Andrology最新文献

Spermatogenesis is primarily controlled by follicle-stimulating hormone and luteinizing hormone-driven testosterone. Luteinizing hormone acts on the Leydig cells, stimulating steroid production, predominantly testosterone, and activating critical inter-related spermatogenesis regulatory pathways. Despite evidence that exogenous gonadotropins containing luteinizing hormone activity, particularly human chorionic gonadotropin, can effectively restore spermatogenesis in azoospermic males with hypogonadotropic hypogonadism, the use of these drugs to treat other forms of non-obstructive azoospermia is the subject of an ongoing debate. In this review, we delve into the molecular properties and functions of human chorionic gonadotropin in spermatogenesis regulation and explore available preparations for therapeutic use. We examine the evidence regarding the effectiveness of human chorionic gonadotropin in treating infertility in men with pre-testicular or testicular non-obstructive azoospermia and, additionally, identify the main areas for future research. Our review highlights the critical role of luteinizing hormone activity in spermatogenesis and emphasizes the potential of human chorionic gonadotropin in treating male infertility. The variation in the characteristics of patients with non-obstructive azoospermia underscores the importance of assessing hormonal profiles when contemplating hormonal treatment for these patients. A novel stratification of male infertility patients, the APHRODITE criteria, which considers clinical and laboratory indicators, may assist in identifying individuals who could benefit from human chorionic gonadotropin therapy. While accumulating evidence suggests promising venues for pharmacological treatment in male infertility, including non-obstructive azoospermia, further research is required to completely elucidate the mechanisms underlying the effects of exogenous gonadotropins with luteinizing hormone activity on sperm production and to establish the most effective dosages and treatment durations.

Background: Cilia are specialized microtubule-based organelles that extend from the cell surface and are classified into non-motile and motile types. The assembly and function of cilia are regulated by a complex molecular network that enables motile cilia to generate fluid flow across epithelial surfaces through coordinated beating. These motile cilia are found in the respiratory, nervous, and reproductive systems. In males, motile cilia are found in the efferent ducts and facilitate the transport of sperm from the testis to the epididymis. In females, they are mainly found in the oviducts, where they help to transport, nourish and fertilize eggs, and are also present in the endometrial epithelium.

Material-methods: This review compares the common factors that affect motile cilia in both male and female reproductive tracts, discusses the origin and development of multiciliated cell and cilia within the efferent ducts and oviducts, and enumerates the infertility or related reproductive diseases that may arise due to motile cilia defects.

Results-discussion: In males, motile cilia in the efferent ducts create turbulence through their beating, which keeps semen suspended and prevents ductal obstruction. In females, motile cilia are distributed on the epithelia of the oviducts and the endometrium. Specifically, motile cilia in the infundibulum of the oviduct aid in capturing oocytes, while cilia in the isthmus region have been found to bind to sperm heads, facilitating the formation of the sperm reservoir. Several common factors, such as miR-34b/c and miR-449, TAp73, Gemc1, and estrogen, etc., have been shown to play crucial regulatory roles in motile cilia within the efferent ducts and oviducts, thereby further influencing fertility outcomes.

Conclusions: Pathogenic mutations that disrupt ciliary function can impair ciliogenesis or alter the structure of sperm flagella, potentially resulting in infertility. Consequently, motile cilia in both the male and female reproductive tracts are crucial for fertility. There are still numerous unresolved mysteries surrounding these cilia that merit further investigation by researchers, as they hold great significance for the clinical diagnosis and treatment of infertility and related reproductive disorders.

Objective: Micropenis is a condition with significant physical and psychological implications caused mainly by decreased androgen action in penile development. Kctd13-knockout (Kctd13-KO) mice have micropenis, cryptorchidism, and fertility defects because of reduced levels of androgen receptor (AR) and SOX9. We hypothesized that normalizing the levels of AR and SOX9 in the Kctd13-KO penis could help us to understand the mechanism of action of these signaling pathways on penile development.

Methods: We generated transgenic mice lacking Kctd13 and conditionally expressing AR in the urethral mesenchyme after Cre activation with Twist2^cre (Kctd13-KO; AR-CMV; Twist2^cre; herein called AR+), and Sox9 in the urethral epithelium after Cre activation with Shh^cre (Kctd13-KO; Sox9-CAG; Shh^cre; herein called SOX9+). Mice penile morphology, fertility, and the effect of KCTD13 on AR and SOX9 ubiquitination were evaluated.

Results and discussion: Kctd13-KO micropenis phenotype was rescued after increasing levels of penile AR or SOX9 as transgenic AR+ and SOX9+ mice have longer penile lengths than Kctd13-KO mice and are comparable to WT mice. In addition, male-urogenital-mating-protuberance and the baculum were significantly shorter and narrower in Kctd13-KO mice compared with transgenic AR+ and SOX9+ mice. The position of the urethral meatus was similar and orthotopic in location in Kctd13-KO, AR+, SOX9+, and WT penises indicating that none of these mice had hypospadias. The subfertility of AR+ and SOX9+ mice was improved. The ectopic expression of KCTD13 in HEK293 cells strongly reduced AR ubiquitination which is abolished when the proteasome pathway is inhibited and this process is mediated by the ubiquitin ligase, STUB1. The effect of KCTD13 on SOX9 ubiquitination is minimal.

Conclusion: KCTD13 regulates AR ubiquitination by modulating STUB1 binding to AR. Penile restoration of AR and SOX9 improved penile development in Kctd13-KO mice allowing us to discern the contribution from individual signaling pathways and cell types in penile development.

Background: 46, XY disorders of sex development (DSD) are a group of highly heterogeneous conditions in which the molecular etiology remains unknown in a significant proportion of patients, even with massive parallel sequencing. Clinically significant copy number variants (CNVs) are identified in 20-30% of cases, particularly among those with gonadal dysgenesis (GD) and no molecular diagnosis.

Methods: Fourteen patients with 46, XY DSD due to GD in whom no pathogenic/likely pathogenic variants were found on next-generation sequencing using a targeted panel of 155 genes were screened for clinically significant CNVs using Affymetrix Comparative Genomic Hybridization (CGH). Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER) and ClinVar were searched for matching genotypes and phenotypes, and chromosomal regions were screened for genes with known or potential association with GD.

Results: Significant CNVs were identified in 6 (43%) of 14 patients with 46, XY GD. A previously unreported 19p13.3 duplication was found in three patients. This CNV was associated with GD based on overlapping CNV regions from previous studies and databases; and the inclusion of CIRBP, a candidate gene implicated in GD. CNVs involving WT1 (11p15) and SOX8 (16p13.3) were also identified.

Conclusions: CGH was helpful in pointing toward the molecular etiology in a significant proportion of patients with "idiopathic" 46, XY GD. However, establishing causality will require additional evidence including functional studies.

The neuroendocrine system that comprises the glycoprotein hormones (GpHs) and their receptors is essential for reproduction and metabolism. Each GpH hormone is an αβ heterodimer of cystine-knot proteins and its cognate receptor is a G-protein coupled receptor (GPCR) distinguished by a large leucine-rich-repeat (LRR) extracellular domain that binds the hormone and a class A GPCR transmembrane domain that signals through an associating heterotrimeric G protein. Hence, the receptors are called LRR-containing GPCRs-LGRs. The vertebrate GpHs and LGRs have co-evolved from homologs in the earliest metazoan animals, including sponges and comb jellies, but these are absent from unicellular organisms and plants. The two GpH subunits and accompanying LGR receptor of the nematode Caenorhabditis elegans are representative of the invertebrate evolutionary predecessors of human GpH proteins and their receptors, for example follicle-stimulating hormone (FSH) and the FSH receptor (FSHR). Atomic structures of the human GpHs and their receptors, which have been determined by X-ray crystallography and cryogenic electron microscopy (cryo-EM), inform the evolutionary process and provide a mechanistic understanding of the transmission of biochemical signals of hormone binding at the cell surface to the elicitation of second messengers such as cyclic AMP in the cytoplasm. There is compelling biochemical and cellular evidence for the importance of receptor dimers in GpH signaling in cells; yet, all of the human receptors are monomeric as defined beautifully by cryo-EM. Fortunately, the LGR of C. elegans is a stable dimer and its structure, when analyzed in the context of structural information from the human counterparts, predicts a hypothetical model for functionally relevant dimeric associations of the human GpH receptors.

Luteinizing hormone (LH), along with its agonist choriongonadotropin (hCG) in humans, is the key hormone responsible for the tropic regulation of the gonadal function. LH and hCG act through their cognate receptor, the luteinizing hormone/choriongonadotropin receptor (LHCGR; more appropriately LHR in rodents lacking CG), located in the testis in Leydig cells and in the ovary in theca, luteal, and luteinizing granulosa cells. Low levels in LHCGR are also expressed in numerous extragonadal sites. Hypogonadism is observed in humans expressing inactivating mutations in the LHβ-subunit (LHB)and LHCGR genes, confirming the crucial role of LH and LHCGR in gonadal development and function. Unraveling of the LHR structure and the advent of gene manipulation techniques enabled the production of mouse models with inactivated LHR function, that is, the LHR knockout (LuRKO) mouse, some 20 years ago. This mouse model has thereafter been instrumental in various experimental settings, alone or combined with other genetically modified mouse models, in providing novel, and in some cases unexpected, details about the LH/LHR function. We will review here the salient findings of these studies.

The hypothalamic-pituitary-gonadal axis is regulated by the gonadotropin-releasing hormone pulse generator in the hypothalamus. This is comprised of neurons that secrete kisspeptin in a pulsatile manner to stimulate the release of GnRH, and, in turn, downstream gonadotropins from the pituitary gland, and subsequently sex steroids and gametogenesis from the gonads. Many reproductive disorders in both males and females are characterized by hypothalamic dysfunction, including functional disorders (such as age-related hypogonadism, obesity-related secondary hypogonadism, hyperprolactinemia, functional hypothalamic amenorrhea and polycystic ovary syndrome), structural pathologies (such as craniopharyngiomas or radiation or surgery-related hypothalamic dysfunction), and pubertal disorders (constitutional delay of growth and puberty and congenital hypogonadotropic hypogonadism). However, in many of these conditions, the relative contribution of hypothalamic dysfunction to the observed hypogonadism is unclear; as to date, there is no direct method of evaluating hypothalamic reproductive function in humans. Indeed, it is not possible to directly measure gonadotropin-releasing hormone levels in the hypothalamo-pituitary portal vessels, such that secondary (i.e., pituitary dysfunction) and tertiary (i.e., hypothalamic dysfunction) hypogonadism are often conflated as one entity. In this review, we examine the evidence for the use of kisspeptin as a method of directly evaluating hypothalamic reproductive dysfunction, and deliberate its potential future role in the evaluation of pubertal and reproductive disorders.

Objectives: Acetylated tubulin is a hallmark of flagellar stability in spermatozoa, and studies have demonstrated the ability of CDYL to function as a tubulin acetyltransferase in spermatozoa. Of note, germline conditional knockout of Cdyl can lead to asthenoteratozoospermia and infertility in male mice. However, the role of CDYL gene in human fertility remains uncharacterized.

Materials and methods: Data were collected through in silico analysis for an infertile man with asthenoteratozoospermia of Han Chinese descent by performing whole-exome sequencing. Light and electron microscopy were used to characterize the sperm cells of the proband, and the pathogenicity of the genetic factors was determined by functional experiments. To overcome fertility problems, intracytoplasmic sperm injections were performed in the couple.

Main results: Here, we recruited an infertile proband, born to first-cousin parents, displaying idiopathic asthenoteratozoospermia. Whole-exome sequencing identified a splicing mutation (c.103+1G>A) in CDYL, recessively cosegregating in the family. In vitro minigene assays demonstrated that the mutation resulted in aberrant alternative splicing. We found that CDYL co-localizes with Ac-tubulin along the flagella of human spermatozoa. In addition, the expression of Ac-tubulin was severely reduced in spermatozoa from the patient with CDYL mutation. Disruption in CDYL results in thin mid-piece related abnormal flagella morphology and decreased sperm motility. The primary manifestation of sperm ultrastructural abnormalities under the electron microscope is primarily characterized by disorder of axonemal protein complex and anulus.

Discussion and conclusion: We demonstrated that a homozygous CDYL splicing mutation specifically induces a decrease in microtubule acetylation, resulting in thin mid-piece related asthenoteratozoospermia, providing a novel marker for genetic counseling and diagnosis of male infertility.

Introduction: Myocardial dysfunction and the presence of calcified and non-calcified coronary plaques are predictors of cardiovascular disease. Masculinizing gender-affirming hormone therapy may increase cardiovascular risk, highlighting the need for prospective studies to evaluate cardiovascular outcomes during gender-affirming hormone therapy.

Objectives: To evaluate changes in cardiac morphology, systolic and diastolic function, and development of coronary plaques after masculinizing gender-affirming hormone therapy.

Methods: Prospective study including 47 transmasculine persons (gender-affirming hormone therapy-naïve, TransM_TN, n = 15 and gender-affirming hormone therapy-ongoing, TransM_TO, n = 32). Included persons were evaluated at study inclusion and after one year of masculinizing gender-affirming hormone therapy. At baseline, the median age of TransM_TN was 22 years (interquartile range 19-28 years) and TransM_TO 26 years (interquartile range 24-37 years) with a median gender-affirming hormone therapy duration of 4 years (interquartile range 2-5 years). Cardiac morphology including left ventricular wall thickness, volume, and mass, as well as left ventricular systolic and diastolic function was evaluated using echocardiography. Coronary artery calcifications and non-calcified coronary plaque were assessed using coronary computed tomography angiography. Paired and unpaired statistical analyses were performed within and between TransM_TN and TransM_TO groups.

Results: In TransM_TN, diastolic function decreased during follow-up with decreased septal and lateral left ventricular relaxation (14-11 cm/s, p = 0.04 and 18-15 cm/s, p = 0.02, respectively). No significant changes were observed in cardiac morphology, systolic function, or formation of coronary artery calcifications and non-calcified coronary plaque in TransM_TN or TransM_TO groups. At baseline, left ventricular end-diastolic internal diameter was significantly higher in TransM_TO compared to TransM_TN, 4.6 cm (interquartile range 4.3-5.0 cm) versus 4.4 cm (interquartile range 4.2-4.6 cm), p < 0.05. Other baseline cardiac outcomes were comparable between TransM_TN and TransM_TO.

Conclusion: Diastolic function declined after the initiation of masculinizing gender-affirming hormone therapy and individuals on long-term masculinizing gender-affirming hormone therapy had larger left ventricular dimensions compared to individuals before gender-affirming hormone therapy initiation. Cardiac morphology, systolic function, and coronary plaque formation remained stable during masculinizing gender-affirming hormone therapy.