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Premature Ovarian Insufficiency (POI) and Autoimmunity-An Update Appraisal

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Premature Ovarian Insufficiency (POI) and Autoimmunity-An Update Appraisal Journal of Assisted Reproduction and Genetics (2019) 36:2207–2215 https://doi.org/10.1007/s10815-019-01572-0 REVIEW Premature ovarian insufficiency (POI) and autoimmunity-an update appraisal Michal Kirshenbaum1,2 & Raoul Orvieto1,2,3 Received: 4 August 2019 /Accepted: 16 August 2019 / Published online: 22 August 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose Primary ovarian insufficiency (POI) represents ovarian dysfunction related to very early aging of the ovaries. While the cause of POI in a majority of clinical cases remains undefined, autoimmunity is responsible for approximately 4–30% of POI cases. In the present paper, we aim to provide a critical appraisal and update review on the role of autoimmunity in POI patients. Methods A literature review was conducted for all relevant articles reporting on POI and autoimmunity. PubMed/MEDLINE and the Cochrane library were searched for the best available evidence on this topic. Results Patients with POI and coexisting autoimmunity are indistinguishable from those with negative autoimmune screen with regard to age of onset, prevalence of primary amenorrhea, or their endocrine profiles. A specific noninvasive reliable diagnostic test for the diagnosis of an autoimmune etiology is lacking; therefore, patients should be screened for the most common autoantibodies, i.e., steroid cell antibodies, anti-ovarian antibodies, and anti-thyroid antibodies. Moreover, treatment strategies to POI infertility are lacking and controversial. Conclusions Nowadays, guidelines for the treatment of autoimmune POI are not available. Moreover, since diagnostic and treatment strategies to POI infertility are still lacking and controversial, further large clinical studies are needed to investigate the true impact of autoimmunity on POI and to identify the selected groups of patients who are most likely to benefit from immunossuprresive treatment. Keywords Primary ovarian insufficiency (POI) . Autoimmunity . Diagnosis . Steroid cell antibodies . Anti-ovarian antibodies . Anti-thyroid antibodies . Immunossuprresive Introduction quality and number, which is responsible to decrease fecundi- ty. While the reductions in oocyte quantity and quality with The number of oocytes in the human ovaries is determined advanced age (typically in the mid-40s) are a normal physio- during fetal life and progressively decreases throughout the logic occurrence termed diminished ovarian reserve (DOR) female reproductive life span. The maximum number of oo- [4], some women experience DOR much earlier and become cytes is 6 to 7 million at approximately 20 weeks gestational prematurely infertile. Of notice, the majority of follicles are age, decreases to approximately 1 to 2 million at birth and to lost to atresia during the maturation process [5, 6]. Within each 300,000–500,000 at puberty. From puberty to the age of woman, there are large variations in the number of oocytes 51 years—coinciding with the average menopausal age and the rate of ovarian oocytes pool depletion [7], with limited [1–3]—there is a progressive age-related decline in both egg knowledge of what controls this number. Premature ovarian failure (POF) is defined by the presence of postmenopausal levels of FSH (> 40 IU/L) in woman under * Raoul Orvieto 40 years of age, with four or more months of secondary amen- [email protected] orrhea [8–11]. POF affects ~ 1% of women before the age of 1 Department of Obstetrics and Gynecology, Chaim Sheba Medical 40 and 0.1% before the age of 30 [12, 13], and is characterized Center, Tel-Hashomer, Ramat Gan, Israel by infrequent or absent periods, infertility, menopausal symp- 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel toms, and long-term adverse effects of estrogen deprivation. Treatment should be therefore primarily directed at symptom 3 The Tarnesby-Tarnowski Chair for Family Planning and Fertility Regulation, Sackler Faculty of Medicine, Tel Aviv University, Tel resolution, including a psychosocial support for women facing Aviv, Israel this devastating diagnosis. Of notice, POF represents the most 2208 J Assist Reprod Genet (2019) 36:2207–2215 extreme cases of a much larger group of 10% women with so- autoimmune screen with regard to age of onset, prevalence of called premature ovarian aging (POA) [14]. primary amenorrhea, or their endocrine profiles, with 30% of Histological examination of ovaries from POF patients those experiencing a return of menstruation had a positive an- shows either a complete loss of ovarian follicles or the persis- tibody screen. Yet, according to the aforementioned ESHRE tence of more or less abundant follicles. The latter represents Guideline Group, the diagnostic autoimmune workup for POI ~ 40% of POF patients [15] and is in agreement with ultra- should be restricted only to the measurements of antibodies to sound studies that have demonstrated residual follicular struc- ACA/21OH and thyroid antibodies and TPO-Ab [21]. tures in 41–60% of patients with POF [16, 17]. Of notice, Prompted by the aforementioned information, in the pres- while follicular depletion might be the consequence of non- ent review, we aim to provide a critical appraisal and update autoimmune causes, it may also be the final stage of an auto- review on the role of autoimmunity in POI infertile patients. immune disease, where inflammation has ceased following the elimination of all autoantigens. A decade ago, the term primary ovarian insufficiency (POI) The immune system and ovarian physiology was introduced to represent ovarian dysfunction related to very early aging of the ovaries. The terminology of POI is The immune system plays a crucial role in ovarian physiology considered to better represent this POA condition [18], be- [27]. Depletion of macrophages/dendritic cells in CD11c- cause there is intermittent and unpredictable ovarian function diptheria toxin receptor transgenic mice resulted in loss of and spontaneous ovulations in 50% and 20%, respectively and ovarian vascular integrity, reduction in mature follicles, and about 5–10% of these women conceive after the diagnosis is impaired ovulation [28–30]. Moreover, systemic pro- made [11, 19]. inflammatory conditions were shown to alter ovarian homeo- In recent years, the known aetiologies of POI have expand- stasis and detrimentally affect follicular dynamics [31]. The ed, although the cause of POI in a majority of clinical cases human ovary is a common target to autoimmune attack, with remains undefined. POI can be iatrogenic (as a consequence the consequent occurrence of ovarian dysfunction manifested of ovarian surgery, chemo-radiotherapy, etc.), caused by by POI, polycystic ovary syndrome, unexplained infertility, or genetic/chromosomal aberrations, infections, environmental endometriosis [32]. In POI patients, evidences for autoim- factors, metabolic (diabetes type 1, galactosemia, etc.), and mune cause relate on the presence of either lymphocytic endometriosis or it can be associated with autoimmune disor- oophoritis, association with other autoimmune disorders, or ders [19, 20]. the presence of AOAs [10, 14]. According to the ESHRE Guideline Group on POI [21], patients with POI should undergo a thorough investigation, Cellular immunity which includes: Abnormalities of the cellular immunity play an important role & Chromosomal analysis in pathogenesis of autoimmune POI [33–35]. The absolute & Autosomal genetic testing only in cases suggestive of a count and percentage of peripheral blood T-lymphocytes, espe- specific mutation (e.g., blepharophimosis–ptosis– cially CD4+ T cells, were found to be increased in patients with epicanthus inversus syndrome) POI [33], while the number and activity of natural killer (NK) & Fragile-X premutation testing cells seemed to be reduced [36, 37]. POI patients were shown & Screening for 21OH-Ab (or alternatively adrenocortical to have low levels of CD8+/CD57+ T cells (cytotoxic T lym- antibodies (ACA) phocytes) and an overall increase of the CD4+/CD8+ ratio [38, & Screening for thyroid antibodies 39], which could be the result of chronic hypoestrogenism [40]. & Routine screening POI women for diabetes or infection is Moreover, blood monocytes of POI patients demonstrated an not recommended abnormal response to chemotactic agents in vitro [36, 40], whereas dendritic cells from the same patients presented a re- Autoimmune causes of POI should be suspected in the duced capacity to aggregate with T-lymphocytes. presence of anti-ovarian antibodies (AOAs), the histological Kobayashi have recently examined the relationship be- evidences of lymphocytic oophoritis, or any associated auto- tween peripheral blood regulatory T (Treg) cells and autoan- immune disorder [15, 22]. While the coexistence of autoim- tibodies in POI. They observed decreased numbers of effector mune disorders is common in POI patients, histological signs Treg cells and increased CD4+ CD69+ activated T cells in of oophoritis were detected only in those with circulating ad- peripheral blood in POI, supporting the aforementioned ob- renal or AOAs [23, 24]. servations suggesting that POI is an autoimmune disease [41]. Autoimmunity is responsible for approximately 4–30% of The role of cytokines has also been described in causing POI cases [25, 26]. Patients with POI and coexisting autoim- follicular atresia in POF [42, 43]. This coexistence of an im- munity are indistinguishable from those with negative paired cellular immune response with autoimmune ovarian J Assist Reprod Genet
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