The Male Genital Tract

The male genital tract (MGT) is the target of a number of viral infections that can have deleterious consequences at the individual, offspring, and population levels. These consequences include infertility, cancers of male organs, transmission to the embryo/fetal development abnormalities, and sexual dissemination of major viral pathogens such as human immunodeficiency virus (HIV) and hepatitis B virus. Lately, two emerging viruses, Zika and Ebola, have additionally revealed that the human MGT can constitute a reservoir for viruses cleared from peripheral circulation by the immune system, leading to their sexual transmission by cured men. This represents a concern for future epidemics and further underlines the need for a better understanding of the interplay between viruses and the MGT. We review here how viruses, from ancient viruses that integrated the germline during evolution through old viruses (e.g., papillomaviruses originating from Neanderthals) and more modern sexually transmitted infections (e.g., simian zoonotic HIV) to emerging viruses (e.g., Ebola and Zika) take advantage of genital tract colonization for horizontal dissemination, viral persistence, vertical transmission, and endogenization. The MGT immune responses to viruses and the impact of these infections are discussed. We summarize the latest data regarding the sources of viruses in semen and the complex role of this body fluid in sexual transmission. Finally, we introduce key animal findings that are relevant for our understanding of viral infection and persistence in the human MGT and suggest future research directions.

Neuropeptides are secretory peptides characterized by small chains of amino acids linked by peptide bonds. They are majorly found in some mammalian neurons and glial cells, where they modulate a variety of physiological homeostasis. In the male genital tract, they are mostly found in the neuronal fibers supplying the vasculature, smooth muscle layer, interstitium, and lamina propria of the tunica mucosa of the various reproductive organs. Functionally, neuropeptides are strongly implicated in vascular temperature regulations, spermatozoa extrusion, epididymal content transportation, and movement of accessory gland secretions. This review provides an overview of neuropeptides with respect to their synthesis, release, and mechanism of actions, with emphasis on the locally acting neuropeptides, such as substance P (SP), neuropeptide Y (NPY), vasoactive intestinal peptides (VIP), calcitonin gene-related peptide (CGRP), galanin (GAL), cholecystokinin (CCK), C-terminal flanking peptide of NPY (CPON), peptide histidine isoleucine (PHI), and met- and leu-enkephalins (M-ENK and L-ENK) along the male genital tract (i.e., the spermatic cord, testis, epididymis, ductus deferens, and accessory sex organs) of 14 species of mammals and their marked influence on reproduction. This review also revealed from documented reports that the vast majority of neuropeptides present in the autonomic nerve supply to the male genital tract probably coexist with other peptides or with various neurotransmitters (tyrosine hydroxylase, dopamine beta hydroxylase, and 5-hydroxytryptamine). In addition, documented evidence of variation in age, season, and intraspecies differences were identified as notable factors of influence in peptidergic nerve fiber distribution.

Exploring the impact of target cell heterogeneity on HIV loads in a within-host model

Vitronectin is an adhesion protein present within the acrosomal cap region of human spermatozoa and is liberated during the acrosome reaction. The purpose of this study was to determine if vitronectin mRNA was synthesized in the male genital tract using the reverse transcriptase in-situ polymerase chain reaction (PCR) technique. Twelve genital tract tissues, which included six testes, one showing Sertoli cells only and one from a 3 year old boy, as well as sections from the prostate, seminal vesicles, and epididymis, were analysed for vitronectin transcripts. PCR-amplified vitronectin cDNA was detected in the seminiferous tubules of the four adult testes that showed normal spermatogenesis and localized to the spermatocytes and round spermatids. PCR-amplified vitronectin cDNA was not detected in the tissues of the prostate, epididymis, and seminal vesicles from the men whose testes did contain the message, nor in the testes with Sertoli cells only or that of the prepubertal boy. It is concluded that, in the male genital tract, vitronectin is transcribed exclusively in the germ cells at the spermatocyte and round spermatid stages. This demonstrates that the translated protein present in the spermatozoon is being produced in situ. Further study is needed to determine the role of this protein in the dynamics of sperm-oocyte interaction.

Zika virus (ZIKV) is a re-emerging mosquito-transmitted flavivirus associated with congenital abnormalities in newborns and with Guillain-Barré syndrome in adults. The virus can also be sexually transmitted and can persist in the male genital tract. Studies evaluating the kinetics of ZIKV in seminal shedding of men who have been infected, as well as in animal and cellular models of infection, have shown that, in addition to the testis and epididymis, the prostate and seminal vesicles could also be involved in persistent ZIKV infection. Additionally, some studies have reported that men infected with ZIKV can present with genitourinary symptoms such as haematospermia, prostatitis, painful ejaculation, penile discharge, and oligospermia; however, little is known about the effect of ZIKV on fertility. Understanding the mechanisms that underlie persistent ZIKV infections in men is crucial to developing guidelines, effective vaccines, and therapies.

We describe a whole-mount RNA in situ hybridization (ISH) method optimized for detection of the cellular and subcellular distributions of specific mRNA within Drosophila testes and male genital tract. Digoxygenin (dig)-labeled antisense RNA probes are in vitro transcribed from a template synthesized by (RT)-PCR; the probe length is reduced by hydrolysis. Testes and male genital tracts are dissected from adult flies, fixed and processed for hybridization. Both probe and fixed testes can be stored before use. Extensive post-hybridization washing reduces the background. Detection is through alkaline phosphatase-conjugated anti-dig antibodies followed by a color reaction. This protocol is suitable for low-medium throughput applications with parallel processing of 2-48 samples, and takes 4-5 d to complete. We have used this protocol, which is similar to other RNA ISH protocols, but optimized for whole-mount Drosophila testes, to document the expression of about 1,000 genes in Drosophila melanogaster male genital tract.

Occurrence of nerves containing vasoactive intestinal polypeptide immunoreactivity in the male genital tract

Penetration of antiretroviral drugs into anatomical HIV-1 reservoirs such as the male genital tract and the central nervous system is important. Data on indinavir (IDV) concentrations in seminal plasma are lacking and IDV concentrations in cerebrospinal fluid are at best borderline. Thirteen patients were treated with zidovudine (or stavudine), lamivudine, abacavir, nevirapine and IDV (1000 mg three times daily). When nevirapine led to low IDV concentrations, IDV was changed into the combination IDV/ritonavir (RTV) 800/100 mg twice daily to improve the pharmacokinetic profile of IDV. A serum pharmacokinetic profile, a semen sample and a cerebrospinal fluid sample were collected at weeks 8, 24, 48 and 72. Addition of RTV increased the median IDV trough concentration in serum from 65 to 336 ng/ml (P = 0.005). Median IDV concentration in seminal plasma increased from 141 to 1634 ng/ml (P = 0.002) (n = 9) and in cerebrospinal fluid from 39 (n = 12) to 104 (n = 7) ng/ml (P < 0.001). In six patients with samples collected both before and after the addition of RTV, the IDV concentration in seminal plasma increased 8.2 times [95% confidence interval (CI) 5.2-11.6], and in cerebrospinal fluid 2.4 times (95% CI 1.8-3.9). IDV penetrates well into the male genital tract. The addition of low-dose RTV not only increases IDV concentrations in serum but also in seminal plasma and cerebrospinal fluid, thereby probably improving the potency of the regimen in these anatomical HIV reservoirs. Higher serum trough levels alone can not sufficiently explain the observed increases in seminal plasma and cerebrospinal fluid concentrations. Inhibition of P-glycoprotein-mediated transport by RTV might be an additional mechanism.

Orexins A (OXA) and B (OXB) and their specific receptors, receptor 1 (OX1R) and 2 (OX2R) for orexins, are hypothalamic peptides involved in orchestrating several functions in the central nervous system and peripheral organs, including sleep, excitement, nutrition, reward, circadian rhythm, anxiety, cognition, and reproduction. The aim of this narrative review is, in particular, to speculate the role of orexins in the male genital tract of animal species and human beings. The experimental evidence collected in recent years assumed that in the testes of the animal species here described, orexins are directly involved in steroidogenesis and spermatogenesis regulation. In the epididymis, these peptides are locally synthesized, thus suggesting their role governing the fertilizing capability of the immature male gamete. In addition to playing a physiological role, orexins are involved in numerous inflammatory and/or neoplastic pathologies too. The expression of the orexinergic system in prostate cancer suggests that they might play a potential therapeutic function. Overall, the future directions of this literature review allow us to hypothesize a role of the orexinergic complex not only as a marker for the diagnosis of certain tumors affecting the male genital tract but also for the treatment of hypo/infertility condition.

Chapter 8 - The Male Genital Tract

FIGURES 14–18. Sinhomidia bicolor male: 14, trochanteral organ; 15, coxal chaetotaxy legs 1, 2 and 3; 16, dens and mucro (only the spines are figured, not the chaetae neither their insertions), 17, male genital tract, 18, head chaetotaxy. Bar 14 = 25 µm, Bar 15,18 = 50 µm, Bar 16 and 17 = 0.1mm.

European Academy of Andrology Newsletter

Distribution of new human β-defensin genes clustered on chromosome 20 in functionally different segments of epididymis

Leptin, a 167 amino acid peptide, is known to influence the gonads via direct and indirect effects. Recent studies provide contradictory proposition about the peripheral impact of leptin in the male gonads. Thus, we examined leptin and its receptors in human seminal plasma and in human ejaculated spermatozoa by Western blot technique and fluorescence microscopy. In seminal plasma we found a free leptin band (16 kDa) by an anti-leptin polyclonal antibody. Incubation of seminal plasma with recombinant leptin caused a statistically significant increase in the amount of free leptin (p < 0.01) and supports this finding. Furthermore, a soluble leptin receptor (145 kDa) was found in human seminal plasma in the same specimen. We also detected a 145-kDa leptin receptor isoform in ejaculated spermatozoa as a possible target of leptin action in the male genital tract, which was localized at the tail of spermatozoa by immunofluorescence microscopy only. This receptor was significantly associated with the intactness of sperm plasma membranes. Spermatozoa with deteriorated membranes contained 49.2 +/- 6.9% leptin receptor signal intensity compared with spermatozoa having intact membranes (p < 0.01). This finding is difficult to interpret and may be caused by a leakage of OB-R due to loss of membrane integrity. In conclusion, these data provide further hints for a peripheral role of leptin in the male genital tract, possibly, by an interaction between leptin and spermatozoa via sperm leptin receptors.

Impact of pubertal imidacloprid exposure on the genital tract of Japanese quail (Coturnix Coturnix japonica): Histomorphometric and ultrastructural study.