Metabolic endotoxaemia--a potential novel link between ovarian inflammation and impaired progesterone production.

INTRODUCTION: Medical conditions such as obesity and inflammatory bowel disease are associated with impaired luteal function, menstrual disturbance and infertility. It is proposed that the disturbance in gut wall integrity ("leaky gut") seen in these conditions may result in the passage of bacterial endotoxin (LPS) from the colonic lumen into the circulation that may initiate inflammation in the ovary and subsequently impair hormone production. METHODS: Quantify the association between systemic levels of LBP, a marker of endotoxin exposure, and levels of inflammation in the ovary (follicular fluid IL-6), plus steroid hormone production in 45 women undergoing IVF treatment. RESULTS: Endotoxaemia (LBP) were positively correlated with plasma CRP and inflammation within the ovary (follicular fluid IL-6). Furthermore, endotoxaemia was negatively correlated with progesterone production. CONCLUSION: The observed correlations, together with previously published animal studies linking endotoxin exposure to impaired luteal function, suggest that the translocation of bacterial endotoxin from the gut lumen into the circulation has the potential to interfere with progesterone production and result in luteal deficiency.

Selective theca cell dysfunction in autoimmune oophoritis results in multifollicular development, decreased estradiol, and elevated inhibin B levels.

We describe the clinical course of three women with presumptive autoimmune oophoritis who developed multiple follicles but very low to undetectable estradiol levels. Multiple follicles developed spontaneously in all subjects and during pulsatile GnRH treatment for ovulation induction in subject 1. The development of multiple dominant follicles was accompanied by LH levels in the postmenopausal range and FSH levels at the upper limit for premenopausal women. Serum inhibin B levels were elevated appropriately in the setting of multifollicular development, but estradiol levels remained low. Measurement of estradiol precursors demonstrated androstenedione and estrone levels below the 95th percentile in normal women. Adrenal cortical antibodies, and antibodies to 21-hydroxylase and P450 side chain cleavage enzymes were identified in all subjects. All subjects met the criteria for premature ovarian failure during follow-up. Subject 1 later developed adrenal failure, whereas subject 3 had adrenal failure at the time of the study. These subjects elucidate the hormonal pattern in autoimmune oophoritis, before the full criteria for premature ovarian failure are met. The elevated inhibin A and B levels, which accompany the development of multiple small and dominant follicles in these women, suppress FSH relative to LH levels, virtually independent of estradiol. These data provide further evidence for an important role of inhibin B and inhibin A in the negative feedback control of FSH. In addition, the normal inhibin A and inhibin B production in the absence of estradiol precursors and estradiol provide insight into the selective dysfunction of the theca cells in autoimmune oophoritis.

Induction and immunohistology of autoimmune ovarian disease in cynomolgus macaques (Macaca fascicularis).

Autoimmune ovarian disease (AOD) is a probable cause of human premature ovarian failure, and a potential complication of contraceptive vaccines based on ovarian antigens. The diagnosis depends on detection of noninfectious ovarian inflammation (oophoritis) and serum antibody to ovarian and placental antigens. Mechanisms underlying AOD have been investigated in mice but not in primates. Herein, we report induction of AOD in primates, and compare the immunopathology between monkey and murine AOD. Four cynomolgus macaques immunized with monkey or human zona pellucida 3 peptide (pZP3) in adjuvant, developed T-cell responses to the immunizing peptide and produced antibody that bound to native zona pellucida in vivo. Immunostaining of ovaries from pZP3-immunized macaques showed numerous clusters of T cells co-localized with major histocompatibility complex II-positive macrophages in the ovarian interstitium. Such foci were not detected in untreated or adjuvant-treated control monkeys. This finding is comparable to murine pZP3-induced AOD. However, unlike murine AOD in which numerous granulomatous lesions are detected, severe granulomatous inflammation was detected in only one of three monkeys with abnormal immunohistology. Similar to mice with pZP3-induced AOD, the immunized monkeys retained normal ovarian function. The results are discussed in the context of complications of ZP-based human immunocontraceptive vaccines and case reports of human autoimmune oophoritis.

Autoimmune ovarian inflammation triggered by proinflammatory (Th1) T cells is compatible with normal ovarian function in mice.

The detection of noninfectious ovarian inflammation (oophoritis) and serum ovarian autoantibodies in a patient with premature ovarian failure is indicative of an autoimmune etiology. The mechanisms of autoimmune ovarian injury leading to loss of function are currently unknown. In this study we investigated the impact of oophoritis on ovarian function based on two murine autoimmune ovarian disease (AOD) models. AOD can be induced by thymectomy at Day 3 after birth (d3tx). D3tx mice develop ovarian inflammation and atrophy with loss of oocytes. In these mice, ovarian atrophy and not oophoritis correlated with abnormal estrous cyclicity. The second AOD model is induced by active immunization of adult mice with a murine ZP3 peptide (pZP3) in adjuvant. After active immunization, the zona pellucida antibody titer, not oophoritis, correlated with reduced fertility. To investigate the effect of oophoritis in the absence of antibody response or ovarian atrophy, pZP3-specific T cells were passively transferred into naive syngeneic mice. This recruited cytokine-producing cells into the ovaries so that elevated cytokine production and its effect on ovarian function could be examined. Recipients of pZP3-specific T cells developed severe granulomatous oophoritis, and the diseased ovaries had elevated ovarian mRNA levels of interferon-gamma, interleukin-1beta, and tumor necrosis factor alpha. Despite these changes, fertility rates and gonadotropin-induced follicular development remained essentially normal. Therefore, normal ovarian function is compatible with severe ovarian inflammation mediated by autoreactive T cells.

Falla ovárica prematura inmunológica / Immunological premature ovarian failure

Se presenta el cuadro de falla ovárica prematura de etiología inmunológica, describiendo sus características fisiopatológicas y clínicas, diagnóstico, tratamiento y pronóstico. Se reporta un caso clínico atendido en el Servicio de Ginecología y Obstetricia del Hospital San Juan de Dios, discutiendo alternativas diagnósticas y terapéuticas

Experimental autoimmune oophoritis. II. Both lymphoid cells and antibodies are successful in adoptive transfer.

Experimental autoimmune oophoritis can be readily induced by passive transfer of peripheral blood lymphocytes, lymph node cells, spleen cells, T- and B-enriched cell suspensions, immune serum and gamma globulins, from ovary antigen immunized rats to naive recipients. Adoptive transfer was markedly enhanced when recipient rats were injected simultaneously with sensitized lymphoid cells and anti-ovary antibodies. Histologically, this passively induced disease was much the same as the actively induced disease. By syngeneic lymph node assay it was shown that regional lymph nodes of neonatally thymectomized rats did not enlarge upon injection of EAOO lymphocytes which otherwise produced a marked effect in lymph nodes of normal recipient rats. Therefore, it appears that enlargement of the draining lymph node was dependent on the participation of host T cells. The possibility that development of EAOO may involve cooperation between antigen-reactive and effector classes of lymphocytes was discussed.

Autoimmune oophoritis: a clinicopathologic assessment of 12 cases.

Twelve cases of histologically confirmed autoimmune oophoritis are described. Eight presented with symptoms and laboratory evidence of premature ovarian failure (POF). Four were diagnosed unexpectedly after hysterectomy for endometrial pathology or for sequelae of cystic enlargement of the ovaries. Two of eight patients tested had serum anti-ovarian autoantibodies (Aab), while five of seven had anti-adrenal Aab. Two women had, or subsequently developed, Addison's disease, and two patients had Hashimoto's disease at presentation. All women with this disease risk the development of adrenal failure and hypothyroidism. Microscopically, 11 cases showed a lymphoplasmacytic infiltrate that spared primordial follicles but involved, with progressive intensity, early and late preovulatory follicles and corpora lutea. Sparse perivascular and perineural inflammatory infiltrates were also present. The twelfth case appeared to be a unique case of granulomatous oophoritis, considered autoimmune because of the folliculotropic nature of the inflammatory process. Three cases showed evidence of follicular dysplasia.

[The dependence of estradiol and progesterone reception in the endometrium on its histological structure in women with the syndrome of luteal phase failure]. / Zavisimost' retseptsii éstradiola i progesterona v éndometrii ot ego gistostruktury u zhenshchin s sindromom nedostatochnosti liuteinovoi fazy tsikla.

A study of the level of the sex steroid receptors in the endometrium of women with the syndrome of insufficiency of the luteal phase of the cycle (ILP-syndrome) has shown that disorders of receptor processes affect, first of all, progesterone receptors. An increase in a degree of a delay of endometrial development was accompanied by a rise of the level of progesterone in the endometrium which depended on the estradiol-progesterone ratio in the circulation, detectable on the 20th day of the menstrual cycle. The ILP-syndrome is characterized by the sufficient induction of progesterone receptors at the end of the proliferative--the beginning of the luteal phase of the cycle and by their insufficient inhibition with a low level of progesterone in the middle of the luteal phase. Insufficient synthesis of receptors as a result of sharp hypoestrogenemia is less frequent. The primary affection of the receptor apparatus as a cause of the ILP-syndrome against a normal hormonal background in the examinees was undetectable.

[The function of the hepatobiliary system in patients who have had inflammatory diseases of the uterus and adnexa]. / Funktsionalno sustoianie na khepato-biliarnata sistema pri bolni, prekarali vuzpalitelni zaboliavaniia na matkata i adneksite.

The function of the hepatobiliary system was studied on 60 women, undergone inflammatory diseases in the uterus and adnexa. The women of the basic group (n = 60) were divided into two subgroups in accordance with the state of genital organs. The first subgroup (n = 39) included women with residual manifestation of chronic salpingo-oophoritis. The second subgroup (n = 21) included women with tumours and tumour-like processes of genital organs, occurred on the back ground of a continuous inflammatory process. The control group included 10 healthy women. Dynamic scintigraphy of the liver and gallbladder utilizing Tc99 radionuclide with short duration of life, was used to determine the functional state of the liver and gallbladder together with biochemical parameters of blood. The obtained results showed that there were significant changes in hepatobiliary system of women with residual manifestations of chronic salpingo-oophoritis. In women with tumours and tumour-like processes of genitals, occurred on the background of continuous inflammatory process, there were significant disturbances in the engulfing-depurating function of the liver and gallbladder of hypokinetic type.