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Purinergic Signalling Dec 2022Within the family of purinergic receptors, the P2X1 receptor is a ligand-gated ion channel that plays a role in urogenital, immune and cardiovascular function.... (Review)
Review
Within the family of purinergic receptors, the P2X1 receptor is a ligand-gated ion channel that plays a role in urogenital, immune and cardiovascular function. Specifically, the P2X1 receptor has been implicated in controlling smooth muscle contractions of the vas deferens and therefore has emerged as an exciting drug target for male contraception. In addition, the P2X1 receptor contributes to smooth muscle contractions of the bladder and is a target to treat bladder dysfunction. Finally, platelets and neutrophils have populations of P2X1 receptors that could be targeted for thrombosis and inflammatory conditions. Drugs that specifically target the P2X1 receptor have been challenging to develop, and only recently have small molecule antagonists of the P2X1 receptor been available. However, these ligands need further biological validation for appropriate selectivity and drug-like properties before they will be suitable for use in preclinical models of disease. Although the atomic structure of the P2X1 receptor has yet to be determined, the recent discovery of several other P2X receptor structures and improvements in the field of structural biology suggests that this is now a distinct possibility. Such efforts may significantly improve drug discovery efforts at the P2X1 receptor.
Topics: Male; Humans; Receptors, Purinergic P2X1; Urinary Bladder; Muscle Contraction; Vas Deferens; Blood Platelets; Receptors, Purinergic P2X; Adenosine Triphosphate
PubMed: 35821454
DOI: 10.1007/s11302-022-09880-4 -
Frontiers in Genetics 2022Congenital bilateral absence of the vas deferens (CBAVD) is clinically characterized by the absence of the bilateral vas deferens; the main clinical manifestation is... (Review)
Review
Congenital bilateral absence of the vas deferens (CBAVD) is clinically characterized by the absence of the bilateral vas deferens; the main clinical manifestation is infertility, accounting for 1-2% of male infertility cases. CBAVD may be accompanied by congenital abnormalities in the urogenital system and cystic fibrosis (CF)-related clinical manifestations. CBAVD can develop as a mild manifestation of CF or can be isolated. The main pathogenic mechanism of CBAVD is gene mutation, and CBAVD and CF have a common genetic mutation background. CFTR mutation is the main pathogenic cause of CBAVD and CF, and ADGRG2 mutation is the second most common cause. Although lack of the vas deferens in CBAVD patients causes infertility due to the inability to release sperm, the testes of CBAVD patients have spermatogenic function. Therefore, CBAVD patients can achieve fertility through sperm retrieval surgery and assisted reproductive technology (ART). However, gene mutations in CBAVD patients can have an impact on the ART outcome, and there is a risk of passing on gene mutations to offspring. For CBAVD patients and their spouses, performing genetic counseling (which currently refers mainly to CFTR mutation screening) helps to reduce the risks of genetic mutations being passed on to offspring and of offspring having CF with concomitant CBAVD.
PubMed: 35222530
DOI: 10.3389/fgene.2022.775123 -
Translational Andrology and Urology Mar 2021Cystic fibrosis (CF) is a rare autosomal-recessive disorder manifested as multisystem organ dysfunction. The cystic fibrosis transmembrane conductance regulator (CFTR)... (Review)
Review
Cystic fibrosis (CF) is a rare autosomal-recessive disorder manifested as multisystem organ dysfunction. The cystic fibrosis transmembrane conductance regulator (CFTR) protein functions as an ion transporter on the epithelium of exocrine glands, regulating secretion viscosity. The gene, encoded on chromosome 7, is required for the production and trafficking of the intact and functional CFTR protein. Literally thousands of human allelic mutations have been identified, each with varying impact on protein quality and quantity. As a result, individuals harboring mutations present with a spectrum of symptoms ranging from CF to normal phenotypes. Those with loss of function but without full CF may present with CFTR-related disorders (CFTR-RDs) including male infertility, sinusitis, pancreatitis, atypical asthma and bronchitis. Studies have demonstrated associations between higher rates of mutations and oligospermia, epididymal obstruction, congenital bilateral absence of the vas deferens (CBAVD), and idiopathic ejaculatory duct obstruction (EDO). Genetic variants are detected in over three-quarters of men with CBAVD, the reproductive abnormality most classically associated with aberrations. Likewise, nearly all men with clinical CF will have CBAVD. Current guidelines from multiple groups recommend screening in all men with clinical CF or CBAVD though a consensus on the minimum number of variants for which to test is lacking. testing is not recommended as routine screening for men with other categories of infertility. While available panels include 30 to 96 of the most common variants, complete gene sequencing should be considered if there is a high index of suspicion in a high-risk couple (e.g., partner is mutation carrier). CF treatments to date have largely targeted end-organ complications. Novel CFTR-modulator treatments aim to directly target CFTR protein dysfunction, effectively circumventing downstream complications, and possibly preventing symptoms like vasal atresia at a young age. Future gene therapies may also hold promise in preventing or reversing genetic changes that lead to CF and CFTR-RD.
PubMed: 33850775
DOI: 10.21037/tau.2020.04.05 -
Frontiers in Endocrinology 2022Purinergic receptors are ubiquitously expressed throughout the body and they participate in the autocrine and paracrine regulation of cell function during normal... (Review)
Review
Purinergic receptors are ubiquitously expressed throughout the body and they participate in the autocrine and paracrine regulation of cell function during normal physiological and pathophysiological conditions. Extracellular nucleotides activate several types of plasma membrane purinergic receptors that form three distinct families: P1 receptors are activated by adenosine, P2X receptors are activated by ATP, and P2Y receptors are activated by nucleotides including ATP, ADP, UTP, UDP, and UDP-glucose. These specific pharmacological fingerprints and the distinct intracellular signaling pathways they trigger govern a large variety of cellular responses in an organ-specific manner. As such, purinergic signaling regulates several physiological cell functions, including cell proliferation, differentiation and death, smooth muscle contraction, vasodilatation, and transepithelial transport of water, solute, and protons, as well as pathological pathways such as inflammation. While purinergic signaling was first discovered more than 90 years ago, we are just starting to understand how deleterious signals mediated through purinergic receptors may be involved in male infertility. A large fraction of male infertility remains unexplained illustrating our poor understanding of male reproductive health. Purinergic signaling plays a variety of physiological and pathophysiological roles in the male reproductive system, but our knowledge in this context remains limited. This review focuses on the distribution of purinergic receptors in the testis, epididymis, and vas deferens, and their role in the establishment and maintenance of male fertility.
Topics: Humans; Male; Testis; Infertility, Male; Nucleotides; Adenosine Triphosphate; Uridine Diphosphate
PubMed: 36419764
DOI: 10.3389/fendo.2022.1049511 -
Urology Video Journal Sep 2021To document a step-by-step guide of crossed transeptal vasoepididymostomy with prioritization of crossover vas deferens measurement.
OBJECTIVE
To document a step-by-step guide of crossed transeptal vasoepididymostomy with prioritization of crossover vas deferens measurement.
DESIGN
Video presentation.
SETTING
University of Miami Lennar Surgical Center.
PATIENTS
The patient undergoing this procedure signed a written, informed consent for video and audio recording.
RESULTS
No intraoperative complications were seen during the surgery, and the patient was discharged 6 h after the procedure. Through the steps detailed in the video and manuscript, a proper tubule into vas deferens invagination was formed.
CONCLUSIONS
Anatomical indications for crossed vasoepididymostomy exists in 6% of azoospermic males and procedural prevalence is increasing. With a standardized step-by-step procedural approach that prioritizes crossover vas deferens measurement, crossed vasoepididymostomy can be considered in couples desiring natural conception, with previous complications of ART or failed ART.
PubMed: 34296077
DOI: 10.1016/j.urolvj.2021.100090 -
Basic and Clinical Andrology Nov 2023Since the release of the combined oral contraceptive pill in 1960, women have shouldered the burden of contraception and family planning. Over 60 years later, this is... (Review)
Review
BACKGROUND
Since the release of the combined oral contraceptive pill in 1960, women have shouldered the burden of contraception and family planning. Over 60 years later, this is still the case as the only practical, effective contraceptive options available to men are condoms and vasectomy. However, there are now a variety of promising hormonal and non-hormonal male contraceptive options being studied. The purpose of this narrative review is to provide clinicians and laypeople with focused, up-to-date descriptions of novel strategies and targets for male contraception. We include a cautiously optimistic discussion of benefits and potential drawbacks, highlighting several methods in preclinical and clinical stages of development.
RESULTS
As of June 2023, two hormonal male contraceptive methods are undergoing phase II clinical trials for safety and efficacy. A large-scale, international phase IIb trial investigating efficacy of transdermal segesterone acetate (Nestorone) plus testosterone gel has enrolled over 460 couples with completion estimated for late 2024. A second hormonal method, dimethandrolone undecanoate, is in two clinical trials focusing on safety, pharmacodynamics, suppression of spermatogenesis and hormones; the first of these two is estimated for completion in December 2024. There are also several non-hormonal methods with strong potential in preclinical stages of development.
CONCLUSIONS
There exist several hurdles to novel male contraception. Therapeutic development takes decades of time, meticulous work, and financial investment, but with so many strong candidates it is our hope that there will soon be several safe, effective, and reversible contraceptive options available to male patients.
PubMed: 37940863
DOI: 10.1186/s12610-023-00204-z -
Reproductive Medicine and Biology Oct 2020At present, one out of six couples is infertile, and in 50% of cases, infertility is attributed to male infertility factors. Genetic abnormalities are found in 10%-20%... (Review)
Review
BACKGROUND
At present, one out of six couples is infertile, and in 50% of cases, infertility is attributed to male infertility factors. Genetic abnormalities are found in 10%-20% of patients showing severe spermatogenesis disorders, including non-obstructive azoospermia.
METHODS
Literatures covering the relationship between male infertility and genetic disorders or chromosomal abnormalities were studied and summarized.
MAIN FINDINGS RESULTS
Genetic disorders, including Klinefelter syndrome, balanced reciprocal translocation, Robertsonian translocation, structural abnormalities in Y chromosome, XX male, azoospermic factor (AZF) deletions, and congenital bilateral absence of vas deferens were summarized and discussed from a practical point of view. Among them, understanding on AZF deletions significantly changed owing to advanced elucidation of their pathogenesis. Due to its technical progress, AZF deletion test can reveal their delicate variations and predict the condition of spermatogenesis. Thirty-nine candidate genes possibly responsible for azoospermia have been identified in the last 10 years owing to the advances in genome sequencing technologies.
CONCLUSION
Genetic testing for chromosomes and AZF deletions should be examined in cases of severe oligozoospermia and azoospermia. Genetic counseling should be offered before and after genetic testing.
PubMed: 33071633
DOI: 10.1002/rmb2.12336 -
Asian Journal of Andrology 2022
Topics: Azoospermia; Humans; Male; Vas Deferens; Vasectomy
PubMed: 31621656
DOI: 10.4103/aja.aja_113_19 -
International Braz J Urol : Official... 2022
Topics: Epididymis; Humans; Male; Spermatozoa; Vas Deferens
PubMed: 35170898
DOI: 10.1590/S1677-5538.IBJU.2022.9907.1