Under the epithelial cover of the penis and prepuce, there are many immune system cells, including macrophages, NK cells, dendritic cells, neutrophils, CD4+ T cells (most subsets, such as Th1, Th17, pTreg, effector CD4+ T cells), CD8+ T cells, γδT cells, etc., which take part in immune processes (see Figure 1). A composition of lymphocytes allows them the development of almost all possible immune processes, including immune inflammation, and many forms of programmed cell death or tolerance. The cells function here and may migrate to the draining inguinal lymph nodes [10]. The penis is innervated by the dorsal nerve, pudendal nerve, and cavernous nerve, and as for females, neuritis of N. pudendis can become a serious problem for a male person [11].

Male testes serve as the spermatogenesis place [2, 3, 13], whereas epididymis is an intermediate point of remodeling [14, 15] on the path of spermatozoa from the testes to fertilization places in the female reproductive tract. All along this long path, spermatozoa must not be attacked by the defensive molecules of the male immune system, and after that, by the more aggressive factors of the female immune system. However, all the time both immune systems have to perform their main function to kill external microbial invaders, their own reactivated opportunistic germs, and newly appearing cancerous cells. Therefore, tests and epididymis are related to autotolerance zones where most autoantigens ontogenetically unfamiliar to the immune system (“sequestrated antigens”) should not be recognized and adaptive immune responses should not be directed against them with the formation of effector autoantibodies, autoreactive CD8+ and CD4+ T cells and lifelong memory cells [16]. This would be a pathway to persistent autoimmune inflammation and infertility. The structure of the epididymis is very complex and is characterized by the presence of at least two distinct sections, the caput and cauda [14, 17]. Such a gateway system is probably a kind of additional guarantee for maintaining self-tolerance. In general, the processes occurring in the epididymis correspond to the classical patterns of natural immunity, adaptive immune responses, and self-tolerance [18]. The end result, fertility or infertility, depends on a balance of all processes, which is most often disturbed by infection.

There is a difference in how the male and female immune systems function. In males, a weaker containment of external infections often falls short of the logical end result—the destruction of pathogens and complete clearance of the body from infection. In women, as a rule, the maximum containment of the pathogen by the forces of innate immunity and invader elimination by effectors of adaptive immune responses. However, women more often develop autoimmune disorders as another extreme of the functioning of the immune system. This transcriptional sexual dimorphism can be explained by many reasons: from genetic (for example, the presence of two X chromosomes) to the strongest influence of estrogens in contrast to androgens [19, 20].

The foreskin and glans penis are not only a source of sexual pleasure but also the first to meet new microbiota, including hostile microbiota, and other human bodies as sexual partners. Evolution would have to endow them with strong protective properties to withstand danger whenever detected. Areas of the penis and the outer foreskin successfully cope with this task by being covered with a keratinized stratified squamous epithelium with its ancient protective keratinization mechanism. However, the inner leaf with the slowly keratinizing epithelium is essentially the “Achilles’ heel” of the male body, because it contains many receptors for such dangerous viruses as HIV and human papillomavirus (HPV), allowing them to enter deep into the tissue of the foreskin and transfer to another person. The presence of such receptors as CD4, CCR5, CXCR4, L1/L2 receptors [21], and EGFR [22, 23] promotes viral acquisition by penile tissues, which has lately been convincingly demonstrated [22, 23]. Male circumcision is a medical procedure, which is scientifically indisputably preventive in terms of reducing the spread of HIV and other sexually transmitted infections, as well as the penetration of pro-oncogenic types of HPV, which significantly diminishes the prevalence of cervical cancer in women, penis cancer in men, and oropharyngeal and colorectal cancer in both [24–31]. The WHO has shown in practice the success of a male circumcision strategy in terms of reducing the spread of HIV [32]. Furthermore, an expert assessment is known to consider that the prepuce is an evolutionary vestige [33–35] and tissue, which too often leads to medical problems.

Epithelial cells covering the male genitals make an essential contribution to innate immunity, as in other barrier organs. However, the epithelium of the male genitalia has another specific function—ensuring enjoyable sexual activity in contact with other people, and close exchange of microbiota, body fluids, and chemical substances of lubricants, creams, lotions, etc. At the evolutionary level, humanity is faced with an increased variety of such contacts, including homosexual ones; the emergence of new types of sexually transmitted infections; the proven influence of some viruses, such as HPV, on tumorigenesis in the male and female genital tracts; and concerned biosocial factors. From the dominant viewpoint of the medical community, an uncircumcised male should be aware of his responsibility for spreading the “silent killer” [36], which is HPV. Fortunately, another effective preventive method against HPV, vaccination has been developed and used for many years. There is no vaccine against HIV yet, however one 100% protection HIV antiretroviral medication is available now. Lenacapavir received breakthrough drug status because it uniquely inhibits several stages of the HIV-1 life cycle and shows the highest clinical efficacy [37].

Microbiota, or microbiome, exist in every barrier organ and spread even deeper than previously thought. For example, it is known that semen is not sterile. Based on the assessment of intestinal microbiota, all microbiotic components can be divided into two parts: (1) opportunistic, which is potentially dangerous to the body; (2) immunoregulatory or tolerogenic, which maintains a state of tolerance when there is no threat of external infection or reactivation of one’s own opportunistic microbes [38]. These useful bacteria such as Lactobacteria spp., Bifidobacteria spp., Clostridia spp., and Bacteroides spp. ferment dietary fibers to eight short-chain fatty acids such as propionate, acetate, butyrate, etc., which are maturation factors for two main cell lineages of the tolerance maintenance system, tolerogenic dendritic cells and peripheral pTreg cells [18]. Nowadays, with the advent of omics technologies, many species of penile microbiota, including bacteria, fungi, and viruses are differentially described in uncircumcised and circumcised males [6, 39–41]. From one point of view, since there are no own tolerogenic microbes in male microbiota, the required factors originate from the gut and, additionally, have to come from the female vagina rich in Döderlein’s flora like Lactobacilli [42]. This can mean that constant heterosexual activity is beneficial for male health.

In uncircumcised men, normal urethral microbiota contains Prevotella spp., Porphyromonas spp., Anaerococcus spp., Streptococcus spp., and Finegoldia spp., whereas in circumcised men, normal urethral microbiota includes Corynebacterium spp., Staphylococcus spp., and Gardnerella spp. [38, 41]. Regardless of circumcision, Prevotella spp., Streptococcus spp., and Corynebacterium spp. are prevalent in the male urethra [40]. An increase in penile microbiota Gardnerella spp. can influence the incidence of bacterial vaginosis in female sex partners [43]. Over 30 viruses are found in the male genital tract [6], and many of them persist in semen, fall into the urethra, and can be spread due to sexual activity.

Allergy to sperm occurs not only in women but also in men either to their own or to the semen of other men. A case history of a patient who developed systemic reactions after anal intercourse has been published, although this patient never displayed sperm allergies after vaginal coitus. This case illustrated that the route of exposure to sperm may play a role in developing allergen tolerance or sperm allergies, including anaphylaxis [85].

In general, patients with intimate allergies are heterosexual men, men who have sex with men, and transgender people. However, an atopic constitution was identified in most of the total number of persons, and some of them already suffered from pre-existing atopic allergic pathology, along with an atopic hereditary burden.

Sperm allergy is an under-researched, poorly identified, and under-estimated disorder. Both mechanisms, IgE-mediated and type IV hypersensitivity, are possible either separately or in combination [86]. Nevertheless, type IV hypersensitivity has to be differentiated from mucosal manifestation of protein contact dermatitis [87]. Specification of proposed mechanisms is conducted using skin prick testing (SPT) [88], however, in most cases, the exact circumstances of suspect allergy in the male genital tract remain undetected [89]. The local allergic reaction to semen typically occurs within 30 min after exposure to sperm manifesting like the early-phase and rarer late-phase atopic response [90] by the following symptoms: vaginal or penile burning, itching, local urticaria, and redness. Unfortunately, there are no statistically reported rates on the prevalence, incidence, and prognosis of sperm allergy [91, 92]. Attempts of allergen-specific immunotherapy (AIT) with autological sperm in Gulf War veteran sexual couples with local reactions to sperm have been published [77]. There are also other publications [93, 94].

The sperm and spermatozoa contain a variety of glycoproteins, which participate in multiple processes in both male and female genital tracts. Additionally, sperm may be contaminated with a mixture of pro-inflammatory and anti-inflammatory factors, such as IL-6, IL-8, CCL-2 (MCP-1), CCL-5 (RANTES), TNF-β, CCL2 (MCP-1), TGF-β, and IL-10, and be a source of possible errors [95]. There are key criteria for the difficult diagnosis of sperm allergy, including the use of condoms, particularly made of lambskin, negative SPT with suspect culprit allergens, and a low value of specific serum IgE [81]. It took a while before Weidinger et al. [96] could isolate from seminal fluid a major allergen, which turned out to be a prostate-specific antigen (PSA) well-known to urologists as an essential diagnostic marker of prostate cancer.

Currently, research continues according to one more sperm-associated disorder, which develops in males only, post-orgasmic illness syndrome (POIS), which was first described by Dutch researcher Waldinger [97].

To date, about sixty cases of POIS have been reported in the medical literature, but its prevalence, incidence, and treatment modality remain unknown [98–106]. The condition develops in both circumcised and uncircumcised men, at medium age, 34.07 ± 6.65 years, and with any exposure to sexual activity. POIS is closely connected to ejaculation and orgasm and develops right away after these events. The first symptoms are a flu-like feeling, nasal obstruction, conjunctivitis, perspiration, then extreme muscle weakness, incoherent speech, and headache. Most patients had a main symptom in common extreme fatigue [104]. The majority of symptoms last for about a week and disappear after that.

Sonkodi et al. [107] proposed a hypothesis of acute compression proprioceptive axonopathy in the muscle spindle and the influence of excitotoxic neurotransmitter L-glutamate [108]. It is possible that “neurogenic inflammation” has an influence here [109]. However, successful attempts of AIT have been described that may be considered in favor of the preferred atopic nature of the disorder [110, 111]. In addition, hormonal therapy, antihistamines, and Silodosin were used to result in full recovery. However, all these treatment modalities are experimental in nature and have not been assessed in placebo-controlled trials [105, 106].

Probably, POIS presents a combination of two phases of allergic inflammation, the early-phase atopy reaction and late-phase atopy inflammation-dependent condition, whereas the chronic phase is aborted [18].