OBJECTIVE: To investigate the detection patterns, clinical phenotypic characteristics, and differences in diagnostic timeliness of Klinefelter syndrome (KS) across prenatal and postnatal stages, with an aim to provide a basis for optimizing strategies for early screening, diagnosis, and intervention. METHODS: A retrospective study was conducted to analyze data from two phases. The prenatal diagnosis group included 33,302 pregnant women who underwent amniocytic karyotyping due to advanced maternal age, abnormal ultrasound findings, or high-risk non-invasive prenatal testing (NIPT). The postnatal diagnosis group included 52,101 patients who underwent peripheral blood karyotyping due to primary infertility, abnormal external genitalia, or growth and developmental abnormalities. Additionally, medical histories of adult diagnosed patients were reviewed retrospectively to identify early occult symptoms. This study was approved by the Medical Ethics Committee of Chengdu Women's and Children's Central Hospital (Ethics No.: LCYJ-2025-030). RESULTS: In the prenatal group, 96 cases of KS were detected (detection rate 0.29%). The primary indications for referral were NIPT indicating sex chromosome abnormalities (45.83%), advanced maternal age (16.66%), and ultrasound abnormalities (17.70%). In the postnatal group, 128 cases of KS were detected (detection rate 0.25%). Clinical presentations were primarily primary infertility/azoospermia (77.34%), and the patients were predominantly adults (84.40%). Retrospective analysis revealed that adult patients presented with specific physical signs that had been overlooked during childhood. CONCLUSION As KS lacks typical early clinical manifestations, diagnosis is often delayed until adulthood when reproductive needs arise, showing a pattern of "passive detection" and resulting in missed opportunities for optimal intervention. By conducting a comparative analysis of prenatal diagnostic data and postnatal retrospective data, a risk association model linking prenatal screening indications with childhood-specific signs was developed. This study has provided empirical evidence for establishing a multidisciplinary, full life-cycle management system of "screening ~ diagnosis ~ monitoring ~ intervention" helping to shift from "passive detection in adulthood" to "proactive management across the entire life course," and laid a foundation for improving early diagnosis rate and long-term quality of life for patients.
Humans ; Klinefelter Syndrome/genetics* ; Female ; Adult ; Pregnancy ; Retrospective Studies ; Prenatal Diagnosis/methods* ; Male ; Phenotype ; Karyotyping ; Young Adult ; Adolescent ; Middle Aged

OBJECTIVE

Previous studies have indicated that clinical hypogonadism is common among males with type 2 diabetes mellitus (T2DM). However, the reported prevalence varies due to the diverse diagnostic criteria used in these studies. This study aims to determine the prevalence of clinical hypogonadism among Malaysian T2DM males and their associated factors.

A total of 360 participants who fulfilled the inclusion criteria were included in this study. Their socio-demographic and clinical parameters were documented and a total testosterone level was sampled from a morning fasting serum. Patients with serum total testosterone of 8-12 nmol/L had their serum total testosterone repeated and their symptoms assessed with the Aging Male Symptoms (AMS) scale. Clinical hypogonadism was diagnosed with total testosterone 26.

The prevalence of clinical hypogonadism among Malaysian T2DM males was 17.5% (n = 63), with 55.6% of them having hypogonadotropic hypogonadism. There is a significant association between clinical hypogonadism with waist circumference > 94 cm (p < 0.001), obesity (p < 0.001), hypertension (p = 0.010), coronary artery disease (p = 0.014) and peripheral artery disease (p = 0.022). There is a significant difference in the weight (p = 0.001), BMI (p < 0.001), waist circumference P < 0.001), serum HDL-C levels (p < 0.001), serum triglycerides levels (p = 0.001) and serum TyG index (p < 0.001). Diabetic males with increasing age (adjusted OR = 1.070, 95% CI 1.004-1.146, p = 0.038), presence of coronary artery diseases (adjusted OR = 2.08, 95% CI 1.220-10.219, p = 0.020) and low total testosterone (adjusted OR = 2.451, 95% CI 1.908-3.155, p < 0.001) are at higher risk of developing clinical hypogonadism.

This study is the first in the Asian region to use stricter criteria for diagnosing hypogonadism. Despite these stringent criteria, the prevalence of hypogonadism remains significantly high among Malaysian T2DM males. It is particularly common in diabetic males over 35 years old with coronary artery disease, regardless of A1c control and the duration of diabetes.

Azoospermia is the complete absence of spermatozoa in the ejaculate in two or more semen analyses after centrifugation. Nonobstructive azoospermia (NOA) represents the most severe form of male factor infertility accounting for 10%-15% of cases and stems from an impairment to spermatogenesis. Understanding of the hypothalamic-pituitary-testicular axis has allowed NOA to be subcategorized by anatomic and/or pathophysiologic level. The etiologies of NOA, and therefore, the differential diagnoses when considering NOA as a cause of male factor infertility, can be subcategorized and condensed into several distinct classifications. Etiologies of NOA include primary hypogonadism, secondary hypogonadism, defects in androgen synthesis and/or response, defective spermatogenesis and sperm maturation, or a mixed picture thereof. This review includes up-to-date clinical, diagnostic, cellular, and histologic features pertaining to the multitude of NOA etiologies. This in turn will provide a framework by which physicians practicing infertility can augment their clinical decision-making, patient counseling, thereby improving upon the management of men with NOA.
Humans ; Azoospermia/diagnosis* ; Male ; Spermatogenesis/physiology* ; Hypogonadism/complications* ; Infertility, Male/etiology* ; Testis/pathology*

Hypogonadotropic hypogonadism (HH) represents a relatively rare cause of nonobstructive azoospermia (NOA), but its knowledge is crucial for the clinical andrologists, as it represents a condition that can be corrected with medical therapy in 3 quarters of cases. There are forms of congenital HH, whether or not associated with an absent sense of smell (anosmic HH or Kallmann syndrome, and normosmic HH, respectively), and forms of acquired HH. In congenital HH, complete absence of pubertal development is characteristic. On the other hand, if the deficit occurs after the time of pubertal development, as in acquired HH patients, infertility and typical symptoms of late-onset hypogonadism are the main reasons for seeking medical assistance. Gonadotropin-releasing hormone (GnRH) or gonadotropin replacement therapy is the mainstay of drug therapy and offers excellent results, although a small but significant proportion of patients do not achieve sufficient responses.
Humans ; Hypogonadism/drug therapy* ; Male ; Azoospermia/drug therapy* ; Gonadotropin-Releasing Hormone/therapeutic use* ; Kallmann Syndrome/drug therapy* ; Hormone Replacement Therapy

Except in cases of hypogonadotropic hypogonadism, the use of medical therapy before microsurgical testicular sperm extraction (micro-TESE) is controversial. In some studies, hormone therapy has been shown to improve the possibility of sperm retrieval during micro-TESE and even lead to the presence of sperm in the ejaculate in some cases, thereby obviating the need for micro-TESE. However, their routine use before micro-TESE in cases of nonobstructive azoospermia (NOA) being associated with hypergonadotropic hypogonadism and eugonadism (normogonadotropic condition) has not been supported with robust evidence. In this review, we discuss different types of medical therapy used before micro-TESE for NOA, their risks and benefits, and the available evidence surrounding their use in this setting.
Humans ; Male ; Azoospermia/therapy* ; Sperm Retrieval ; Hypogonadism/complications* ; Microsurgery

Testosterone affects several organs in the body and is very important for male well-being. Aging men with late-onset hypogonadism (LOH) experience physiologic, psychiatric, and sexual symptoms related to a decline in the serum concentration of testosterone with age. However, it is well-known that the extent of the decline in testosterone concentration does not correlate with the severity of LOH-related symptoms. Therefore, it is difficult to diagnose and treat patients with LOH. In addition, the symptoms, response to testosterone replacement therapy (TRT), and medical insurance coverage differ among ethnicities and countries. The evaluation of testosterone is essential for the diagnosis and treatment of LOH. The effects of testosterone are determined not only by the serum testosterone concentration but also by the androgen receptor sensitivity. A low number of glutamine repeats is indicative of high androgenic activity, and the number shows ethnicity-related differences (fewer in African American than in Caucasian people and more in East Asian people). The diagnosis of LOH is typically made using subjective symptoms and the serum testosterone concentration. The Aging Male Symptoms scale is widely used to evaluate the symptoms. The normal range of total testosterone concentration varies around the world; therefore, clinicians should follow the guidelines of their regional academic society. The principal treatment for LOH is TRT. There are many types of TRT and other treatment strategies are also available. Thus, physicians should treat LOH according to each patient's situation, considering related disorders, such as diabetes, osteoporosis, metabolic syndrome, and depression.
Humans ; Male ; Hypogonadism/drug therapy* ; Testosterone/blood* ; Hormone Replacement Therapy/methods* ; Japan ; Age of Onset ; Aging ; Aged ; Androgens/therapeutic use*

The circadian clock is an important internal time regulatory system for a range of physiological and behavioral rhythms within living organisms. Testosterone, as one of the most critical sex hormones, is essential for the development of the reproductive system, maintenance of reproductive function, and the overall health of males. The secretion of testosterone in mammals is characterized by distinct circadian rhythms and is closely associated with the regulation of circadian clock genes. Here we review the central and peripheral regulatory mechanisms underlying the influence of circadian clock genes upon testosterone synthesis. We also examined the specific effects of these genes on the occurrence, development, and treatment of common male diseases, including late-onset hypogonadism, erectile dysfunction, male infertility, and prostate cancer.
Testosterone/metabolism* ; Humans ; Male ; Circadian Clocks/genetics* ; Circadian Rhythm Signaling Peptides and Proteins/metabolism* ; Circadian Rhythm/physiology* ; Hypogonadism/metabolism* ; Erectile Dysfunction/metabolism* ; Infertility, Male/metabolism* ; Prostatic Neoplasms/metabolism* ; Men's Health

Non-obstructive azoospermia is a common condition associated with significant health risks, including increased mortality, cancer, and chronic diseases such as metabolic and cardiovascular disorders. This review aims to highlight the potential health challenges faced by men with this condition compared to fertile counterparts. Through a comprehensive bibliographic search on PubMed, using the following algorithm: ("infertility, male" [MeSH Terms] OR "azoospermia" [MeSH Terms]) AND ("mortality" [MeSH Terms] OR "neoplasms" [MeSH Terms] OR "chronic disease" [MeSH Terms] OR "diabetes mellitus" [MeSH Terms] OR "heart diseases" [MeSH Terms]), we analyzed existing literature to explore the associations between infertility, specifically azoospermia, and adverse health outcomes. Findings indicate that infertile men are at a higher risk of death, various cancers (particularly testicular cancer), metabolic syndrome, diabetes, hypogonadism, and cardiovascular disease. Although research specifically addressing azoospermia is limited, available studies support the notion that men with this condition may experience heightened health vulnerabilities. Given these risks, it is imperative for healthcare professionals, especially urologists, to conduct thorough health assessments for men diagnosed with azoospermia. Informing patients of these potential health issues and integrating comprehensive evaluations into their care can facilitate early detection and intervention for life-threatening conditions. Ultimately, men with azoospermia should receive ongoing monitoring to address their specific health concerns, thus improving their long-term health outcomes.
Humans ; Male ; Azoospermia/epidemiology* ; Cardiovascular Diseases/etiology* ; Metabolic Syndrome/epidemiology* ; Infertility, Male/complications* ; Testicular Neoplasms/epidemiology* ; Hypogonadism/epidemiology* ; Diabetes Mellitus/epidemiology* ; Risk Factors ; Neoplasms/epidemiology*

Humans ; Child ; Klinefelter Syndrome/complications* ; Lupus Erythematosus, Systemic/complications*

Puberty is a pivotal biological process that completes sexual maturation to achieve full reproductive capability. It is a major transformational period of life, whose timing is strongly affected by genetic makeup of the individual, along with various internal and external factors. Although the exact mechanism for initiation of the cascade of molecular events that culminate in puberty is not yet known, the process of pubertal onset involves interaction of numerous complex signaling pathways of hypothalamo-pituitary-testicular (HPT) axis. We developed a classification of the mechanisms involved in male puberty that allowed placing many genes into physiological context. These include (i) hypothalamic development during embryogenesis, (ii) synaptogenesis where gonadotropin releasing hormone (GnRH) neurons form neuronal connections with suprahypothalamic neurons, (iii) maintenance of neuron homeostasis, (iv) regulation of synthesis and secretion of GnRH, (v) appropriate receptors/proteins on neurons governing GnRH production and release, (vi) signaling molecules activated by the receptors, (vii) the synthesis and release of GnRH, (viii) the production and release of gonadotropins, (ix) testicular development, (x) synthesis and release of steroid hormones from testes, and (xi)the action of steroid hormones in downstream effector tissues. Defects in components of this system during embryonic development, childhood/adolescence, or adulthood may disrupt/nullify puberty, leading to long-term male infertility and/or hypogonadism. This review provides a list of 598 genes involved in the development of HPT axis and classified according to this schema. Furthermore, this review identifies a subset of 75 genes for which genetic mutations are reported to delay or disrupt male puberty.
Adolescent ; Male ; Humans ; Adult ; Child ; Gonadotropin-Releasing Hormone ; Gonadotropins/metabolism* ; Hypogonadism ; Testis/metabolism* ; Puberty/physiology* ; Sexual Maturation