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Autoimmune primary ovarian insufficiency (premature ovarian failure)

Autoimmune primary ovarian insufficiency (premature ovarian failure)
Literature review current through: Jan 2024.
This topic last updated: Sep 28, 2023.

INTRODUCTION — 46,XX primary ovarian insufficiency (POI) is defined as the development of primary hypogonadism before the age of 40 years in females who have a normal karyotype. The presenting symptoms are similar to those of menopause. The condition was previously referred to as "premature menopause" and "premature ovarian failure." The age-specific incidence of spontaneous POI is approximately 1 in 250 by age 35 years and 1 in 100 by age 40 years.

Autoimmune POI due to autoimmune oophoritis is one of the rare causes of POI.

This topic review will discuss the pathogenesis, clinical features, diagnosis, and management of autoimmune POI. An overview of the evaluation and treatment of spontaneous POI are reviewed separately. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)" and "Management of primary ovarian insufficiency (premature ovarian failure)".)

EPIDEMIOLOGY — Autoimmune oophoritis is found in approximately 4 percent of females who present with spontaneous primary ovarian insufficiency (POI) [1]. It was first confirmed histologically in a female with coexisting autoimmune adrenal insufficiency [2] and subsequently in additional series of females with similar presentations. There is strong histologic evidence that POI, when it occurs in association with adrenal autoimmunity, is autoimmune-mediated ovarian insufficiency. However, there is only circumstantial evidence to suggest that autoimmune POI occurs in the absence of steroid cell autoimmunity [3].

Autoimmune oophoritis may occur as part of type I and type II syndromes of polyglandular autoimmune failure, which are associated with autoantibodies to multiple endocrine and other organs (table 1). (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Type 1 (monogenic)' and "Causes of primary adrenal insufficiency (Addison disease)", section on 'Type 2 (polygenic)'.)

POI has also been described in females with nonendocrine autoimmune disorders such as systemic lupus erythematosus, pernicious anemia, and myasthenia gravis [4-6].

PATHOGENESIS — The mechanism by which ovarian autoimmunity is initiated is unknown [3,7]. It could be by exposure to a virus or other substance similar in structure to some component of ovarian tissue. Due to such "molecular mimicry," activated lymphocytes or antibodies might react with ovarian tissue. It is also possible that a virus or other agent could damage ovarian tissue in such a way that it becomes antigenic. Alternatively, a basic failure in immune regulation might develop, leading to loss of specific tolerance to some ovarian component, and ultimately, ovarian autoimmunity [2]. AIRE mutations may be involved in some patients. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Autoimmune adrenalitis'.)

CLINICAL FEATURES

Features unique to this disorder — There are several clinical features that are unique to autoimmune oophoritis, including enlarged cystic ovaries [8-12], the presence of antiadrenal antibodies (and often primary adrenal insufficiency), and evidence of theca cell (but not granulosa cell) destruction. The presence of large ovarian cysts may be an early feature of autoimmune ovarian insufficiency. Late in the course of the disorder, the ovaries are small, lack follicles, and are not different than ovaries affected by other causes of primary ovarian insufficiency (POI).

Symptoms — The clinical presentation of females with autoimmune POI is similar to that of females with other causes of POI and includes a change in menstrual function (oligomenorrhea and/or amenorrhea) and symptoms of estradiol deficiency, such as hot flashes and vaginal dryness. However, because intermittent ovarian function occurs in approximately 50 to 75 percent of females with spontaneous POI, the absence of vasomotor symptoms or vaginal dryness should not dissuade one from considering the diagnosis of POI in a female who presents with menstrual irregularity. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)", section on 'Clinical features'.)

In females with autoimmune oophoritis, the development of irregular menses usually precedes the development of symptomatic adrenal insufficiency by several years [4]. However, adrenal insufficiency can precede POI [11]. Symptoms that suggest the onset of primary adrenal insufficiency include anorexia, weight loss, vague abdominal pain, weakness, fatigue, salt craving, or increased skin pigmentation (see "Clinical manifestations of adrenal insufficiency in adults", section on 'Chronic adrenal insufficiency'). Approximately 3 percent of females with spontaneous POI develop adrenal insufficiency, a 300-fold increase compared with the general population.

A personal or family history of autoimmune diseases might suggest type I or type II syndromes of polyglandular autoimmune failure. Type I autoimmune failure most commonly occurs in children associated with adrenal insufficiency, hypoparathyroidism, and mucocutaneous candidiasis. Type II autoimmune typically occurs with adrenal insufficiency, type I diabetes, and hypothyroidism or Graves' disease. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Autoimmune adrenalitis'.)

Laboratory findings — The biochemical findings of females with autoimmune POI are also similar to those of females with other causes of POI and include a low serum estradiol and high serum gonadotropin concentrations. Steroid cell autoantibodies detected by indirect immunofluorescence have been identified in patients with POI associated with Addison disease [13-15]. These antibodies may also be present in patients with isolated POI [1,16-18]. One study demonstrated that steroid cell autoantibodies as detected by indirect immunofluorescence (using adrenal tissue substrate) are significantly associated with the presence of histologically-confirmed autoimmune oophoritis [1]. Measurement of 21-hydroxylase autoantibodies in this context is considered essentially equivalent to measurement of steroid cell autoantibodies [1]. (See "Causes of primary adrenal insufficiency (Addison disease)".)

In one report of three females with presumptive autoimmune oophoritis and multifollicular development, the following biochemical findings were noted [12]:

Serum estradiol and androstenedione concentrations were extremely low, but inhibin B concentrations were high (unlike normal menopause and other causes of POI, where serum inhibin level is extremely low).

This observation of normal inhibin B production in the absence of estradiol precursors (or estradiol) suggests that theca cells are selectively affected while granulosa cells are spared in patients with autoimmune oophoritis [12].

Serum luteinizing hormone (LH) concentrations were in the postmenopausal range, while follicle-stimulating hormone (FSH) concentrations were at the upper limit of normal for premenopausal females. This pattern is different from the pattern in normal menopause and other causes of POI, where serum FSH concentrations generally are higher than LH concentrations. This difference is likely due to the differences in inhibin B production (normal in autoimmune POI and low in normal menopause). (See "Clinical manifestations and diagnosis of menopause", section on 'Menstrual cycle and endocrine changes'.)

In a second study, serum inhibin B concentrations were significantly higher in 22 females with autoimmune POI (and steroid cell autoantibodies) when compared with 71 females with non-autoimmune "idiopathic" POI (median concentrations 109 versus 18 pg/mL, respectively) [19]. The authors concluded that cutoff values of 133 pg/mL for total inhibin and 60.5 pg/mL for inhibin B provided 86 percent sensitivity and 81 to 85 percent specificity for autoimmune versus idiopathic POI.

Histology — In some cases, ovarian biopsy of females with POI (premature ovarian failure) has shown autoimmune oophoritis, characterized by lymphocytic infiltration involving secondary and antral follicles but sparing primordial follicles (picture 1) [20]. The lymphocytic infiltration was most intense in the theca of developing follicles and was associated with intense luteinization of follicles [1,2,21,22]. These findings are found almost exclusively in females who have circulating antibodies against adrenal antigens [1,3]. The fact that the inflammatory reaction is confined to growing follicles that have a theca suggests that the antigens are fully expressed only in these follicles, consistent with the hypothesis that steroid hormone-producing cells express the antigens that stimulate the immune response [1,2].

DIAGNOSIS

Criteria for diagnosis — The diagnosis of autoimmune oophoritis is based upon:

Clinical evidence of primary ovarian insufficiency (POI), including menstrual dysfunction, low estradiol and high serum gonadotropin concentrations

The presence of steroidogenic cell autoantibodies

The exclusion of other causes of POI such as X chromosome defects and the fragile X messenger ribonucleoprotein 1 (FMR1) premutation (see "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)", section on 'Additional evaluation once diagnosis is made')

Testing for the presence of 21-hydroxylase autoantibodies or adrenal autoantibodies is sufficient to make the diagnosis of autoimmune oophoritis in a female with proven spontaneous POI. The presence of another autoimmune disorder, such as autoimmune thyroid disease, does not necessarily indicate that the POI is also autoimmune.

At present, the only validated marker to detect autoimmune oophoritis is the presence of steroidogenic cell autoantibodies as measured by the presence of anti-21-hydroxylase antibodies by immunoprecipitation assay or indirect immunofluorescence using adrenal tissue as substrate [1].

The predictive value of a commercially available serum anti-ovarian antibody test (an indirect immunofluorescence assay using cynomolgus monkey ovary) to identify these females is poor. As an example, in a study of 26 females with 46,XX spontaneous POI and 26 normal cycling females, 50 percent (13 of 26) of females with POI and 31 percent (8 of 26) of normal females had ovarian antibodies [23]. Thus, this test has an unacceptably high false-positive rate.

Although ovarian biopsy to detect autoimmune oophoritis was done in the past, we currently do not recommend this approach in view of the availability of validated autoantibody testing for steroidogenic cell autoimmunity [24].

Differential diagnosis — The differential diagnosis of autoimmune POI includes any non-autoimmune cause of POI. This includes chromosomal abnormalities (Turner syndrome) and premutations in the FMR1 gene, the gene responsible for fragile X syndrome. The non-autoimmune causes of POI are reviewed in detail elsewhere. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)

Additional autoimmune evaluation after diagnosis — In addition to testing for antiadrenal cortex or 21-hydoxylase antibodies, all females with 46,XX spontaneous POI should be evaluated for autoimmune thyroid disease with measurement of serum thyrotropin (TSH) and antithyroid antibodies. Any other evaluation searching for possible associated autoimmune disorders should be based on the presence of separate clinical indications.

Autoimmune thyroid disease – Young adult females with spontaneous POI are also at increased risk of autoimmune hypothyroidism and should be screened for this condition. Testing should therefore include TSH, free thyroxine (T4), and antithyroid peroxidase antibodies.

Adrenal insufficiency – If proper screening is performed, approximately 3 percent of females with spontaneous POI will be found to have asymptomatic autoimmune adrenal insufficiency [7]. As a screen for the presence of asymptomatic autoimmune adrenal insufficiency, serum anti-21-hydroxylase antibodies or antiadrenal cortex antibodies should be measured at the time of diagnosis of spontaneous POI in all females. Those with positive antibodies should be carefully evaluated for the presence of adrenal insufficiency. If the initial evaluation is negative, ongoing surveillance may be indicated. This topic, as well as the treatment of adrenal insufficiency, is discussed in greater detail elsewhere. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)" and "Determining the etiology of adrenal insufficiency in adults".)

Other – Other disorders associated with autoimmune polyglandular syndrome are discussed elsewhere. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Autoimmune adrenalitis' and "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)" and "Disorders that cause hypothyroidism".)

TREATMENT — The management of females with autoimmune primary ovarian insufficiency (POI) is the same as for any female with POI. Management focuses on (see "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Importance of estrogen therapy'):

Consequences of estrogen deficiency (vasomotor symptoms, vaginal atrophy, osteoporosis, and a possible increased risk of coronary heart disease and stroke if not treated with estrogen)

Emotional health/psychosocial support

Fertility, which is reduced

Other autoimmune disorders

The approach to management of all of these concerns is reviewed in detail separately. (See "Management of primary ovarian insufficiency (premature ovarian failure)".)

For those with autoimmune oophoritis who are interested in fertility, an experimental strategy is immunosuppression with glucocorticoids. Although there are no clinical trial data, there are reports of females with autoimmune POI who have responded to treatment with prednisone in doses of 20 to 40 mg daily for one to six months with resumption of menstrual cycles; a smaller number have had successful pregnancies [25-31]. However, both iatrogenic Cushing syndrome and osteonecrosis have been reported (image 1) [27]. There are currently no active clinical trials of glucocorticoid therapy to improve fertility.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary ovarian insufficiency".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Primary ovarian insufficiency (The Basics)")

Beyond the Basics topics (see "Patient education: Primary ovarian insufficiency (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

General principles – Autoimmune oophoritis is one of the known causes of primary ovarian insufficiency (POI; commonly referred to as premature ovarian failure) and is found in approximately 4 percent of females who present with spontaneous POI. It may occur as part of type I and type II syndromes of polyglandular autoimmune failure, which are associated with autoantibodies to multiple endocrine and other organs (table 1). (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Autoimmune adrenalitis'.)

Clinical features – The clinical presentation of females with autoimmune POI is similar to that of females with other causes of POI and includes a change in menstrual function (oligomenorrhea and/or amenorrhea) and symptoms of estradiol deficiency, such as hot flashes and vaginal dryness. Intermittent ovarian function may occur such that vasomotor symptoms or vaginal dryness may be absent. (See 'Clinical features' above.)

Diagnostic evaluation – We suggest that all females who present with spontaneous POI be tested for 21-hydroxylase antibodies by immunoprecipitation or antiadrenal antibodies by indirect immunofluorescence to identify those females who have autoimmune oophoritis. (See 'Diagnosis' above.)

Additional autoimmune evaluation

The serum antiadrenal and/or anti-21-hydroxylase antibodies, which are measured to diagnose autoimmune oophoritis, will also identify patients with or at risk for asymptomatic adrenal insufficiency (eg, testing for antiadrenal and anti-21-hydroxylase antibodies may serve the dual purpose of making the diagnosis of autoimmune oophoritis and screening for autoimmune adrenal insufficiency). Those with positive antibodies should be carefully evaluated for the presence of adrenal insufficiency and repeat testing may be indicated. (See 'Additional autoimmune evaluation after diagnosis' above.)

Females should also be screened for autoimmune thyroid disease by thyrotropin (TSH), thyroxine (T4), and antithyroid peroxidase antibodies. (See 'Additional autoimmune evaluation after diagnosis' above.)

Treatment – Management of females with autoimmune POI is the same as that of females with other causes of POI. Estrogen replacement is necessary to prevent bone loss. (See "Management of primary ovarian insufficiency (premature ovarian failure)".)

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