Henry Ford Hospital Medical Journal

Volume 39 Number 1 Festschrift: In Honor of Raymond C. Article 5 Mellinger

3-1991

Hyperandrogenemia and Virilization with Simultaneous Pituitary and Adrenal Adenomas

Jeffrey A. Jackson

Raymond C. Mellinger

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Recommended Citation Jackson, Jeffrey A. and Mellinger, Raymond C. (1991) "Hyperandrogenemia and Virilization with Simultaneous Pituitary and Adrenal Adenomas," Henry Ford Hospital Medical Journal : Vol. 39 : No. 1 , 22-24. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol39/iss1/5

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Hyperandrogenemia and Virilization with Simultaneous Pituitary and Adrenal Adenomas

Jeffrey A. Jackson, MD,* and Raymond C. Mellinger, MD^

We describe a postmenopausal woman who presented with virilizing hyperandrogenemia and was found to have an intrasellar tumor and a large left adrenal mass. Pathologic studies showed an undifferentiated hypophyseal adenoma with immunostaining for chromogranin only and a benign adrenocortical adenoma. In Ught of current understanding of the regulation qf adrenal androgen secreUon and adrenocorUcal mitogenesis. we postulate that this ca.se may be explained hy secretion of adrenal androgen-sUmulating and mitogenic factors hy the pituitary tumor. (Heniy Ford Hosp Med J 1991:39:22-4)

"No other single structure in the body is so doubly pro­ Transsphenoidal hypophysectomy was performed with apparent tected, so centrally placed, so well hidden. Her acts being complete resection of an obvious adenoma. Severe pancreatitis ensued, purposeful, nature must have had abundant reason for possibly related to perioperative glucocorticoid therapy. Left adre­ this, and man's prying curiosity impels him to ask what nalectomy was performed one month later without complications. The they were," (Harvey Cushing, 1930) (1) right adrenal was normal by palpation and was not biopsied. Postoperatively, masculine features gradually receded (Fig IB) as onsiderable evidence supports the existence of pituitary- did papilledema, and androgen and 17-KS levels normalized. Mild hy­ C derived factors other than adrenocorticotropic hormone pertension and hyperprolactinemia (42 to 63 pg/L while taking a- (ACTH) which modulate adrenal androgen secretion (2-5) and methyldopa and tricyclic antidepressants) persisted with preserved an­ exert mitogenic effects on the adrenal cortex (6,7). We describe terior pituitary function. During 13 years of subsequent follow-up, no recurrence of either tumor has occurred. a postmenopausal woman who presented with hyperandrogene­ mia and virilization and was found to have simultaneous benign pituitary and adrenal neoplasms. The pathophysiology underly­ Pathologic studies ing this unusual case may relate to such pituitary-derived factors The pituitary tumor was composed of uniform cells with granular and thereby represent an endocrinologic syndrome. cytoplasm. Immunohistochemical studies, performed in 1985, dis­ closed specific immunoreactivity for chromogranin in individual cells: Case Report immunostaining for a-melanocyte-stimulating hormone (MSH). [3- MSH, prolactin. (3-endorphin, ACTH, and leucine-enkephalin was neg­ Patient summary ative. These findings were consistent with a null cell or undifferentiated A 64-year-old woman developed progressive hirsutism and fronto- pituitary adenoma. The encapsulated adrenal tumor was hemorrhagic temporal balding following menopause at age 56. She first presented to and composed of well-differentiated pleomorphic polygonal cells with her physician for evaluation in September 1976, Blood pressure was prominent nucleoli, occasional mitoses, and minimal necrosis. Adreno­ 170/100 mm Hg, and she was noted to have truncal obesity, bilateral cortical tumor cells did not display immunoreactivity for any of the papilledema, and abnormal glucose tolerance. polypeptide hormones mentioned above. Upon referral to Henry Ford Hospital, examination revealed striking male facial appearance (Fig 1 A), body hair distribution, and mild clito- romegaly. Features of Cortisol excess were not present. Endocrine stud­ Discussion ies included 24-hour urinary Cortisol (195 nmol [normal < 330 nmol]). Few well-documented cases of simultaneous pituitary and 17-hydroxycorticosteroids (25 pmol [normal < 22 pmol]), and 17- adrenocortical adenomas have been reported (8-11); all of these ketosteroids (17-KS) (410 to 520 pmol [normal < 70 pmol]). Serum were associated with Cortisol excess. To our knowledge, our pa- testosterone was 5,3 nmol/L (normal 0,7 to 2,4 nmol/L) with dehy- droepiandrosterone-sulfate (DHEA-S) levels at 20,000 to 30,500 pg/L (normal 200 to 3,350 pg/L). Plasma ACTH was 14 to 20 pmol/L (nor­ mal < 26 pmol/L) with serum prolacrin 34,4 pg/L (normal < 20 pg/L) Submitled for publication: November 29, 1989, and suppressed gonadotropin levels. Thyroid function tests were nor­ Accepled for publication: January 19, 1990, *Fellow, 1983-1985, Division of Endocrinology, Henry Ford Hospital, Currently Divi­ mal. Intravenous pyelography with nephrotomograms and subsequent sion of Endocrinology, Scott & While Clinic, Scotl & While Memorial Hospital, Temple, angiography showed a hypervascular 4 x 8 cm left adrenal mass. Com­ TX, puted tomography showed an intrasellar pituitary tumor with mild su­ tDivision of Endocrinology and Melabnlism, Henry Ford Hospital. Address correspondence lo Dr, Jackson, Division of Endocrinology, Scou & White prasellar extension; visual field testing was intact. Clinic, Scott & White Memorial Hospital, 2401 South 31 st Street, Temple, TX 76508,

22 Henry Ford Hosp Med J—Vol 39, No 1, 1991 Dual Pituitary/Adrenal Adenomas with Virilism—Jackson & Mellinger (A) (B)

Fig 1—Facial appearance ofa patient with virilization and simultaneous pituitary and left adrenal adenomas: A) preoperatively in December 1976; B) postoperatively in January 1979.

tient is unique in having severe androgen excess and virilism nalectomy (21). Pro-y-MSH N-terminal POMC peptides have without ACTH hypersecretion accompanying the dual tumors. potent mitogenic effects on the adrenal in vitro and in vivo Although possibly coincidental, we believe that the pituitary (6,22). Mitogenically active N-terminal POMC peptides also and adrenal neoplasms in this patient may be interrelated. appear to be physiologically important in adrenal regeneration Several experimental and clinical findings suggest that ACTH after bilateral adrenal enucleation in rats (23). N-terminal is not the sole modulator of adrenal androgen secretion (3). The POMC also enhances adrenocortical responsiveness to ACTH dramatic increases in serum DHEA and DHEA-S (12) and ac­ (24). companying differentiation and growth of the zona reticularis Also pertinent to this case is the suggestion that long-standing (13) that consritute adrenarche (and later decline in adreno- adrenocortical hyperplasia may predispose to adenoma forma­ pause) occur without alterations in ACTH or Cortisol levels. Bo­ tion (8-11). Macronodular adrenocortical hyperplasia in Cush­ vine pituitary extract induces greater adrenal androgen secretion ing's disease (25) may be a transitional state in this regard (10, than ACTH preparations in the castrated dexamethasone-sup- 11). We have reported a patient with Cushing's disease and pressed dog (14), and DHEA-S levels are suppressed despite macronodular hyperplasia who had marked elevation of serum maintenance of Cortisol production in the hypophysectomized DHEA-S (26). We hypothesized that chronic cosecretion of ad­ ACTH-replaced chimpanzee (5). The putative adrenal andro­ renal androgen-stimulating and adrenocortical mitogenic fac­ gen-stimulating factor (2-4) appears distinct from gonadotro­ tors with ACTH may underlie the pathophysiology in this un­ pins (15), growth hormone (16), prolactin (16), p-lipotropin usual case. (16), p-endorphin (16,17), and a-MSH (16). This factor may in­ Fig 2 shows a similar pathophysiologic explanation proposed duce 17,20-desmolase and sulfatase enzymatic activity (and for the present case which was not accompanied by ACTH hy­ perhaps suppress 3-P-hydroxysteroid dehydrogenase activity); persecretion or hypercortisolism. We postulate that secretion of altematively, an adrenarchal factor may solely stimulate devel­ adrenal androgen-stimulating and adrenocortical mitogenic fac­ opment of the zona reticularis which possesses enzymatic func­ tors by the pituitary tumor could account for the clinical features tion and response to ACTH intrinsically distinct from that of the observed in this patient—severe hyperandrogenemia and adre­ zonafasciculata(18). The hinge-portion of N-terminal proopio­ nal adenoma formation over time. Selective hypersecretion of melanocortin (POMC) has been identified as having potent non-ACTH POMC peptides by pituitary tumors is not without stimulator effects on DHEA production by human adrenal cells precedent (27). We predict that this syndrome will be further that are potentiated by ACTH (19). substantiated by careful investigation (including high-resolu­ Likewise, adrenocortical mitogenesis may be mediated by tion pituitary and adrenal imaging) of a subset of women pre­ factor(s) other than ACTH itself (7). ACTH inhibits adrenocor­ senting with severe adrenal hyperandrogenemia (serum DHEA- tical cell proliferation in vitro (20), while anti-ACTH antiserum S > 8,000 to 10,000 pg/L), hirsutism with or without viriliza­ does not cause adrenal atrophy (6,21) nor alter compensatory tion, and oligomenorrhea. Further characterization of the struc­ adrenocortical hyperplasia occurring in rats after unilateral adre­ ture and function of these factors in the future will likely provide

Henry Ford Hosp Med J—Vol 39, No 1, 1991 Dual Pituitary/Adrenal Adenomas with Virilism—Jackson & Mellinger 23 Hypothalamus 7, Lowry PJ, Estivariz FE, Silas L, Linton EA, McLean C, Crocombe K, The case for pro-gamma-MSH as the adrenal growth factor, Endocr Res 1985; 10: 243-58, 8, Hartison RJ, Abelson D, Carcinoma of the adrenal cortex with endocrine manifestations: Reportofaca.se, BrMedJ 1952;1:303-6, 9, Hartemann P, LeClerc J, MoIIet J, et al. Syndrome de Cushing par hyperpla- sie surrenale bilaterale et adenoma secretant unique, Ann Endocrinol (Paris) 1971:32:788-800, 10, Cohen RB, Observations on cortical nodules in human adrenal glands: Their relationship to neoplasia. Cancer 1966:19:552-6, Adrenal androgen (DHEA, DHEA-S) 11, Schteingart DE. 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24 Henry Ford Hosp Med J—Vol 39, No i, 1991 Dual Piluilary/Adrcnal Adenomas with Virilism—Jackson & Mellinger