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PubMed2003

Contraceptive vaccines.

The control of human fertility would be revolutionised by the development of a safe, effective, long-acting contraceptive vaccine. The pursuit of this objective has involved the selection of appropriate targets within the reproductive process that are amenable to interference with antibodies. To date, three major targets have been researched. The zona pellucida (ZP) plays key roles in folliculogenesis, fertilisation and early development, and is comprised of powerful cell-specific antigens. The induction of infertility requires high ZP antibody titres that are difficult to maintain without inducing ovarian pathology characterised by a premature loss of primordial follicles. As a premature menopause would be a high price to pay for long-term contraception, this approach to a vaccine cannot progress until the cause of the ovarian pathology has been resolved. Sperm surface antigens represent another promising approach to contraceptive vaccine development. While there is some clinical data to support the likely efficacy of this strategy, none of the gamete-specific molecules characterised to date have fulfilled this promise. Anti-human chorionic gonadotropin (hCG) vaccines terminate pregnancy by preventing the maternal recognition of pregnancy. This vaccine has reached the stage of clinical trials, and preliminary indications are that the approach is safe and potentially effective. However, reliability may be an issue, given the observed inter-individual variability in antibody generation. The future of contraceptive vaccine development will clearly involve a continuation of the intense search for suitable targets and the development of improved immunisation procedures that exploit the latest innovations in vaccine technology.

Adjuvants, Immunologic↗
PubMed1998

Molecular basis of sperm-egg interaction and the prospects for immunocontraception.

As the molecular basis of sperm-egg interaction is resolved, so new opportunities are created for the development of immunological approaches to disrupt the process of conception. Thus, realisation that the zona glycoprotein, ZP3, serves as a specific receptor for spermatozoa, has prompted a detailed examination of its contraceptive potential. In primate models, recombinant ZP3 has been shown to suppress fertility very efficiently, however this efficacy is tempered by the appearance of adverse side-effects involving accelerated primordial follicle depletion and a lymphocytic infiltration of the ovarian stroma. Synthetic peptides encoding B-cell epitopes have been found to circumvent the lymphocyte response although the effectiveness of such reagents in preventing the loss of primordial follicles has not yet been determined. The induction of active immunity against sperm-specific antigens has also been shown to generate long term infertility in both males and females. Molecular and immunological techniques are now being used to produce a rapidly expanding list of unique sperm antigens which are currently being evaluated to determine their potential contribution to the development of safe, effective, contraceptive vaccines.

Animals↗
PubMed1978

The effect of sexual hormones on skin graft survival, thymic morphology and serum levels of glycoproteins and albumin in mice.

Inbred mice of the B10LP strain were injected subcutaneously over a period of 28 days with chloromadinone acetate, mestranol, both hormones together, and the carrier alone. Treatment with the gestagen chloromadinone acetate alone or in combination with mestranol caused a significant prolongation of the H-2 different skin graft survival. This was not seen after mestranol treatment alone. All the hormone-treated mice developed characteristic cysts in the thymic medulla and changes in the concentration of some plasma proteins, e.g. a fall of albumin level and a simultaneous increase of glycoprotein level. Therefore, it is necessary to look for such side-effects in humans also to prevent or to notice early alterations of immunological surveillance.

Animals↗
PubMed1979

Experimental findings with spermantibodies: condom therapy (a case report).

A couple with no demonstrable cause for their infertility, except for a pronounced antisperm activity in the blood serum of the female partner, were instructed to use a condom while our laboratory monitored the wifes antibody titer. The antibody activity declined sufficiently and an artificial husband insemination were performed after seven months of therapy. A precise report of the spermantibody activity over an eleven month period are given by the authors.

Antibodies↗
PubMed1982

Problems in the measurement of putative serum immune complexes by the method of Beaumont.

A methodological investigation of the procedure used by Beaumont et al for measuring a "serum immune complex" precipitated by 25% ammonium sulfate and alleged to contain an ethynyl-estradiol binding immunoglobulin has found major problems with reproducibility and with the correlation of total protein as measured by the Lowry method and the IgG content as determined by a specific nephelometric procedure.

Antigen-Antibody Complex↗
PubMed1980

Estimating the outcome of a pregnancy test: women's judgements in foresight and hindsight.

Previous research on judgement under uncertainty has suggested that, when we know the outcome of some event, we perceive that outcome as more likely than when we do not have outcome knowledge. That is, in comparison with judgements made in foresight, judgements made in hindsight are biased in the direction of the outcome the judge believes to have happened. While the effect appears to be robust in the laboratory, it has very seldom been tested in real life. This experiment therefore went outside the laboratory, and examined women's estimates of the outcome of a pregnacy test. It was predicted that those who knew the result of their test (hindsight) would perceive that outcome as more likely than those asked to make the estimate before they knew the result (foresight). The prediction was supported only for women whose result was positive and, furthermore, the positive group made consistently higher estimates than the negative group, both in hindsight and foresight. The findings were therefore less marked and more complex than in previous laboratory research, and support the argument that experiments and materials must be constructed with salience for the subjects. The findings are interpreted in the light ot Tversky & Kahneman's (1974) work on heuristic rules of thinking.

Contraception Behavior↗
PubMedDate not supplied

Prospects of the clinical utilization of melatonin.

This review summarizes the present knowledge on melatonin in several areas on physiology and discusses various prospects of its clinical utilization. Ever increasing evidence indicates that melatonin has an immuno-hematopoietic role. In animal studies, melatonin provided protection against gram-negative septic shock, prevented stress-induced immunodepression, and restored immune function after a hemorrhagic shock. In human studies, melatonin amplified the antitumoral activity of interleukin-2. Melatonin has been proven as a powerful cytostatic drug in vitro as well as in vivo. In the human clinical field, melatonin appears to be a promising agent either as a diagnostic or prognostic marker of neoplastic diseases or as a compound used either alone or in combination with the standard cancer treatment. Utilization of melatonin for treatment of rhythm disorders, such as those manifested in jet lag, shift work or blindness, is one of the oldest and the most successful clinical application of this chemical. Low doses of melatonin applied in controlled-release preparation were very effective in improving the sleep latency, increasing the sleep efficiency and rising sleep quality scores in elderly, melatonin-deficient insomniacs. In the cardiovascular system, melatonin seems to regulate the tone of cerebral arteries; melatonin receptors in vascular beds appear to participate in the regulation of body temperature. Heat loss may be the principal mechanism in the initiation of sleepiness caused by melatonin. The role of melatonin in the development of migraine headaches is at present uncertain but more research could result in new ways of treatment. Melatonin is the major messenger of light-dependent periodicity, implicated in the seasonal reproduction of animals and pubertal development in humans. Multiple receptor sites detected in brain and gonadal tissues of birds and mammals of both sexes indicate that melatonin exerts a direct effect on the vertebrate reproductive organs. In a clinical study, melatonin has been used successfully as an effective female contraceptive with little side effects. Melatonin is one of the most powerful scavengers of free radicals. Because it easily penetrates the blood-brain barrier, this antioxidant may, in the future, be used for the treatment of Alzheimer's and Parkinson's diseases, stroke, nitric oxide, neurotoxicity and hyperbaric oxygen exposure. In the digestive tract, melatonin reduced the incidence and severity of gastric ulcers and prevented severe symptoms of colitis, such as mucosal lesions and diarrhea.

Adjuvants, Immunologic↗
PubMed2002

Immunological response of female macaques to the PH-20 sperm protein following injection of recombinant proteins or synthesized peptides.

Because of its location on the sperm surface and its multiple functions during fertilization, the PH-20 protein is a potential target for contraceptive vaccines. Cynomolgus macaques were immunized using four different adjuvants together with synthesized peptides or recombinant proteins representing selected regions of macaque PH-20. The synthesized peptide (amino acids 387-412, designated Peptide 4) was used as a linear molecule in a 1:1 ratio with a peptide sequence of tetanus toxoid, as well as a multiple antigenic peptide (MAP) matrix held together by scaffolding lysine residues. In the MAP construct, the ratio of Peptide 4 to tetanus peptide was 4:1. To circumvent the poor production of recombinant PH-20 in bacterial cells, two truncated forms of the molecule were expressed in Escherichia coli, G18 (encoding amino acids 143-510) and E10 (encoding amino acids 291-510). The adjuvants were Montanide ISA 51, Titermax Gold, Syntex adjuvant formulation (SAF), and QS-21. All of the antigen/adjuvant combinations produced significant immune responses as measured by ELISA. The circulating antibodies from immunized animals recognized macaque sperm surface PH-20 on Western blots and were shown by indirect immunofluorescence to bind to the surface of macaque sperm. Montanide and Titermax were associated with higher titers of anti-PH-20 antibodies than QS-21 and SAF adjuvants. Immunization with Titermax, however, resulted in sterile abscesses in 4 of 8 animals injected. We conclude that antigens derived from synthesized peptides and recombinant proteins representing selected regions of the PH-20 molecule can be used as vaccine components in combination with the adjuvant Montanide to elicit a significant sperm-directed antibody response in immunized macaques.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Decreased suppressor T-lymphocytes in women who received progestogen injections.

Decreased levels of suppressor T-cells (CD8+) were found in 17 normal women who received progestogen (Depoprovera) injection, 150 mg intramuscularly every three months for contraceptive purposes, for more than 30 months. The helper: suppressor T-cells (CD4+ : CD8+ ratio) was significantly elevated in this group compared to 30 normal female controls. No significant change of T-lymphocyte was found in 53 normal women who received the injection for less than 30 months or who received combined oral contraceptive pills. In conclusion, long term progestogen injection induced a lowering of suppressor T-cell levels, which is the same immunological change found in several autoimmune diseases.

CD4-CD8 Ratio↗
PubMed1991

A neutrophilic reaction of Sweet's syndrome type associated with the oral contraceptive.

A case is presented of a Sweet's syndrome-like eruption in association with the oral contraceptive. A 46 year old caucasian woman developed recurrent episodes of erythematous tender plaques on her trunk six weeks after commencement of the oral contraceptive (OC). Her condition clinically and histologically resembled Sweet's dermatosis. On cessation of the OC there was complete resolution of her lesions and she remains well 12 months later. This is the first report, to our knowledge, of a neutrophilic reaction to the oral contraceptive, and we believe that drugs may be implicated in the aetiology of atypical neutrophilic reactions simulating Sweet's syndrome in patients who are otherwise well.

Contraceptives, Postcoital, Hormonal↗
PubMed2001

Quantification of immunoglobulins and cytokines in human cervical mucus during each trimester of pregnancy.

OBJECTIVES: Our aims were to determine immunoglobulin and cytokine levels in cervical mucus obtained from women during each trimester of pregnancy and to compare these levels with those reported in normally menstruating women and in women taking oral contraceptives. STUDY DESIGN: Cervical mucus samples were collected at specified intervals from 36 pregnant women. An enzyme-linked immunosorbent assay was used to quantitate the presence of immunoglobulins A and G and interleukins 1 beta, 6, and 10 in cervical mucus. RESULTS: Immunoglobulin A in cervical mucus remained stable during each trimester of pregnancy (26 mg/dL). Cervical mucus immunoglobulin G decreased from a first-trimester high of 44.4 mg/dL to lower levels in the second and third trimesters. Levels of interleukin 1 beta increased significantly from the first trimester (4261 pg/mL) to 12,899 pg/mL in the second trimester (P <.01). CONCLUSION: These data suggest a possible correlation of reproductive hormones and immunologic factors in the female reproductive tract during pregnancy.

Adult↗
PubMed1994

Chlamydial serologic characteristics among intrauterine contraceptive device users: does copper inhibit chlamydial infection in the female genital tract?

OBJECTIVE: Our objective was to assess the association between copper intrauterine contraceptive device use and the level of antichlamydial antibodies. STUDY DESIGN: Fifty-four women (29 with history of ectopic pregnancy, 2 with non-tubal factor infertility, 1 with tubal factor infertility, and 22 with intact intrauterine pregnancies) with current or prior intrauterine contraceptive device use were compared with 60 prenatal control subjects with respect to antichlamydial antibodies. RESULTS: When the intrauterine contraceptive device user group was subdivided into copper users and Lippes Loop device users, a significantly lower geometric mean serum antibody titer among copper intrauterine contraceptive device users was detected. The odds ratio estimates for past chlamydial exposure (> or = 1:64 immunoglobulin G, > or = 1:128 immunoglobulin G) in users of noncopper versus copper intrauterine contraceptive devices were 9.1 (95% confidence interval 1.9 to 43.0) and 10.5 (95% confidence interval 1.5 to 71.8), respectively. CONCLUSIONS: The lower geometric mean serum antibody titer of antichlamydial antibody among copper versus Lippes Loop device users and the large association measured between past chlamydial infection and noncopper intrauterine contraceptive device use suggest that copper may have a protective effect against Chlamydia trachomatis infection or a suppressive effect on development of antichlamydial antibodies.

Adult↗