in Bangladesh. The pattern of gonadal function in transfusion-dependent thalassemia patients must be characterized before planning a generalized management plan. Moreover, since iron overload is a key reason behind hypogonadism in thalassemia patients, investigating the role of serum ferritin level as a diagnostic tool for hypongadism was also an aim of this study. Methods: This cross-sectional study was conducted at the Department of Transfusion Medicine of the Bangabandhu Sheikh Mujib Medical University. According to the inclusion and exclusion criteria, a total of 94 patients were enrolled in this study. A detailed history and thorough clinical examination were carried out in each patient and recorded using a pretested structured questionnaire. In addition, the laboratory assessment of serum ferritin, luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and estradiol in serum were also performed. The data were analyzed using the STATA (v.16). Results: The mean age of the patients with transfusion-dependent thalassemia was 18.81 ± 4.65 (SD), with 53.3% of the patients being male. The overall prevalence of hypogonadism was 35.11%, 18.1% being normogonadotropic, 11.7% being hypogonadotropic and 5.3% being hypergonadotropic. The serum ferritin level was significantly higher (p < 0.001) in patients with hypogonadism (Eugonadal: 2,174.79 (± 749.12) ng/ml; Hypogonadal: 3,572.59 (± 1,199.49) ng/ml). The area under the receiver operating characteristic (ROC) curve of serum ferritin was high (0.83) and the p-value was highly significant (< 0.001). Conclusion: Therefore, the serum ferritin level and gonadal hormone analysis of transfusion-dependent thalassemia patients can be considered a screening tool for assessing gonadal function and early detection and prevention of hypogonadism.

Clinical Features and Mutation Analysis of Gordon Holmes Syndrome Associated with RNF216 Gene Mutation and a Literature Review / 罕见病研究

  Objective  To summarize the clinical characteristics and RNF216 gene mutation of a patient with Gordon Holmes syndrome (GHS), and to improve the understanding of the genetic and clinica characteristics of this disease through literature review.  Methods  We collected the clinical data of the patient with GHS, extracted the DNA from 2 mL peripheral venous blood of the patient and his parents for whole exome gene detection, and then we analyzed the clinical and genetic characteristics of all previously reported patients with RNF216 gene mutation.  Results  The young male patient was short in stature at sixyearsold and was diagnosed growth hormone deficiency.He had no secondary sexual characteristics by the age of 15 and was diagnosed hypogonadal hypogonadism.After the age of 22, he gradually developed abnormal gait and had progressive decline in speech, motor, and cognitive functions.Whole exome sequencing revealed a homozygous, nonsense mutation c.1549C>T (p.R517*) in the RNF216 gene.His parents were consanguineous and were heterozygous carriers of the mutations with phenotypic normality.Combined with literature review and this case report results showed that a total of 21 patients of the disease in the world and among them 15 had pathogenic variants of RNF216 gene mutation.7 of the 15 had truncated mutations, 5 had missense mutations, and 1 synonym mutation, 1 splice mutation, and 1 deletion mutation respectively.RNF216 gene mutation can be seen in neurodegenerative diseases with multiple overlapping symptoms of GHS, Huntington-like disease, and 4H syndrome.The main clinical manifestations are hypogonadotropic hypogonadism and early-onset progressive neurological dysfunction in adolescence or early adulthood.The median age of onset of neurological symptoms is 28 years old, featuring cerebellar ataxia, dysarthria, and cognitive impairment, as well as imaging manifestations of extensive white matter lesions and cerebellar atrophy.  Conclusions  The mutation of RNF216 gene can cause GHS.Genetic testing is helpful to the diagnosis and treatment of rare diseases.

Evaluation of sexual functional status and consistency of scales in patients with hypogonadotropic hypogonadism before and after testosterone replacement therapy: a single-center experience

ABSTRACT Objective: This study aimed to investigate the frequency of sexual dysfunction and the effect of short-term testosterone replacement therapy on sexual functions in congenital hypogonadism patients. Furthermore, we sought to reveal the consistency of the self-report scales used for the diagnosis of sexual dysfunction and the relationship between biochemical parameters. Materials and methods: The study was conducted on 47 young male patients aged above 18 years who were diagnosed with hypogonadotropic hypogonadism. Short (IIEF-5) and long (IIEF-15) forms of the International Index of Erectile Function and Arizona Sexual Experiences Scale (ASEX) were applied before treatment under the supervision of a physician. The patients' blood pressure, height, and weight were measured, and their luteinizing hormone (LH), FSH, and total testosterone levels were recorded. Patients who started their treatments were called for a follow-up checkup after 6 months. Their blood pressure, height, and weight were measured by reapplying the ASEX, IIEF-5, and IIEF-15. In addition, their LH, FSH, and total testosterone levels in the biochemical tests were rerecorded. Results: In this study, the sexual dysfunction status of patients diagnosed with hypogonadotropic hypogonadism before and after treatment was evaluated using the ASEX, IIEF-15, and IIEF-5 scales. A decrease in sexual dysfunction was observed in all three scales after treatment compared with that before treatment. The IIEF-5 and IIEF-15 scales were found to be uncorrelated in terms of the pretreatment values but were correlated in terms of the post-treatment values. Although a correlation was observed between ASEX and IIEF-5 before treatment, no correlation was detected between ASEX and IIEF-15. After the treatment, ASEX was found to be correlated with both IIEF-5 and IIEF-15. The results of the scales indicated the correlation in all categories, except the pretreatment results of the IIEF-15 scale. Conclusion: The results of the current study demonstrated a significant improvement in the sexual function of hypogonadism patients undergoing short-term testosterone therapy. The ASEX, IIEF-5, and IIEF-15 scales used in the diagnosis and follow-up of sexual dysfunction were useful for evaluating sexual functions in hypogonadotropic hypogonadism patients.

Type 1 diabetes in DKA with hypogonadotropic hypogonadism and pituitary apoplexy � A diagnostic dilemma

A 17-year-old underweight boy came with a classical emergency of diabetic ketoacidosis associated with two additional clinical features; persistently low blood pressure despite adequate fluid resuscitation and hypogonadal features with Tanner stage 3 pubic hair, absent facial, and axillary hair along with a high-pitched voice. These findings triggered an endocrine workup which revealed hypogonadotropic hypogonadism. Suspecting primary pituitary pathology, an magnetic resonance imaging brain, was done which showed a well-defined hyperintense lesion in the pituitary suggestive of pituitary apoplexy. In the absence of headache, diplopia, and visual field defects, this incidental finding posed a dilemma regarding the diagnosis and management of diabetic ketoacidosis in the presence of apoplexy.

Spermatogenesis of combined HCG and HMG in patients with idiopathic hypogonadotropic hypogonadism and congenital combined pituitary hormone deficiency / 中华内分泌代谢杂志

Objective:To compare the spermatogenes response of human chorionic gonadotropin(HCG)combined with human menopausal gonadotropin(HMG)in patients with idiopathic hypogonadotropic hypogonadism(IHH)and congenital combined pituitary hormone deficiency(CCPHD), and to explore related factors.Methods:Clinical data of 90 IHH patients and 61 CCPHD patients from January, 2014 to November, 2018 were retrospectively analyzed. Spermatogenesis was compared between the two groups receiving combined gonadotropin therapy. The patients were then divided into two subgroups: spermatogenesis subgroup and nonspermatogenesis subgroup. Related factors of spermatogenesis after the combined gonadotropin therapy were investigated.Results:After the combined treatment of HCG/HMG for 3, 6, and 9 months, the patients with CCPHD revealed lower testicular sizes than those with IHH( P=0.004, 0.021 and 0.032, respectively). Compared with IHH patients, CCPHD patients had larger testicular volume increments( P<0.001), higher spermatogenesis rates( P=0.048), and shorter initial time for sperm appearance( P<0.001)after 24-month treatment. Multivariate logistic regression analysis showed that lower total cholesterol(TC)(IHH group: OR=5.508, 95% CI 1.110-27.326, P=0.037; CCPHD group: OR=4.068, 95% CI 1.077-15.371, P=0.039)was an independent risk factor of poorer spermatogenesis in patients with IHH and CCPHD. Conclusions:The patients with CCPHD demonstrate a better response to combined gonadotropin treatment than those with IHH. Lower TC is an independent risk factor for poor spermatogenesis of combined HCG/HMG therapy in patients with IHH or CCPHD.

ANOS1 variants in a large cohort of Chinese patients with congenital hypogonadotropic hypogonadism / 中南大学学报(医学版)

Objective: Congenital hypogonadotropic hypogonadism (CHH) is a rare congenital gonadal dysplasia caused by defects in the synthesis, secretion or signal transduction of hypothalamic gonadotropin releasing hormone. The main manifestations of CHH are delayed or lack puberty, low levels of sex hormones and gonadotropins, and may be accompanied with other clinical phenotypes. Some patients with CHH are also accompanied with anosmia or hyposmia, which is called Kalman syndrome (KS). ANOS1, located on X chromosome, is the first gene associated with CHH in an X-linked recessive manner. This study aims to provide a basis for the genetic diagnosis of CHH by analyzing the gene variant spectrum of ANOS1 in CHH and the relationship between clinical phenotype and genotype. Methods: In this study, whole exome sequencing (WES) was used to screen rare sequencing variants (RSVs) of ANOS1 in a Chinese cohort of 165 male CHH patients. Four commonly used in silico tools were used to predict the function of the identified RSVs in coding region, including Polyphen2, Mutation Taster, SIFT, and Combined Annotation Dependent Depletion (CADD). Splice Site Prediction by Neural Network (NNSPLICE) was employed to predict possibilities of intronic RSVs to disrupt splicing. American College of Medical Genetics and Genomics (ACMG) guidelines was used to assess the pathogenicity of the detected RSVs. The ANOS1 genetic variant spectrum of CHH patients in Chinese population was established. The relationship between clinical phenotype and genotype was analyzed by collecting detailed clinical data. Results:Through WES analysis for 165 CHH patients, ANOS1 RSVs were detected in 17 of them, with the frequency of 10.3％. A total of 13 RSVs were detected in the 17 probands, including 5 nonsense variants (p. T76X, p. R191X, p. W257X, p. R262X, and p. W589X), 2 splicing site variants (c. 318+3A>C, c. 1063-1G>C), and 6 missense variants (p. N402S, p. N155D, p. P504L, p. C157R, p. Q635P, and p. V560I). In these 17 CHH probands with ANOS1 RSVs, many were accompanied with other clinical phenotypes. The most common associated phenotype was cryptorchidism (10/17), followed by unilateral renal agenesis (3/17), dental agenesis (3/17), and synkinesia (3/17). Eight RSVs, including p. T76X, p. R191X, p. W257X, p. R262X, p. W589X, c. 318+3A>C, c. 1063-1G>C, and p. C157R, were predicted to be pathogenic or likely pathogenic ANOS1 RSVs by ACMG. Eight CHH patients with pathogenic or likely pathogenic ANOS1 variants had additional features. In contrast, only one out of nine CHH patients with non-pathogenic (likely benign or uncertain of significance) ANOS1 variants according to ACMG exhibited additional features. And function of the non-pathogenic ANOS1 variants accompanied with other CHH-associated RSVs. Conclusion: The ANOS1 genetic spectrum of CHH patients in Chinese population is established. Some of the correlations between clinical phenotype and genotype are also established. Our study indicates that CHH patients with pathogenic or likely pathogenic ANOS1 RSVs tend to exhibit additional phenotypes. Although non-pathogenic ANOS1 variants only may not be sufficient to cause CHH, they may function together with other CHH-associated RSVs to cause the disease.

Genotype-phenotype and genetic analysis in five patients with Kallmann syndrome / 中华内分泌代谢杂志

To study the genotype-phenotype and genetic characteristics of Kallmann syndrome. Five patients with Kallmann syndrome were enrolled. Clinical data collection, chromosome karyotyping, whole exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA) were used. All the five patients were males, aging from 2 months to 45 years old. Three of the five patients complained cryptorchidism, one complained gonadal dysgenesis, and one complained fasting hyperglycemia. The clinical feature was hypogonadotropic hypogonadism with anosmia, and all karyotype was 46 XY. Magnetic resonance imaging (MRI) showed undeveloped olfactory bulbs and tracts. Kallmann syndrome related gene novel variants were found in all the 5 patients. The hypoplasia of right kidney was found in a patient with c. 1795_1799del (p.Asn599Profs*66) of anosmin 1 (ANOS1) variant. Clinical heterogeneity and incomplete penetrance were seen in a patient with c. 2824A>G (p.Thr942Ala) of chromodomain helicase DNA binding protein 7 (CHD7). Besides, WES indicated a 109 bp-deletion on Xp22.31 (chrX: 8507699-8507804), which was the deletion of exon 10 on ANOS1 gene verified by MLPA. The deletion variant was inherited form his mother, and conformed to X-linked recessive inheritance. Kallmann syndrome is genetic and clinical heterogeneous. WES is helpful for early diagnosis. MLPA and genome copy number variation analysis (CNV) are also recommend if necessary.

Target gene panel method versus whole-exome sequencing in detection of idiopathic hypogonadotropic hypogonadism in males / 中华男科学杂志

Objective@#To compare the efficiency of the target gene panel method and whole-exome sequencing (WES) in detecting idiopathic hypogonadotropic hypogonadism (IHH), and select a more suitable gene detection method.@*METHODS@#We selected 24 genes closely related to the molecular pathogenesis of IHH to make up the gene panel, detected the mutation sites in 73 patients with IHH using the panel method, and verified the results of sequencing with the Sanger method. Using the key words "idiopathic hypogonadotropic hypogonadism", we searched databases for relevant literature, calculated the positive rate of IHH detected by WES and compared it with that detected with the panel method.@*RESULTS@#Of the 73 cases of IHH detected with the panel method, 7 were found with pathogenic mutations, including 2 cases of FGFR1, 2 cases of CHD7, 2 cases of KISS1R, and 1 case of NR5A1 mutation. Sanger sequencing showed that the positive rate of the panel method was 9.7%. Of the 1 336 articles retrieved, 5 met the inclusion criteria and were included, in which WES revealed a positive rate of about 30%.@*CONCLUSIONS@#For detection of the diseases with clear mutated genes, the panel method is relatively inexpensive and has a high sequencing depth, while for detection of the diseases with complicated genetic patterns and unclear mutated genes, WES is more efficient. Further studies are needed for choice of the two methods for different purpose of detection./.

Whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism / 亚洲男科学杂志(英文版)

Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism (IHH) and an oligogenic etiology has been suggested. However, the associated genes may account for only approximately 50% cases. In addition, a genomic systematic pedigree analysis is still lacking. Here, we conducted whole exome sequencing (WES) on 18 unrelated men affected by IHH and their corresponding parents. Notably, one reported and 10 novel variants in eight known IHH causative genes (AXL, CCDC141, CHD7, DMXL2, FGFR1, PNPLA6, POLR3A, and PROKR2), nine variants in nine recently reported candidate genes (DCAF17, DCC, EGF, IGSF10, NOTCH1, PDE3A, RELN, SLIT2, and TRAPPC9), and four variants in four novel candidate genes for IHH (CCDC88C, CDON, GADL1, and SPRED3) were identified in 77.8% (14/18) of IHH cases. Among them, eight (8/18, 44.4%) cases carried more than one variant in IHH-related genes, supporting the oligogenic model. Interestingly, we found that those variants tended to be maternally inherited (maternal with n = 17 vs paternal with n = 7; P = 0.028). Our further retrospective investigation of published reports replicated the maternal bias (maternal with n = 46 vs paternal with n = 28; P = 0.024). Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.

Role of Kisspeptin in Puberty in Humans

Kisspeptin or GPR-54 is a product of KISS 1 gene regulating the production of gonadotropin releasing hormone (GnRH), luteinizing (LH) as well follicle stimulating hormone (FSH). Both LH and FSH are important hormones for reproduction in animals as well in humans. The recognition of Kisspeptin has a landmark bearing in reproductive biology. Few recent pilot studies have convincingly proven it to be a promising molecule in treating infertile couples especially those having hypogonadotropic hypogonadism not responding to conventional treatment

Gonadotropin treatment for male partial congenital hypogonadotropic hypogonadism in Chinese patients / 亚洲男科学杂志(英文版)

Partial congenital hypogonadotropic hypogonadism (PCHH) is caused by an insufficiency in, but not a complete lack of, gonadotropin secretion. This leads to reduced testosterone production, mild testicular enlargement, and partial pubertal development. No studies have shown the productivity of spermatogenesis in patients with PCHH. We compared the outcomes of gonadotropin-induced spermatogenesis between patients with PCHH and those with complete congenital hypogonadotropic hypogonadism (CCHH). This retrospective study included 587 patients with CHH who were treated in Peking Union Medical College Hospital (Beijing, China) from January 2008 to September 2016. A total of 465 cases were excluded from data analysis for testosterone or gonadotropin-releasing hormone treatment, cryptorchidism, poor compliance, or incomplete medical data. We defined male patients with PCHH as those with a testicular volume of ≥4 ml and patients with a testicular volume of <4 ml as CCHH. A total of 122 compliant, noncryptorchid patients with PCHH or CCHH received combined human chorionic gonadotropin and human menopausal gonadotropin and were monitored for 24 months. Testicular size, serum luteinizing hormone levels, follicle-stimulating hormone levels, serum total testosterone levels, and sperm count were recorded at each visit. After gonadotropin therapy, patients with PCHH had a higher spermatogenesis rate (92.3%) than did patients with CCHH (74.7%). During 24-month combined gonadotropin treatment, the PCHH group took significantly less time to begin producing sperm compared with the CCHH group (median time: 11.7 vs 17.8 months, P < 0.05). In conclusion, after combined gonadotropin treatment, patients with PCHH have a higher spermatogenesis success rate and sperm concentrations and require shorter treatment periods for sperm production.

Manifestaciones clínicas asociadas al síndrome de Prader-Willi / Clinical Manifestations Associated with Prader-Willi Syndrome

RESUMEN El síndrome de Prader-Willi (SPW) es un trastorno genético, que afecta el neurodesarrollo que, a pesar de su baja frecuencia, merece ser considerado como un trastorno de relevancia clínica al ser la causa más frecuente de obesidad de origen genético. Las manifestaciones clínicas que derivan de SPW tienen origen en la desregulación hipotalámica, por lo que al comprender la trascendencia e implicación de ésta se entenderá la amplia gama de manifestaciones que pueden presentarse con severidad variable y cuyas complicaciones a su vez afectan la salud y socialización a largo plazo lo que influye sobre la calidad de vida de los pacientes con SPW. El diagnóstico preciso permite distinguir este síndrome de otros trastornos genéticos y de otras patologías que afectan la función hipotalámica a la vez que posibilita estimar la gravedad de las manifestaciones y el riesgo de repetición en una misma familia. Por ello, esta revisión se presenta con el objetivo de describir las manifestaciones clínicas del síndrome de Prader-Willi que orienten la sospecha clínica, las similitudes que comparte éste con otros trastornos, así como dar a conocer las técnicas de diagnóstico disponibles que favorecen el abordaje de los pacientes y facilitar su manejo integral oportunamente.

ABSTRACT Prader-Willi syndrome (PWS) is a genetic disorder that affects neurodevelopment, which, despite its low frequency, deserves to be consideredaclinically relevant disorder since it is themost frequent cause of genetically derived obesity. The clinical manifestations that derive from SPW correlate to those from a hypothalamic dysregulation, so that, understanding the importance and implication of the hypothalamic involvement, the wide range of manifestations that can present with variable severity and whose complications in turn affect the health can be understood. and long-term socialization affecting the quality of life of patients with PWS. An accurate diagnosis can discriminate this syndrome from other genetic disorders and from non-genetic pathologies that affect hypothalamic function, while also allowing to estimate the severity in a specific patient and the risk of repetition in other family members. Therefore, the present descriptive review is aimed to describe the clinical manifestations of Prader-Willi syndrome to guide the clinical diagnosis; the signs and symptoms that can differentiate this syndrome from other disorders, as well as presenting a description of the actual diagnostic techniques that can allow a prompt and precise diagnosis, and thus, translate in a comprehensive and timely approach of the patients with PWS.

Testosterone undecanoate supplementation together with human chorionic gonadotropin does not impair spermatogenesis in males with isolated hypogonadotropic hypogonadism: A retrospective study / 亚洲男科学杂志(英文版)

Gonadotropin therapy is commonly used to induce virilization and spermatogenesis in male isolated hypogonadotropic hypogonadism (IHH) patients. In clinical practice, 5.6%-15.0% of male IHH patients show poor responses to gonadotropin treatment; therefore, testosterone (T) supplementation can serve as an alternative therapy to normalize serum T levels and promote virilization. However, treatment with exogenous T impairs spermatogenesis and suppresses intratesticular T levels. This retrospective study aimed to determine whether oral testosterone undecanoate (TU) supplementation together with human chorionic gonadotropin (hCG) would negatively affect spermatogenesis in IHH patients compared with hCG alone. One hundred and seven IHH patients were included in our study. Fifty-four patients received intramuscular hCG and oral TU, and 53 patients received intramuscular hCG alone. The median follow-up time was 29 (range: 12-72) months in both groups. Compared with the hCG group, the hCG/TU group required a shorter median time to normalize serum T levels (P < 0.001) and achieve Tanner stage (III and V) of pubic hair and genital development (P < 0.05). However, there were no significant differences in the rate of seminal spermatozoa appearance, sperm concentration, or median time to achieve different sperm concentration thresholds between the groups. In addition, there were no significant differences in side effects, such as acne and gynecomastia, observed in both groups. This study indicates that oral TU supplementation together with hCG does not impair spermatogenesis in treated IHH patients compared with hCG alone, and it shortens the time to normalize serum T levels and promote virilization.

Evaluation of gonadotropin-replacement therapy in male patients with hypogonadotropic hypogonadism / 亚洲男科学杂志(英文版)

Hypogonadotropic hypogonadism (HH) is a rare disease in which medical treatment has a high success rate to achieve fertility. This study aimed to analyze the efficacy of hormone replacement therapy and determine predictive factors for successful spermatogenesis and spontaneous pregnancy in patients with idiopathic HH. A total of 112 patients with low testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and normal prolactin levels were diagnosed with HH and administered LH and FSH analogs as hormone replacement therapy. During treatment, 96 (85.7%) patients had sperm present in ejaculate samples. Among these patients, 72 were married and wanted a child. Of these 72 patients, 48 (66.7%) of couples had pregnancies from natural conception. After initiation of treatment, the mean time for the appearance of sperm in semen was 9.48 months. There were no significant differences between baseline FSH, T, and LH levels; however, older age, larger testicular size, and low rate of undescended testes were favorable factors for successful spermatogenesis. Larger testicular size and older age were also the main predictive factors for natural conception. We found that patients with undescended testes had a younger age, smaller testes, and lower T levels compared with patients exhibiting descended testes. The rate of sperm found in the ejaculate was not significantly decreased in patients with undescended compared with descended testis (73.7% vs 87.6%, P = 0.261). The medical approach for males with HH and azoospermia provides a successful treatment modality in regard to successful spermatogenesis and achievement of pregnancy.

Evaluation of gonadotropin-replacement therapy in male patients with hypogonadotropic hypogonadism / 亚洲男科学杂志(英文版)

Hypogonadotropic hypogonadism (HH) is a rare disease in which medical treatment has a high success rate to achieve fertility. This study aimed to analyze the efficacy of hormone replacement therapy and determine predictive factors for successful spermatogenesis and spontaneous pregnancy in patients with idiopathic HH. A total of 112 patients with low testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and normal prolactin levels were diagnosed with HH and administered LH and FSH analogs as hormone replacement therapy. During treatment, 96 (85.7%) patients had sperm present in ejaculate samples. Among these patients, 72 were married and wanted a child. Of these 72 patients, 48 (66.7%) of couples had pregnancies from natural conception. After initiation of treatment, the mean time for the appearance of sperm in semen was 9.48 months. There were no significant differences between baseline FSH, T, and LH levels; however, older age, larger testicular size, and low rate of undescended testes were favorable factors for successful spermatogenesis. Larger testicular size and older age were also the main predictive factors for natural conception. We found that patients with undescended testes had a younger age, smaller testes, and lower T levels compared with patients exhibiting descended testes. The rate of sperm found in the ejaculate was not significantly decreased in patients with undescended compared with descended testis (73.7% vs 87.6%, P = 0.261). The medical approach for males with HH and azoospermia provides a successful treatment modality in regard to successful spermatogenesis and achievement of pregnancy.

Testosterone undecanoate supplementation together with human chorionic gonadotropin does not impair spermatogenesis in males with isolated hypogonadotropic hypogonadism: a retrospective study / 亚洲男科学杂志(英文版)

Gonadotropin therapy is commonly used to induce virilization and spermatogenesis in male isolated hypogonadotropic hypogonadism (IHH) patients. In clinical practice, 5.6%-15.0% of male IHH patients show poor responses to gonadotropin treatment; therefore, testosterone (T) supplementation can serve as an alternative therapy to normalize serum T levels and promote virilization. However, treatment with exogenous T impairs spermatogenesis and suppresses intratesticular T levels. This retrospective study aimed to determine whether oral testosterone undecanoate (TU) supplementation together with human chorionic gonadotropin (hCG) would negatively affect spermatogenesis in IHH patients compared with hCG alone. One hundred and seven IHH patients were included in our study. Fifty-four patients received intramuscular hCG and oral TU, and 53 patients received intramuscular hCG alone. The median follow-up time was 29 (range: 12-72) months in both groups. Compared with the hCG group, the hCG/TU group required a shorter median time to normalize serum T levels (P < 0.001) and achieve Tanner stage (III and V) of pubic hair and genital development (P < 0.05). However, there were no significant differences in the rate of seminal spermatozoa appearance, sperm concentration, or median time to achieve different sperm concentration thresholds between the groups. In addition, there were no significant differences in side effects, such as acne and gynecomastia, observed in both groups. This study indicates that oral TU supplementation together with hCG does not impair spermatogenesis in treated IHH patients compared with hCG alone, and it shortens the time to normalize serum T levels and promote virilization.

Pituitary magnetic resonance imaging abnormalities in young female patients with hypogonadotropic hypogonadism

OBJECTIVE: To elucidate the association between clinical and laboratory characteristics and pituitary magnetic resonance imaging (MRI) abnormalities in young female patients with hypogonadotropic hypogonadism (HH). METHODS: We retrospectively investigated a series of 74 female patients (age range, 14–42 years) with normoprolactinemic HH who underwent pituitary MRI. Pubertal milestones and hormonal features of patients with small pituitary glands (PGs) and space-occupying lesions were compared with those of patients with normal PGs. RESULTS: The overall frequency of abnormal PGs was 35.1%, with space-occupying lesions observed in 8 patients (10.8%), and small PG observed in 18 patients (24.3%). The mean serum gonadotropin level was not different between patients with and without pituitary MRI abnormalities (P>0.05). Space-occupying lesions were not associated with low gonadotropin levels, type of amenorrhea, or presence of secondary sex characteristics. The frequency of space-occupying lesions was higher in patients with interrupted puberty (25.0%) than in patients who did not go through puberty (4.8%) or had a normal puberty (9.8%), but were not statistically significant (P>0.05). Small PG was associated with low gonadotropin levels and type of amenorrhea (P<0.05). CONCLUSION: Clinically significant space-occupying lesions were not associated with low gonadotropin levels, type of amenorrhea, or presence of secondary sex characteristics. However, the frequency of space-occupying lesions was higher in patients with interrupted puberty than in patients who did not go through puberty or who with normal puberty.

Retro-and orthonasal olfactory function in relation to olfactory bulb volume in patients with hypogonadotrophic hypogonadism / Função olfativa retro e ortonasal em relação ao volume do bulbo olfatório em pacientes com hipogonadismo hipogonadotrófico

Abstract Introduction: Idiopathic hypogonadotrophic hypogonadism with an olfactory deficit is defined as Kallmann syndrome and is distinct from normosmic idiopathic hypogonadotrophic hypogonadism. Objective: Because olfactory perception not only consists of orthonasally gained impressions but also involves retronasal olfactory function, in this study we decided to comprehensively evaluate both retronasal and orthonasal olfaction in patients with idiopathic hypogonadotrophic hypogonadism. Methods: This case-control study included 31 controls and 45 idiopathic hypogonadotrophic hypogonadism patients. All participants whose olfactory and taste functions were evaluated with orthonasal olfaction (discrimination, identification and threshold), retronasal olfaction, taste function and olfactory bulb volume measurement. The patients were separated into three groups according to orthonasal olfaction: anosmic idiopathic hypogonadotrophic hypogonadism, hyposmic idiopathic hypogonadotrophic hypogonadism and normosmic idiopathic hypogonadotrophic hypogonadism. Results: Discrimination, identification and threshold scores of patients with Kallmann syndrome were significantly lower than controls. Threshold scores of patients with normosmic idiopathic hypogonadotrophic hypogonadism. were significantly lower than those of controls, but discrimination and identification scores were not significantly different. Retronasal olfaction was reduced only in the anosmic idiopathic hypogonadotrophic hypogonadism group compared to controls. Identification of bitter, sweet, sour, and salty tastes was not significantly different when compared between the anosmic, hyposmic, and normosmic idiopathic hypogonadotrophic hypogonadism groups and controls. Olfactory bulb volume was lower bilaterally in all patient groups when compared with controls. The olfactory bulb volume of both sides was found to be significantly correlated with threshold, discrimination and identification scores in idiopathic hypogonadotrophic hypogonadism patients. Conclusion: 1) There were no significant differences in gustatory function between controls and idiopathic hypogonadotrophic hypogonadism patients; 2) retronasal olfaction was reduced only in anosmic patients but not in orthonasally hyposmic participants, possibly indicating presence of effective compensatory mechanisms; 3) olfactory bulb volumes were highly correlated with olfaction scores in the hypogonadotrophic hypogonadism group. The current results indicate a continuum from anosmia to normosmia in idiopathic hypogonadotrophic hypogonadism patients.

Resumo Introdução: O hipogonadismo hipogonadotrófico idiopático com déficit olfatório é definido como síndrome de Kallmann e é distinto de hipogonadismo hipogonadotrófico idiopático normósmico. Objetivo: Pelo fato de a percepção olfativa não apenas consistir em impressões obtidas ortonasalmente, mas também envolver a função olfativa retronasal, neste estudo decidimos avaliar de maneira abrangente o olfato retronasal e ortonasal em pacientes com hipogonadismo hipogonadotrófico idiopático. Método: Este estudo caso-controle incluiu 31 controles e 45 pacientes com hipogonadismo hipogonadotrófico idiopático. Todos os participantes tiveram as funções olfativas e de paladar avaliadas com olfação ortonasal (discriminação, identificação e limiar), olfação retronasal, função do paladar e medida do volume do bulbo olfatório. Os pacientes foram separados em três grupos de acordo com a olfação ortonasal: hipogonadismo hipogonadotrófico idiopático anósmico, hipogonadismo hipogonadotrófico idiopático hipósmico e hipogonadismo hipogonadotrófico idiopático normósmico. Resultados: Os escores de discriminação, identificação e limiar de pacientes com síndrome de Kallmann foram significativamente menores do que os controles. Os escores dos limiares de pacientes com hipogonadismo hipogonadotrófico idiopático normósmico foram significativamente menores do que os dos controles, mas os escores de discriminação e identificação não foram significativamente diferentes. A olfação retronasal foi reduzida apenas no grupo hipogonadismo hipogonadotrófico idiopático anósmico em comparação com os controles. A identificação de gostos amargos, doces, azedos e salgados não foi significativamente diferente quando comparada entre os grupos e controles de hipogonadismo hipogonadotrófico idiopático anósmicos, hipósmicos e normósmicos. O volume do bulbo olfatório foi menor bilateralmente em todos os grupos de pacientes quando comparado com os controles. O volume do bulbo olfatório de ambos os lados foi significativamente correlacionado com os escores de limiar, discriminação, identificação em pacientes com hipogonadismo hipogonadotrófico idiopático. Conclusão: 1) Não houve diferenças significativas na função gustativa entre controles e pacientes com hipogonadismo hipogonadotrófico idiopático; 2) A olfação retronasal foi reduzida apenas em pacientes anosmáticos, mas não em participantes ortonasalmente hipósmicos, possivelmente indicou presença de mecanismos compensatórios efetivos; 3) Os volumes do bulbo olfatório foram altamente correlacionados com os escores de olfação no grupo hipogonadismo hipogonadotrófico. Os resultados atuais indicam um contínuo da anosmia à normosmia em pacientes com hipogonadismo hipogonadotrófico idiopático.

Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism / 亚洲男科学杂志(英文版)

Pulsatile gonadotropin-releasing hormone (GnRH) may induce spermatogenesis in most patients with congenital hypogonadotropic hypogonadism (CHH) by stimulating gonadotropin production, while the predictors for a pituitary response to pulsatile GnRH therapy were rarely investigated. Therefore, the aim of our study is to investigate predictors of the pituitary response to pulsatile GnRH therapy. This retrospective cohort study included 82 CHH patients who received subcutaneous pulsatile GnRH therapy for at least 1 month. Patients were categorized into poor or normal luteinizing hormone (LH) response subgroups according to their LH level (LH <2 IU l-1 or LH ≥2 IU l-1) 1 month into pulsatile GnRH therapy. Gonadotropin and testosterone levels, testicular size, and sperm count were compared between the two subgroups before and after GnRH therapy. Among all patients, LH increased from 0.4 ± 0.5 IU l-1 to 7.5 ± 4.4 IU l-1 and follicle-stimulating hormone (FSH) increased from 1.1 ± 0.9 IU l-1 to 8.8 ± 5.3 IU l-1. A Cox regression analysis showed that basal testosterone level (β = 0.252, P = 0.029) and triptorelin-stimulated FSH60min(β = 0.518, P = 0.01) were two favorable predictors for pituitary response to GnRH therapy. Nine patients (9/82, 11.0%) with low LH response to GnRH therapy were classified into the poor LH response subgroup. After pulsatile GnRH therapy, total serum testosterone level was 39 ± 28 ng dl-1 versus 248 ± 158 ng dl-1 (P = 0.001), and testicular size was 4.0 ± 3.1 ml versus 7.9 ± 4.5 ml (P = 0.005) in the poor and normal LH response subgroups, respectively. It is concluded that higher levels of triptorelin-stimulated FSH60minand basal total serum testosterone are favorable predictors of pituitary LH response to GnRH therapy.

Diagnosis and treatment of idiopathic hypogonadotropic hypogonadism in males / 中华男科学杂志

Idiopathic hypogonadotropic hypogonadism (IHH) is often caused by hyposecretion of gonadotropin and consequently affects male fertility. The patient with IHH has a smaller penis and testes with spermatogenic dysfunction. At present, IHH is treated mainly with hCG, hMG, GnRH, and their different combinations. However, due to the lack of large-sample evidence, it is not yet clear which therapy is the best option. This article presents an overview of our experience in the treatment of IHH in the last decade and a review of relevant literature, aiming at a deeper insight into this male disease.