Clinical Features and Diagnosis of Autoimmune Primary Ovarian Insufficiency (Premature Ovarian Failure) - Uptodate

2/9/2020 Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure) - UpToDate

Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure)

Author: Corrine K Welt, MD Section Editors: Robert L Barbieri, MD, William F Crowley, Jr, MD Deputy Editor: Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2020. | This topic last updated: Aug 22, 2019.

INTRODUCTION

46,XX primary ovarian insufficiency (POI) is defined as the development of primary hypogonadism before the age of 40 years in women 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 spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Management of spontaneous primary ovarian insufficiency (premature ovarian failure)".)

EPIDEMIOLOGY

Autoimmune oophoritis is found in approximately 4 percent of women who present with spontaneous primary ovarian insufficiency (POI) [1]. It was first confirmed histologically in a woman with coexisting autoimmune adrenal insufficiency [2] and subsequently in additional series of women 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]. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-autoimmune-primary-ovarian-insufficiency-premature-ovarian-failure/print?… 1/14 2/9/2020 Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure) - UpToDate 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's disease)", section on 'Polyglandular autoimmune syndrome type 1' and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 2'.)

POI has also been described in women 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's 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 women with autoimmune POI is similar to that of women 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 women with spontaneous POI, the absence of vasomotor symptoms or vaginal dryness should not dissuade one from considering the diagnosis of POI in a woman who presents with menstrual irregularity. (See "Clinical manifestations and diagnosis of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'Clinical features'.)

In women with autoimmune oophoritis, the development of irregular menses usually precedes the development of symptomatic adrenal insufficiency by several years [4]. However, adrenal

https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-autoimmune-primary-ovarian-insufficiency-premature-ovarian-failure/print?… 2/14 2/9/2020 Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure) - UpToDate 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 primary adrenal insufficiency'). Approximately 3 percent of women 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's disease)", section on 'Autoimmune adrenalitis'.)

Laboratory findings — The biochemical findings of women with autoimmune POI are also similar to those of women 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's 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's disease)".)

In one report of three women 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 women. 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

https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-autoimmune-primary-ovarian-insufficiency-premature-ovarian-failure/print?… 3/14 2/9/2020 Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure) - UpToDate 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 women with autoimmune POI (and steroid cell autoantibodies) when compared with 71 women 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 women 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 women 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

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 FMR1 premutation (see "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Clinical manifestations and diagnosis of spontaneous 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 woman 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]. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-autoimmune-primary-ovarian-insufficiency-premature-ovarian-failure/print?… 4/14 2/9/2020 Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure) - UpToDate The predictive value of a commercially available serum anti-ovarian antibody test (an indirect immunofluorescence assay using cynomolgus monkey ovary) to identify these women is poor. As an example, in a study of 26 women with 46,XX spontaneous POI and 26 normal cycling women, 50 percent (13 of 26) of women with POI and 31 percent (8 of 26) of normal women 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 spontaneous primary ovarian insufficiency (premature ovarian failure)".)

Additional autoimmune evaluation after diagnosis — In addition to testing for antiadrenal cortex or 21-hydoxylase antibodies, all women 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.

Adrenal insufficiency — If proper screening is performed, approximately 3 percent of women 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 women. Those with positive antibodies should be carefully evaluated for the presence of adrenal insufficiency. This topic, as well as the treatment of adrenal insufficiency, is discussed in greater detail elsewhere. (See "Clinical manifestations and diagnosis of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Diagnosis of adrenal insufficiency in adults".)

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

TREATMENT https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-autoimmune-primary-ovarian-insufficiency-premature-ovarian-failure/print?… 5/14 2/9/2020 Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure) - UpToDate The management of women with autoimmune primary ovarian insufficiency (POI) is the same as for any woman with POI. Management focuses on:

● Emotional health/psychosocial support

● 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)

● Contraception and fertility, which is dramatically reduced

● Other autoimmune disorders

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

Experimental fertility treatment — For those with autoimmune oophoritis who are interested in fertility, a potential ovulation induction strategy is immunosuppression with glucocorticoids. Although there are no clinical trial data, there are reports of women 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's 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 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-autoimmune-primary-ovarian-insufficiency-premature-ovarian-failure/print?… 6/14 2/9/2020 Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure) - UpToDate subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Early menopause (primary ovarian insufficiency) (The Basics)")

● Beyond the Basics topics (see "Patient education: Early menopause (primary ovarian insufficiency) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● 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 women 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's disease)", section on 'Autoimmune adrenalitis'.)

● We suggest that all women who present with spontaneous POI be tested for 21-hydroxylase antibodies by immunoprecipitation or antiadrenal antibodies by indirect immunofluorescence to identify those women who have autoimmune oophoritis. The predictive value of a commercially available serum anti-ovarian antibody test (an indirect immunofluorescence assay using cynomolgus monkey ovary) has an unacceptably high false-positive rate, so we do not recommend its use. (See 'Diagnosis' above.)

● The serum antiadrenal and/or anti-21-hydroxylase antibodies, which are measured to diagnose autoimmune oophoritis, will also identify patients with 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. (See 'Additional autoimmune evaluation after diagnosis' above.)

● We recommend against ovarian biopsy for diagnosis of autoimmune oophoritis. (See 'Diagnosis' above.)

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

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

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REFERENCES

1. Bakalov VK, Anasti JN, Calis KA, et al. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. Fertil Steril 2005; 84:958.

2. Irvine WJ, Chan MM, Scarth L, et al. Immunological aspects of premature ovarian failure associated with idiopathic Addison's disease. Lancet 1968; 2:883.

3. Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr Rev 1997; 18:107.

4. Escobar ME, Cigorraga SB, Chiauzzi VA, et al. Development of the gonadotrophic resistant ovary syndrome in myasthenia gravis: suggestion of similar autoimmune mechanisms. Acta Endocrinol (Copenh) 1982; 99:431.

5. Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update 2005; 11:391.

6. González LA, McGwin G Jr, Durán S, et al. Predictors of premature gonadal failure in patients with systemic lupus erythematosus. Results from LUMINA, a multiethnic US cohort (LUMINA LVIII). Ann Rheum Dis 2008; 67:1170.

7. Nelson LM. Autoimmune ovarian failure: comparing the mouse model and the human disease. J Soc Gynecol Investig 2001; 8:S55.

8. Biscotti CV, Hart WR, Lucas JG. Cystic ovarian enlargement resulting from autoimmune oophoritis. Obstet Gynecol 1989; 74:492.

9. Burrell LM, Murdoch A, Angus B, White MC. Autoimmune ovarian failure with elevated serum levels of luteinizing hormone and enlarged ovaries. Case report. Br J Obstet Gynaecol 1990; 97:362.

10. Lonsdale RN, Roberts PF, Trowell JE. Autoimmune oophoritis associated with polycystic ovaries. Histopathology 1991; 19:77.

11. Welt CK, Hall JE, Adams JM, Taylor AE. Relationship of estradiol and inhibin to the follicle- stimulating hormone variability in hypergonadotropic hypogonadism or premature ovarian failure. J Clin Endocrinol Metab 2005; 90:826.

12. Welt CK, Falorni A, Taylor AE, et al. Selective theca cell dysfunction in autoimmune oophoritis results in multifollicular development, decreased estradiol, and elevated inhibin B https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-autoimmune-primary-ovarian-insufficiency-premature-ovarian-failure/print?… 8/14 2/9/2020 Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure) - UpToDate levels. J Clin Endocrinol Metab 2005; 90:3069.

13. Elder M, Maclaren N, Riley W. Gonadal autoantibodies in patients with hypogonadism and/or Addison's disease. J Clin Endocrinol Metab 1981; 52:1137.

14. Uibo R, Aavik E, Peterson P, et al. Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison's disease. J Clin Endocrinol Metab 1994; 78:323.

15. Winqvist O, Gebre-Medhin G, Gustafsson J, et al. Identification of the main gonadal autoantigens in patients with adrenal insufficiency and associated ovarian failure. J Clin Endocrinol Metab 1995; 80:1717.

16. Betterle C, Rossi A, Dalla Pria S, et al. Premature ovarian failure: autoimmunity and natural history. Clin Endocrinol (Oxf) 1993; 39:35.

17. Chen S, Sawicka J, Betterle C, et al. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison's disease, and premature ovarian failure. J Clin Endocrinol Metab 1996; 81:1871.

18. Weetman AP. Autoimmunity to steroid-producing cells and familial polyendocrine autoimmunity. Baillieres Clin Endocrinol Metab 1995; 9:157.

19. Tsigkou A, Marzotti S, Borges L, et al. High serum inhibin concentration discriminates autoimmune oophoritis from other forms of primary ovarian insufficiency. J Clin Endocrinol Metab 2008; 93:1263.

20. Sedmak DD, Hart WR, Tubbs RR. Autoimmune oophoritis: a histopathologic study of involved ovaries with immunologic characterization of the mononuclear cell infiltrate. Int J Gynecol Pathol 1987; 6:73.

21. Bannatyne P, Russell P, Shearman RP. Autoimmune oophoritis: a clinicopathologic assessment of 12 cases. Int J Gynecol Pathol 1990; 9:191.

22. Gloor E, Hurlimann J. Autoimmune oophoritis. Am J Clin Pathol 1984; 81:105.

23. Novosad JA, Kalantaridou SN, Tong ZB, Nelson LM. Ovarian antibodies as detected by indirect immunofluorescence are unreliable in the diagnosis of autoimmune premature ovarian failure: a controlled evaluation. BMC Womens Health 2003; 3:2.

24. Khastgir G, Abdalla H, Studd JW. The case against ovarian biopsy for the diagnosis of premature menopause. Br J Obstet Gynaecol 1994; 101:96.

25. Rabinowe SL, Berger MJ, Welch WR, Dluhy RG. Lymphocyte dysfunction in autoimmune oophoritis. Resumption of menses with corticosteroids. Am J Med 1986; 81:347. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-autoimmune-primary-ovarian-insufficiency-premature-ovarian-failure/print?… 9/14 2/9/2020 Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure) - UpToDate

26. Luborsky JL, Visintin I, Boyers S, et al. Ovarian antibodies detected by immobilized antigen immunoassay in patients with premature ovarian failure. J Clin Endocrinol Metab 1990; 70:69.

27. Kalantaridou SN, Braddock DT, Patronas NJ, Nelson LM. Treatment of autoimmune premature ovarian failure. Hum Reprod 1999; 14:1777.

28. Coulam CB, Kempers RD, Randall RV. Premature ovarian failure: evidence for the autoimmune mechanism. Fertil Steril 1981; 36:238.

29. Taylor R, Smith NM, Angus B, et al. Return of fertility after twelve years of autoimmune ovarian failure. Clin Endocrinol (Oxf) 1989; 31:305.

30. Blumenfeld Z, Halachmi S, Peretz BA, et al. Premature ovarian failure--the prognostic application of autoimmunity on conception after ovulation induction. Fertil Steril 1993; 59:750.

31. Corenblum B, Rowe T, Taylor PJ. High-dose, short-term glucocorticoids for the treatment of infertility resulting from premature ovarian failure. Fertil Steril 1993; 59:988.

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GRAPHICS

Types of endocrine and nonendocrine autoimmune syndromes associated with adrenal insufficiency

Prevalence Disorder (percent)

Polyglandular autoimmune syndrome type I

Endocrine

Hypoparathyroidism 89

Chronic mucocutaneous candidiasis 75 Adrenal insufficiency 60 Primary hypogonadism 45 Hypothyroidism 12 Type 1 diabetes mellitus 1 Hypopituitarism <1 Diabetes insipidus <1 Nonendocrine

Malabsorption syndromes 25

Alopecia totalis or areata 20 Pernicious anemia 16 Chronic active hepatitis 9 Vitiligo 4

Polyglandular autoimmune syndrome type II

Endocrine

Adrenal insufficiency 100

Autoimmune thyroid disease 70 Type 1 diabetes mellitus 50 Primary hypogonadism 5 to 50 Diabetes insipidus <1 Nonendocrine

Vitiligo 4

Alopecia, pernicious anemia, myasthenia gravis, immune thrombocytopenia purpura, Sjogren's ≤1 syndrome, rheumatoid arthritis

Data from: 1. Leshin M. Polyglandular autoimmune syndromes. Am J Med Sci 1985; 290:77. 2. Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 1981; 60:355.

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Lymphocytic infiltration in autoimmune primary ovarian insufficiency

Hematoxylin and eosin stains panels A and C; immunoperoxidase stains panels B and D. (A) Heavy lymphocytic infiltration of the theca (middle). (B) Same area as A, with the heavy infiltration of lymphocytes highlighted by staining for the leukocyte common antigen. (C) High power magnification of an early secondary follicle showing three layers of granulosa cells surrounding an unremarkable oocyte. (D) Same area as C, showing absence of lymphocytic infltration (no leukocyte common antigen positive cells with immunoperoxidase stain).

Reproduced with permission from: Kalantaridou SN, Braddock DT, Patronas NJ, Nelson LM. Treatment of autoimmune premature ovarian failure. Hum Reprod 1999; 14:1777. Copyright © 1999 Oxford University Press/Human Reproduction.

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MRI of osteonecrosis in POI patient after glucocorticoids

MRI of osteonecrosis of the right knee (arrow) in a patient who had received glucocorticoids for treatment of POI.

MRI: magnetic resonance imaging; POI: primary ovarian insufficiency.

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Contributor Disclosures

Corrine K Welt, MD Consultant/Advisory Board (Spouse): Medtronic [Cardiac stents for catheterization]. Robert L Barbieri, MD Nothing to disclose William F Crowley, Jr, MD Equity Ownership/Stock Options: Dare Bioscience [Endocrinology]. Consultant/Advisory Boards: Dare Bioscience [Endocrinology]. Kathryn A Martin, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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