Virilizing adrenal adenoma and primary amenorrhea in a girl with adrenal hyperplasia

Abstract

We report a 14-year-old girl with primary amenorrhea and virilization. The chromosomal analysis showed a normal 46,XX female karyotype and the hormonal assays disclosed high serum levels of testosterone (T): 450 ng/dL (normal 5-90), dehidroepiandrosterone-sulfate (DHEA-S): 690 microg/dL (normal 30-450) and 17-hydroxiprogesterone (17-OHP) >20 ng/mL (normal <2). A pelvic ultrasound disclosed a small uterus and bilateral enlargement of the ovaries, a computed axial tomographic scan of the abdomen identified a large right mass in the adrenal gland and a norcholesterol-I 131 adrenal gammagraphy revealed a functional adrenal tumor. The histological analysis of the surgical removed tumor revealed and adrenal adenoma. After surgery, a steep decline to normal serum levels of T and DHEA-S was observed, remaining an elevated level of 17-OHP: 5.4 ng/mL. During the first three months of follow up, the hirsutism declined sharply and spontaneous mammary development occurred, remaining elevated the 17-OHP serum level: 4.8 ng/mL. Prednisone 5 mg/day, was initiated decreasing the 17-OHP to normal level: 1.4 ng/mL, appearing the menarche followed by cyclical menses. One year after surgery, prednisone was withdrawn during one week, and an ACTH test and HLA typing were done, disclosing a 17-OHP response of an heterozygote for adrenal hyperplasia, and identifying B65 a subtype of B14, and DR1, that are frequently associated to adrenal hyperplasia. Previous reports have informed silent adrenal tumors associated to adrenal hyperplasia, but this is the first report of a functional adrenal tumor associated to adrenal hyperplasia.

Sex Hormone Receptor Repertoire in Breast Cancer

“…Even though the actions of androgens are believed to oppose that of estrogens, the inhibitory effect of androgens on breast tissue depends largely on the relative tissue concentrations of both types of hormones as well as their receptor-mediated actions. This conclusion is consistent with two observations: (1) breasts do not undergo normal development in girls diagnosed with androgen-secreting adrenal tumors despite adequate circulating estrogens [68] and (2) development of gynecomastia in men treated with AR blockers for prostate cancer [69]. Clinically, a possible link has been established between AR expression and outcomes in certain subsets of breast cancer [70, 71].…”

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

“…This ability is simply exemplified by the lack of mammary gland development in healthy pubertal males. In the clinical context, pathological or pharmaceutical elevation of circulating androgen hormones inhibits breast development; as seen in women with adrenal hyperplasia that manifest with normal oestrogen and progesterone levels but have high androgens levels [73]. This naturally occurring scenario illustrates the striking ability of androgens to modulate pubertal mammary gland development and MEC function.…”

Bringing androgens up a NOTCH in breast cancer

“…During puberty in humans, rodents and non-human primates, various androgenic compounds have been shown to inhibit ductal elongation (Casey & Wilson 1984, Jayo et al 2000, Peters et al 2011) and proliferation of MECs (Pashko et al 1981, Peters et al 2011, suggesting that AR signalling acts to antagonise the stimulatory actions of ERa in the regulation of this developmental process. The broad growth inhibitory, anti-oestrogenic influence of androgens in breast development is exemplified by cases of pubescent girls with adrenal hyperplasia, where breast growth is suppressed due to abnormally highcirculating androgen levels in the presence of normal levels of oestrogens (Forsbach et al 2000). One proposed mechanism for the ability of androgens to reduce MEC proliferation in adult primates is via inhibition of ERa expression and its consequential effect on expression of critical ERa-target genes (Zhou et al 2000).…”

“…prostate and testes) or ERa and PR signalling in the breast. This is somewhat remarkable, particularly with respect to the breast, as it has long been known that androgen hormones inhibit pubertal and post-pubertal breast growth, and that treatment with androgen can cause regression of breast tumours (Lamar & Rezek 1958, Thomas et al 1962, Tormey et al 1983, Forsbach et al 2000, Rose et al 2000. Indeed, AR is the most frequently expressed sex steroid receptor in both primary and secondary (metastatic) breast cancers, making it a highly prevalent therapeutic target (McNamara et al 2013, Santagata et al 2014, Tsang et al 2014.…”