A common antigenic target found in autoimmune adrenal failure is the 21-hydroxylase enzyme; however, women with autoimmune POI are more likely to demonstrate antibodies against 17-alpha hydroxylase or P450scc enzymes [25]. Anti-adrenal antibodies, detectable using indirect immunofluorescence, provide the clinician with a relatively straightforward assessment for the presence of autoimmune adrenal failure. However, clinical disease may not be evident in all individuals with a positive test. Some of the adrenal antibodies detected in women with POI who have adrenal autoimmunity target the ovary as well, yet the ovary does not always fail in women with adrenal autoimmunity. Patients with anti-adrenal antibodies should carry notification on their person that they are potentially susceptible to an adrenal crisis should a sudden stress occur. A Medic-Alert bracelet or wallet card is recommended.

Physical signs of primary adrenal failure include hyperpigmentation of the mucous membranes, particularly the gums and skin, salt cravings (since mineralocorticoid production is impaired along with glucocorticoid production), hypotension, excessive fatigue, and in extreme cases, acute nausea and vomiting. Clinicians should have a low threshold for emergent treatment with stress doses of corticosteroids for women with known POI who exhibit signs and symptoms of adrenal insufficiency, such as dehydration, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, or hypoglycemia. In nonacute situations, clinical suspicion can be confirmed with a 250 mg cortrosyn stimulation test—considered the ‘gold standard’ for diagnosis. A 250 mcg dose of corticotropin is administered after obtaining a blood sample for ACTH. Corticotropin is then administered as an IV bolus and serum cortisol is measured 30 min afterward. A cortisol response that is below 500–550 nmol/L (18–20 mcg/dl) is suggestive of adrenal insufficiency [26, 27]. A baseline plasma ACTH> twice the upper limit of the normal reference range is also consistent with adrenal insufficiency [28].

Whereas adrenal antibody testing is sensitive and specific for adrenal autoimmunity [24], the same is not true for antiovarian antibody testing, with the latter having many false positive and negative tests. Antibodies against the ovary in women with premature menopause were first demonstrated in 1966 using indirect immunofluorescence in rabbit ovaries [29]. Testing was facilitated by the development of an ELISA assay that used human instead of rabbit ovarian tissue [30], but its usefulness remains limited because of a high rate of false positive tests when applied to a broader population of women [31]. There are many more antigens beyond steroidogenic enzymes that lead to ovarian autoimmunity, including zona pellucida proteins, LH and FSH receptors, and numerous oocyte plasma proteins [32]. Because the human ovary releases an oocyte into the peritoneal cavity (along with some blood and granulosa cells) approximately monthly in a normal woman’s reproductive life span, there is an opportunity to sensitize a woman over time to products of her own ovaries. One group has found that albumin is a common nonspecific target for antiovarian antibody testing, and a measurement protocol that involved blocking for albumin resulted in a reduced rate of false positive tests [33]. It is hoped that further refinement of these methods will be able to be applied to this problem, allowing for accurate clinical testing for autoantibodies directed against the ovary.

Virtually all of the other polyglandular endocrine failure syndromes have been reported in at least one woman with POI. A woman diagnosed with POI can have concomitant or eventual beta cell failure or any of the other organ failures identified in Table 6.1. A hemoglobin A1c is recommended to rule out the former and a complete metabolic panel can screen for parathyroid failure resulting in hypocalcemia and other autoimmune conditions such as hepatitis [34]. Other screening should be targeted to symptoms [35]. A recommended workup for women with a diagnosis of POI/POF is provided in Table 6.2.

In addition to thyroid and adrenal autoimmunity, there are numerous case reports and case series of systemic lupus erythematosus, Sjogren Syndrome, pernicious anemia, celiac disease, vitiligo, and autoimmune hepatitis in association with POI and/or APS type I [37, 38]. Unexplained vitamin deficiencies may be a harbinger of undiagnosed celiac disease.