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The main micro-organisms able to interfere with the reproductive function have been considered. In particular, the problems concerning the vaginal environment and its interactions with spermatozoa, immunological aspects and contraception. Lastly, reference has been made to methods of prevention and study in the field of diagnostics and of clinical management.
Immunization of female bonnet monkeys (Macaca radiata) with pig zona pellucida glycoprotein ZP3 using adjuvants permissible for human use leads to infertility. Fifty per cent of the animals conceived after antibody titres declined. Animals that failed to regain their fertility did not show any obvious ovarian changes. As part of the attempt to design an effective immunocontraceptive vaccine based on synthetic peptides, the epitopes recognized by monoclonal antibodies (mAb) against pig ZP3 alpha and ZP3 beta and possessing contraceptive efficacy in vitro were mapped. These studies identified an N-blocked decapeptide from the N-terminus corresponding to 23-32 amino acids of the precursor protein of pig ZP3 beta. As an alternative approach to using synthetic peptides, DNA encoding bonnet monkey ZP3 was cloned and sequenced. The deduced primary amino acid sequence revealed an overall similarity of 93.9% with human ZP3. Bonnet monkey ZP3 corresponding to an internal 975 nucleotide fragment excluding the N-terminus signal sequence and the C-terminus transmembrane domain has been expressed in Escherichia coli. These results will assist in the design of an immunocontraceptive vaccine based on either synthetic peptides or recombinant glycoproteins or proteins corresponding to ZP.
Within the limitations of the available data, it has been reported that oral contraceptive use versus other contraceptive methods is associated with a greater or similar frequency of candidiasis, increased numbers of anaerobic microorganisms, an increased or similar frequency of chlamydia trachomatis, and a reduced frequency of bacterial vaginosis and trichomoniasis. The impact of contraceptive steroids on cellular and humoral immunologic factors may explain these observations. Intrauterine contraceptive device use is reported to be associated with an increased rate of bacterial vaginosis and anaerobic organism recovery from the vagina regardless of symptoms. Patients having a contraceptive vaginal ring were found to have the same number and types of vaginal organisms as oral contraceptive users. Levonorgestrel-releasing subdermal implant (Norplant, Wyeth-Ayerst, Philadelphia, Pa.) users have been reported to have approximately half the rate of vaginitis and vaginosis compared with that of Copper T-200 intrauterine device users.
Progressive antithrombin activity and the immunological levels of antithrombin III, alpha 2-macroglobulin, and alpha 1-antitrypsin were measured in women at various intervals during treatment with oral contraceptives and in a group of untreated women. No significant changes were observed in any of the above parameters. In both control and treated women, there was a positive statistical correlation between progressive antithrombin activity and antithrombin III immunological levels, whereas no correlation was found between the former and alpha 1-antitrypsin or alpha 2-macroglobulin immunological levels. This study questions the possibility of thrombin inhibitors being selective signs of hypercoagulability during treatment with oral contraceptives.
The global population is currently expanding at the unprecedented rate of nearly 1 billion per decade, with 94% of the increase occurring in the developing world. New methods of fertility regulation are urgently needed, and the development of birth control vaccines by active immunization against antigens specific for reproduction has made substantial progress during the last two decades. These vaccines are meant to have an outstanding impact on future control of worldwide population growth by providing safe, effective, long-lasting and reversible contraception. The most advanced of these vaccines are based on the placental pregnancy hormone human chorionic gonadotropin (hCG), and have already entered clinical trials. However, immunological cross-reactivity and lack of efficacy of anti-hCG antibodies seriously challenge this strategy. Conversely, efforts to understand the molecular events involved in the fusion of sperm and egg have led to the identification of new target structures for the development of fertility-regulating vaccines. Herein, we summarize the current state of birth control vaccines and discuss the risks and drawbacks of this approach to fertility regulation.
Syncytial trophoblast fusion is an essential step in the process of implantation. This project is aimed at the immunological inhibition of syncytial trophoblast fusion as a novel approach to contraception. Fusion-inhibiting recombinant antibodies were generated and used together with autoantibodies from patients with repetitive in vitro fertilization (IVF) failure that were shown to inhibit syncytial fusion and are expected to inhibit implantation, to generate anti-idiotypic peptides. These peptides mimic trophoblast epitopes essential for syncytial fusion and are, therefore, considered specific immunogens for the generation of antibodies that will inhibit implantation. To verify their physiological role in humans, 300 anti-idiotypic peptides were tested for their binding capacity to patient autoantibodies associated with repetitive IVF failure, habitual abortion and preeclampsia. Of these, only three peptides were found to selectively bind to autoantibodies of patients with repetitive IVF failure and were considered safe and efficient enough for evaluation in preclinical and clinical studies required for the development of immune contraceptives. When used as immunogens, these peptides are expected to elicit an antibody response inhibiting syncytial fusion and thus implantation. Furthermore, the action of these antibodies needs to be restricted to the stage of syncytium formation at the time of implantation so as not to cause complications of pregnancy in those cases where they fail to have a contraceptive effect. To exclude potential side effects on other systems, toxicological experiments in animals are in progress.
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The presence of sperm antibodies correlates with nearly every pathological condition of the male reproductive tract. In the seasonal breeder, mink, a decrease in gonadotrophin secretion and testicular regression also induces sperm antibodies. Because the Sertoli cells and the principal cells of the epididymis (i.e. the cells mainly responsible for protection of germ cells from autoimmune destruction) are dependent on androgens, and because the androgen concentration decreases in both the testis and epididymis during male hormonal contraception, the presence of IgG class sperm antibodies in serum was studied in rats during the suppression and recovery phases of testosterone contraception and after vasectomy. Five-centimetre long testosterone implants were placed under the dorsal skin of rats under pentobarbitone anaesthesia. The control rats received empty implants. All implants were left in the rats for 27 or 53 days. The total number of testicular antigens detected by sera from the vasectomized rats increased significantly until 66 days post-operation, and then decreased to the levels of intact rats. The number of testicular antigens detected by sera from rats receiving contraceptive doses of testosterone did not increase before the testosterone capsules were removed, but at 40 days post removal of the silastic capsules, the number of antigens detected by the sera was significantly higher than in intact rats and at 77 days post removal of the silastic capsules, the number of antigens detected by the sera was significantly higher than at 27 days after starting testosterone administration. No significant changes in the number of antigens detected by the sera could be observed after the implanting of empty capsules or after their removal. Vasectomy mostly induced antibodies against testicular antigens in the molecular ratio ranges of 70-82, 25-33 and 21-24.5 kD. Antibodies against antigens in these molecular ratio ranges were not significantly induced during or after treatment with contraceptive doses of testosterone. Cell nuclei with apoptotic morphology could be observed in the seminiferous tubules of the vasectomized rats, but DNA in situ 3'-end labelling of testes could not confirm any differences between the testes of vasectomized and sham-operated rats or between testosterone-treated and empty implant-treated rats. CD3+ T cells could not be observed in the testes of any of the treatment groups. These results suggest that the immunological conditions remain stable in the testes after vasectomy and during testosterone treatment, but that the animals are more prone to develop autoantibodies after vasectomy and during recovery from treatment with exogenous testosterone.
Determinations by immunologic methods of histidine-rich glycoprotein (HRG) and plasminogen, were made in plasma samples collected during one normal or hormone induced cycle in 15 young, normal women and in 11 women using oral contraceptives with 30 micrograms ethinyl estradiol and 150 micrograms levo-norgestrel. The hormone group showed an increase in plasminogen level to about 150% of normal, while the concentration of HRG was decreased to about 75% of normal. This resulted in a considerable relative increase in the concentration of free plasminogen in the hormone group (calculated from the equilibrium: HRG . plasminogen in equilibrium HRG + plasminogen, using KD = 1.0 microM), representing a doubling of that in the normal group. Hence, more plasminogen is available for binding to fibrin and activation in the hormone group.
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AIDS cases attributable to heterosexual vaginal intercourse constitute a growing proportion of new AIDS cases in the United States. Major cofactors that possibly increase the efficiency of heterosexual transmission of HIV-1 include genital ulcer disease, multiple sexual exposures, lack of male circumcision, and primary and advanced stages of HIV-1 disease. I report the case of a 33-year-old woman who was recently infected with HIV-1 after one to three nontraumatic episodes of vaginal intercourse with a healthy-appearing, HIV-1-infected, bisexual man. An investigation of her exposure history revealed the precise time frame during which infection occurred. The patient developed a primary HIV-1-infection syndrome and became seropositive for HIV-1 within eight weeks of her last sexual contact with the infected man. An epidemiological and laboratory evaluation of the index patient and her sexual partner identified only one risk factor for enhanced HIV-1 transmission: the patient's use of oral contraceptives. Her partner was immunologically intact, HIV-1 antigen negative, and circumcised. Both of the individuals were from Minnesota, as were their recent sexual partners. This case illustrates that HIV-1 infection by vaginal intercourse can occur in the absence of the major risk factors believed to increase the efficiency of transmission. Even in a low HIV-1 prevalence area like Minnesota, efforts to promote awareness of HIV-1 status, abstinence, non-penetrative sex, or barrier protection need to be expanded and the behaviors adopted by sexually active persons if HIV-1 transmission is to be minimized.
In recent years the need to develop vaccines against a variety of sexually transmitted diseases, the desire to treat male infertility and interest in developing alternative contraceptive methods have focused research interest on the immunology of the male reproductive tract. This paper reviews the current state of knowledge of immunity in the male tract. Both physical and immune mechanisms that operate to maintain the blood-testis barrier are discussed with regard to (i) their importance in preventing autoimmune responses against spermatozoa and (ii) how these can be overcome to induce specific immunity in the testis and efferent ducts. The role of both the systemic and mucosal arms of the humoral immune response are discussed both in terms of immune-mediated infertility and the induction of specific immunity. Finally some novel approaches to elicit immunity in the male reproductive tract are discussed.
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Heterologous anti-HCG and anti-beta-HCG sera failed to effect complement-dependent lysis of purified 51chromium-labeled syncytiotrophoblast in vitro. The progesterone synthetic activity of syncytiotrophoblast was also preserved in the presence of the anti-HCG sera. Binding of the anti-HCG antibodies to the syncytiotrophoblast was demonstrated in an immunofluorescence test. The potential of the anti-HCG sera to participate in complement dependent lysis of other HCG-bearing cell types was revealed using BeWo cells as the targets; 53%-68% of the latter were killed by exposure to anti-HCG sera and complement. The possible mechanism(s) whereby syncytiotrophoblast resists damage by the anti-HCG sera are considered.
Use of oral contraceptives was associated with a significant increase in the frequency of dry socket after extraction of mandibular third molars. The probability of dry socket increases with the estrogen dose in the oral contraceptive. The risk of dry socket associated with oral contraceptives can be minimized by performing extractions during days 23 through 28 of the tablet cycle.
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Development of zona pellucida (ZP) based contraceptive vaccines raises a number of complications that challenge current immunological capabilities. Our research examines two aspects of these immunological problems. First, recent studies demonstrate that one bacterially expressed rabbit ZP recombinant vaccine (rec55) induces autoantibodies in primates that prevent sperm-ZP binding and induction of the acrosome reaction in the homologous ZP in vitro. Immunization with rec55 does not induce ovarian pathology, and the duration of antibody titres indicates that this vaccine would have reversible effects on fertility. However, the immunogenicity of the rec55 protein produced in the pEX bacterial expression vector is low. We have therefore expressed the cDNA encoding rec55 using the pGEX vector for the following reasons: (i) the pGEX expressed recombinant proteins are soluble in aqueous solution; (ii) affinity purification of recombinant proteins on glutathione Sepharose columns is more effective for obtaining larger quantities of purified protein; and (iii) the availability of protease cleavage sites between the ZP and glutathione S transferase fusion proteins should eliminate the possibility of carrier-mediated suppression of immune responses. These improvements in protein production and purification yield immunogen which is more malleable to immunological studies. Second, while it is clear that ZP recombinant vaccines can eliminate the problem of ovarian pathology, it is important to understand how such pathology results from immunization with native ZP proteins and certain recombinant ZP proteins. To this end, we have initiated immunization studies in baboons comparing rabbit ZP and pig ZP immunogens in Titremax adjuvant. Unilateral ovariectomies at different time points after immunization (1.5, 2, 4 and 6 months) will allow studies on the time course of pathology within the ovary. Comparison of these results with ongoing rabbit ZP immunizations will help elucidate the differences in immunogenicity of ZP proteins isolated from the two species.