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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Case Report
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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. 1
) 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 1970; Fig. 2
), a free testosterone of
221 pg/mL (normal 310), and dehydroepiandrosterone sulfate of 134
µg/dL (normal 23366). Her thyroxine was 9.8 µg/dL (normal 512),
the free thyroxine index was elevated at 11.7 (normal 610.5), and her
TSH was suppressed to 0.1 µU/mL (normal 0.54.0). 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.
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 1
).
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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Discussion
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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 patients 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 2545% 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.
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Footnotes
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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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References
|
---|
-
Lobo RA. 1991 Ovarian hyperandrogenism and
androgen-producing tumors. Endocrinol Metab Clin North Am. 20:773805.[Medline]
-
Barnes RB, Rosenfield RL, Burstein S, Ehrmann DA. 1989 Pituitary-ovarian responses to nafarelin testing in the polycystic
ovary syndrome. N Engl J Med. 320:559565.[Abstract]
-
Doppman JL. 1995 Adrenal imaging. In: DeGroot LJ,
ed. Endocrinology. 3rd ed. Philadelphia: W. B. Saunders Company;
17111730.
-
Young RH, Scully RE. 1994 Sex cord-stromal,
steroid cell, and other ovarian tumors with endocrine, paraendocrine,
and paraneoplastic manifestations. In: Kurman RJ, ed. Blausteins
pathology of the female genital tract. 4th ed. New York:
Springer-Verlag; 783847.
-
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. 42:585593.[Medline]
-
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. 158:13131322.[Medline]
-
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. 64:287295.[Abstract]
-
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. 48:241245.[Abstract]
-
Mclellan AR, Mowat A, Cordiner J, et al. 1990 Hilus cell pathology and hirsutism. Clin Endocrinol (Oxf). 32:203212.[Medline]
-
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. 35:264269.[Medline]
-
Clement PB. 1994 Nonneoplastic Lesions of the
Ovary. In: Kurman RJ, Ed. Blausteins pathology of the female genital
tract. 4th ed. New York: Springer-Verlag; 597645.
-
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. 41:259262.[Medline]
-
Tucci JS, Zah W, Kalderon AE. 1973 Endocrine
studies in an arrhenoblastoma responsive to dexamethasone, ACTH and
human chorionic gonadotropin. Am J Med. 55:687694.[CrossRef][Medline]
-
Nagamani M, Gonzalez-Vitale JC. 1981 Steroid
secretion patterns of a hilus cell tumor of the ovary. Obstet Gynecol. 58:521527.[Abstract]
-
Davidson BJ, Waisman J, Judd HL. 1981 Long-standing
virilism in a woman with hyperplasia and neoplasia of ovarian lipidic
cells. Obstet Gynecol. 58:753759.[Abstract]
-
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 46:10051010.
-
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. 32:363369.[Medline]
-
Friedman CI, Schmidt GE, Kim MH, Powell J. 1985 Serum testosterone concentrations in the evaluation of
androgen-producing tumors. Am J Obstet Gynecol. 153:4449.[Medline]
-
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. 65:194197.[Abstract]
-
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. 743:901905.
-
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. 64:13201322.[Abstract]
-
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. 54:450454.[Abstract]