Diagnostics and Pharmacology of Male Reproduction

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 15246

Special Issue Editors

Department of Laboratory Diagnostics, Wroclaw Medical University, Borowska Street 211A, 50-556 Wrocław, Poland
Interests: glycobiology; glycoprotein glycosylation; oxidative-antioxidant balance; markers of oxidative stress; diagnostics of male infertility; diagnostics of endometriosis; diagnostics of rheumatoid arthritis; immunochemistry; laboratory diagnostics; metalloproteinases
Teaching and Research Diagnostic Laboratory, Department of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Borowska Street 211A, 50-556 Wrocław, Poland
Interests: male infertility; metabolic disorders; insuline resistance; metabolic syndrome; medical laboratory science

Special Issue Information

Dear Colleagues,

Male infertility is a growing problem, especially among developed countries. Globally, 20–30% of infertility cases are because of the male factor alone. In the face of the growing problem of male infertility, which is reflected in the systematically deteriorating quantitative and qualitative parameters of human sperm in recent years, timely diagnosis and treatment have become particularly important.

Drugs affecting the male reproductive system include androgens (male steroid hormones), anabolic steroids, and drugs that improve penile dysfunction. The aim of the Special Issue "Diagnostics and Pharmacology of Male Reproduction" is a presentation of multidisciplinary manuscripts on a wide range of molecular, genetic, and biochemical aspects of diagnostic and pharmacological male infertility management. Studies focused on two aspects of male infertility—the identification of biomarkers for early and accurate diagnosis as well as factors and mechanisms with the potential to be used as targets for effective pharmacotherapy, including new drugs, methods and procedures of pharmacotherapy—are especially welcome. Updated reviews and research articles with comprehensive theoretical and experimental details are invited. Short communications are also accepted; there is no restriction on the length of the manuscript.

Dr. Ewa Maria Kratz
Dr. Sylwia Płaczkowska
Guest Editors

Manuscript Submission Information

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Keywords

  • male reproductive health
  • diagnostics of male infertility
  • male infertility biomarkers
  • male infertility therapy
  • male contraception
  • sexual dysfunction
  • toxicity

Published Papers (7 papers)

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Research

Jump to: Review

17 pages, 2478 KiB  
Article
Antigen Unmasking Is Required to Clinically Assess Levels and Localisation Patterns of Phospholipase C Zeta in Human Sperm
by Junaid Kashir, Bhavesh V. Mistry, Lujain BuSaleh, Michail Nomikos, Sarah Almuqayyil, Raed Abu-Dawud, Nadya AlYacoub, Hamdan Hamdan, Saad AlHassan, F. Anthony Lai, Abdullah M. Assiri and Serdar Coskun
Pharmaceuticals 2023, 16(2), 198; https://doi.org/10.3390/ph16020198 - 28 Jan 2023
Cited by 3 | Viewed by 1466
Abstract
Mammalian oocyte activation is initiated by intracellular calcium (Ca2+) oscillations, driven by the testis-specific phospholipase C zeta (PLCζ). Sperm PLCζ analysis represents a diagnostic measure of sperm fertilisation capacity. The application of antigen unmasking/retrieval (AUM) generally enhanced the visualisation efficacy of [...] Read more.
Mammalian oocyte activation is initiated by intracellular calcium (Ca2+) oscillations, driven by the testis-specific phospholipase C zeta (PLCζ). Sperm PLCζ analysis represents a diagnostic measure of sperm fertilisation capacity. The application of antigen unmasking/retrieval (AUM) generally enhanced the visualisation efficacy of PLCζ in mammalian sperm, but differentially affected the PLCζ profiles in sperm from different human males. It is unclear whether AUM affects the diagnosis of PLCζ in human sperm. Herein, we examined whether the application of AUM affected the correlation of PLCζ profiles with sperm parameters and fertilisation capacity. PLCζ fluorescence levels and localisation patterns were examined within the sperm of males undergoing fertility treatment (55 patients aged 29–53) using immunofluorescence in the absence/presence of AUM. The changes in PLCζ profiles following AUM were examined in relation to sperm health and fertilisation outcome. AUM enhanced the observable levels and specific localisation patterns of PLCζ in relation to both optimal sperm parameters and fertilisation outcome, without which significant differences were not observed. The extent of the change in levels and localisation ratios of PLCζ was also affected to a larger degree in terms of the optimal parameters of sperm fertility and fertilisation capacity by AUM. Collectively, AUM was essential to accurately assesses PLCζ in human sperm in both scientific and clinical contexts. Full article
(This article belongs to the Special Issue Diagnostics and Pharmacology of Male Reproduction)
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12 pages, 2834 KiB  
Article
Established Immortalized Cavernous Endothelial Cells Improve Erectile Dysfunction in Rats with Cavernous Nerve Injury
by Sang Hong Bak, Jae Heon Kim, Seung U. Kim, Dong-Seok Lee, Yun Seob Song and Hong J. Lee
Pharmaceuticals 2023, 16(1), 123; https://doi.org/10.3390/ph16010123 - 13 Jan 2023
Viewed by 2092
Abstract
The main cause of erectile dysfunction (ED) is the damage in penile cavernous endothelial cells (EC). Murine primary ECs have a limited growth potential, and the easy availability of murine ECs will facilitate the study of cavernous endothelial dysfunction in rats. This study [...] Read more.
The main cause of erectile dysfunction (ED) is the damage in penile cavernous endothelial cells (EC). Murine primary ECs have a limited growth potential, and the easy availability of murine ECs will facilitate the study of cavernous endothelial dysfunction in rats. This study was performed to establish immortalized rat penile cavernous ECs (rEC) and investigate how they could repair erectile dysfunction in rats with cavernous nerve injury (CNI). rEC was isolated enzymatically by collagenase digestion and were cultured. An amphotropic replication-incompetent retroviral vector encoding v-myc oncogene was used to transfect rEC for immortalization (vREC). Morphological and immunohistochemical properties of vREC were examined. Eight-week-old male Sprague-Dawley rats were divided into three groups of five rats each, including group 1 = sham operation, group 2 = bilateral CN injury, group 3 = vREC (1 × 106 cells) treatment after CNI. Erectile response was assessed at 2, 4 weeks after transplantation of vREC., Penile tissue were harvested at 4 weeks after transplantation and immune–histochemical examination was performed. vREC showed the expression of CD31, vWF, cell type-specific markers for EC by RT-PCR and flowcytometry. At 2, 4 weeks after transplantation, rats with CNI had significantly lower erectile function than control group (p < 0.05). The group transplanted with vREC showed higher erectile function than the group without vRECs (p < 0.05). vREC was established and repaired erectile dysfunction in rats with CNI. This cell line may be useful for studying mechanisms and drug screening of erectile dysfunction of rats. Full article
(This article belongs to the Special Issue Diagnostics and Pharmacology of Male Reproduction)
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19 pages, 3970 KiB  
Article
Topiramate Reprofiling for the Attenuation of Cadmium-Induced Testicular Impairment in Rats: Role of NLRP3 Inflammasome and AMPK/mTOR-Linked Autophagy
by Hany H. Arab, Hayat A. Abd El Aal, Shuruq E. Alsufyani, Azza A. K. El-Sheikh, El-Shaimaa A. Arafa, Ahmed M. Ashour, Ahmed M. Kabel and Ahmed H. Eid
Pharmaceuticals 2022, 15(11), 1402; https://doi.org/10.3390/ph15111402 - 14 Nov 2022
Cited by 6 | Viewed by 1954
Abstract
Topiramate, a promising drug classically used for the management of neurological disorders including epilepsy and migraine, has demonstrated marked anti-inflammatory and anti-apoptotic actions in murine models of cardiac post-infarction inflammation, wound healing, and gastric/intestinal injury. However, its potential impact on cadmium-induced testicular injury [...] Read more.
Topiramate, a promising drug classically used for the management of neurological disorders including epilepsy and migraine, has demonstrated marked anti-inflammatory and anti-apoptotic actions in murine models of cardiac post-infarction inflammation, wound healing, and gastric/intestinal injury. However, its potential impact on cadmium-induced testicular injury remains to be elucidated. Herein, the present study aimed to explore the effect of topiramate against cadmium-invoked testicular impairment with emphasis on the molecular mechanisms linked to inflammation, apoptosis, and autophagy. Herein, administration of topiramate (50 mg/kg/day, by gavage) continued for 60 days and the testes were examined by histology, immunohistochemistry, and biochemical assays. The present data demonstrated that serum testosterone, sperm count/abnormalities, relative testicular weight, and histopathological aberrations were improved by topiramate administration to cadmium-intoxicated rats. The rescue of testicular dysfunction was driven by multi-pronged mechanisms including suppression of NLRP3/caspase-1/IL-1β cascade, which was evidenced by dampened caspase-1 activity, lowered IL-1β/IL-18 production, and decreased nuclear levels of activated NF-κBp65. Moreover, curbing testicular apoptosis was seen by lowered Bax expression, decreased caspase-3 activity, and upregulation of Bcl-2. In tandem, testicular autophagy was activated as seen by diminished p62 SQSTM1 accumulation alongside Beclin-1 upregulation. Autophagy activation was associated with AMPK/mTOR pathway stimulation demonstrated by decreased mTOR (Ser2448) phosphorylation and increased AMPK (Ser487) phosphorylation. In conclusion, combating inflammation/apoptosis and enhancing autophagic events by topiramate were engaged in ameliorating cadmium-induced testicular impairment. Full article
(This article belongs to the Special Issue Diagnostics and Pharmacology of Male Reproduction)
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23 pages, 4723 KiB  
Article
Repositioning Linagliptin for the Mitigation of Cadmium-Induced Testicular Dysfunction in Rats: Targeting HMGB1/TLR4/NLRP3 Axis and Autophagy
by Hany H. Arab, Alzahraa A. Elhemiely, Azza A. K. El-Sheikh, Hana J. Al Khabbaz, El-Shaimaa A. Arafa, Ahmed M. Ashour, Ahmed M. Kabel and Ahmed H. Eid
Pharmaceuticals 2022, 15(7), 852; https://doi.org/10.3390/ph15070852 - 11 Jul 2022
Cited by 7 | Viewed by 2429
Abstract
Cadmium, a ubiquitous environmental toxicant, disrupts testicular function and fertility. The dipeptidyl peptidase-4 inhibitor linagliptin has shown pronounced anti-inflammatory and anti-apoptotic features; however, its effects against cadmium-evoked testicular impairment have not been examined. Herein, the present study investigated targeting inflammation, apoptosis, and autophagy [...] Read more.
Cadmium, a ubiquitous environmental toxicant, disrupts testicular function and fertility. The dipeptidyl peptidase-4 inhibitor linagliptin has shown pronounced anti-inflammatory and anti-apoptotic features; however, its effects against cadmium-evoked testicular impairment have not been examined. Herein, the present study investigated targeting inflammation, apoptosis, and autophagy by linagliptin for potential modulation of cadmium-induced testicular dysfunction in rats. After 60 days of cadmium chloride administration (5 mg/kg/day, by gavage), testes, epididymis, and blood were collected for analysis. The present findings revealed that linagliptin improved the histopathological lesions, including spermatogenesis impairment and germ cell loss. Moreover, it improved sperm count/motility and serum testosterone. The favorable effects of linagliptin were mediated by curbing testicular inflammation seen by dampening of HMGB1/TLR4 pathway and associated lowering of nuclear NF-κBp65. In tandem, linagliptin suppressed the activation of NLRP3 inflammasome/caspase 1 axis with consequent lowering of the pro-inflammatory IL-1β and IL-18. Jointly, linagliptin attenuated testicular apoptotic responses seen by Bax downregulation, Bcl-2 upregulation, and suppressed caspase 3 activity. With respect to autophagy, linagliptin enhanced the testicular autophagy flux seen by lowered accumulation of p62 SQSTM1 alongside upregulation of Beclin 1. The observed autophagy stimulation was associated with elevated AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation, indicating AMPK/mTOR pathway activation. In conclusion, inhibition of testicular HMGB1/TLR4/NLRP3 pro-inflammatory axis and apoptosis alongside stimulation of autophagy were implicated in the favorable actions of linagliptin against cadmium-triggered testicular impairment. Full article
(This article belongs to the Special Issue Diagnostics and Pharmacology of Male Reproduction)
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Review

Jump to: Research

13 pages, 595 KiB  
Review
Extra-Gonadal and Non-Canonical Effects of FSH in Males
by Matteo Spaziani, Francesco Carlomagno, Marta Tenuta, Franz Sesti, Francesco Angelini, Ilaria Bonaventura, Davide Ferrari, Chiara Tarantino, Marco Fiore, Carla Petrella, Luigi Tarani, Daniele Gianfrilli and Carlotta Pozza
Pharmaceuticals 2023, 16(6), 813; https://doi.org/10.3390/ph16060813 - 30 May 2023
Cited by 1 | Viewed by 2442
Abstract
Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which [...] Read more.
Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which confers specificity of biological action by interacting with its surface receptor (FSHR), predominantly located in granulosa and Sertoli cells. However, FSHRs also exist in extra-gonadal tissues, indicating potential effects beyond male fertility. Emerging evidence suggests that FSH may have extra-gonadal effects, including on bone metabolism, where it appears to stimulate bone resorption by binding to specific receptors on osteoclasts. Additionally, higher FSH levels have been associated with worse metabolic and cardiovascular outcomes, suggesting a possible impact on the cardiovascular system. FSH has also been implicated in immune response modulation, as FSHRs are expressed on immune cells and may influence inflammatory response. Furthermore, there is growing interest in the role of FSH in prostate cancer progression. This paper aims to provide a comprehensive analysis of the literature on the extra-gonadal effects of FSH in men, with a focus on the often-conflicting results reported in this field. Despite the contradictory findings, the potential for future development in this area is substantial, and further research is needed to elucidate the mechanisms underlying these effects and their clinical implications. Full article
(This article belongs to the Special Issue Diagnostics and Pharmacology of Male Reproduction)
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24 pages, 15027 KiB  
Review
PUFAs and Their Derivatives as Emerging Players in Diagnostics and Treatment of Male Fertility Disorders
by Kamil Rodak and Ewa Maria Kratz
Pharmaceuticals 2023, 16(5), 723; https://doi.org/10.3390/ph16050723 - 10 May 2023
Cited by 2 | Viewed by 1911
Abstract
About 15% of couples worldwide are affected by infertility, with the male factor responsible for approximately 50% of reproductive failures. Male fertility can be influenced by various factors, including an unhealthy lifestyle and diet, often associated with oxidative stress. These changes are frequently [...] Read more.
About 15% of couples worldwide are affected by infertility, with the male factor responsible for approximately 50% of reproductive failures. Male fertility can be influenced by various factors, including an unhealthy lifestyle and diet, often associated with oxidative stress. These changes are frequently the reason for spermatozoan dysfunction, malformations, and lowered count. However, sometimes even with proper semen parameters, fertilization does not occur, and this is referred to as idiopathic infertility. Of particular importance may be molecules contained in the spermatozoan membrane or seminal plasma, such as polyunsaturated fatty acids, including omega-3 (docosahexaenoic and eicosapentaenoic acids) and omega-6 (arachidonic acid) fatty acids and their derivatives (prostaglandins, leukotrienes, thromboxanes, endocannabinoids, isoprostanes), which are vulnerable to the effects of oxidative stress. In the present review, we discuss the influence of these molecules on human male reproductive health and its possible causes, including disrupted oxidative–antioxidative balance. The review also discusses the potential use of these molecules in the diagnostics and treatment of male infertility, with a particular focus on the innovative approach to isoprostanes as biomarkers for male infertility. Given the high occurrence of idiopathic male infertility, there is a need to explore new solutions for the diagnosis and treatment of this condition. Full article
(This article belongs to the Special Issue Diagnostics and Pharmacology of Male Reproduction)
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25 pages, 1284 KiB  
Review
The Therapeutic and Diagnostic Potential of Phospholipase C Zeta, Oocyte Activation, and Calcium in Treating Human Infertility
by Haia M. R. Abdulsamad, Zoha F. Murtaza, Hessa M. AlMuhairi, Wjdan S. Bafleh, Salma A. AlMansoori, Shaikha A. AlQubaisi, Hamdan Hamdan and Junaid Kashir
Pharmaceuticals 2023, 16(3), 441; https://doi.org/10.3390/ph16030441 - 15 Mar 2023
Cited by 3 | Viewed by 2225
Abstract
Oocyte activation, a fundamental event during mammalian fertilisation, is initiated by concerted intracellular patterns of calcium (Ca2+) release, termed Ca2+ oscillations, predominantly driven by testis-specific phospholipase C zeta (PLCζ). Ca2+ exerts a pivotal role in not just regulating oocyte [...] Read more.
Oocyte activation, a fundamental event during mammalian fertilisation, is initiated by concerted intracellular patterns of calcium (Ca2+) release, termed Ca2+ oscillations, predominantly driven by testis-specific phospholipase C zeta (PLCζ). Ca2+ exerts a pivotal role in not just regulating oocyte activation and driving fertilisation, but also in influencing the quality of embryogenesis. In humans, a failure of Ca2+ release, or defects in related mechanisms, have been reported to result in infertility. Furthermore, mutations in the PLCζ gene and abnormalities in sperm PLCζ protein and RNA, have been strongly associated with forms of male infertility where oocyte activation is deficient. Concurrently, specific patterns and profiles of PLCζ in human sperm have been linked to parameters of semen quality, suggesting the potential for PLCζ as a powerful target for both therapeutics and diagnostics of human fertility. However, further to PLCζ and given the strong role played by Ca2+ in fertilisation, targets down- and up-stream of this process may also present a significantly similar level of promise. Herein, we systematically summarise recent advancements and controversies in the field to update expanding clinical associations between Ca2+-release, PLCζ, oocyte activation and human fertility. We discuss how such associations may potentially underlie defective embryogenesis and recurrent implantation failure following fertility treatments, alongside potential diagnostic and therapeutic avenues presented by oocyte activation for the diagnosis and treatment of human infertility. Full article
(This article belongs to the Special Issue Diagnostics and Pharmacology of Male Reproduction)
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