ReviewAutoimmune primary ovarian insufficiency☆
Introduction
The improvement of assisted reproductive technology has helped infertile men and women worldwide [1]. However, even recent treatments rely mainly on oocyte quality and quantity, otherwise known as ovarian reserve [2]. The most relevant factors that influence ovarian reserve and primordial follicle loss are: aging [3], gynecologic surgery, radiation, smoking [2], infections, genetic, immunosuppressive agents and autoimmune diseases [4], [5], [6], [7], [8], [9], [10], [11], [12], [13].
Usually, autoimmunity occurs in women during reproductive age, and retrospective or cross-sectional studies have already reported an increased risk of premature menopause [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], also named primary ovarian insufficiency (POI) [14], [15], [16], premature ovarian insufficiency [17] or premature ovarian failure (POF) [18], and/or diminished ovarian reserve (DOR) [2] in autoimmune diseases, such as systemic lupus erythematosus (SLE) [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], thyroiditis [13], [18] and dermatomyositis [7].
POI is defined as sustained amenorrhea before the age of 40 years, high follicle stimulating hormone (FSH) levels greater than 40 IU/L [6], [8], [9], [11], [12], [17], [19] and hypoestrogenism associated with infertility [14]. The term “insufficiency” is preferable to “failure” [15], because it encompasses ovarian dysfunction ranging from subfertility with residual follicular activity to complete follicle exhaustion [14], and is less stigmatizing [17].
As POI is the late manifestation of the follicular pool loss [8], alterations of more specific ovarian reserve tests, mainly anti-Müllerian hormone (AMH) and antral follicle count (AFC), precede this event [9], [14]. In this review, we will adopt the term POI [14], [15], [16], to describe women with advanced ovarian dysfunction and DOR to describe women with initial alterations of ovarian reserve tests [2].
Section snippets
Etiology and epidemiology
The etiology of POI is multifactorial and includes different causes, such as idiopathic, X-chromosome alterations, autosomal genetic disorders, radiation therapy, infections, immunosuppressant drugs and autoimmune oophoritis [15], [17], [20], [21].
Autoimmune disease is characterized by autoreactive T-cells and the presence of organ and non-organ-specific autoantibodies [11], [14]. Autoimmune oophoritis can be diagnosed in women with histological inflammatory features in ovary biopsy and
Clinical features and ovarian reserve markers
Autoimmune oophoritis per se is in most cases asymptomatic. However, acute abdominal pain, adnexal mass, and enlarged ovarian cysts have been reported [26].
Clinically, amenorrhea is the hallmark of POI [20], [27], however before menstruation stops completely, irregular cycles occur. Infertility, hot flushes, vaginal atrophy, and dyspareunia are common symptoms [27]. Early menopause also increases the risk of sexual dysfunction, osteoporosis, cardiovascular mortality, psychological problems [20]
Pathogenesis and autoantibodies
The follicle includes the oocyte encompassed by granulosa and thecal cells that are relevant for follicles development [5], [8], [20]. A plausible hypothesis for autoimmune oophoritis is a selective involvement of developing follicles, sparing primordial follicle in early phase, with increased ovaries size with luteinized cysts [26]. The subsequent progressive decrease of ovarian function and reserve was demonstrated to be due to activation of CD4 + T cells and ovary lymphocytic infiltration in
Histology
Ovarian biopsy may be indicated in patients with circulating organ-specific autoantibodies to confirm autoimmune oophoritis [15], [26]. The ovaries are not large organs, have considerable mobility inside the pelvis, and are surrounded by important vessels, including iliac vein and artery, all features that complicate the procedure. Therefore, the experience with ovarian histology in autoimmune oophoritis is limited [26], and relies mostly in patients with APS type I and type I, adrenocortical
Diagnosis criteria of autoimmune POI/DOR
There is no consensus of autoimmune POI or DOR diagnostic criteria. We propose herein that this autoimmune abnormality may be confirmed by ovarian histology in women with serum ovarian, adrenocortical and/or steroidogenic autoantibodies with or without autoimmune diseases and in POI patients with autoimmune Addison's disease and adrenocortical and/or steroidogenic autoantibodies. The exclusion of other etiologies of POI/DOR is also mandatory, particularly genetic, previous ovarian surgery,
Treatment
Unfortunately, up to date guidelines for the treatment of autoimmune oophoritis are not available. Strategies to POI treatment include hormone replacement and infertility therapy [33]. Corticosteroid may restore ovarian function [17]. However, the use of this immunosuppressive agent is controversial [26] and need prospective, randomized and controlled studies [17]. Assisted conception with donated oocytes has been proven to achieve pregnancy by intracytoplasmic sperm injection in POI [18]. The
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Financial support: This study was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2008/58238-4 to CAS, 2009/51897-5 to EB and CAS, 11/12471-2 to CAS), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ 302724/2011-7 to CAS, 300665/2009-1 to JFC and 301411/2009-3 to EB), Federico Foundation (to CAS, JFC and EB) and by the Núcleo de Apoio à Pesquisa “Saúde da Criança e do Adolescente” da USP (NAP-CriAd) to CAS.