The ageing male reproductive tract

Ageing of the male reproductive system is characterized by changes in the endocrine system, hypogonadism, erectile dysfunction and proliferative disorders of the prostate gland. Stochastic damage accumulating within ageing leads to progressive dysregulation at each level of the hypothalamic-pituitary-gonadal (HPG) axis and in local auto/paracrine interactions, thereby inducing morphological changes in reproductive target organs, such as the prostate, testis and penis. Despite age-related changes in the HPG axis, endocrine functions are generally sufficient to maintain fertility in elderly men. Ageing of the male reproductive system can give rise to clinically relevant manifestations, such as benign prostatic hyperplasia (BPH), prostate cancer (PCa) and erectile dysfunction (ED). In this review, we discuss morphological/histological changes occurring in these organs and current views and concepts of the underlying pathology. Moreover, we emphasize the molecular/cellular pathways leading to reduced testicular/penile function and proliferative disorders of the prostate gland.     

Besnoitiosis of the reproductive tract of male goats

Because of high morbidity of caprine besnoitiosis in different provinces of Iran and its significant adverse economic impact on goat production in this area, this study was undertaken to study the macroscopic and microscopic changes of the scrotum, testis, and epididymis of animals at different age groups associated with Besnoitia spp. The testicles, epididymides, and scrotums of 106 male goats slaughtered at Shiraz slaughterhouse from different surrounding villages at different time intervals were randomly selected for pathological studies. From 106 examined goats of different age groups, 20 (18.9%) were infected with Besnoitia cysts. Grossly, most of the infected testicles showed mild to extensive mineralization on the surface of their longitudinal incision. While goats less than 1 year old showed no sign of infection, the prevalence of the infection increased with the age of the animals. The head of the epididymis showed the highest rate of infection, and it was followed by the scrotum, testis, and tail of the epididymis. Some of the infected epididymides and testicles also showed mild to severe tubular degeneration, necrosis, fibrosis, mineralization, sperm retention, sperm granuloma, chronic interstitial orchitis, and epididymitis. Granulomatous reactions were also found around the degenerating cysts. Cysts were localized in the tunica albugina and tunica vaginalis too. The lumina of some of the blood vessels in the epididymis and testis were partially or completely occluded by the Besnoitia cysts. Spermatogenic activity was retarded relevant to the rate of infection of the testicles. The scrotums showed mild to severe besnoitiosis, and the cysts were mainly localized in the superficial regions of their dermis and to some extent in the deep dermis. It seems that besnoitiosis is a serious problem in this area and not only has an impact on economical loss in the skin and leather industries but it also could have an adverse effect on spermatogenesis in male goats and indirectly affect goat production.     

Follistatin and activin A in extra-embryonic coelomic and amniotic fluids and maternal serum in early pregnancy

Follistatin is a specific binding protein which controls bioavailability of activins and inhibins which have an important role in fetal development. In the first trimester of pregnancy bioactive dimeric inhibins are found at high concentrations in the extra- embryonic coelomic fluid, but the distribution of follistatin and activins is not known. We have used recently developed immunoassays for follistatin, activin A and activin AB to determine their presence in the intrauterine compartments during early pregnancy. Follistatin was present in highest concentrations in the extra-embryonic coelomic fluid (11.72 +/- 1.70 ng/ml; median +/- SEM), with less in maternal serum (6.35 +/- 4.58) and lowest amounts in amniotic fluid (0.97 +/- 0.52). Follistatin concentrations in extra-embryonic coelomic fluid were highly correlated with both dimeric inhibin isoforms. Activin A was present in only barely detectable amounts in some samples of extra- embryonic coelomic fluid (41% of samples) and maternal serum (26%) and was undetectable in all amniotic fluid samples. Activin AB was undetectable in all compartments. The presence of follistatin in the amniotic and extra-embryonic coelomic fluids may regulate the availability of bioactive activins and inhibins which are released into the intrauterine compartments during the development of the fetus and placenta in early pregnancy.      

Follistatin is a candidate endogenous negative regulator of activin A in experimental allergic asthma

BACKGROUND: Activin A is a member of the transforming growth factor-beta superfamily which is directly implicated in airway structural change and inflammation in asthma. In vitro, the biological effects of activin A are neutralized by the soluble binding protein follistatin. OBJECTIVE: To determine the potential of endogenous follistatin to suppress activin A in vivo by analysing their relative tissue and kinetic compartmentalization during the effector phase of subchronic Th2-driven mucosal inflammation in a murine model of allergic asthma. METHODS: Eosinophilic mucosal inflammation was elicited by triggering Th2 recall responses by antigen challenge in ovalbumin-sensitized BALB/c mice. The kinetics and distribution of activin A and follistatin protein were assessed in lung tissue and bronchoalveolar lavage fluid and measured in relation to airway eosinophilia, goblet cell metaplasia and Th2 cytokine production in mediastinal lymph nodes. RESULTS: Follistatin was released concurrently with activin A suggesting it acts as an endogenous regulator: peak BAL concentrations coincided with maximal airway eosinophilia, and frequency of IL-4, IL-5 and IL-13 producing cells in mediastinal lymph nodes but induction lagged behind the onset of inflammation. Follistatin and activin A immunoreactivity were lost in airway epithelial cells in parallel with goblet cell metaplasia. Exogenous follistatin inhibited the allergen-specific Th2 immune response in mediastinal lymph nodes and mucus production in the lung. CONCLUSION: Follistatin is preformed in the normal lung and released in concert with activin A suggesting it serves as an endogenous regulator. Disturbance of the fine balance between activin A and its endogenous inhibitor follistatin may be a determinant of the severity of allergic inflammation or tissue phenotypic shift in asthma.     

Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome.

BACKGROUND: Activin promotes ovarian follicular development, inhibits androgen production and increases FSH and insulin secretion. Follistatin, an activin-binding protein, neutralizes activin bioactivity. Therefore, a decrease in the ratio of activin/follistatin might encourage characteristic features of polycystic ovary syndrome (PCOS). We investigated whether women with PCOS showed disordered follistatin and/or activin serum concentrations. METHODS: The study group included 24 obese and 20 non-obese (body mass index vertical line and <27 kg/m2 respectively) clomiphene-failure PCOS patients. The control group included 16 obese and 46 non-obese patients with normal ovulatory cycles. Blood samples were obtained from the patients on day 3-5 of a progesterone-induced or spontaneous cycle and were assayed for LH, FSH, testosterone, 17-hydroxy-progesterone, androstenedione, follistatin, activin A, fasting glucose and insulin. RESULTS: Follistatin concentrations were comparable between obese and non-obese PCOS patients (mean +/- SE; 1171 +/- 103 and 1045 +/- 159 pg/ml respectively) and significantly higher than their respective controls (628 +/- 61 and 592 +/- 49 pg/ml, P < 0.0001 and P < 0.02 respectively). Activin A concentrations were comparable between the four groups (590 +/- 35, 513 +/- 74, 661 +/- 87 and 595 +/- 43 pg/ml in obese and non-obese PCOS and controls respectively). Stepwise regression analyses for relationships between follistatin or activin A levels and all other variables indicated that follistatin was significantly and independently positively affected by PCOS (P < 0.0001), age (P < 0.02), androstenedione (P < 0.03) and weight (P < 0.05). Activin A was significantly and independently negatively affected by PCOS (P < 0.003) and FSH (P < 0.03), and positively affected by weight (P < 0.009) and androstenedione (P < 0.02). CONCLUSIONS: Serum follistatin is increased in PCOS patients, regardless of obesity. PCOS is the most significant variable that relates to high follistatin and low activin A serum concentration. A high follistatin/activin ratio could well contribute to the pathophysiology of PCOS.     

Biology of the male reproductive tract: its cellular and morphological considerations

For many years, the focus of attention in the study of semen has been on spermatozoa, its major cellular component, given their importance in the process of reproduction, and the role of the seminal fluid as their transport medium. More recently, evidence has accumulated of the complexity of seminal fluid, its components that perturb the female reproductive tract in ways promoting both survival of spermatozoa there-in and facilitating the implantation of embryos within the endometrium, hence initiating pregnancy. These same factors, however, may also make the female reproductive tract susceptible to invasion not only by spermatozoa but viruses, playing a significant role in the male-to-female transmission of HIV. Knowledge of the histology, anatomy, and immunology of the male reproductive tract is essential in understanding its role in HIV pathogenesis.     

The role of dendritic cells in male reproductive tract

Dendritic cells (DCs) are the most potent professional antigen‐presenting cells. The central role of various DC subsets as bridges between innate and adaptive immunity has become more and more evident. However, the role of DC subsets in male reproductive tract remains largely unexplored, in particular distinct DC subsets (including myeloid and plasmacytoid DCs), their maturation stage, and tissue distribution, as well as state of health or disease. Furthermore, infection and inflammation of male genital tract are thought to be a primary etiological factor of male infertility. This review sheds some light on this complex and rapidly growing field. It summarized the recent findings and deals with the characterization and role of DCs in male reproductive tract, that is, testis, epididymis, prostate, seminal vesicle, semen, and foreskin, which might help to understand the immunopathological mechanisms of male infertility and design effective vaccines for male reproductive health.     

Antimicrobial responses in the male reproductive tract of lipopolysaccharide challenged rats

Citation
Biswas B, Yenugu S. Antimicrobial responses in the male reproductive tract of lipopolysaccharide challenged rats. Am J Reprod Immunol 2011; 65: 557–568 Problem Innate immune machinery including the Toll‐like receptors (TLRs) confers the first line of defense mechanisms to counter pathogenic microorganisms that enter the body. The male reproductive tract is vulnerable to infection and the role of TLRs and the antimicrobial responses that operate to counter infections in this organ system are poorly understood. Method of Study Caput and cauda epididymides, testes and seminal vesicles were collected at 0, 3, 6, 9, 12, 15 and 24 h from rats injected intraperitoneally with a single dose of LPS. Plasma testosterone was measured using ELISA. Expression pattern of defensins and Spag11 isoforms were analysed using RT‐PCR. Immunohistochemical analyses was performed to determine SPAG11E protein expression following LPS treatment. Results We provide the first line of evidence that the male reproductive tract induces the expression of Sperm Associated Antigen 11 (Spag11) mRNA variants and defensins when challenged with lipopolysaccharide (LPS) with a concomitant increase in protein expression. However, there was an inverse relationship between induction of antimicrobial gene expression and plasma testosterone. An increase in the mRNA levels of proinflammatory cytokines was observed parallel to the induction of Spag11 variants and majority of defensin expression in the male reproductive tract. Conclusion The increase in Spag11 and defensin mRNA in response to LPS administration demonstrates their importance in protecting the male reproductive tract during infection. Results of this study help to understand male reproductive tract innate immune defense mechanisms and to design novel peptide antibiotics to prevent sexually transmitted diseases.     

Sperm maturation in the male reproductive tract: Development of motility

Rabbit spermatozoa were removed from various levels of the male reproductive tract. They were examined in Hanks' solution at room temperature with a phase contrast microscope and their motility characteristics were recorded cinematographically. Spermatozoa from the seminiferous tubules and ductuli efferentes show weak, vibratory movements with no forward progress. Little change in motility occurs until the sperm reach the flexure of the caput epididymidis where some are capable of moving more vigorously in a circular fashion. Samples from the distal caput epididymidis show a sudden increase in sperm activity and a consistent pattern of tight, circular movement. As the sperm traverse the corpus epididymidis, increasing numbers show progressive, forward movement with longitudinal rotation. The proportion of such sperm becomes significant only in samples from the upper cauda epididymidis and more distal regions. Sperm from the ductus deferens rarely retain the circular movement. It is concluded that rabbit spermatozoa undergo a distinct sequence of changes in their swimming movements as they mature in the epididymis. A similar change was noted in epididymal spermatozoa from the rat and guinea pig suggesting that this process is fundamental to sperm maturation in several species.     

Functional significance of white blood cells in the male and female reproductive tract

The functional significance of white blood cells in the modulation of an anti-sperm antibody response, prevention of infection (including HIV) sperm transport/storage and sperm function is extensively discussed. A critical review of the existing literature is presented with future experimental lines of investigation outlined. A lack of controlled clinical studies in the human to validate data from animal species--for example--the involvement of white blood cells in the transport and storage of sperm in the female tract and the possible adverse effect of pathology (i.e. endometriosis) on these functions are presented. In conclusion, with the advent of modern techniques, e.g. monoclonal antibodies and sophisticated sperm function tests, many of the questions raised should be answered in the near future.     

Hyperplastic and metaplastic lesions in the reproductive tract of male rats induced by neonatal treatment with diethylstilbestrol

Summary Newborn male Wistar rats were castrated on the day of birth (=day 1) and treated daily with diethylstilbestrol (DES) from days 1 to 30; 1 g for the first 10 days of life, 2 g for the next 10 days and 4 g for the last 10 days. The animals were autopsied at 30, 90 and 270 days of age. The epithelium of the coagulating glands (CGs) and ejaculatory ducts (EDs) underwent metaplastic transformation in all DES-treated rats. These pathological changes were more marked with age. The most striking changes were found in the periurethral regions of the CGs and EDs and associated regions of the dorsal urethral wall. The normal transitional epithelial lining almost disappeared and large papillary epithelial outgrowths occurred near the opening of the EDs and CGs. This type of neoplastic change was most marked in the group of rats sacrificed at 9 months of age.     

Hypothesis: epididymis inhibits sperm motility inside male reproductive tract

Epididymis (ES) inhibits the total activities of spermatozoa (SA) in male reproductive tract. It keeps SA motionless throughout the length of system by its inhibitory factors (IFs), which are nullified by the secretary products of other glands after formation of semen externally.     

Effects of dietary isoflavone aglycones on the reproductive tract of male and female mice

We assessed the effects of dietary consumption of soy isoflavone aglycones on the reproductive tract of sexually mature male and female mice. Isoflavone concentrates with a ratio of 10:1, 2:1 or 1:10 genistein:daidzein (G:D) were added to provide 120 mg total isoflavones/1800 Calories (approximately 40 mg/kg body weight) to diets having either casein/lactalbumin or soy protein isolate as the source of protein. After 16 weeks, mice were necropsied and gross and histopathologic assessments of uterus, vagina, testes and accessory sex glands were completed. Effects of the 10G:1D isoflavone concentrates were absent or minimal in females but in males included atrophy of accessory sex glands. In contrast, the 2G:1D and 1G:10D concentrates caused dramatic estrogenic effects in both male and female mice. Effects in females included endometritis and effects typical of estrogenic stimulation (i.e., uterine enlargement, keratinization of vaginal epithelium, increased height of endometrial surface epithelial cells, and uterine squamous metaplasia). Effects in males included reduced plasma testosterone concentrations, atrophy of seminiferous epithelium, atrophy of accessory sex glands, and squamous metaplasia of seminal vesicles. Some effects varied with protein source. We conclude that a diet containing approximately 40 mg/kg soy isoflavone aglycones with a genistein:daidzein ratio of 2:1 or less has marked estrogenic effects on the reproductive system of male and female mice.