Autoimmune Diseases in Patients with Premature Ovarian Insufficiency-Our Current State of Knowledge.

Premature ovarian insufficiency (POI), previously known as premature ovarian failure or premature menopause, is defined as loss of ovarian function before the age of 40 years. The risk of POI before the age of 40 is 1%. Clinical symptoms develop as a result of estrogen deficiency and may include amenorrhea, oligomenorrhea, vasomotor instability (hot flushes, night sweats), sleep disturbances, vulvovaginal atrophy, altered urinary frequency, dyspareunia, low libido, and lack of energy. Most causes of POI remain undefined, however, it is estimated that anywhere from 4-30% of cases are autoimmune in origin. As the ovaries are a common target for autoimmune attacks, an autoimmune etiology of POI should always be considered, especially in the presence of anti-oocyte antibodies (AOAs), autoimmune diseases, or lymphocytic oophoritis in biopsy. POI can occur in isolation, but is often associated with other autoimmune conditions. Concordant thyroid disorders such as hypothyroidism, Hashimoto thyroiditis, and Grave's disease are most commonly seen. Adrenal autoimmune disorders are the second most common disorders associated with POI. Among women with diabetes mellitus, POI develops in roughly 2.5%. Additionally, autoimmune-related POI can also present as part of autoimmune polyglandular syndrome (APS), a condition in which autoimmune activity causes specific endocrine organ damage. In its most common presentation (type-3), APS is associated with Hashomoto's type thyroid antibodies and has a prevalence of 10-40%. 21OH-Antibodies in Addison's disease (AD) can develop in association to APS-2.

Streptococcal toxic shock syndrome following group A streptococcal vulvovaginitis in a breastfeeding woman.

Streptococcal toxic shock syndrome (STSS) is a systemic, life-threatening illness usually caused by invasive respiratory tract or skin and soft tissue infections of Streptococcus pyogenes (group A streptococcus, GAS). We report the case of an adult woman with lactational amenorrhea and GAS vulvovaginitis progressing to STSS. She was admitted to our hospital because of fever, lethargy, and a 2-week history of vaginal discharge; she also had hypotension and multiple organ failure. Blood and urine cultures yielded gram-positive cocci and GAS. After 14 days of antimicrobial therapy, she fully recovered without any complications. The vulvovaginitis was most likely the portal of entry for GAS, which is rarely recognized as a causative pathogen of vulvovaginitis. Lactational amenorrhea is thought to be a risk factor for GAS vulvovaginitis. It is important for clinicians to recognize the possibility of GAS vulvovaginitis in breastfeeding women with vaginal symptoms and consider the necessity of prompt antibiotic treatment.

Impact of CD4+ lymphocytes and HIV infection on Anti-Müllerian Hormone levels in a large cohort of HIV-infected and HIV-uninfected women.

PROBLEM: Effects of HIV infection on ovarian function and aging are unclear. METHOD OF STUDY: Anti-Müllerian Hormone (AMH) levels were analyzed in 2621 HIV-infected and 941 uninfected participants using left-censored longitudinal models. RESULTS: Age-adjusted AMH levels were 16% lower in women with undetectable viraemia and 26% lower in detectable viraemia, relative to uninfected women. Current CD4 count associated with higher AMH in both HIV-infected and HIV-uninfected women. After controlling for current and nadir CD4, AMH was ~15% higher in HIV-infected relative to uninfected women, regardless of HIV viraemia. Gravidity, amenorrhea, and nadir total lymphocyte counts associated with higher AMH; hormonal contraceptive use and past weight loss associated with lower AMH. CONCLUSIONS: CD4 +  lymphocyte counts were associated with AMH in both HIV-infected and uninfected women. After adjustment for CD4 counts and age, HIV infection was associated with higher AMH. CD4 T cells and cellular activation may influence ovarian granulosa cell function.

Mucosal immune function comparison between amenorrheic and eumenorrheic distance runners.

This study examined the effects of amenorrhea on mucosal immune function and susceptibility to upper respiratory tract infection (URTI) in elite female distance runners. Based on their menstrual cycles during the prior year, 21 elite, collegiate, female distance runners were designated as eumenorrheic runners (ERs; n = 8; 19.9 ± 0.8 years) or amenorrheic runners (ARs; n n = 13; 20.0 ± 0.3 years). Resting saliva and blood samples were collected in the morning. The secretory immunoglobulin A (SIgA) concentration was measured using enzyme-linked immunosorbent assay. The SIgA secretion rate was calculated. Serum 17ß-estradiol concentrations and serum progesterone concentrations were measured using radioimmunoassay. Subjects reported the appearance of URTI symptoms (sore throat, headache, runny nose, coughing, or fever), if any, during the prior month. The serum estradiol concentration and salivary SIgA secretion rate were significantly lower for ARs than for ERs (p < 0.05). Serum progesterone concentration was not significantly different between groups. Higher frequencies of headache, runny nose, coughing, and fever were observed in ARs than in ERs. Results show that athletic amenorrhea with low estrogen might accelerate downregulation of mucosal immune function in athletes and enhance susceptibility to infection.

Prolactin and autoimmunity.

Sex hormones, especially estrogen and prolactin (PRL), have an important role in modulating the immune response. PRL is secreted from the pituitary gland as well as other organs and cells particularly lymphocytes. PRL has an immune stimulatory effect and promotes autoimmunity. PRL interferes specifically with B cell tolerance induction, enhances proliferative response to antigens and mitogens and increases the production of immune globulins, cytokines and autoantibodies. Hyperprolactinemia (HPRL) in women present with clinical manifestations of galactorrhea, primary or secondary amenorrhea, delayed menarche or a change in the menses either in the amount or in the regularity. Furthermore in the last 2 decades multi-organ and organ specific autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS), Hashimoto's thyroiditis (HT), multiple sclerosis (MS), psoriasis, hepatitis C patients, Behçet's disease, peripartum cardiomyopathy (PPCM) and active celiac disease were discussed to be associated with HPRL. There is data showing correlation between PRL level and diseases activity in few diseases. Genetic factors may have a role in humans as in animal models. The PRL isoforms based on the differences in the amino acid sequence and size of the cytoplasmic domain have an important effect on the bioactivity on prolactin receptors (PRL-Rs).

Gliadin allergy manifested with chronic urticaria, headache and amenorrhea.

Gluten intolerance is an autoimmune enteropathy caused by heterogeneous mixture of wheat storage proteins. Malabsorption symptoms imply diarrhoea, abdominal pain/bloating and weight loss. This case describes a 22-year-old female subject, who had chronic headache, joint pain, urticaria and long period of amenorrhea. Skin prick tests revealed a sensitisation to α-gliadin, while neurological, gynaecological, endocrine and clinical-laboratory examinations did not justify the above-mentioned symptoms. Gluten-free diet resolved chronic symptoms and re-established the menstrual cycle, whereas a temporary gliadin daily diet re-exacerbated all clinical symptoms. Urticaria occurred 20 min and the chronic headache the next day after exposure to the gliadin-rich diet. In addition, the missing of the expected menstrual bleeding was observed. This case demonstrates that gliadin intake can induce malabsorption and 'idiopathic' neuronal or gynaecological symptoms.

Menstrual function, menstrual suppression, and the immunology of the human female reproductive tract.

Analyses of menstrual function are important to our understanding of human evolution and can help to assess the risks of menstrual suppression, a practice increasingly recommended for women. Two evolutionary issues, however, are insufficiently appreciated in these analyses: the selection pressure infections pose to the human female reproductive system, and the variety of different-and possibly conflicting-immunological functions in the healthy human female reproductive and genital tract. Part of the reason why these issues are inadequately addressed is that reproduction is not sufficiently contextualized in evolutionary and immunological accounts. I argue that expanding the immunological context for menstrual function reinvigorates Margie Profet's (1993a) hypothesis that menstruation defends against sperm-borne pathogens. This expanded context also suggests that menstruation may have more than one function. Thus, until more is known about menstruation, we should proceed cautiously with regard to menstrual suppression.

Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis.

OBJECTIVE: To determine whether fluctuations in functional T-cell subsets can explain why multiple sclerosis (MS) relapses decline during pregnancy and increase in the postpartum period. DESIGN: Case-control study. SETTING: Kaiser Permanente Northern California and Stanford University. PARTICIPANTS: Twenty-six pregnant women with MS and 24 age-matched, pregnant controls. Intervention We prospectively followed up the pregnant women with MS and the age-matched, pregnant controls; conducted structured interviews; and collected peripheral blood mononuclear cells during each trimester and 2, 4, 6, 9, and 12 months post partum. MAIN OUTCOME MEASURES: Sixteen functional cell types, including interferon-gamma (IFN-gamma)- and tumor necrosis factor-producing T-cell subsets, were measured using multicolor flow cytometry. Since these cell types may also fluctuate with pregnancy, lactational amenorrhea, or MS treatment, the data were analyzed taking into account these factors. RESULTS: Fifteen women with MS (58%) had relapses during the postpartum year. CD4(+)IFN-gamma-producing cells fluctuated with MS relapses, declining during pregnancy in women with MS (P < .001) and continuing to decline after parturition in women with relapses (P = .001), yet rising or remaining stable in women with nonrelapsing MS or healthy pregnant women. Lactational amenorrhea was associated with a rise in CD4(+)IFN-gamma-producing cells in women with MS (P = .009). In contrast, CD4(+) tumor necrosis factor-producing cells decreased during lactational amenorrhea in all groups of women and, once this was taken into account, obscured any relationship to MS relapses. CD8(+)IFN-gamma-producing cells were elevated in women with MS throughout the study (P < .001) but did not fluctuate with relapses. CONCLUSIONS: Our findings suggest that a decline in circulating CD4(+)IFN-gamma-producing cells leads to postpartum MS relapses. Our findings also suggest that the decline in these cells may begin during late pregnancy and that lactational amenorrhea induced by exclusive breastfeeding may be able to interrupt this process.

Primary ovarian insufficiency due to steroidogenic cell autoimmunity is associated with a preserved pool of functioning follicles.

CONTEXT: Primary ovarian insufficiency (POI) is defined as hypergonadotropic amenorrhea before the age of 40 yr. In 4-5% of patients with POI, an ovarian autoimmune process is present. DESIGN: Serum concentrations of antimüllerian hormone (AMH) have been determined in 26 women with POI due to steroidogenic cell autoimmunity (SCA-POI), 66 with nonautoimmune idiopathic POI (iPOI), 40 postmenopausal women (PMW), and 44 healthy fertile women (HW). SCA-POI was diagnosed according to presence of steroidogenic enzyme autoantibodies (17alpha-hydroxylase, side chain cleavage, and 21-hydroxylase autoantibodies). RESULTS: AMH concentrations were significantly higher in women with SCA-POI than women with iPOI (P = 0.018) or PMW (P = 0.03) but significantly lower than HW (P < 0.0001). AMH was detected in 11 of 26 women with SCA-POI (42%) and seven of 66 with iPOI (11%) (P = 0.002). Serum concentrations above the fifth percentile of the normal range (0.6 ng/ml) were detected in nine of 26 women with SCA-POI (35%) and four of 66 with iPOI (6%) (P = 0.001). Eight of 12 women with SCA-POI with less than 5 yr (67%) and one of 14 with longer disease duration (7%) had AMH concentrations within the normal range (P = 0.003). AMH concentrations correlated inversely with disease duration in women with SCA-POI (rho = -0.563, P = 0.003) but not women with iPOI. AMH correlated inversely with FSH serum concentrations in HW (rho = -0.584, P < 0.001) but not PMW or women with POI. CONCLUSIONS: Two thirds of women with recent-onset SCA-POI had normal AMH concentrations. Women with SCA-POI, differently from those with iPOI, present a preserved ovarian follicle pool for several years after diagnosis of ovarian insufficiency.

[Activity of succinate dehydrogenase from peripheral blood lymphocytes in girls with sexual maturation disturbance of chromosome genesis].

We carried out a comparative analysis of activity of enzymes characterizing metabolic (SDG) and catabolic (KF) processes in immune system cells of 195 girls with sexual maturation disturbance of chromosome (Shereshevsky-Terner syndrome--STS) and non-chromosome genesis. KF activity was similar in the compared groups and 14 control girls, while SDG activity and FSH levels were much higher in STS girls compared to control girls and girls with amenorrhea of non-chromosome genesis. Thus, FSH has a considerable influence upon metabolic parameters of immune system cells.

[Autoimmune ovarian failure in adolescent girls]. / Autoimunitní poskození ovarii u dospívajících dívek.

BACKGROUND: The aim of the study was to map the incidence of antiovarian antibodies (AOA) in adolescent girls with ovarian cycle irregularities in comparison with girls with the regular cycle. The relation between the AOA positivity and structural changes in the bioptic samples of ovaria was examined. MATERIAL AND RESULTS: The studied cohort included 39 girls with primary amenorrhea (N = 18) and oligo/secondary amenorrhea (N = 21). All patients were tested for the presence of antiovarian antibodies (AOA) in the serum and levels of FSH and LH. The examination was done at the beginning of the study and after six months of therapy, in most of the cases by the hormone substitution treatment. In indicated cases the laparoscopic ovarian biopsy was done. A patients with serious failure of ovarian cycle the positivity of antibodies against various components of ovaria was found. Significantly higher levels of FSH was also found, LH levels were not higher. In our patients the depletion and alteration of the follicular apparatus in the cortex of ovaria belonged to the common findings. The control examination after the six month of hormonal substitution brought about lower levels of AOA, in some patients AOA fully disappeared. CONCLUSIONS: Incidence mapping of antiovarian antibodies in patients with ovarian cycle irregularities correlate with findings of elevated atresia. Ovarian cycle irregularities can later or earlier turn into the extinction of the follicular apparatus and fibrotization of the ovarian cortex.

Anti-nuclear antibodies in patients with premature ovarian failure.

We examined the prevalence of anti-nuclear antibodies (ANA) in 32 consecutive patients with premature ovarian failure with and without chromosomal abnormalities. Blood samples were taken for karyotype determination as well as detection of autoantibodies, X-terminal microdeletions and spontaneous follicular growth. The correlation between ANA positivity and the age at onset of amenorrhoea, as well as the presence of karyotype abnormalities, X-terminal microdeletions and follicular growth was determined. Ten of the 24 patients with normal karyotype and none of the 8 patients with karyotype abnormalities were ANA positive. ANA were found more frequently in patients with premature ovarian failure with normal karyotypes than in control amenorrhoeic patients (42 versus 6, P < 0.01). ANA were found in 77% (10/13) of premature ovarian failure patients with normal karyotypes who developed amenorrhoea at or under the age of 30 years, but not in the patients who developed amenorrhoea later in life. Follicular growth was evident in 50% (5/10) of karyotypically normal patients with ANA, 71% (10/14) of karyotypically normal patients without ANA and 38% (3/8) of patients with karyotype abnormalities. X-terminal microdeletions were not found in any of the patients studied. These results suggest that patients with premature ovarian failure and ANA are an aetiologically and clinically distinct group.

Prevalence, specificity and significance of ovarian antibodies during spontaneous premature ovarian failure.

Autoimmunity may be involved in idiopathic premature ovarian failure (POF). However, the frequency, physiopathology and potential reversibility of autoimmune oophoritis needs clarification. Using an ELISA against whole tissue homogenate as antigen, from human ovaries at different ages, positive circulating ovarian antibodies (AOA) were found in 59% of patients with primitive idiopathic POF (27/46); 20/27 were positive for IgG isotype, 9/27 for IgM and 8/27 for IgA. Specificity of AOA was examined (i) by comparison to different control groups; mean values of the three subclasses of immunoglobins were significantly higher in POF women than in normally cycling fertile young women (n = 23) and fertile young men (n = 17), in untreated Grave's disease (n = 35) or in women with positive antinuclear factor (n = 25); and (ii) by assessing possible cross-reaction; only six out of the 27 positive sera reacted with other tissues (thyroid, pancreas, adrenal), including four clinical polyendocrinopathies. Significance of AOA was explored (i) by comparison with postmenopausal women (n = 40) and older women (n = 15), who did not have enhanced ratios of AOA, thereby excluding a potential role of high FSH values; (ii) by analysing the factors time and surgery; no relation could be found either with the duration of amenorrhoea (6 months to 21 years) or with the history of an ovarian biopsy (12/47) in the absence of any associated pelvic surgery; and (iii) by screening for other immunological factors; familial or personal autoimmune disease (8/46), HLA DR3 (10/42), HLA DR4 (11/42), associated autoantibodies (thyroperoxidase, adrenal, beta islets, parathyroid, DNA, smooth muscles) (12/42). If one positive AOA isotype was present, a second immunological factor was found in 45% of cases. Spontaneous pregnancies during oestrogen therapy occurred in four cases, including three women with positive AOA. Circulating AOA detected by an ELISA may represent a practical and suitable marker for diagnosis of POF. Its use for prognosis and rational treatment needs further evaluation.

Circulating ovarian autoantibodies and FSH and LH levels in adolescent girls with primary menstrual cycle disorders.

Seventy three adolescent patients with primary menstrual disturbances were studied by immunofluorescent methods for prevalence of ovarian autoantibodies (O-Ab), the enzyme immunoassay (EIA) method for examination of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) hormonal levels was used. Clinically healthy girls (40) served as controls. Patients were divided into a group of 13 girls with primary amenorrhea (PA) and a group of 60 girls with oligo and/or secondary amenorrhea (OSA). In the PA group 38.5% positivity linked to ooplasm (OO), zona pellucida (ZP), and membrana granulosa cells (MG), as well as 46.2% to theca folliculi interna (TI) and 53.8% to lutein cells (LC), was detected. Statistically significant differences (p < .05) of LH levels between OO immunopositive and negative girls (19.0 and 9.4 mU/ml) were found, while FSH values were not different. In the OSA group a 16.7% positivity linked to OO, 23.3% to ZP and MG, 38.3% to TI, and 58.3% to LC were detected. Significant linkage between MG immunopositive and negative girls and FSH:LH ratio values were estimated. FSH values were significantly different (p < .05) for PA and OSA groups (23.7 and 6.7 IU/l) which corresponded particularly with higher findings of Ab in germ line-cells (OO-, ZP-, and MG-Ab). A striking correlation between evidence of O-Ab and menstrual cycle irregularities was found. It could support a possible coincidence of autoimmune mechanism in these dysfunctions. Localization of O-Ab-binding was verified at the electron microscopic level.

Detection of antibodies to ovarian antigens in women with premature ovarian failure.

Premature ovarian failure is a common condition of uncertain aetiology in most cases, although autoimmunity is thought to play a role in a proportion of cases. The frequency of ovarian antibodies, which may be markers for an autoimmune aetiology in this condition, remains unclear. To define this further, we have examined the sera of 45 women with premature ovarian failure (five with iatrogenic ovarian failure, nine with an associated autoimmune disease, and 27 with idiopathic ovarian failure), as well as four women with infertility due to Turner's syndrome and 41 pre- and post-menopausal controls. Using two human ovarian antigen preparations, 24% and 60% of the ovarian failure patients reacted in an ELISA (P < 0.05 and P < 0.001 compared with controls), but frequent cross-reactivity was found with fallopian tube antigens. The apparent aetiology of ovarian failure did not correlate with the presence of ovarian antibodies. Using bovine ovary as an antigen, there was a significant overall increase in binding by the ovarian failure patients, but this was almost identical to binding in an ELISA with bovine fallopian tube. In contrast to a previous report, there was no significant increase of binding to soluble or Triton-extracted membrane fractions of bovine corpora lutea containing the LH/hCG receptor by the patients with ovarian failure. These results suggest that ovarian antibodies are common in premature ovarian failure, but their specificity and pathogenic role are questionable.

Menopause before 40--premature, but not always permanent.

Seventy-five women with premature menopause presented to a reproductive endocrinologist over a 3-year interval. Thirty-five had an identifiable cause, usually a chromosomal defect, autoantibodies or cytotoxic chemotherapy. Forty had no apparent cause and of this group 5 conceived on hormone replacement therapy (HRT). Overall, this group of oestrogen deficient women had spent nearly half of their menopausal years to date, not on HRT.

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.