Reduction of testosterone levels in Schistosoma haematobium- or Schistosoma mansoni-infected men: a cross-sectional study in two schistosomiasis-endemic areas of the Adamawa region of Cameroon

Schistosomiasis is an acute and chronic disease caused by Schistosoma blood flukes. In Cameroon, three species of human schistosomes occur S. haematobium, S. mansoni, and S. guineensis. People are infected while exposed to infested water during routine agricultural, domestic, occupational, and recreational activities. In 2016, the global burden of schistosomiasis was estimated at 2.50 million disability-adjusted life years (DALYs). Schistosomiasis remains a major public health problem, with at least 229 million people worldwide, and almost 90% of them lived in sub-Saharan Africa, requiring preventive chemotherapy in 2018 [1]. In Cameroon, it was estimated that 47% of the population (9,484,894 million) was at risk of schistosomiasis infection and needed preventive treatment in 2010 [2]. The country’s three northern regions, the Far North, North, and Adamawa, are the most affected. Some health districts in the South-West, Littoral, West, and Centre regions showed a high prevalence of infection. Epidemiological data collected in some schools of the Adamawa region in 2006 revealed that 14.2% of the children were infected with at least one schistosome species [3]. The strategy of choice to control schistosomiasis remains preventive chemotherapy with praziquantel. School-aged children are the primary target of these therapeutic interventions since they are the most vulnerable and most affected by the infection [4]. In Cameroon, fishermen, farmers, and irrigation workers are also high-risk groups for schistosome infection, but they are not enrolled in deworming campaigns with praziquantel [3, 5]. Schistosoma-positive adults generally suffer from chronic schistosomiasis with severe consequences such as liver fibrosis, portal hypertension, ascites, calcification of the bladder, kidney failure, and genital dysfunction [2]. Genital schistosomiasis occurs when Schistosoma circulating eggs invade the reproductive tissues of the host. It has been associated with female and male reproductive health problems such as ectopic pregnancies, abortion, low sperm count, coitus pain, vaginal bleeding, genital organ enlargement and infertility [6‐8]. Female genital schistosomiasis (FGS) is well documented, and its prevalence is considerable in S. haematobium endemic areas (33 to 75%) [6, 9‐12]. In contrast to FGS, male genital schistosomiasis (MGS) is underreported, and its burden is underestimated. S. haematobium and S. mansoni are the two species involved in MGS. The main findings reported in patients who have traveled or lived in schistosomiasis endemic areas are swelling of the scrotum and other genital organs, dilatation, and calcification of the prostate and seminal vesicles, haemospermia, hydrocele, changes in semen/ejaculate, infertility, and urethral discharge [7, 13]. Case reports have mentioned the presence of S. haematobium or S. mansoni eggs in male genital organs and semen of some young and adult patients [14‐24]. Variation in the levels of sex hormones was also reported in some male patients with S. haematobium and/or S. mansoni [25‐29].

In Cameroon, investigations on the association of schistosomiasis and the male reproductive tract have drawn no attention from researchers. To the best of our knowledge, this is the first report on male genital schistosomiasis in Cameroon. This study aimed to investigate the impact of infection with S. haematobium or S. mansoni on the reproductive tract of men of reproductive age in Tibati and Wouldé, two endemic schistosomiasis areas in the Adamawa region of Cameroon.

In schistosomiasis endemic areas, people are infected during their routine activities when exposed to contaminated water. In this study, approximately half of the population was exposed to schistosomiasis transmission sites due to their agricultural and fishing activities. Three-quarters of the study population in Wouldé was made up of farmers working in marshy fields around the Wouldé River. The study population in Wouldé was then a high-risk group for schistosomiasis infection [3]. The prevalence of S. haematobium or S. mansoni infection was within the interval of 10–49%, which reflects a moderate occurrence in the study population in Tibati or Wouldé. Despite this moderate endemicity of schistosomiasis, 80% of men with S. haematobium heavy-intensity infection presented visible hematuria. It reflects the increase in egg population in the urothelium and is sometimes linked to bladder and ureteral calcification and renal failure [32].

Among other complications of urogenital schistosomiasis, male reproductive function impairment and even infertility are quite common. S. haematobium is more involved than S. mansoni [33]. The symptoms include epididymitis, haemospermia, pain during urination, prostatitis, dilatation and calcification of seminal vesicles, and testicular inflammation [7, 34, 35]. In the current study, the mean testicular circumference of S. mansoni-positive men was significantly higher than that of S. haematobium-positive men. The increased size of the testes could presumably be the consequence of numerous eggs trapped in that organ or/and the inflammation induced by their presence in the testes. The presence of S. haematobium or S. mansoni ova in the testes has effectively been reported in men living in SCH-endemic areas or tourists who have visited these areas [14, 19, 21‐23, 36]. Schistosoma ova trapped in the testes directly damages the testicular tissue through inflammation and granuloma formation [37], thus impairing testicular steroidogenesis. The testis is an exocrine and endocrine gland that synthesizes and produces testosterone through steroidogenesis in Leydig cells and sperm through spermatogenesis in the seminiferous tubules [38]. When Schistosoma eggs invade the testes, inflammatory cells migrate around eggs and generate granulomatous lesions. Lenzi et al. [39] described the bilharzial granuloma as a structure composed of macrophages, lymphocytes, eosinophils, neutrophils, giant cells, and fibroblasts surrounding schistosome eggs. The modulation of Leydig cell steroidogenesis by macrophages has been demonstrated [40‐42]. Under normal physiological and noninflammatory conditions, testicular interstitial macrophages play an essential role in Leydig cell proliferation and differentiation and stimulate steroidogenic function [40, 41]. When macrophages are activated, they produce inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) that inhibit Leydig cell steroidogenesis and thus testosterone production. They also act as transcriptional repressors of steroidogenic enzyme gene expression [40, 43]. In fact, the exposure of TM3 Leydig cells to the inflammatory cytokines TNF-α, IL-1β, and IL-6 resulted in a decrease in Leydig cell viability and testosterone concentrations [42]. Moreover, the endocrine function of the testis is perturbed by the reactive oxygen species (ROS) generated by macrophages. They impair Leydig cell mitochondria by inhibiting steroidogenic acute regulatory (StAR) protein expression [40]. The significant decrease in testosterone concentration recorded during the current study in S. haematobium-positive men and S. mansoni-positive men could be linked to the inhibition of Leydig cell steroidogenesis by secretory products of granuloma inflammatory cells. In addition, a significant correlation between S. haematobium or S. mansoni infection and reduced testosterone levels was established in our study. Hormonal imbalance in SCH-infected individuals is less reported. Authors have recorded decreased levels of hydroxyprogesterone, testosterone, and dihydrotestosterone in boys and men presenting hepatosplenic schistosomiasis [26‐29]. This was associated with an increased concentration of estradiol, estrone, and estriol [25, 29], suggesting an intense aromatization of androgens to estrogens in SCH-infected persons. Such sex steroid imbalance has delayed puberty in young boys and induced hypogonadism in men [27, 29].

Authors have described hydrocele, testicular atrophy, and nodular scrotum in patients presenting testicular schistosomiasis [21]. Therefore, this study denoted genital tract pathologies in SCH-positive men such as scrotal abnormalities, nodular epididymis, varicocele, hydrocele, and inguinal hernia. Since the prevalence of these pathologies was statistically comparable between SCH-positive and SCH-negative men, it would have become a challenge to establish a correlation between schistosomiasis or reduced testosterone levels and these pathologies. However, the testosterone level of SCH-negative men in this study was similar to that of a control group of men of reproductive age involved in a survey on the effect of agropesticides on the male reproductive function of farmers in a village in the West region of Cameroon [44].

The consequence of testosterone depletion in SCH-positive men in Tibati and Wouldé would be poor semen quality since spermatogenesis relies on the ability of Leydig cells to produce testosterone [38]. Unfortunately, due to traditional and cultural beliefs, it was impossible to conduct semen analysis in this study; the population of our study areas considered masturbation (method of sperm collection) as taboo. However, some authors have reported Schistosoma egg excretion in the semen, low volume of ejaculate, decreased sperm viability, oligoasthenoteratozoospermia, azoospermia, and sperm apoptosis [15‐18, 20, 36, 45‐47]. In addition, leukocytospermia, mainly eosinophilia, and secretion of inflammatory cytokines in the semen were also reported in SCH-positive men [15, 17, 20, 36, 45]. Therefore, a clinical scheme presenting a low testosterone level and/or poor semen quality could presumably be conducted for subfertility or infertility.

This study demonstrated that S. haematobium and S. mansoni infections are associated with reducing the male reproductive hormone testosterone of men of reproductive age living in schistosomiasis endemic areas in Cameroon. The recommendations from this study are that the National Control Programme for Schistosomiasis and Intestinal Helminthiasis in Cameroon should accelerate the extension of schistosomiasis treatment to reach all individuals at risk in communities. In addition, a program of sensitization and surveillance of young people and adults suffering from male genital schistosomiasis should be set up in endemic areas.