Long-Term Suppression of Testosterone After Treatment with a Gonadotropin-Releasing Hormone Agonist in a Woman with a Presumed Testosterone Secreting Ovarian Tumor

Randall B. Barnes and David A. Ehrmann

Departments of Obstetrics and Gynecology (R.B.B.) and Medicine (D.A.E.), University of Chicago, Pritzker School of Medicine, Chicago, Illinois 60637


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A 57-yr-old women was referred to our institution in May 1990 for symptoms of androgen excess. She had a one year history of rapidly progressing hair growth and of bilateral temporal balding. She denied voice deepening or increased libido. The patient had a history of regular monthly menses and no previous hirsutism, and she had undergone menopause at age 50. She was noted to have exophthalmos but denied symptoms of hyperthyroidism. Her past medical history was significant for chronic renal failure secondary to hyperparathyroidism and nephrocalcinosis, which was diagnosed at age 30. At that time she had undergone parathyroidectomy. About one year before her presentation to us, a renal biopsy for increasing proteinuria was performed, which revealed membranous glomerulonephritis. Evaluation for collagen vascular disease was negative. She was treated with prednisone from May to November, 1989, in doses up to 50 mg/day. Current medications were nifedipine 60 mg/day. She denied taking any other medications or hormones.

On physical examination, her blood pressure was 164/100 mm Hg, and pulse was 104 beats per minute. Exophthalmos was present. She had temporal balding (Fig. 1Go) and marked hirsutism of her face, chest, abdomen, back, and thighs with a Ferriman-Gallwey score of 21 (normal <= 7). Her clitoris was enlarged to 1.5 cm in diameter, and no adnexal masses were felt on bimanual examination. Initial laboratory test at our institution showed a total testosterone of 634 ng/dL (normal 19–70; Fig. 2Go), a free testosterone of 221 pg/mL (normal 3–10), and dehydroepiandrosterone sulfate of 134 µg/dL (normal 23–366). Her thyroxine was 9.8 µg/dL (normal 5–12), the free thyroxine index was elevated at 11.7 (normal 6–10.5), and her TSH was suppressed to 0.1 µU/mL (normal 0.5–4.0). Her antimicrosomal antibodies were elevated with a titer of 20,480, and antithyroglobulin antibodies were negative. The patient underwent radioactive iodine therapy for her Graves’ disease in July 1990 and subsequently began thyroxine 0.1 mg/day in November 1990.



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Figure 1. Profile of patient showing temporal balding, hirsutism, and exophthalmos.

 


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Figure 2. Testosterone values before, during, and after depot leuprolide therapy.

 
A computer tomography (CT) scan, ordered by her referring nephrologist in April 1990, showed bilateral medullary nephrocalcinosis, normal adrenal glands, and a normal left ovary, but the right ovary was not well visualized. A transvaginal ultrasound evaluation at our institution in July 1990 showed a normal uterus except for a thickened endometrium and normal postmenopausal ovaries (right 1.9 x 1.2 and left 2.1 x 1.2 cm).

Because of her postmenopausal status and normal adrenal CT scan, a total abdominal hysterectomy and bilateral salpingo-oophorectomy was recommended as therapy for a presumed androgen secreting ovarian tumor (1). However, the patient was unwilling to have surgery because she was concerned that it might result in a worsening of her renal failure.

The patient agreed to a trial of gonadotropin-releasing hormone agonist (GnRHa) to attempt to suppress ovarian androgen production. Initially she underwent a GnRHa stimulation test to determine if her tumor was gonadotropin sensitive (2). There was a marked elevation in baseline 17-hydroxyprogesterone, androstenedione, and testosterone with about a 2-fold increase in 17-hydroxyprogesterone and androstenedione in response to gonadotropin stimulation by nafarelin (Table 1Go).


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Table 1. Nafarelin stimulation test

 
The patient received 7.5 mg of depot leuprolide im in September 1990 and then at monthly intervals for 3 doses. After 1 month, her LH and FSH were 11 and 16 mIU/mL respectively, total testosterone was 26 ng/dL, and free testosterone was 7 pg/mL. Her leuprolide dose was decreased to 3.75 from December 1990 through December 1991, for a total of 16 months of therapy. Testosterone levels in January and March 1991 were less than 20 ng/dL. Ultrasounds in December 1990 and June 1991 were unchanged from her initial examination. Physical examination in October 1991 showed resolution of her hirsutism and some increase in temporal hair growth. Pelvic examination revealed persistent clitoromegaly.

The patient was seen in April 1992, four months after completing depot leuprolide therapy. She was free of androgen excess symptoms. Her total testosterone level was less than 20 ng/dL, and her pelvic ultrasound remained unchanged. In October 1992 the patient remained free of androgenic systems. LH (112 mIU/mL) and FSH (110 mIU/mL) were postmenopausal, testosterone was less than 20 ng/dL, and the ultrasound was unchanged. The patient was next seen in May 1994. She had remained free of any symptoms of androgen excess. Her ultrasound was unchanged, and testosterone was less than 20 ng/dL. The patient returned in June of 1995. Her history and physical examination were unchanged, and her total testosterone was 22 ng/dL. The patient remains free of symptoms at this time.


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As far as we are aware this is the first report of complete resolution of a presumed ovarian androgen secreting tumor after suppression by GnRHa. The abrupt onset of rapidly progressive virilization together with markedly elevated testosterone levels strongly suggest an androgen secreting tumor in this patient. Because the CT scan reliably excludes even small adrenal tumors (3), our assumption was that the patient’s androgen excess was caused by a small ovarian tumor.

Although the tumor type in this patient is unknown, small ovarian androgen secreting tumors in postmenopausal women are most likely Leydig cell tumors of the hilus cell or nonhilus cell type, or what have variously been described as lipid, lipoid or steroid cell tumors not otherwise specified (4, 5, 6). These tumors cause symptoms even when small enough to escape detection by laparoscopy (5), CT scan (7), or ultrasound (6, 8, 9, 10). Leydig cell tumors are virtually never malignant, however 25–45% of lipid cell tumors are. Malignancy is much more common in lipid cell tumors of seven or more cm in diameter than in small tumors. An alternate possibility is that the patient had hyperthecosis. We believe this is unlikely because hyperthecosis usually occurs in premenopausal women, and there are only a few case reports of symptomatic postmenopausal hyperthecosis (11, 12). Additionally ultrasound almost always demonstrates bilaterally enlarged ovaries even in postmenopausal hyperthecosis, which this patient did not have. Because in this patient a malignant ovarian androgen secreting tumor was unlikely, we initiated a trial of GnRHa therapy.

Androgen secreting ovarian tumors are usually gonadotropin sensitive. CG stimulation has been reported to result in a 1.5- to 10-fold increase in 17-hydroxyprogesterone, androstenedione, and testosterone (7, 8, 13, 14, 15, 16, 17). Our patient responded to nafarelin with an approximately 2-fold increase in 17-hydroxyprogesterone and androstenedione; however, she was unusual, but not unique, in that testosterone was unchanged (9). These tumors also respond to treatment with the oral contraceptive pill, with testosterone suppressing to normal or near normal levels in some (16, 17, 18, 19, 20) but not all cases (13, 14).

We are aware of one report of a Leydig cell tumor in a postmenopausal woman who was treated with the GnRHa buserelin for 16 days, resulting in a 50% decrease in testosterone before undergoing surgery (21). Depot leuprolide injections were successful in suppressing plasma testosterone and relieving symptoms in our patient for 16 months. We presume that testosterone suppression was a result of GnRHa-induced gonadotropin suppression. However, GnRHa has also been shown to directly suppress testosterone secretion by a Sertoli-Leydig cell tumor in vitro (22).

As far as we know this patient is unique in that upon completion of therapy her testosterone has remained low, and she has continued symptom free for over 4 yr. This would suggest that small ovarian androgen secreting tumors in postmenopausal women are not only suppressible by GnRHa, but may be treatable as well. Thus GnRHa may be considered for therapy in these patients who are high risk or otherwise unwilling to undergo surgery, provided that they receive careful follow-up including periodic androgen levels and ovarian imaging.


    Footnotes
 
Address all corresponding and requests for reprints to: Randall B. Barnes, M.D., Department of Obstetrics and Gynecology (MC 2050), University of Chicago, 5841 S. Maryland Avenue, Chicago, Illinois 60637.

Received May 16, 1996.

Accepted February 18, 1997.


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 Case Report
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 References
 

  1. Lobo RA. 1991 Ovarian hyperandrogenism and androgen-producing tumors. Endocrinol Metab Clin North Am. 20:773–805.[Medline]
  2. Barnes RB, Rosenfield RL, Burstein S, Ehrmann DA. 1989 Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N Engl J Med. 320:559–565.[Abstract]
  3. Doppman JL. 1995 Adrenal imaging. In: DeGroot LJ, ed. Endocrinology. 3rd ed. Philadelphia: W. B. Saunders Company; 1711–1730.
  4. Young RH, Scully RE. 1994 Sex cord-stromal, steroid cell, and other ovarian tumors with endocrine, paraendocrine, and paraneoplastic manifestations. In: Kurman RJ, ed. Blaustein’s pathology of the female genital tract. 4th ed. New York: Springer-Verlag; 783–847.
  5. Moltz L, Pickartz H, Sorensen R, Schwartz U, Hammerstein J. 1984 Ovarian and adrenal vein steroids in seven patients with androgen-secreting ovarian neoplasms: selective catheterization findings. Fertil Steril. 42:585–593.[Medline]
  6. Surrey ES, deZiegler D, Gambone JC, Judd HL. 1988 Preoperative localization of androgen-secreting tumors: clinical, endocrinologic, and radiologic evaluation of ten patients. Am J Obstet Gynecol. 158:1313–1322.[Medline]
  7. Barkan AL, Cassorla F, Loriaux DL, Kelch RP, Marshall JC. 1984 Steroid and gonadotropin secretion in a patient with a 30-year history of virilization due to lipoid-cell ovarian tumor. Obstet Gynecol. 64:287–295.[Abstract]
  8. Adashi EY, Rosenwaks Z, Lee PA, Jones GS, Migeon CJ. 1979 Endocrine features of an adrenal-like tumor of the ovary. J Clin Endocrinol Metabol. 48:241–245.[Abstract]
  9. Mclellan AR, Mowat A, Cordiner J, et al. 1990 Hilus cell pathology and hirsutism. Clin Endocrinol (Oxf). 32:203–212.[Medline]
  10. Hill GA, Herbert CM, DeBold CR, Wentz AC. 1990 Use of hypothalamic releasing factors to examine the effects of increased testosterone on pituitary response in a postmenopausal woman. J Reprod Med. 35:264–269.[Medline]
  11. Clement PB. 1994 Nonneoplastic Lesions of the Ovary. In: Kurman RJ, Ed. Blaustein’s pathology of the female genital tract. 4th ed. New York: Springer-Verlag; 597–645.
  12. Koroscil TM, Harter SB, Ouweleen J, Blauer KL. 1996 Use of a gonadotropin-releasing hormone agonist in the evaluation of postmenopausal virilization due to ovarian hyperthecosis. J Reprod Med. 41:259–262.[Medline]
  13. Tucci JS, Zah W, Kalderon AE. 1973 Endocrine studies in an arrhenoblastoma responsive to dexamethasone, ACTH and human chorionic gonadotropin. Am J Med. 55:687–694.[CrossRef][Medline]
  14. Nagamani M, Gonzalez-Vitale JC. 1981 Steroid secretion patterns of a hilus cell tumor of the ovary. Obstet Gynecol. 58:521–527.[Abstract]
  15. Davidson BJ, Waisman J, Judd HL. 1981 Long-standing virilism in a woman with hyperplasia and neoplasia of ovarian lipidic cells. Obstet Gynecol. 58:753–759.[Abstract]
  16. Taylor L, Ayers JWT, Gross MD, Peterson EP, Menon KMJ. 1986 Diagnostic considerations in virilization: iodomethyl-norcholesterol scanning in the localization of androgen secreting tumors. Fertil Steril 46:1005–1010.
  17. Rosenfield RL, Cohen RM, Talerman A. 1987 Lipid cell tumor of the ovary in reference to adult-onset congenital adrenal hyperplasia and polycystic ovary syndrome. A case report. J Reprod Med. 32:363–369.[Medline]
  18. Friedman CI, Schmidt GE, Kim MH, Powell J. 1985 Serum testosterone concentrations in the evaluation of androgen-producing tumors. Am J Obstet Gynecol. 153:44–49.[Medline]
  19. Brumsted JR, Chapitis J, Riddick D, Gibson M. 1987 Norethindrone inhibition of testosterone secretion by an ovarian Sertoli-Leydig cell tumor. J Clinic Endocrinol Metab. 65:194–197.[Abstract]
  20. Haning Jr RV, Loughlin J, Shapiro SS. 1989 Diagnosis and resection of an oral contraceptive-suppressible Sertoli-Leydig cell tumor with preservation of fertility and a 7-year follow-up. Obstet Gynecol. 743:901–905.
  21. Kennedy L, Traub AI, Atkinson AB, Sheridan B. 1987 Short term administration of gonadotropin-releasing hormone analog to a patient with a testosterone-secreting ovarian tumor. J Clin Endocrinol Metab. 64:1320–1322.[Abstract]
  22. Lamberts SWJ, Timmers JM, Oosterom R, Verleun T, Rommerts FG, deJohn FH. 1982 Testosterone secretion by cultured arrhenoblastoma cells: suppression by a luteinizing hormone-releasing hormone agonist. J Clin Endocrinol Metab. 54:450–454.[Abstract]