A Recently Married 27-Year-Old With Hot Flashes, Amenorrhea

This patient's body weight was normal. An excessively low body weight, seen with bulimia or anorexia nervosa, can be associated with hypothalamic amenorrhea. The physiologic stress of being underweight may inhibit normal reproductive function and, therefore, pregnancy; other causes of stress are also believed to inhibit reproductive function at the hypothalamic level.

An excessively high body weight, on the other hand, is frequently associated with PCOS, which is characterized by the triad of hyperandrogenism, oligo-ovulation or anovulation, and polycystic ovaries (figures 2-4), with the presence of two of these criteria being necessary for diagnosis. The manifestations of the PCOS triad can vary, and most women have irregular menses rather than amenorrhea.^[4,5]

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Figure 2.

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Figure 3.

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Figure 4.

Although the etiology of PCOS is uncertain, it is probably a multifactorial process in which insulin resistance leads to hyperinsulinism, which in turn leads to ovarian hyperandrogenesis, which results in hyperaromatization (conversion of androgens to estrogens) in adipose tissue; this causes hyperestrogenemic tonic inhibition of the ovulatory gonadotropin surge, leading to ovulatory dysfunction and polycystic ovaries. PCOS therapies have targeted various points in this process through treatments such as weight loss, insulin sensitizers, antiandrogens, aromatase inhibitors, and ovulation inducers, albeit with varying degrees of success.

Because this patient did not manifest galactorrhea or an elevated prolactin level, hyperprolactinemia, another cause of SA, was ruled out. Generally, the prolactin levels would be relatively high, usually five- to ten-fold greater than normal, in this diagnosis This increase often occurs as a result of a prolactin-secreting pituitary tumor. The occurrence of galactorrhea requires prolactin and sufficient estrogen to promote lactogenesis. In extreme cases, however, the lack of estrogen may not support galactorrhea, so its absence cannot rule out hyperprolactinemia.

Asherman syndrome was also unlikely in this case. In Asherman syndrome, uterine adhesions (most often resulting from uterine surgery) can block the outflow tract. Almost all patients in which this occurs have a history of dilatation and curettage (D&C), which was not elicited in this patient's history. Many such cases also manifest uterine pain resulting from distention of retained menstrual blood.

Almost one-half of patients with POF may have an autoimmune etiology, which is sometimes associated with other endocrinopathies. This patient had clinical and biochemical evidence of autoimmune thyroiditis with her goiter, elevated TSH, and anti-TPO antibodies. Primary adrenal insufficiency was also suggested and was later confirmed; the patient was fatigued, with postural hypotension, mild hyperkalemia, and eosinophilia. Upon closer scrutiny, her skin was hyperpigmented in nonsuntanned areas of the body, and she had an elevated adrenocorticotropic hormone (ACTH) level, as well as an inadequate adrenal cortisol response to exogenous ACTH. Further confirmation of an autoimmune adrenal etiology is possible with measurement of adrenal 21-hydroxylase antibodies, but the test was not performed in this case.

Direct confirmation of autoimmune oophoritis with ovarian antibodies is not yet possible, but lymphocytic infiltration, which has been found in patients' ovaries, suggests this etiology.

Based on this patient's workup, evidence for the failure of three endocrine glands—ovary, thyroid, and adrenal—were found. The presence of multiple autoimmune endocrine diseases in the same patient suggested the existence of an autoimmune polyglandular syndrome (APS; also referred to as polyglandular autoimmune syndrome), either APS-I, APS-II, or APS-III.^[8,9]

APS-I is characterized by the classic triad of hypoparathyroidism, chronic mucocutaneous candidiasis, and adrenal dysfunction, with diagnosis requiring the presence of at least two of these conditions. The disease, an autosomal-recessive disorder that begins in infancy, is associated with an autoimmune regulatory (AIRE) gene mutation that alters thymus-mediated cellular immunity.

In APS-II, the manifestations include adrenal insufficiency, type 1 diabetes mellitus, gonadal failure, celiac disease, and autoimmune hyperthyroidism or autoimmune hypothyroidism. It has a variable inheritance but is predominantly found in females, with peak onset being between the ages of 20 and 60 years.^[8] APS-III is characterized by autoimmune thyroiditis occurring in association with another organ-specific autoimmune disease, such as pernicious anemia, type 1 diabetes mellitus, or vitiligo and/or alopecia. This patient's combination of conditions suggested APS-II with gonadal, thyroid, and adrenal involvement.

The mechanistic explanation for the three APS syndromes is unknown, but assignment of a patient to one of them should raise awareness of the possibility of, and perhaps lead to screening for, other associated glandular disorders. For example, assignment of this patient to APS-II prompted testing for celiac disease and/or type 1 diabetes mellitus. The results for her celiac and diabetes autoantibody panels were negative.

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