Virilization in Bilateral Macronodular Adrenal Hyperplasia Controlled by Luteinizing Hormone

Abstract

We report a case of a virilized 59-yr-old woman with elevated serum testosterone levels and bilateral macronodular adrenal hyperplasia. The patient underwent laparoscopic right adrenalectomy, after which the elevated testosterone level transiently normalized. The immediate postoperative depression of the testosterone level suggested that the process was driven by gonadotropins that were suppressed by the stress of surgery. The excised right adrenal mass contained testosterone by immunohistochemistry and LH receptor mRNA by in situ hybridization. The recurrence of hyperandrogenemia suggested that the enlarged left adrenal was also secreting testosterone. The serum testosterone level increased in response to im injection of human chorionic gonadotropin, suggesting control by aberrant LH receptors. Injection of leuprolide acetate (7.5 mg im) to suppress LH levels resulted in normalization of the testosterone level 12 d later that persisted for several weeks. Ectopic receptors mediating Cushing's syndrome have been described in several cases of bilateral adrenal hyperplasia and adrenal adenoma. This is the first case to our knowledge in which pure androgen overproduction in adrenal hyperplasia has been shown to be controlled by LH receptors. In our patient, the control of androgen secretion by LH may explain the postmenopausal onset of virilization and the transient postoperative normalization of the serum testosterone level.

Targeted therapy for adrenocortical tumors in transgenic mice through their LH receptor by Hecate-human chorionic gonadotropin conjugate

“…The LHR is expressed at low levels in normal human adrenal cortex (Pabon et al 1996), and hCG stimulates dehydroepiandrosterone sulfate synthesis of human fetal adrenals (Jaffe et al 1981). LHR expression has been shown in different kinds of human adrenal pathologies i.e., virilizing or Cushing's syndrome (CS)-related adrenocorticotropin-independent macronodular adrenal hyperplasias (AIMAH; Lacroix et al 1999, Bourdeau et al 2001, Miyamura et al 2002, Feelders et al 2003, Goodarzi et al 2003, Mijnhout et al 2004. Pregnancy-associated CS is also a known condition (Sheeler 1994).…”

Cushing's syndrome secondary to ACTH-Independent macronodular adrenal hyperplasia

“…Some cases with secretion of cortisol and mineralocorticoids, cortisol and estrone and androgens only have also been reported (12)(13)(14)(15). In some patients, the adrenal lesions are found incidentally in the process of radiological investigation of another disease.…”

“…Some cases of aberrant receptors for LH/hCG in combination with serotonin or other receptors have been reported (16,56,57). A 59-yr-old virilized woman with androgen-secreting AIMAH regulated by hCG was shown to express the LH/hCGR in one resected adrenal; suppression of endogenous LH with leuprolide acetate normalized androgen secretion from the contralateral adrenal, avoiding bilateral adrenalectomy (15).…”

“…In catecholamine-dependent CS in AIMAH, β-adrenergic receptor antagonists were efficient in the long-term control of hormonal hypersecretion (42,72). In LH/hCG-dependent AIMAH and CS, suppression of endogenous LH levels with long-acting leuprolide acetate controlled steroid secretion and avoided bilateral adrenalectomy (15,55). It is possible that tumor regression might not occur, despite complete blockade of the aberrant receptors, because other genetic events (other than aberrant receptors) inducing proliferation can appear over time (30,41).…”

The adrenal gland may be a target of LH action in postmenopausal women

“…LH-responsive tumours in nonadrenocorticotrophin (ACTH)-dependent Cushing's syndrome have been identified (8)(9)(10)(11)(12)(13) and cases of pregnancy-associated ACTH-independent Cushing's syndrome have been reported (14,15), presumably caused by ectopic expression of LH receptors responding to human chorionic gonadotrophin (hCG). Moreover, 'thecal metaplasia' in the adrenal gland in both sexes in conditions with elevated gonadotrophin levels is a well known but poorly investigated condition (16,17).…”