The involvement of autoimmune mechanisms in premature ovarian failure has been put forward by numerous investigators. In various other ovarian pathologies, such as idiopathic infertility, polycystic ovary syndrome, or endometriosis, similar mechanisms have been suggested. However, the exact role of autoimmunity in the pathophysiology of these diseases still remains controversial. The diagnosis of autoimmune ovarian disease relies on several clinical, biological and histological findings, but special interest has been focused on antiovarian autoantibodies. The search for these antibodies has been undertaken by several authors and yielded somewhat conflicting results which might be conditioned by methodological differences and by the multiplicity of potential immune targets. These targets, which comprise various steroidogenic enzymes, gonadotrophins and their receptors, the corpus luteum, zona pellucida and oocyte, are reviewed. Further investigation of these targets is required to improve the diagnostic tools that will lead to a precocious and reliable diagnosis of autoimmune ovarian disease, an appropriate clinical surveillance as well as the selection of patients who may benefit from immune-modulating therapy and possibly recover ovarian function and fertility.

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Autoimmunity and antigenic targets in ovarian pathology.

Background The functional reproductive alterations seen in women with type 1 diabetes (T1D) have changed as therapy has improved. Historically, patients with T1D and insufficient metabolic control exhibited a high prevalence of amenorrhea, hypogonadism and infertility. This paper reviews the impact of diabetes on the reproductive axis of female T1D patients treated with modern insulin therapy, with special attention to the mechanisms by which diabetes disrupts hypothalamic-pituitary-ovarian function, as documented mainly by animal model studies. Methods A comprehensive MEDLINE search of articles published from 1966 to 2012 was performed. Animal model studies on experimental diabetes and human studies on T1D were examined and cross-referenced with terms that referred to different aspects of the gonadotropic axis, gonadotrophins and gonadal steroids. Results Recent studies have shown that women with T1D still display delayed puberty and menarche, menstrual irregularities (especially oligomenorrhoea), mild hyperandrogenism, polycystic ovarian syndrome, fewer live born children and possibly earlier menopause. Animal models have helped us to decipher the underlying basis of these conditions and have highlighted the variable contributions of defective leptin, insulin and kisspeptin signalling to the mechanisms of perturbed reproduction in T1D. Conclusions Despite improvements in insulin therapy, T1D patients still suffer many reproductive problems that warrant specific diagnoses and therapeutic management. Similar to other states of metabolic stress, T1D represents a challenge to the correct functioning of the reproductive axis.

/pdf/female-reproduction-and-type-1-diabetes-from-mechanisms-to-3dmlj3ozqe.pdf

Female reproduction and type 1 diabetes: from mechanisms to clinical findings

Mayer-Rokitansky-Küster-Hauser Syndrome: Sexuality, Psychological Effects, and Quality of Life

Menstrual irregularity is a common occurrence during adolescence, especially within the first 2-3 years after menarche. Prolonged amenorrhea, however, is not normal and can be associated with significant medical morbidity, which differs depending on whether the adolescent is estrogen-deficient or estrogen-replete. Estrogen-deficient amenorrhea is associated with reduced bone mineral density and increased fracture risk, while estrogen-replete amenorrhea can lead to dysfunctional uterine bleeding in the short term and predispose to endometrial carcinoma in the long term. In both situations, appropriate intervention can reduce morbidity. Old paradigms of whom to evaluate for amenorrhea have been challenged by recent research that provides a better understanding of the normal menstrual cycle and its variability. Hypothalamic amenorrhea is the most prevalent cause of amenorrhea in the adolescent age group, followed by polycystic ovary syndrome. In anorexia nervosa, exercise-induced amenorrhea, and amenorrhea associated with chronic illness, an energy deficit results in suppression of hypothalamic secretion of GnRH, mediated in part by leptin. Administration of recombinant leptin to women with hypothalamic amenorrhea has been shown to restore LH pulsatility and ovulatory menstrual cycles. The use of recombinant leptin may improve our understanding of the pathophysiology of hypothalamic amenorrhea in adolescents and may also have therapeutic possibilities.

http://www.nccpeds.com/ContinuityModules-Fall/Fall%20Continuity%20Source%20Materials/Amenorrhea-pathophys.pdf

The pathophysiology of amenorrhea in the adolescent.

Detection of specific autoantibodies remains the most practical clinical and research marker of autoimmune disease. The lack of consensus on ovary specific antibodies as a marker for ovarian autoimmunity has clinical and research consequences. The objective of this review is to summarize the evidence for ovarian autoimmunity and the detection of ovary specific autoantibodies in humans. Evidence favors the presence of an autoimmune disease of the ovary. Ovarian autoantibodies are associated primarily with premature ovarian failure (POF) and unexplained infertility. Variations in detection of ovarian autoantibodies are likely to be due to study design elements such as antibody test format, antigen preparation, and criteria for study and comparison groups. In addition, multiple targets appear to be involved in ovarian autoimmunity including ovarian cellular elements and oocyte related antigens. Many studies only assess one target antigen, leaving individuals with ovarian autoimmunity unidentified. The next most significant advance in characterizing ovarian autoimmunity will be definitive identification of the specific antigens and development of standardized tests based on use of specific antigens.

Ovarian autoimmune disease and ovarian autoantibodies.

In previous papers, we referred to studies of the influence of antiovarian autoantibodies on menstrual cycle disorders in adolescent girls. We examined autoantibodies against ooplasma, zona pellucida, membrana granulosa, theca folliculi interna, and lutein cells. In infertile women in the IVF/ET program, we studied the positivity of antiovarian antibodies and cytokines, namely, TNF-alpha and IL-1 beta, in follicular fluid correlated with the following subgroups, characterized by the outcome of in vitro fertilization, as follows: G, pregnant; F, fertilized; N, nonfertilized; and O, no oocyte gained. The presence of autoantibodies corresponds to the success or failure of the IVF/ET program. Our results support the hypothesis that antiovarian autoantibodies play an important role in both the endocrine and the reproductive function of the human ovary and that it can influence them negatively.

Autoimmune Antiovarian Antibodies and Their Impact on the Success of an IVF/ET Program

Premenarchal and postmenarchal girls with insulin-dependent diabetes mellitus: ovarian and other organ-specific autoantibodies, menstrual cycle.

The sexual development and sex life of 12 women with the Kustner-Rokitansky syndrome, in whom the developmental anomaly (vaginal agenesis) was corrected through surgery, were examined through structured interviews and by means of questionnaires. The comparison group was 22 women who had regular menses and a functional sex life. All differences between the groups were statistically nonsignificant. Only in one questionnaire was there a slight trend toward retarded heterosexual development in the patient sample.

Sexual life of women with the Küstner-Rokitansky syndrome.

Circulating Ovarian Autoantibodies and FSH and LH Levels in Adolescent Girls With Primary Menstrual Cycle Disorders

From 1973 through 1987, 19 girls with malformation of the urogenital drainage system were observed, treated, and followed-up. Each had a double uterus: one uterus emptied into a normally developed vagina; the other either ended blindly (hemihematometra, 8 cases) or led into an atretic vagina (hemihematocolpos, 11 cases). On the non-communicating side, the kidney and ureter were undeveloped, probably due to nondevelopment of the mesonephric (wolffian) duct on the affected side. The proper diagnosis (using x-ray, ultrasonography, and biopsy) is very important for surgical correction. When the hemihematocolpos was present, establishing a wide communication between the two vaginas was always sufficient. Extirpation of the uterus in these cases was not the treatment of choice. In hemihematometra, extirpation of the uterus on the atretic side was required in three cases. Several patients became pregnant and delivered healthy children.

Jan Hořejší

Papers

Autoimmune Antiovarian Antibodies and Their Impact on the Success of an IVF/ET Program

Premenarchal and postmenarchal girls with insulin-dependent diabetes mellitus: ovarian and other organ-specific autoantibodies, menstrual cycle.

Sexual life of women with the Küstner-Rokitansky syndrome.

Circulating Ovarian Autoantibodies and FSH and LH Levels in Adolescent Girls With Primary Menstrual Cycle Disorders

Incomplete reduplication of internal genitalia and unilateral renal aplasia syndrome