Schistosomiasis: a neglected cause of infertility in females and males.

At least six possible mechanisms may contribute to impaired fertility in people with schistosome infections ( Figure 1 ). Each is described below. Histopathological case reports have documented obstruction of fallopian tubes by schistosome ova with surrounding granulomata in females with infertility [ 21** , 28 , 29 ]. Extensive adhesions between fallopian tubes, adnexa, and other pelvic structures, thought to distort tubal architecture and flexibility, have also been described [ 28 , 30 ]. In a case series of 13 females with infertility in Egypt, two were anovulatory and were found to have schistosome ova in the ovaries, potentially causing physical interference with the follicle’s ability to develop and rupture [ 28 ]. Anovulatory cycles and other menstrual abnormalities may also be caused by dysregulation of the hypothalamic-pituitary-gonadal axis. The production of estrogen-like molecules by schistosome worms has recently been eloquently reviewed [ 31** ]. Estrogen-like metabolites have been identified in S. haematobium worm extracts and appear to be secreted by the parasite [ 32 ]. These metabolites can downregulate human estrogen receptors and potentially interfere with fertility [ 31** , 32 ]. In support of this finding, females with S. haematobium ova in urine had higher urinary levels of estrogen-like metabolites and a four-fold higher odds of self-reported infertility than females without ova in urine [ 33 ]. Females in this study were not queried about their menstrual cycles, nor were male partners identified or studied, making localization of the problem within the fertility pathway difficult. However, S. haematobium infection has been associated with irregular menstruation in other studies [ 34 ], underscoring the plausibility of hypothalamic-pituitary-gonadal hormone dysregulation in infected females. Analogously to females, schistosome ova deposition and granuloma formation in the male genital tract can cause partial or complete obstruction of the seminal vesicles or vas deferens [ 35 , 36 ]. Less commonly, ova deposition in the testicles and prostate can occur, and in these locations has been linked with erectile dysfunction [ 35 ]. Functional changes in semen quality may also contribute to infertility. Several reports have documented associations of schistosome ova in the seminal vesicles and prostate with altered seminal fluid. Examination of semen samples from males with S. haematobium in Madagascar showed higher rates of sperm apoptosis and lower volume of seminal fluid compared to uninfected males [ 37 ]. Seminal fluid from schistosome-infected animals had lower fructose and plasma content, which can negatively affect sperm motility [ 38 ]. Sperm motility and viability can also be reduced by inflammation, as indicated by the presence of debris, neutrophils, and schistosome ova in the ejaculate [ 39 ]. In another case study, sperm in a male infected with S. haematobium were found to have curled tails, affecting the sperm motility [ 39 ]. In males, estrogen-like metabolites secreted by schistosomes, as described above, may be a pretesticular cause of infertility. Elevated estradiol levels can inhibit the hypothalamic-pituitary-gonadal axis, leading to lower secretion of follicle-stimulating hormone, luteinizing hormone, and ultimately lower testosterone levels [ 26 , 38 , 40 ]. Alternatively, immune cells recruited by schistosome ova to granulomas can inhibit the steroidogenesis of Leydig cells in the testes, lowering testosterone [ 38 ]. Male mice with schistosome infection had lower-weight epididymis and seminal vesicles, which was thought to be attributable to the accompanying lower testosterone levels observed in these animals, than uninfected mice [ 38 ]. Some observed lower fertility may be attributable to less frequent sexual contact in individuals with genital schistosome infections. Both males and females with genital schistosomiasis can experience dyspareunia and bleeding. These symptoms can lead to avoidance of intercourse, either by the symptomatic person or by partners who may mistakenly assume that these symptoms indicate a sexually transmitted infection. In support of this possibility, husbands of women with FGS more frequently had children with other women than did husbands of women without FGS [ 41 ]. The vaginal and cervical epithelium plays a critical role in supporting fertilization by facilitating sperm passage, migration, and survival once it enters the female genital tract. Estrogens, secreted both by the parasite and by the infected female [ 42 , 43 ], induce the proliferation of basal epithelial cells in the vagina [ 44 ]. At the molecular level, females with schistosome infection have genital tract gene expression consistent with epithelial compromise, tissue fibrosis, and inflammation [ 45 ]. The downstream impact on local microenvironment with concomitant release of mediator molecules and alarmins remains unreported. Estrogens, moreover, also regulate cervical mucus production. Abnormalities of cervical secretions are believed to be responsible for infertility in about 5–10% of infertile females and could impact the passage of sperm through the cervix [ 46 ]. An increase in cervical mucus production in response to parasites in the genital tract would be plausible as a host defense mechanism, as is known to occur in gastrointestinal worm infection [ 47 ]. Mucus production and composition has not been reported in women with FGS and poses a promising subject for further investigation. Intra-tubal lesions could physically block transit of sperm through fallopian tubes, or of a fertilized egg through the fallopian tube to implant in the uterus. Ectopic pregnancies may result, although the frequency with which lesions block fertilization or conceptus migration is virtually unknown. In Gabon, among 225 ectopic pregnancies that were documented serially over two years, three patients with tubal ectopic pregnancies were found to have S. haematobium ova in tube walls [ 30 ]. Schistosome ova deposition occurs less frequently in the uterus than other genital organs, possibly because tortuous venules in the muscular uterine wall make it difficult for ova to reach the uterus [ 48 ]. Notably, several studies have demonstrated effects of schistosome antigens, which are detectable in systemic circulation, on placental trophoblast cells. In in vitro studies, the addition of schistosome egg antigens to first-trimester human trophoblast cells or to trophoblast cells from healthy placentas of full-term deliveries caused increased secretion of pro-inflammatory cytokines [ 49 , 50 ]. This pro-inflammatory environment at the maternal-placental interface could impair migration and invasion of trophoblast cells during implantation, contributing to early spontaneous abortions and/or impairing fetal growth. Future studies from women with chronic schistosome exposures and infections would enable further understanding of these observations, and are particularly important given the unstudied added effects of local microenvironments, epigenetic reprogramming, and cellular crosstalk and trained immunity [ 51 ].

It is commonly embraced that the immunological response to schistosome infection shifts in parallel to the parasite’s lifecycle. In mice, migrating schistosomulae are reported to evoke a moderate T helper (T H ) 1 inflammatory response, which then switches to a profound T H 2 response at the onset of parasite egg deposition. As the infection transitions into chronicity, the T H 2 response wanes and a regulatory response, marked by expansion of regulatory T cells (Tregs), emerges [ 52 ]. A recent study comparing T cell profiles in controlled human infection with endemic infection, however, suggests a multifaceted mixed T H 1/T H 2 response in the chronic stage [ 53 ]. Further, S. haematobium -infected children with bladder pathology had higher frequencies of circulating T H 17 cells and higher T H 17/Treg ratios than uninfected children and infected children without pathology [ 54* ]. Interleukin (IL)-17, produced by T H 17 cells, impairs sperm motility and viability [ 55 , 56 ], and elevated IL-17 has been directly associated with male infertility [ 57 ]. In females with unexplained infertility, increased T H 17/Treg ratios are likewise observed [ 58 ], though potential mechanisms remain to be established. Decidual Th17 cells can activate decidual NK cells and reduce the vascular reactivity of uterine arteries, resulting in the resorption of the embryo [ 59 ]. After pregnancy is established, elevated peripheral blood T H 1/T H 2 ratios, reflecting a more inflammatory T H 1 profile, may contribute to immunological rejection of embryos and fetuses. This has been observed in other conditions [ 60 , 61 ] but not studied in schistosome infections. Similarly, infertile males as compared to fertile males have also been found to have an overall pro-inflammatory signature in peripheral blood and in semen, together with higher proportions of neutrophils in the semen [ 62* ]. The far-reaching immunogenicity of schistosome infection leads to the expansion of eosinophils, macrophages, and neutrophils, which produce reactive oxygen species that can damage host tissues via oxidative stress [ 63 ]. Oxidative stress has been associated with poor sperm quality [ 64 ] and, in females, with pre-eclampsia, endometriosis, and spontaneous abortions [ 65 ]. Beyond CD4 + T cell populations and neutrophils, almost nothing is known about genital mucosal immune cell populations in schistosome infection. Further, to our knowledge, no study has linked immune cells in schistosome infection with fertility.

The principal pathology of schistosome infections is caused by parasite ova as they migrate through tissue. Ova secrete proteolytic enzymes and provoke formation of granulomata that surround the ova as the host immune system strives to contain tissue damage [ 21** ]. After the ovum dies, the breakdown of the granuloma leads to formation of tissue fibrosis that can impair organ structure and function [ 22 ]. Disease manifestations and effects on fertility vary depending on where ova are found and the burden of ova deposited in tissue, which correlates with intensity of the worm infection [ 23 ]. In females, the organ most frequently affected is the cervix, followed by the vagina, ovaries, uterus, and fallopian tubes [ 23 , 24 ]. Resulting symptoms include hematuria, dysuria, stress incontinence, bleeding during intercourse, dyspareunia, and genital discomfort. In males, the seminal vesicles are most frequently affected, followed by the vas deferens, prostate, testes, and epididymis [ 23 - 25 ]. Symptoms in males may include hematospermia, dysuria, dyspareunia, epididymitis, and prostatitis [ 13 , 26 , 27 ].

Schistosome infection causes genital tract damage and, via multiple local, hormonal, and systemic effects, may contribute to lower fertility in females and males. Impaired fertility has major ramifications on health and social well-being, particularly in some of the same regions where schistosome infections are endemic. Efforts to clarify mechanisms underlying lower fertility in schistosome infections, and to use these data to investigate ways to reverse impacts on fertility through parasite-directed and/or host-directed interventions, are urgently needed.

Infertility, defined by the World Health Organization as the inability to conceive after regular, unprotected intercourse for greater than one year, affects approximately 1 in 6 people of reproductive age [ 1 , 2 ]. Across cultures and genders, the inability to conceive has been associated with depression, anxiety, and psychosocial distress [ 3 ]. Further, inability to bear children is highly stigmatized in many settings, particularly those with strong cultural connections between a woman’s worth with her fertility [ 4 ]. A scoping review in sub-Saharan Africa concluded that being infertile was more stigmatized for women than receiving an HIV diagnosis [ 5 ]. Infections are well-recognized causes of infertility. Bacterial infections including N. gonorrhoeae , C. trachomatis, M. genitalium, and M. tuberculosis may cause scarring and blockage in the upper female reproductive tract, while viruses including HIV and mumps can impair sperm production. An estimated 211 million people contract gonorrhea or chlamydia each year [ 6 ]. Yet schistosome infections, affecting 250 million people annually, are scarcely considered among etiologies of infertility [ 7 ]. Here, we synthesize the growing body of data supporting multiple mechanisms by which parasitic Schistosoma worms may contribute to the global burden of infertility, with effects in both females and males. We will begin by summarizing epidemiologic evidence for and against associations between schistosome infections and infertility. We will then consider each step of the physiologic pathway from ovulation, to spermatogenesis and semen production, to implantation and establishment of a healthy pregnancy. Increasing evidence suggests possible impacts of schistosome infection throughout this pathway. Our goal is to summarize current data and outline areas needing further investigation to understand mechanisms and putative treatment strategies to combat impaired fertility in people living with schistosomiasis.

Schistosomiasis is a disease of poverty, primarily affecting people in rural and underdeveloped urban areas who depend on open surface water sources for work and daily activities [ 7 ]. Parasitic worms residing in the vesical venous plexus lay ova that migrate through mucosal tissue towards the urinary bladder or gastrointestinal tract for excretion in urine or stool and continuation of the parasite life cycle. However, worms also reside in nearby venous plexi surrounding reproductive organs, and ova can become entrapped in these organs. Most commonly, this occurs with S. haematobium infection, but S. mansoni and S. japonicum ova in the genital tract have also been reported [ 8 , 9 ]. Schistosome infections have a range of effects in the human host that include disruption of tissue integrity and local mucosal immune cell populations, interference with the endocrine system, and systemic immune modulation. Among the 250 million people with schistosome infections, the numbers with parasite eggs in genital tissue, known as female and male genital schistosomiasis (FGS and MGS), is unknown due to challenges in diagnosis. It has been estimated that FGS affects at least 40 million women and girls in Africa, with a potentially similar burden of MGS among men and boys [ 10 , 11** ]. Among these millions affected, a small but growing number of studies have investigated associations between schistosome infection and impaired fertility. Positive tests for serum anti-schistosome antibodies, which do not differentiate between active and past infection or between schistosome species, have been linked with infertility in cross-sectional analyses. In Zambia, women who had anti-schistosome antibodies in serum were less likely to be pregnant than those without antibodies [ 12 ]. Among 338 African male migrants to Spain, serum anti-schistosome antibodies were associated with self-reported infertility (odds ratio (OR)=1.69 [interquartile range, 1.0-2.8]) [ 13 ]. Migrants had lived in Spain for a median of 17 years and very few had schistosome ova seen in urine. Together, these two antibody studies suggest that long-term tissue damage by schistosome infections may be a mechanism of infertility that, once established, may persist for years even after exposure to new worm infections ceases. A geographic association between S. haematobium and infertility was shown in a mapping study that used ten-year Demographic and Health Survey data from Ethiopia, Kenya, Tanzania, and Uganda. Higher odds of infertility were seen in women living in areas with high versus low prevalence of S. haematobium , but not in those living in areas with high S. mansoni prevalence [ 14 ]. Two additional studies, from Kenya and Zimbabwe, found higher odds of infertility among women in an S. haematobium endemic area who had not received anti-schistosome praziquantel treatment before age 21 and 20 years compared to those who were treated when young [ 15 , 16 ]. In Zimbabwe, a cross-sectional study of 483 females reported 3.5-fold higher odds of infertility among women with S. haematobium ova present on Papanicolaou smear [ 17 ]. In contrast, a recent cross-sectional study of 265 females in Ghana reported that those with visible characteristic abnormalities on the cervix had a lower odds of infertility (adjusted OR=0.29 [0.17-0.50]) than those without [ 18 ]. Challenges with this study include the low specificity of visual diagnosis for FGS [ 19 , 20 ] and the fact that cervical abnormalities do not necessarily reflect the presence of upper genital tract lesions or of other putative mechanisms of schistosome-induced infertility, including hormonal, immune cell, and genital mucosal alterations, discussed below. Given these strengths and weaknesses and taken together, these observational studies mostly support a potential impairment of fertility by schistosome infection.