Clinical evaluation of the effects of combined treatment with bromocriptine and spironolactone in two women with the polycystic ovary syndrome

Vol. 35, No.6, June 1981 Printed in UBA.

FERTILITY AND STERILITY Copyright © 1981 The American Fertility Society

CLINICAL EVALUATION OF THE EFFECTS OF COMBINED TREATMENT WITH BROMOCRIPTINE AND SPIRONOLACTONE IN TWO WOMEN WITH THE POLYCYSTIC OVARY SYNDROME

ILANA BLUM, M.D.* SHELLY BRUHIS, M.Sc. HAYUTA KAUFMAN, PH.D. Department of Internal Medicine B and the Endocrinological Laboratories, Beilinson Medical Center, Petah Tiqva, The Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel

Two women with the polycystic ovary syndrome were treated with bromocriptine (15 to 20 mg/day) in combination with spironolactone (100 mg/day). In the first woman the combined therapy induced a marked reduction of hirsutism, with ensuing ovulation and pregnancy. In the second woman, who had hyperthecosis and had been refractory to treatment with clomiphene and wedge resection, the combined therapy resulted in abolition of hirsutism, normalization of blood pressure, weight reduction, and improvement in glucose intolerance. In this patient fertility could not be established by the above treatment, but the symptomatic amelioration was so great that she accepted no further attempts to induce ovulation. In view of the marked amelioration of the polycystic ovary syndrome induced by combined bromocriptine and spironolactone treatment, this mode of therapy should receive further consideration. Fertil Steril 35:629, 1981

Since its discovery, bromocriptine has become more and more widely used in the treatment of infertility. 1 The principal indication for bromocriptine therapy is hyperprolactinemia,2.3 but pregnancies have been reported with bromocriptine therapy in women with the polycystic ovary syndrome. 4 Spironolactone, an aldosterone antagonist,5 has recently been used by Ober and Henessy6 and by ourselves 7 for the treatment of the polycystic ovary syndrome. We herewith report the results of combined treatment with bromocriptine and spironolactone in two women with the polycystic ovary syndrome who responded only partially to bromocriptine therapy alone.

CASE REPORTS

Patient 1. Patient 1, a 21-year-old nulligravida, was admitted to our clinic for investigation of hirsutism and menstrual irregularities. Physical examination was noncontributory except for excessive hair growth on her face, chest, limbs, and abdomen. Basal laboratory results are shown in Table 1 and the results of a combined lutein-releasing hormone (LRH)-thyrotropin-releasing hormone (TRH) stimulation test are shown in Table 2. The patient had mild hyperandrogenicity expressed by increased dehydroepiandrosterone (DHEA) and testosterone values, mild hyperprolactinemia, and increased luteinizing hormone (LH) values as compared with follicle-stimulating hormone (FSH), with exaggerated LH responses to LRH (Tables 1 and 2). Bromocriptine was administered in increasing dosages up to 15 mg/day for a period of 5 months. During this period, although the prolactin (PRL)

Received December 3, 1980; accepted February 2, 1981. *Reprint requests: Ilana Blum, M.D., Deputy Head, Department of Internal Medicine B, Beilinson Medical Center, Petah Tiqva, Israel.

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BLUM ET AL.

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June 1981

TABLE 1. Pertinent Laboratory Data of Patient 1 Honnoneo

FSH (mIU/ml) LH (mIU/ml) E2 (pg/ml) Progesterone' (ng/ml) Prolactin (ng/ml) DHEA (ng/dl) Androstenedione (ng/dl) Testosterone (ng/dl) 17-KS (mg) 17-0HCS (mg) ll-OHCS (f..Lg) Pregnanetriol (mg)

N annal values

1.5-6 1.5-6 70-200 8-20 1O~14

300 80-200 25-60 6-14 8-16 150 2.0

Before treatment

Bromocriptine, 15 mg

Bromocriptine, 15 mg, + spironolactone, 100 mg

8.0 18.0 63.0 0.4 29.0 500.0 81.0 100.0 6.7 11.6 91.0 0.5

7.2 7.2 180.0 0.8 3.3 425.0

2.1 7.7 230.0 8.0 1.2

50.0

50.0 4.2 9.5

a All examinations were performed on day 16 of the cycle. E 2, estradiol; 17 -KS, 17 -ketosteroids; 17 -OHCS, 17 -ketogenic steroids; 11-0HCS, free cortisol.

levels decreased to normal, slight improvement was noticed in the increased facial and body hair but none in the menstrual irregularities (cycles appearing at irregular intervals, the longest being 3 months). Five months after starting bromocriptine therapy, spironolactone was added at a dosage of 100 mg/day. Three months after beginning the combined treatment an increased loss of the excessive body hair was observed. Three months after this, all excessive hair fell and at the end of this period she was married. Regular menstrual cycles occurred after the 2nd month of initiation of treatment, and she had a biphasic basal body temperature pattern. One year after beginning the combined therapy the dosages of bromocriptine and spironolactone could be tapered down to 5 and 50 mg, respectively. Repeated trials to lower the dosages below the above values resulted in the appearance of increased facial hair growth. At the time of this writing, the patient is 1 month pregnant. Patient 2. Patient 2, a 32-year-old nulligravida, had been diagnosed as having ovarian hyperthecosis on the basis of obesity, severe hirsutism, glucose intolerance, hypertension, menstrual irregularities, and infertility. Laboratory examinations showed extremely elevated plasma LH values (28 mIUlml) and plasma testosterone levels ranging from 100 to 150 ng/ml. She was treated in another department with three courses of clomiphene in dosages ranging from 50 to 100 mg/day for the first 5 days of each cycle. Clomiphene treatment failed to induce ovulation, and her condition markedly worsened: her blood pressure rose to values of 220/140, her glucose tolerance curve deteriorated significantly, and she was obliged to shave every 2nd day. Because of the marked deterioration in her condition, an ovarian wedge resection was per-

formed. During the exploration two enlarged ovaries were found with glistening capsule cysts and several subcapsular cysts protruding from their surfaces. Bilateral wedge resection was performed and pathologic examination confirmed the diagnosis of ovarian hyperthecosis. Immediately after the operation the patient's blood pressure dropped to normal and an oral glucose tolerance test was normal. Within 1 month she lost 10 kg in weight and the superfluous body hair started to fall. Two months after the operation she had regular menstrual cycles, although her basal body temperature remained monophasic. By the 3rd month after surgery her weight had increased by 6 kg, her blood pressure rose to 170/110 mm Hg and she again noticed increased growth of hair on her face, limbs, chest, and abdomen. Plasma testosterone values rose again to 90 to 125 ng/ml. Insulin resistance and glucose intolerance were again noted on oral glucose tolerance testing (Fig. 1).

At this stage the patient was transferred to our department. Physical examination was noncontributory except for obesity, hirsutism, and blood pressure of 180/120 mm Hg. The pertinent and clinical laboratory data are shown in Table 3. Since we had had favorable results with bromocriptine therapy in another patient with the same TABLE 2. TRH-LRH Stimulation TesF in Patient 1 Time

Thyroid-stimulating hormone

min

iJ.Ulml

0 15 30 45 60

8.2 12.5 19.5 15 15

FSH

LH

mlUlml mlUlm/

8 12 14 17 23

18 19 25 25 28

Prolactin

Estradiol

nglml

pglml

23 63 64 59 56

66

~RH, 200 f..Lg, and LRH, 100 f..Lg intravenously. The test was performed on day 5 of the cycle.

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BROMOCRIPTINE AND SPIRONOLACTONE IN POLYCYSTIC OVARY SYNDROME

syndrome, bromocriptine treatment was initiated in increasing dosages up to 20 mg/day according to the patient's blood pressure. This dosage was reached 1 month after beginning treatment. Immediately after starting bromocriptine therapy the patient started to lose weight and her blood pressure values began to fall; they reached normal values within 1 month. Since no improvement was observed in her hirsutism, spironolactone, 100 mg/day, was added. From the beginning of the combined therapy the excessive body hair began to fall and her glucose tolerance test returned to normal (Fig. 1). Menstrual cycles remained irregular. Her plasma estrogen values, which had decreased markedly after surgery, remained low. Plasma progesterone levels rose slightly at periods which corresponded to days 16 to 18 of each cycle, and her basal body temperature remained monophasic. Since her husband was found to be oligospermic and the couple chose to adopt a child, the patient decided to make no further attempts to establish her fertility. DISCUSSION

The above described patients had the polycystic ovary syndrome, the second one harboring the more severe form of the disease, ovarian hyperthecosis. 8 Ovarian hyperthecosis is notoriously resistant to treatment, and surgery is generally recommended. 9 Bromocriptine has proved to be very effective in the treatment of hyperprolactinemic anovulation. 2 , 3 Some normoprolactinemic amenorrheic patients have also responded to the drug.lO In a recently reported patient, bromocriptine ameliorated markedly all of the symptoms and signs of hyperthecosis and induced ovulatory cycles. 7 Spironolactone, an antagonist of aldosterone and other mineralocorticoids, 5 has also been successfully employed in the treatment of hyperandrogenicity of the polycystic ovary syndrome. B,7 Although our two patients responded to bromocriptine with decreased hirsutism and reduced LH levels, the amelioration was incomplete. The addition of spironolactone induced a complete regression of the marked hirsutism and renewal of ovulatory cycles in the first patient. The second patient had failed to improve upon treatment with clomiphene, and ovarian wedge resection induced only temporary relief of her symptoms. In this patient bromocriptine treatment resulted in weight reduction, marked lower-

631

ing of her blood pressure, and some improvement of her hirsutism. The addition of spironolactone accelerated the disappearance of the superfluous body hair and also induced a marked amelioration of her glucose tolerance curve. The actions of the two drugs seem to be complementary. Bromocriptine induced a decrease in hirsutism and lowered the testosterone level in the first patient, possibly by reducing the increased plasma prolactin ll and LH values. 12 In the second patient, in addition to the above effect, bromocriptine induced lowering of her markedly elevated blood pressure. This could be caused by suppression of aldosterone levels 13 , 14 or by a direct action of this dopaminergic agonist on the

>200 200

, ,

I

I

I

180

e

r------

I I

I

160

{

~140 ~

c: 120

.-

3100

o

c: 80 60

Before 'treatment II During

40 170

~150 E 130 Q)

~ 110

, I

I

I

I

I

I

~

... ......

,

,

,

"

I

\

\

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~

CJ

.2 90

"

TIME (MIN.) FIG. 1. Oral glucose tolerance tests in patient 2 before and during treatment with spironolactone and bromocriptine.

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BLUM ET AL.

TABLE 3. Pertinent Clinical and Laboratory Data of Patient 2 Treatment period"

Clinical data Weight (kg) Blood pressure (mmlHg) Hirsutism Glucose intolerance Laboratory data LH (mIU/ml) FSH (mIU/ml) Estradiol (pg/ml) Progesterone (ng/ml) Prolactin (ng/ml) DHEA (ng/dl) Androstenedione (ng/dl) Testosterone (ng/dl) Urinary excretionl24 hrb 17-KS (mg) 17-0HCS (mg) 11-0HCS (j.l.g) Pregnanetriol (mg)

II

III

IV

V

80 220/140

70 110170

76 170/110

69 130/80

67 130/80

+++ ++

+

++ +

++ +

10.3 2.1 102.0 0.8 30.0 314.0 169.0 140.0

28.0 4.0 50.0 0.5 20.0 33.0 52.0 50.0

4.3 3.7 56.0 1.9 15.0 160.0 50.0 90.0

5.3 2.9 60.0 2.0 4.0 140.0 174.0 86.0

9.3 8.5 100.0 0.8.

4.5 9.0

8.0 10.0

3.1 3.5 60.0 2.2 2.5 40.0 50.0 60.0

aI, Clomiphene treatment, 100 mg/day, for 5 days; II, ovarian wedge resection; III, 3 months after wedge resection; IV, bromocriptine, 20 mg/day; V, bromocriptine, 20 mg, plus spironolactone, 100 mg/day. b17-KS, 17-ketosteroids; 17-0HCS, 17-ketogenic steroids; 11-0HCS, free cortisol.

kidney, thereby inducing diuresis and natriuresis. 15 Spironolactone completed the antiandrogenic action of bromocriptine by reducing the action of androgens at receptors,16 reducing their synthesis,17 increasing their catabolism,18 and increasing slightly their conversion to estrogens. 19 The reduction of glucose intolerance in the second patient was probably secondary to reduction of her androgen levels. 20 The combined therapy did not induce ovulatory cycles in the second patient. She had low plasma levels of estrogens after massive ovarian wedge resection which could be responsible for the lack of ovulatory response. Although fertility was not established in this patient, in whom other modes of therapy had failed, the marked symptomatic improvement warrants further trials with this therapy. The encouraging results obtained in these two patients with combined bromocriptine-spironolactone therapy indicate that continued trials in the polycystic ovary syndrome are warranted.

REFERENCES 1. Parkes D: Bromocriptine. N Engl J Med 301:873,

1979 2. Bergh T, Nillius SJ, Wide L: Hyperprolactinemil. amenorrhea-results of treatment with bromocriptine. Acta Endocrinol [Suppl] (Kbh) 216:147, 1978

3. Thorner MO, Besser GM: Bromocriptine treatment ofhyperprolactinemic hypogonadism. Acta Endocrinol [Suppl] (Kbh) 216:131, 1978 4. Thorner MO, Besser GM, Jones A, Dacie J, Jones AE: Bromocriptine treatment of female infertility: report of 13 pregnancies. Br Med J 4:694, 1975 5. Kagawa CM: Blocking the renal electrolyte effects of mineralocorticoids with orally active steroidal spironolactone. Endocrinology 67:125, 1960 6. Ober KP, Henessy JF: Spironolactone therapy for hirsutism in a hyperandrogenic woman. Ann Intern Med 89:643, 1978 7. Blum I, Kaufman H, Marilus R, Rusecki Y, Chovers I: Successful treatment of polycystic ovary syndrome with spironolactone or bromocriptine. Obstet Gynecol. In press 8. Farber M, Daoust PR, Rogers J: Hyperthecosis syndrome. Obstet Gynecol 44:35, 1974 9. Abraham GE, Buester JE: Peripheral and ovarian steroids in ovarian hyperthecosis. Obstet Gynecol 47:581, 1976 10. van der Steeg HJ, Coelingh Bennink HJT: Bromocriptine for induction of ovulation in normoprolactinaemic postpill anovulation. Lancet 1:502, 1977 11. Del Pozo E, Fluckiger E: Pharmacological aspects of the prolactin inhibitor bromocriptine. In Clinical Neuroendocrinology: A Pathophysiological Approach, Edited by G Tolis, F Labrie, JB Martin, F Naftolin. New York, Raven Press, 1979, p 429 12. Judd SJ, Rigg LA, Yen SSC: The effects of ovariectomy and estrogen treatment on the dopamine inhibition of gonadotropin and prolactin release. J Clin Endocrinol Metab 49:182,1979 13. Noth RH, McCallum RW, Contino C, Havelick J: Tonic dopaminergic suppression of plasma aldosterone. J Clin Endocrinol Metab 51:64,1980 14. Norbiato G, Bevilacqua M, Raggi U, Micossi P, Nitti F, Lanfredini M, Barbieri S: Effect of metoclopramide, a

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BROMOCRIPTINE AND SPIRONOLACTONE IN POLYCYSTIC OVARY SYNDROME

dopaminergic inhibitor, on renin and aldosterone in idiopathic edema: possible therapeutic approach with levodopa and carbidopa. J Clin Endocrinol Metab 48:37,1979 15. Goldberg LI: Dopamine--clinical use of an endogenous catecholamine. N Engl J Med 291:707,1974 16. Rifka SM, Pita JC, Vigersky RA, Loriaux DL: Interaction of digitalis and spironolactone with human sex steroid receptors. J Clin Endocrinol Metab 46:338, 1978 17. Menard RH, Stripp B, Gillette JR: Spironolactone and testicular cytochrome P-450: decreased testosterone formation in several species and changes in hepatic drug metabolism. Endocrinology 94:1628,1974

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18. Tidd MJ, Horth CE, Ramsay LE, Shelton JR, Palmer RF: Endocrine effect of spironolactone in man. Clin Endocrinol (OxO 9:389, 1978 19. Rose LI, Underwood RH, Newmark SH, Kisch ES, Williams GH: Pathophysiology of spironolactone-induced gynecomastia. Ann Intern Med 87:398,1977 20. Burghen GA, Givens JR, Kitabchi AE: Correlation ofhyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 50:113, 1980