Iran J Reprod Med Vol. 13. No. 8. pp: 461-472, August 2015 Review article

The role of autoimmunity in premature ovarian failure

Mahbod Ebrahimi M.D., Firouzeh Akbari Asbagh M.D.

Department of Obstetrics and Abstract Gynecology, Moheb-e-Yas Women General Hospital, Faculty of Premature ovarian failure (POF) is a heterogeneous syndrome with several causative Medicine, Tehran University of factors. Autoimmune mechanisms are involved in pathogenesis of 4-30 % of POF Medical Sciences and Health cases. The present review focuses on the role of autoimmunity in the Services, Tehran, Iran. pathophysiology of POF. The evidences for an autoimmune etiology are:

demonstration of ovarian autoantibodies, the presence of lymphocytic oophoritis, and association with other autoimmune disorders. Several ovarian antigenic targets have been identified in POF patients. The oocyte seems to be the most often targeted cell. Lymphocytic oophoritis is widely present in POF associated adrenal

s disease is one of the most common autoimmune disordersۥinsufficiency. Addison associated with POF. Early detection of this potentially life threatening disease was recommended in several studies. The gold standard for detecting autoimmune POF is ovarian biopsy. This procedure

is not recommended due to unknown clinical value, expense, and risks. Several immunoassays have been proposed as substitute diagnostic tools. Nevertheless, there is no clinically proven sensitive and specific serum test to confirm the diagnosis of autoimmune POF or to anticipate the patient’s chance of developing POF or Corresponding Author: Mahbod Ebrahimi,, Department of associated diseases. Obstetrics and Gynecology, Some authors suggested the possible effects of immuno-modulating therapy on the Moheb-e-Yas Women General resumption of ovarian function and fertility in a selected group of autoimmune POF Hospital, North Oustad Nejatollahi patients. However, in most instances, this treatment fails to reverse the course of the Ave, Karim Khan St., Tehran, Iran. Postal code: 1597856511 disease. Email: [email protected] Numerous studies illustrated that standard treatment outcome for is less Tel: (+98) 21-88897761-3 effective in the presence of ovarian autoimmunity. The -induced damage

could be a pathogenic factor. Nevertheless, the precise cause remains obscure. Received: 16 November 2014 Revised: 25 March 2015 Key words: Premature ovarian failure, Premature ovarian insufficiency, Autoimmune Accepted: 28 March 2015 oophoritis, Autoimmunity.

Introduction reflect reversible nature of this condition (11- 14). The disease affects 0.3-1% of general remature ovarian failure (POF) is a population (6, 15-17). Follicle depletion and term to define the women younger follicle dysfunction are two main etiological than 40 years of age who present mechanisms (9, 18). Follicle depletion can be P with lasting more than 4 the consequence of a primitive reduced pool months and hypoestrogenic- of oocytes or an accelerated follicular atresia hypergonadotropic serum profile (follicle (10). FSH-receptor mutation, inappropriate stimulating hormone (FSH) levels≥ 40 mIU/mL luteinization related to low follicular count, and on two occasions) (1-5). This disorder is autoimmune oophoritis were suggested as the characterized by anovulation, amenorrhea, causes of follicle dysfunction (9, 19). The sex steroid deficiency, and infertility (1). The etiology of the disease varies in different most common presentation is secondary patients: chromosomal/genetic abnormalities, amenorrhea and the main consequences are metabolic/enzymatic factors, autoimmunity, infertility and psychological stress (6-8). infections, environmental toxins, and However, POF is an important cause of iatrogenic influences involve in development secondary amenorrhea and infertility, some of the disease (1, 10, 20-22). Nevertheless, patients may continue to ovulate and conceive the precise cause is undetermined in a (7-10). Therefore, "premature ovarian significant portion of patients. These cases insufficiency" and "premature ovarian were classified as idiopathic (2, 23-28). Based dysfunction" are more accurate phrases to on clinical observations, immunological data, Ebrahimi et al and histological findings, autoimmunity may antibody-mediated mechanism for ovarian be the pathogenic mechanism in 30% of involvement (2, 18, 35, 36, 45). The presence cases of idiopathic POF (23). The following of these is in association with review article presents the role of increased risk of ovarian failure independent autoimmunity in pathogenesis of POF, of reproductive hormonal levels (50). AOAs obtained by MEDLINE, EMBASE, Pub Med, may be detected in serum prior to the onset of Google Scholar, the Cochrane Library, and clinical presentation of POF (51). hand searches of pertinent references of The antibodies binding to the various English literature on POF and autoimmunity, steroid hormone-producing cells (52-56), cited between the January 2000 and gonadotropins and their receptors (57-60), December 2013. Reference lists of review zona pellucida (61, 62), oocyte (63, 64), articles, relevant trials, immunology and corpus luteum (23, 65, 66), and several other gynecology textbooks, and abstracts of antibodies such as anticardiolipin and scientific meetings were also searched. The antinuclear antibodies (34, 43) have been literature search was performed using reported as the markers of ovarian PubMed keywords: premature ovarian failure, autoimmunity. The multiplicity of the premature ovarian insufficiency, premature suspected auto antigens and related ovarian dysfunction, hyper gonadotropic antibodies illustrates the variety of pathologic hypogonadisem, autoimmune oophoritis, and process causing ovarian damage. autoimmunity. The antibodies directed against steroid- producing cells of various endocrine glands Autoimmunity and POF such as adrenal cortex cells, Leydig cells of The lack of a high sensitive and specific the testis, syncytiotrophoblast of the placenta, test has precluded accurate estimation of the and theca cells of the named as steroid prevalence of autoimmune type of POF (23, cell antibodies (StCAs). These antibodies are 29). Nevertheless, depended on some studies polyclonal immunoglobulins of the IgG class results, autoimmunity is responsible for (67). Some enzymes involved in approximately 4-30% of POF cases (5-33). steroidogenesis pathways are the targets of The autoimmune involvement is base on the these autoantibodies. The main antigenic presence of antiovarian antibodies (AOAs), targets of StCAs are P450-17α-hydroxylase the histological evidences of lymphocytic (17α-OH), P450-side-chain cleavage oophoritis, and association with other (P450scc), and 21- hydroxylase (21-OH) (68). autoimmune disorders (2, 18, 23, 34-42). StCAs are present in some autoimmune diseases such as autoimmune polyendocrine AOAs syndromes (APS); type I, type II, Addison’s The exact mechanism of autoimmunity in disease (AD), and POF (35, 69). Their pathophysiology of this disorder remains prevalence is 60% in APS-I patients, 25-40% obscure; probably the genetic or in APS-II patients, 60-87% in POF associated environmental factors initiate the activation of AD, and 3-10% in isolated POF (35, 43, 54- (5, 23). A review of literature 56). Reato et al. suggested that primary regarding POF with autoimmune involvement amenorrhea in association with StCAs leads reveals that the presence of autoantibodies to autoimmune background of the ovarian directed against ovarian tissues and elements, failure (55). Some studies demonstrated that and their targets in cellular and molecular the presence of these autoantibodies is a levels hold important issues (23, 35, 43-45). predictive marker for developing POF in Nevertheless, it should be mention that patients with autoimmune AD (23, 55). It is alteration in cellular immunity such as likely that 17α-OH and P450scc are the main macrophage and dendrite cells abnormalities, molecular targets of StCAs in sera positive change in CD4+/CD8+ ratio, as well as patients with POF associated AD (23, 35, 54, inappropriate expression of class II MHC 55, 68). Nevertheless, in sera of antigens by granulose cells has been seen in approximately 10% of these patients, neither POF patients (28, 46-48). P450scc nor 17α-OH antibodies were Vallotton and Forbes were the first to detected (35). This observation illustrates the detect AOAs in sera of POF patients (49). presence of some unidentified autoimmune After that, numerous studies showed targets for StCAs. Falroni and colleagues

462 Iranian Journal of Reproductive Medicine Vol. 13. No. 8. pp: 461-472, August 2015 Premature ovarian failure and autoimmunity found that the women with AD related POF to inhibit FSH or Luteinizing hormone (LH) are often (>91%) positive for one of three activity. Gobert and colleagues demonstrated major immune markers of steroid–cell the existence of anti-βFSH antibodies in sera autoimmunity [17α-OH antibodies, P450scc of POF patients (57), their clinical significance, antibodies, and 3β–Hydroxysteroid and diagnostic relevance still needs to be dehydrogenase (3β-HSD) antibodies]. In their investigated through well-designed diagnostic study, only 3% of the patients with isolated studies. POF are positive for these markers (35). Zona pellucida (ZP) is an extracellular These data are consistent with other studies matrix surrounding the mammalian oocyte. Its that StCAS are not major antibodies in molecular structure consists of glycoproteins isolated POF or POF associated with non- with strong antigenic potency. Takamizawa et adrenal . These al. detected anti-ZP antibodies in sera from autoantibodies seem to be main serologic idiopathic POF patients. They introduced a markers for ovarian failure in AD related POF new microdot assay with high specificity for patients (23, 54, 70-72). Falroni and detecting anti-ZP antibodies (79). Their results colleagues also showed that 3β-HSD is not a are in agreement with the various independent major auto antigen in autoimmune POF. They reports on the existence of anti-ZP antibodies concluded that autoantibodies against this (61, 62, 80). The suspected pathological effect enzyme have limited application in routine is the impaired communication between clinical practice. In fact, the presence of 3β- oocyte and granulose cells (62). At present HSD autoantibodies could be the secondary time, there are no well-designed diagnostic consequence of activation of immune system studies to demonstrate the prevalence of (35). In contrast with this study, Arif et al. these antibodies in POF patients. Thus, the suggested that 3β-HSD autoantibodies have a exact importance of these autoantibodies is higher diagnostic sensitivity than other StCAs still unclear. for autoimmune POF (73). The discrepancy Anti-oocyte cytoplasm antibodies have been detected in patients with POF (63, 64). between these studies could be explained in Pires and his group demonstrated that the part by the differences in laboratory cytoplasm of oocyte probably contains the techniques used to measure antibodies; radio most autoimmune targets in POF patients (78, binding assay with in vitro translated 81). Although, the exact nature of the recombinant 35S-labelled auto antigens for antigenic targets are still unclear, MATER Falroni and immunoblotting technique for Arif (Maternal Antigen That Embryo Require), a (35, 73). 125KDa protein may be a possible candidate In earlier published studies, some (26, 82-84). Very little is known about the autoantibodies have been detected on the precise nature of this protein. We need further surface of granulose cells by indirect studies to provide information about MATER immunofluoresence. The researchers have and aid in deciphering its role in ovarian suggested that gonadotropin receptors are the biology. The other identified antigens are targets for these antibodies (30, 63, 74). The Aldehyde dehydrogenase1A1 (ALDH1AI), inhibition of biological activity of gonadotropins Selenium Binding Protein 1 (SBP1), α- and the decline in binding capacity of enolase, and Heat Shock Protein 90 (HSP90) (70, 81, 85, 86). According to Pires et al. gonadotropins to their receptors are two main study, HSP90ß is the most immunodominant suggested mechanisms (75, 76). The findings antigen (78, 81). In contrast with these of the earliest studies regarding the role of studies, the autoantibodies against oocyte these autoantibodies in development of were also found in sera of healthy individuals autoimmune POF were not supported by and a number of neoplastic, autoimmune, and subsequent researches (58, 77). In other way, inflammatory diseases (86-91). anti-gonadotropin receptor antibodies were In various studies, AOAs were detected by also detected in iatrogenic ovarian failure (37). different methods (eg; enzyme-linked In fact, the real significance of these immunosorbent assay, immunohistochemistry, antibodies remains to be determined (78). Western blotting, and indirect In order to detect autoantibodies directed immunofluorescence). The most common against gonadotropins, some researchers used methods are indirect investigated serum factors that might be able immunofluorescence (IIF) and enzyme-linked

Iranian Journal of Reproductive Medicine Vol. 13. No. 8. pp: 461-472, August 2015 463 Ebrahimi et al immunosorbent assay (ELISA) (23). Few association with isolated POF (14). Cellular studies have considered the measuring of infiltration of follicles by macrophages, natural autoantibodies against 21-OH by killer cells, T-lymphocytes, plasma cell, and B- immunoprecipitation assay equivalents to lymphocytes is the characteristic sign of an measurement of these autoantibodies by (IIF) autoimmune oophoritis. The steroid-producing (92, 93). In the other way, Novosad et al. cells are the main target of autoimmune attack showed that validity of immunofluorescence (18, 98). In some cases, abnormal activation for detecting AOAs is questionable (29). of epithelial cells and subsequent follicular The prevalence of AOAs in POF women depletion and fibrosis were seen (98). varies greatly, ranging from 3 to 66.6 percent Nevertheless, the specific histological picture (23, 28, 35, 94, 95). These conflicting results is sparing of primordial and primary follicles could be explained by the difference in design and involvement of developing follicles by elements of studies such as criteria for study lymphocytic infiltration of theca cells (56, 99, and comparison groups, sample size, method 100). With respect to the multifollicular of antigen preparation and antibody detection appearance of in this condition, the (2, 10, 18, 23, 94, 96). We suppose that the size of the involved ovaries could be normal or assessment of only one of several antigenic enlarged on sonographic view (56). Although, targets in some of studies, the differences in follicular depletion is the final stage of this antigen sources, heterogeneity of histological autoimmune attack, the histological samples targets, selection of animal or human ovaries of ovarian tissues reveal the developing at different ages or at different periods of follicles in varying sizes in the majority of menstrual cycle, and transient appearance of patients (101, 102). This observation supports some of antiovarian antibodies have also the positive effect of immunosuppressive changed the outcome of above-mentioned agents in restoring ovarian functions. experiences. Massin and colleagues showed pelvic AOAs might be the main cause of ultrasonography and hormonal profile (FSH, pathogenesis of autoimmune POF, or might LH, estradiol, inhibin B serum levels) are be the result of ability of antibodies production insufficient to predict the presence or absence by this autoimmune disease. In the other of follicular structures in POF patients with hand, there is poor correlation between normal karyotype. They recommended antibody levels and severity of disease (18). ovarian biopsy as the reliable assessment for Some authors conclude that clinical diagnosis detecting follicle presence and activity in these of autoimmune POF, exclusively based on the patients (102). Ovarian biopsy is the gold detection of presence or absence of AOAs will standard for detecting autoimmune be a great mistake (2). involvement of ovarian tissue and the A major weakness in the assessment of the presence of developing follicles in involved role of AOAs is the high rate of false positive ovary (28, 37, 40). Nevertheless, this results (poor specificity) (29). These procedure is invasive and expensive. In other autoantibodies could be found in significant way, few studies demonstrated that the ability numbers of control groups (13, 29). It might be of ovarian biopsy in representing of follicular due to the presence of naturally occurring density of the whole ovary is questionable (10, antibodies (NAA) (97). 14, 103). We need a noninvasive screening At present time, there is no valid serum test to avoid unnecessary ovarian biopsy and marker to certainly prove the diagnosis of to select the women with possibility of autoimmune POF. autoimmune oophoritis. The antibodies to steroid–producing cells have been frequently Lymphocytic oophoritis and POF found in the patients with histological The histopathological evidences of evidences of lymphositic infiltration of the autoimmune ovarian involvement have been ovarian tissue (37, 54). Bakalov et al. showed illustrated in 9.1-11% of the samples of a positive correlation between the presence of ovarian biopsies belong to normal karyotype autoimmune oophoritis and serum adrenal women with hyper gonadotropic amenorrhea cortex antibodies. In light of this observation, (37, 40). Autoimmune oophoritis is usually they recommended the measuring of adrenal detected in AD associated POF patients. cortex autoantibodies in sera of POF patients Rarely, this pathologic picture was seen in to select the patients with possibility of

464 Iranian Journal of Reproductive Medicine Vol. 13. No. 8. pp: 461-472, August 2015 Premature ovarian failure and autoimmunity autoimmune oophoritis (56). Unfortunately, we insufficiency could be associated with serious did not find the published placebo-controlled fetal and maternal complications such as randomized clinical trials with appropriate postpartum adrenal crisis (13, 109). powers to support this finding. Therefore, identification of this subgroup of POF patients with subclinical adrenal POF in association with other autoimmune insufficiency is essential before decision diseases making for egg or embryo donation. Bakalov Ovary is a common target of autoimmune et al. suggested that the morning serum attack in organ-specific and systemic cortisol level has low sensitivity and autoimmune diseases (18, 23, 54, 89, 104, specificity, when used as a screening test in 105). Approximately 10%-55% of patients with POF patients. Based on their findings, the POF have associated autoimmune disorders measuring of adrenal cortex autoantibodies by (18, 23). Hypothyroidism is the most common indirect immunofluorescence technique or associated autoimmune disorder with POF antibodies against 21-OH by (25-60%) (3, 106, 107). Coincidence with immunoprecipitation assay are effective diabetes mellitus is 2.5% (18). Autoimmune screening tests to detect asymptomatic adrenal insufficiency may present as an adrenal insufficiency in these patients (108). It isolated disease or may be associated with is in agreement with the previous reports on other autoimmune disorders (68). this subject (71, 92, 108). They also Approximately 10-20% of Addison patients recommended that the presence of adrenal have POF, and 2.5-20% of women with POF insufficiency could be confirmed by the showing some evidences of autoimmunity standard ACTH stimulation test (108). We against the adrenal gland (18, 55, 108). Dal suggest referral of POF patients with positive Pra et al. showed no difference in the age at adrenal cortex antibodies to endocrinologist onset of POF in patients with or without for additional evaluations and long–term Addison’s disease (54). Autoimmune POF follow-up of adrenal functions. We also usually occurs before the onset of adrenal propose routine screening of thyroid function involvement (23). In Reato et al. study, AD and glucose tolerance in POF patients. Due to preceded POF. Nevertheless, the mean ages the low frequency of the other associated at onset of each disease were close (27 years autoimmune diseases, wider endocrine for AD and 28.5 years for POF) (55). The function screening is not recommended. association of POF with AD could be due to Autoimmune polyglandular syndromes the presence of cross-reacting autoantibodies (APS) are a series of disorders characterized that react against auto antigens common to by autoimmunity against two or more steroid producing cells with different origins endocrine organs (10, 27). APS-I is a rare (54, 55, 108). StCAs were detected in 60-87% autosomal recessive disorder caused by of POF-associated adrenal involvement and mutation in the AIRE (autoimmune regular) 3-10% of patients with isolated form of this gene. The role of this gene is regulation of disorder (35, 37, 43, 52-56). The detection of immune tolerance (105). POF develops in 41- antibodies against 17α-OH and P450scc in 72% of patients with APS type I (13, 18, 55, Addison patients is a predictor factor of for 101, 104). Gonadal failure tends to appear at development of POF (68, 92). In the other a younger age and in the highest prevalence hand, some authors suggested that the compared with the other forms of APS (54, 55, presence of 21-OH antibodies in sera from 68). This event could be due to the mutations women with autoimmune POF might be of AIRE gene in patients with APS-I (54, 55, important marker in identifying patients at risk 68). APS-II is an autosomal dominant disease. of developing autoimmune adrenal The prevalence of ovarian failure in APS-ll is insufficiency (35, 54, 68, 92). As already 10-25% (55, 105, 110). Autoantibodies recognized by above mentioned reports, the directed against steroidogenic enzymes and POF patients with positive sera for StCAs are ovarian steroid–producing cells mediate at risk for adrenal insufficiency, a potentially ovarian dysfunction (111). In general, AD fatal condition, especially during pregnancy precedes POF in patients with APS-I, and (10, 13, 35, 68, 108). Untreated adrenal follows POF in those with APS-II (55). Reato

Iranian Journal of Reproductive Medicine Vol. 13. No. 8. pp: 461-472, August 2015 465 Ebrahimi et al and colleagues suggested that StCAs, 17α- the immunization process against exogenous OHAb, and P450sccAb are the immunological gonadotropins and the development of anti- predictive markers of potential autoimmune FSH and anti-LH antibodies were considered POF in the patients with autoimmune as the cause of poor responding to IVF Addison’s disease and the different types of program (118). In the other hand, some APS (55). authors suggested that anti-ZP antibodies are A review of literature regarding the relation one of the causes of IVF failure by their between POF and autoimmunity indicates that blocking effects on sperm-ZP binding and autoimmune involvement is the main sperm penetration (79, 119-122). In light of mechanism of POF in cases associated with this observation, Mardesic et al. other autoimmune diseases, but in isolated recommended intracytoplasmic sperm POF the evidences supporting this subject is injection (ICSI) as the method of choice in weak (23, 43). However, the higher anti- anti-ZP antibody-positive infertile couples Mullerian hormone and inhibin levels, a low (123). Pires proposed the evaluation of AOAs incidence of histological evidences of as a prognostic factor in patients undergoing oophoritis, and frequent reports of IVF-ET program (78). Later on, Khole spontaneous pregnancy in isolated recommended that serological assessment of autoimmune POF could be the best evidences AOAs before starting IVF protocols would be of transient ovarian damage and some justified in poor responder patients (2). degrees of function preservation (24, 112, With respect to the possibility of the 113). We need the placebo-controlled presence of AOAs in sera of POF women randomized clinical trials to determine the true years before the onset of clinical presentation roles of autoimmunity in pathogenesis of as well as detection of these autoantibodies in isolated POF. one third of patients with unexplained infertility (95), some authors suggested this form of Infertility and autoimmune POF infertility as an early stage of autoimmune The involvement of autoimmune POF. They also recommended the evaluation mechanisms have been suggested in various of ovarian autoimmunity as part of an infertility ovarian pathology, such as polycystic ovarian workup to predict the chance of development syndrome, unexplained infertility, recurrent of gonadal failure in future and identify the pregnancy loss, endometriosis, and other best candidates for oocyte retrieval before conditions with poor reproductive outcome follicular depletion (23, 70). In fact, we have (14, 23, 30, 43, 51, 114). little information about the predictive value of Numerous studies illustrated that standard AOAs in ovarian reserve assessment. We treatment outcome for infertility is less need well-designed studies to clarify this effective in the presence of ovarian subject. autoimmunity. The presence of anti-oocyte cytoplasm antibodies in follicular fluid was The effect of Immunosuppressive associated with unsuccessful oocyte retrieval treatments and fertilization failure in IVF patients (115). Lymphocytic infiltration of theca layer of Some studies demonstrated association developing follicles and sparing of primary and between the presence of serum AOAs and primordial follicles presents the possibility of lower pregnancy rate in women seeking resumption of ovarian function by infertility treatment (34, 51, 116). Furthermore, immunosuppressive treatments (99, 100). a high correlation was seen between poor Although in most instances, treatment with response to IVF programs and the presence immunosuppressive agents failed to reverse of AOAs in sera of infertile women (34, 117, the course of the ovarian autoimmunity or 118). Monnier-Barbarino and colleagues enhance the ovarian response to suggested that hormonal stimulation and gonadotropins (18, 124). Numerous studies ovarian trauma during follicular puncture could have recommended cell-mediated and be the causes of developing or enhancing of humoral immunity suppression by AOAs formation in patients with history of glucocorticoids or anti-B-cell therapies for repeated IVF attempts (117). In another study, reversal of infertility or resumption of ovarian

466 Iranian Journal of Reproductive Medicine Vol. 13. No. 8. pp: 461-472, August 2015 Premature ovarian failure and autoimmunity function in the selected groups of patients with and IVF (in vitro fertilization) using donor autoimmune POF (101, 111, 125-128). It gametes or embryos (10, 136). should be in mind that none of these studies was randomized controlled trial with well- Conclusion selected autoimmune POF patients (129). Indeed, these reports were mostly case series In conclusion, an abundance of evidence studies (127, 130, 131). On the other hand, shows that autoimmunity is responsible for some patients developed serious development of POF especially in cases complications such as Cushing syndrome and associated with other autoimmune diseases. knee osteonecrosis after receiving Several potential immune targets in various corticosteroids (132). Bats et al. parts of ovary have been proposed for recommended tissue diagnosis of local antibody-mediated autoimmune attack. The autoimmune reaction by ovarian biopsy before oocyte seems to be the most often targeted starting immunosuppressive agents (98). cell. Despite the considerable scientific work, Although, the gold standard for detecting the precise nature of molecular targets autoimmune POF is ovarian biopsy (28, 37, responsible for this autoimmune process 40), this procedure is not recommended due remained unclear. The studies regarding to unknown clinical value, expense, and risks antiovarian antibodies have conflicting results, (10, 14, 103). With respect to the association partly due to differences in the detection between the presence of adrenal cortex methods, heterogeneity of the patients and antibodies and autoimmune oophoritis, the control groups, and the lack of high specificity measuring of these autoantibodies in serum and sensitivity tests. This fact illustrates the has been proposed as noninvasive screening need for accurate diagnostic tools in order to test to avoid unnecessary ovarian biopsy and identification the specific antigenic targets and select the patients with possibility of related autoantibodies. autoimmune oophoritis (56). Numerous studies illustrated that standard Dehydroepiandrosterone (DHEA) is an treatment outcome for infertility is less endogenous steroid agent. Zona reticularis effective in the presence of ovarian layer of the adrenal cortex and ovarian theca autoimmunity. Subsequently, some authors cells are sources of secretion in healthy suggested the possible effects of immuno- women. This molecule is precursor of modulating therapy on the resumption of testosterone, androstenedione, and estradiol ovarian function and fertility in a selected (133). DHEA promotes activation of the group of POF patients. Nevertheless, in most oocytes and inhibits atretic phenomena (134). instances, this treatment fails to reverse the Barad et al. noted higher pregnancy rates with course of the disease. DHEA supplementation in patients with The further information regarding diminished ovarian function (134, 135). autoimmune actions of AOAs will lead to Mamas and Mamas reported successful elucidate the underlying mechanisms of pregnancy following DHEA therapy in women ovarian damage. It also will help the with POF (130). Barad and colleagues development of better approaches to believed that the patients in this study did not diagnose, and effective therapeutic regiments. fulfill the criteria of POF. They recommend the We also suppose that the specific noninvasive termination of “premature ovarian aging” tests are essential to detect associated (POA) for definition of these patients with disorders, as well as to select the women with increased FSH levels and diminished ovarian acceptable chance of restoring of ovarian reserve (135). We did not find a specific function and fertility by immunosuppressive treatment modality for autoimmune oophoritis therapy. with proven efficacy and safety confirmed by prospective randomized placebo-controlled Acknowledgements studies. Other suggested fertility options in POF This study has been supported by Tehran patients are IVM (in vitro maturation) of oocyte University of Medical Sciences and Health derived from primordial follicles or stem cells Services. We give special thanks to Mr.

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