The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 73-77
Copyright © 2003 by The Endocrine Society
Virilization in Bilateral Macronodular Adrenal Hyperplasia Controlled by Luteinizing Hormone
Mark O. Goodarzi,
David W. Dawson,
Xian Li,
Zhenmin Lei,
Peter Shintaku,
Chalama V. Rao and
Andre J. Van Herle
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine and Gonda Diabetes Center (M.O.G., A.J.V.H.) and Department of Pathology and Laboratory Medicine (D.W.D., P.S.), University of California Los Angeles School of Medicine, Los Angeles, California 90095; and Department of Obstetrics, Gynecology, and Women’s Health (X.L., Z.L., C.V.R.), University of Louisville Health Sciences Center, Louisville, Kentucky 40292
Address all correspondence and requests for reprints to: Mark O. Goodarzi, M.D., UCLA School of Medicine, Division of Endocrinology, Diabetes, and Hypertension, 200 UCLA Medical Plaza, Suite 530, Los Angeles, California 90095-7065. E-mail: mgoodarzi{at}mednet.ucla.edu.
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Abstract
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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.
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Introduction
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VIRILIZING TUMORS OF the adrenal gland are very rare, accounting for 5–6% of all adrenal tumors (1). A subset of these has been found to secrete androgens in response to administration of human chorionic gonadotropin (hCG). Normally the adrenal glands do not secrete steroids in response to gonadotropin stimulation (2). Ectopic ovarian tissue in the adrenals and ovarian thecal metaplasia have been proposed to explain adrenal responsiveness to gonadotropins (3, 4, 5, 6, 7). Early studies of neoplastic adrenal tissue suggested the possibility of steroid secretion in response to ectopic receptors (8). Recently, investigators have described in adrenal adenomas or macronodular hyperplasia the occurrence of ectopic or aberrant receptors that drive the secretion of cortisol in ACTH-independent Cushing’s syndrome (9, 10, 11). We describe a virilized woman with bilateral macronodular adrenal hyperplasia under the control of LH and propose that aberrant receptors in the adrenal glands can promote the secretion of androgens as well as cortisol.
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Case History
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A 59-yr-old woman presented with a 2-yr history of virilization. Scalp hair on the frontal, bitemporal, and vertex regions was very thin, with a slightly thicker patch of hair in the frontal region in which hair transplants had been placed (Fig. 1A
). Profuse terminal hairs covered her back (Fig. 1B). She reported frequent mechanical removal of facial hair, increased libido and a 14-kg weight gain and denied acne or voice change. Before this she had had an unremarkable reproductive history. She weighed 96 kg and was normotensive. Stigmata of Cushing’s syndrome (facial plethora, striae, dorsocervical or supraclavicular fat pads) were not present.
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Figure 1. Manifestations of hyperandrogenemia in the patient. A, Extensive scalp hair loss, with a patch of transplanted hair in the frontal region. B, Profuse terminal hairs on the back.
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Baseline laboratory values included a total testosterone of 5.2 nmol/liter (normal, 0.2–1.8 nmol/liter), bioavailable testosterone of 0.7 nmol/liter (normal, 0.01–0.15 nmol/liter), estradiol of 110 pmol/liter (normal, 7–73 pmol/liter), FSH of 50 IU/liter (normal, 21–106 IU/liter), and LH of 20 IU/ liter (normal, 16–63 IU/liter). Dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and 17-hydroxyprogesterone levels were normal. Transvaginal ultrasound showed two normal ovaries. A computed tomographic scan of the adrenals showed a 4-cm mass in the right adrenal and a left adrenal that was enlarged with a nodular contour (Fig. 2). Urinary cortisol excretion was 91 nmol/24 h (normal, 55–248 nmol/24 h), and administration of 1 mg dexamethasone suppressed her serum cortisol to 72 nmol/liter.
The patient underwent a laparoscopic right adrenalectomy. The right adrenal contained a 4.3-cm circumscribed adrenal adenoma with no evidence of vascular invasion. Immediately postoperatively the patient had a total testosterone of 1.4 nmol/liter. Three months later the patient reported no improvement in her alopecia or hirsutism, at which point blood tests revealed a total testosterone of 5.1 nmol/liter.
The persistence of hyperandrogenemia suggested that the nodular left adrenal was also secreting testosterone and prompted us to perform further studies.
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Materials and Methods
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Hormonal assays
LH, FSH, estradiol, cortisol, and dehydroepiandrosterone sulfate measurements were determined by sandwich immunoassay. RIA was used to measure testosterone, bioavailable testosterone (Esoterix Endocrinology, Calabasas Hills, CA), dehydroepiandrosterone, androstenedione, and 17-hydroxyprogesterone (Quest Diagnostics, Inc., San Juan Capistrano, CA).
Testosterone immunohistochemistry
Paraffin sections (3 µm) were baked overnight at 60 C, deparaffinized in xylene and graded ethyl alcohols, and brought to water. Slides were treated with 3% hydrogen peroxide in methyl alcohol for 10 min. Heat-induced epitope retrieval was performed for 25 min with a steamer using 0.001 M EDTA (pH 8.0), followed by cooling and washing in 0.01 M PBS. Slides were immunostained on an autostainer (DAKO Corp., Carpenteria, CA) for 45 min with rabbit polyclonal antibody against testosterone (ICN Biomedical, Aurora, OH), diluted 1:700, followed by Envision+ (antirabbit peroxidase, DAKO Corp.) for 30 min. Diaminobenzidine and hydrogen peroxide were used as the substrate for the peroxidase enzyme and hematoxylin as a counterstain. For the negative control, rabbit immunoglobulin negative control (DAKO Corp.) was used in place of the primary antibody.
In situ hybridization for LH receptor mRNA
In situ hybridization for LH receptor mRNA was performed by a nonradioactive method. The sections were treated for 30 min at 37 C [5 µg/ml proteinase K, 50 mM Tris-HCl, 5 mM EDTA (pH 7.5)], prehybridized for 3 h at 55 C (50% formamide, 5x saline sodium citrate (SSC), 1x Denhardt’s, 1 mg/ml yeast tRNA, 100 µg/ml heparin, 5 mM EDTA), and hybridized overnight with fluorescein-uridine 5-triphosphate-labeled antisense or sense riboprobes transcribed from human LH/hCG receptor cDNA (a gift from Dr. Aaron J. Hsueh, Stanford University Medical Center, Palo Alto, CA). The sections were then washed twice for 30 min at 55 C (1x SSC and 0.2x SSC) and hybridization signals detected using an antifluorescein alkaline phosphatase conjugate and 4-nitroblue tetrazolium/5-bromo-4-chloro-3-indolylphosphate.
hCG stimulation test
hCG (5000 IU; Pregnyl, Organon, West Orange, NJ) was injected im on d 1, 2, and 3. Testosterone was measured on d 3, 4, and 5. The patient gave informed consent for all tests performed.
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Results
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The excised right adrenal gland was entirely replaced by a circumscribed adenomatous nodule measuring 4.3 cm (Fig. 3). The mass was primarily composed of sheets and cords of large cells with small nuclei and pale-staining, lipid-rich cytoplasm resembling adrenal zona fasciculata (Fig. 4A). The mass also contained scattered nests of cells with compact eosinophilic cytoplasm resembling zona reticularis (Fig. 4A). Because testosterone was the only elevated androgen, we performed immunostaining for testosterone in the right adrenal mass. The eosinophilic nests of cells stained positive for testosterone (Fig. 4B).
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Figure 4. Histology of right adrenal nodule. A, Hematoxylin and eosin (H&E) stain, x20 magnification. The tumor was composed mainly of pale-staining, lipid-rich cells of zona fasciculata appearance interspersed with nests of eosinophilic cells of resembling zona reticularis. B, Positive immunostain with polyclonal rabbit antitestosterone antibody. Testosterone was present in the eosinophilic nests of cells; magnification, x20. C, Control stained with nonspecific rabbit immunoglobulin. The immunostains were visualized with antirabbit peroxidase; magnification, x20.
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The transient decrease in testosterone level on the morning after the adrenalectomy suggested that the androgen secretion was under gonadotropin control, with the gonadotropins suppressed transiently by the stress of surgery. Because adrenal Cushing’s syndrome under control of the LH/hCG receptor was recently described (9), we decided to investigate whether the testosterone secretion in our patient was also controlled by this receptor. The excised right adrenal nodule contained LH receptors, assayed by in situ hybridization for LH receptor mRNA (Fig. 5).
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Figure 5. In situ hybridization for LH receptor mRNA. A, The right adrenal tissue stained positive with an antisense probe to LH receptor mRNA; magnification, x150. B, Sense probe was used as a control; magnification, x150 magnification.
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The persistent hyperandrogenemia despite removal of the larger right adrenal suggested the patient had bilateral macronodular adrenal hyperplasia secreting testosterone. We administered hCG to determine whether LH mediated testosterone secretion by the hyperplastic left adrenal. In response, the patient’s testosterone level increased from 5.7 nmol/liter to 8.1 nmol/liter (Fig. 6). Two weeks later the testosterone level had returned to baseline levels.
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Figure 6. Serum total testosterone level in the virilized patient with bilateral macronodular adrenal hyperplasia during gonadotropin stimulation and suppression. The arrows indicate administration of specific agents. The striped area indicates the normal range for testosterone (0.2–1.8 nmol/liter). Testosterone can be converted from nanomoles per liter to nanograms per deciliter by dividing by 0.03467.
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We then administered 7.5 mg leuprolide acetate im. The serum testosterone level steadily decreased over the following several days, reaching normal range within a month, at which point the LH level had fallen to 2 IU/liter (Fig. 6
). Normalization of the testosterone level persisted for almost 2 months, after which the LH level was 11 IU/liter and the testosterone level increased to high normal levels, prompting a second injection of leuprolide acetate that again suppressed the testosterone level (Fig. 6). The patient reported a decrease in the amount and thickness of hair on her back and an increase in the amount of hair on her scalp during this treatment. Given the expense and inconvenience of intermittent leuprolide acetate injections, oral contraceptive pills were instituted instead to achieve gonadotropin suppression, with continued improvement in hirsutism and alopecia, allowing us to avoid left adrenalectomy and iatrogenic adrenal insufficiency.
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Discussion
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We determined that our patient had a LH-dependent virilizing syndrome caused by testosterone secretion by bilateral macronodular adrenal hyperplasia. In support of this conclusion is the presence of testosterone and LH receptors in the excised nodule, increase in serum testosterone level in response to exogenous hCG administration, and normalization of the testosterone level during gonadotropin suppression by GnRH agonist therapy. This is the first case to our knowledge demonstrating pure androgen secretion by bilateral macronodular hyperplasia under control of the LH/hCG receptor.
We identified 14 cases in the literature of androgen-secreting unilateral adrenal tumors that responded to hCG or LH stimulation with an increase in androgen level (5, 6, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). Because gonadotropins normally regulate only gonadal steroid production, early theories on how gonadotropins could stimulate adrenal androgen output focused on the presence of ovarian tissue within the adrenal glands, either by deposition of ovarian cells in the adrenals during development or by transformation of embryologically competent cells in the adrenal to become ovarian thecal cells (3, 7). Several cases of testosterone-secreting adrenal neoplasms have been reported in which the tumor had Reinke’s crystals, a hallmark of steroidogenic ovarian hilus cells and testicular Leydig cells (3, 4, 24, 25, 26). In none of these cases was the response to gonadotropin administration tested.
None of the 14 cases of hCG-responsive adrenal virilization reported in the literature had Reinke’s crystals or ovarian morphology (5, 6, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). In fact, the tumor histology in all of these cases was characteristic of adrenocortical tissue, with features of zona reticularis histology alone or mixed with zona fasciculata. These tumors represent a unique mechanism of androgen secretion distinct from ovarian ectopia or metaplasia. The fact that they secrete androgens in response to LH or hCG suggests the presence of aberrant control by the LH/hCG receptor. This receptor was demonstrated to exist in the zona reticularis and part of the zona fasciculata (27). Normally these receptors do not play a significant role in adrenal steroid secretion (2). Thus, in adrenal neoplasms that secrete steroids in response to LH and hCG, a cellular event has occurred that allows the normally quiescent LH/hCG receptor to trigger steroidogenesis.
Most but not all cases of LH/hCG-responsive adrenal virilization have occurred in postmenopausal women (5, 13, 14, 19, 22, 23, 28). These tumors may have been present for many years but only became clinically evident once stimulated by elevated postmenopausal gonadotropin levels. Stress is known to affect the hypothalamic GnRH pulse generator, causing decreased gonadotropin secretion. In our patient as well as others (5, 22), a transient postoperative reduction in androgen levels was observed. To control gonadotropin-dependent tumors, GnRH agonists such as leuprolide acetate have been used in both ovarian androgen-secreting tumors as well as LH/hCG-dependent adrenal Cushing’s syndrome (9, 29). This approach succeeded in our patient.
Bilateral adrenal neoplasia has been found more often in illicit receptor-controlled cortisol secretion (30), but a unilateral process has been more frequently reported in LH/hCG receptor-controlled adrenal androgen secretion. Perhaps in these syndromes cellular proliferation and steroid secretion progress asynchronously, beginning in one adrenal and then developing in the other. This has been documented in a case of gastric inhibitory polypeptide-dependent Cushing’s syndrome (31). It is possible that more unilateral adrenal neoplasms have been found in androgen secretion because women with virilization may present for medical care earlier than patients with the more subtle symptoms of Cushing’s syndrome. In fact, in some patients in whom the source of excess androgens was clearly unilateral, the contralateral adrenal was enlarged or producing clinically insignificant levels of androgens (3, 12, 19).
Most cases of illicit receptors controlling adrenal steroidogenesis have been described in adrenal Cushing’s syndrome. Our case, as well as a case of androgen secretion-driven by the gastric inhibitory peptide receptor (32), demonstrates that aberrant receptor function can occur not only in the zona fasciculata but also in the zona reticularis in bilateral macronodular hyperplasia.
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Acknowledgments
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Footnotes
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Abbreviations: hCG, Human chorionic gonadotropin; SSC, saline sodium citrate.
Received August 14, 2002.
Accepted September 24, 2002.
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Abstract
Introduction
