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1 FERTILITY AND STERILITY Copyright" 1979 The American Fertility Society Vol. 31, No. 2, February 1979 Prinf d in U.S.A. BROMOCRIPTINE IN THE TREATMENT OF HYPEROLACTINEMIC AMENORRHEA ALBERTO R. BADANO, M.D. HECTOR R. MIECHI, M.D.* ABRAHAM MIRKIN, M.D. OMAR A. ARCANGELI, M.D. NESTOR J. APARICIO, M.D. ANIBAL RODIUGUEZ, M.D. ALEJANDRO OLIVA, M.D. DIEGO TURNER, PH.D. PEDRO R. FIGUEROA CASAS, M.D. Grupo de Estudio en Fertilidad y Endocrinologies de Rosario, 2000 Rosario, Argentina Thirty women with secondary amenorrhea and hyperprolactinemia were studied; galactorrhea was present in 25 of them, and 18 were infertile. Serum prolactin (PRL) levels were high in all cases, between 26 and 120 nglml. All women were treated with bromocriptine in increasing doses from 2.5 to 5.0 or 7.5 mg daily, according to the response obtained, for 4 months. In 27 patients a PRL determination was performed during treatment; values returned to normal (up to 20 nglml) in 23 women and remained high in 4. Galactorrhea disappeared in 21 of 25 women. Ovulatory menses were re-established in 17 patients (56.6%). Seven women became pregnant (38.8%), one of them after bromocriptine and clomiphene were given simultaneously in the same cycle. According to our results and a literature review the following conclusions may be drawn: (1) bromocriptine is a useful therapeutic tool for re-establishing menstruation and inducing ovulation in patients with the hyperprolactinemic-amenorrhea syndrome; (2) the association of bromocriptine and clomiphene could be the next step in the treatment of patients who fail to ovulate with bromocriptine alone. Fertil Steril31:124, 1979 The two most important advances in the treatment of anovulation in the last 25 years have been human menopausal gonadotropins and clomiphene citrate (CC). However, even in reports with the best results, the success in achieving pregnancy does not exceed 65% for human menopausal gonadotropins 1 and 50% for CC.2 Studies performed in the last 10 years have demonstrated the important role of prolactin (PRL) in the physiology of the hypothalamic-pitui- Received June 12, 1978; revised September 18, 1978; accepted September 28, * Reprint requests: Hector R. Miechi, M.D., Casilla de Correo No. 999, 2000 Rosario, Argentina. 124 tary-gonadal axis.3 4 The development of bromocriptine, a semisynthetic ergot alkaloid derivative which inhibits the pituitary release ofprl,5 offers a new approach for the treatment of anovulatory patients. A number of etiologies may be ascribed for hyperprolactinemia, such as pituitary tumors, certain neuroendocrinologic diseases, and drugs acting on the central nervous system. However, there are several cases in which no etiologic factors can be demonstrated; they are called "functional" hyperprolactinemias. It has been reported that up to 30% of amenorrheic patients have hyperprolactinemia. 6 7 Two mechanisms could explain this association: (1)

2 Vol. 31, No.2 BROMOCRIPTINE IN THE TREATMENT OF HYPERPROLACTINEMIC AMENORRHEA 125 I I ~ I hyperprolactinemia inhibits ovulation, interfering with the synthesis and release offollicle-stimulating hormone (FSH); consequently, the circulating levels of this hormone remain under the threshold required by the ovary for normal follicular developments; (2) high levels of PRL act directly on the ovary by blocking gonadotropin receptors.s,9 Prolactin secretion can be pharmacologically inhibited by drugs that act as dopamine precursors, like L-dopa, or as dopamine agonists, like bromocriptine.10 The purpose of this report is to show the results obtained with the latter drug in women with amenorrhea and hyperprolactinemia. MATERIALS AND METHODS Clinical data from 30 women with secondary amenorrhea of 6 to 60 months' duration and hyperprolactinemia are shown in Table 1. Their ages ranged between 17 and 40 years; 25 had galactorrhea which was classified as follows: + + +, spontaneous (n = 5); ++, provoked by light pressure (n = 15); and +, provoked by moderate pressure (n = 5). Twenty patients who responded with withdrawal bleeding after 200 mg of progesterone in oil intramuscularly were considered to be normoestrogenic. Ten who did not respond to that test were classified as hypoestrogenic. Sixteen patients had been previously treated for three to twelve cycles with CC (100 to 150 mg daily for 5 days); one received CC plus luteinizing hormone (LH) releasing hormone (LH-RH)l1 during two cycles; ten of them were treated by our group without obtaining ovulation. Eighteen patients had primary infertility without other factors, except for two whose husbands had oligospermia. Four women had been taking oral contraceptives for 6 to 18 months. Neither contraceptives nor other drugs capable of inducing hyperprolactinemia had been taken by the patients in the last 3 months prior to the study. Other endocrine diseases were excluded in all patients except for one who had polycystic ovaries. None was obese or had hypertrichosis. Planimetric x-ray studies of the sella were performed in all cases; when a tumor was suspected tomographic studies were carried out. FSH, LH, and PRL levels in plasma were determined by radioimmunoassay.12 Basal levels of the three hormones were determined in all women. During treatment, between the 4th and 6th weeks, an additional PRL determination was performed in 27 cases. Normal values during the follicular phase are as follows: FSH, 5 to 13 miu/ml; LH, 5 to 15 miu/ml; PRL, 5 to 20 ng/ml. Bromocriptine was administered orally beginning between days 3 and 5 of an induced cycle. The initial dose was 2.5 mg daily after dinner for 7 to 10 days. When there were no side effects, the dosage was increased to 5 mg daily for 7 weeks. If at the end ofthis period ovulation or menstruation failed to occur the dose was increased to 7.5 mg daily. The treatment lasted for 16 weeks, except in those cases in which pregnancy was obtained or relevant side effects appeared. At the end of the study seven patients received additional treatment for 2 months: four were treated simultaneously with bromocriptine (5 mg daily) and CC (100 mg daily for 5 days beginning on cycle day 5), and three were treated with CC alone. Ovulatory parameters investigated were basal body temperature, urinary pregnanediol excretion, and, in some cases, endometrial biopsy. RESULTS FSH levels ranged between <1.56 and 13 miu/ml; in six cases they were low and in twentyfour in the normal range. LH levels ranged between <1.56 and 18 mivlml; in six patients they were low, in four high, and normal in 20. PRL values were high in all cases, between 26 and 120 ng/ml (Table 1). Planimetric x-rays of the sella were normal in 24 cases; these studies were repeated in 12 patients between 1 and 3 years after the first studies and there were no changes. Conventional tomography (section intervals 5 mm) was performed in five women. In three the results were normal. In one woman (B. R.) the study revealed erosion of the sella, but she refused surgery. In another patient (V. M.) the tomographic study was not conclusive. In the sixth (C. P.) hypocycloidal tomography (section intervals 1 mm) was carried out and showed signs of pituitary microadenoma later confirmed by transsphenoidal surgery (Table 2). During treatment PRL returned to normal values in 23 of 27 cases. Galactorrhea disappeared in 21. Menstruation resumed in 17 women, and all of them ovulated-14 with 5 mg daily and 3 with 7.5 mg daily. Seven became pregnant (Table 2), all with the dosage of 5 mg daily (three in the first cycle of treatment, three in the second, and the other one when CC was associated with bromocriptine). Three ofthem have delivered normal infants at term after uncomplicated pregnancies. Two

3 126 BADANO ET AL. February 1979 TABLE 1. Clinical Data of Thirty Women with Amenorrhea and Hyperprolactinemia Duration of Patient Age amenorrhea Galactorrhea Progesterone test Previous treatments FSH LH PRL ma Z.C Positive J. T Positive B.S Positive A.T Positive E.P Negative M.R Positive L. B Negative B.P Positive K.L Positive M.M Positive G.M Positive L.D Positive E. Y Positive M.B Positive C. C Negative J. V Positive M.S Positive S. S Positive R. V Positive C.CH Negative M.C Positive S.K Positive A.S Positive G.F Negative E.B Negative S. L S.B Negative Positive +++ Negative +++ Negative V.M Negative C. P. B. R women are now between the 28th and 32nd weeks of uneventful pregnancies. Two patients aborted between the 8th and the 10th week of pregnancy. Six of the patients who had ovulated under bromocriptine treatment were followed for 6 months after treatment. In four, amenorrhea and galactorrhea reappeared immediately; one woman menstruated regularly for two cycles but had subsequent amenorrhea; in another patient (C. P.) a pituitary adenoma was excised with restoration of menses 30 days after surgery and pregnancy 4 months later. Seven patients received additional treatment; three of four who received bromocriptine plus CC ovulated and one (V. M.) became pregnant; two of three who received only CC also ovulated. Eleven patients showed side effects: seven had nausea and/or vomiting three constipation, and one mild headache. In two cases the treatment had to be stopped, in one for severe constipation and in the other for persistent nausea. DISCUSSION As a consequence of the application of radioimmunoassay in clinical practice a new entity has miulml miulml nglml CC, 8 cycles CC + LH-RH, 2 cycles CC, 5 cycles CC, 3 cycles None CC, 10 cycles None None None None None None None CC, 10 cycles None CC, 8 cycles None None CC, 3 cycles CC, 10 cycles None CC, 8 cylces None CC, 6 cycles CC, 3 cycles CC, 3 cycles CC, 3 cycles CC, 3 cycles CC, 12 cycles CC, 3 cycles CC, 4 cycles been recognized in endocrine gynecology: the hyperprolactinemic-anovulatory syndrome. 4 All patients with long-lasting amenorrhea, with or without galactorrhea, require a PRL determination. In five of our cases and in one-third of those reported by Jacobs and Franks7 galactorrhea was absent. A direct relationship between the amount of galactorrhea and PRL levels was not found in our cases, nor in another report.7 In 27 of our patients no etiology for hyperprolactinemia could be demonstrated. This finding could be questioned since a tomographic study of the sella was performed in only six; therefore, although 12 patients did not show changes in follow-up planimetric x-rays, the presence of a microadenoma could not be completely ruled out. The wide range of basal FSH and LH levels registered in our cases could be ascribed to individual variations. Pepperell et aj.8 reported similar findings. Bromocriptine was very effective in the suppression of galactorrhea, as this symptom disappeared during treatment in 26 patients (86.6%). In the other four cases breast secretion persisted, although it was reduced. Seventeen patients re-

4 Vol. 31, No.2 BROMOCRIPl'INE IN THE TREATMENT OF HYPERPROLACTINEMIC AMENORRHEA 127 TABLE 2. Results of Treatment with Bromocriptine in Thirty Women with Amenorrhea and Hyperpro1actinemia Prolactin Patient Etiology Ceaaation of Restoration of Baeal 2-6wk galactorrhea mej1m8 Ovulation Pregnancy 1IIflml 1IIflml wit. wit. Z.C. Functional No Yes Yes J.T. Functional Yes Not wished B.S. Functional Yes Not wished A.T. Functional Persistence No No Not wished E.P. Functional Persistence No No No M.R. Functional Yes Not wished L.B. Functional Persistence No No Not wished B.P. Functional Yes Not wished K. L. Functional 34 Persistence No No No M.M. Functional Yes Not wished G.M. Functional Yes Not wished L.D. Functional No Yes Yes E. Y. Functional 26 4 No No No M.B. Functional No No No C.C. Functional No No J. V. Functional Yes No M.S. Functional Yes Not wished S.S. Functional No Yes Yes R.V. Functional Yes Yes C.CH. Functional No No M.C. Functional 34 4 No No No S. K. Functional Yes No A.S. Functional Absent 4 Yes Yes G.F. Functional Absent No No No E.B. Functional Absent No No No S.L. Functional Absent No No Not wished S.B.. Functional Absent 6 No Not wished C.P. Microadenoma Yes Yes B. R. Microadenoma Yes Not wished V.M. Microadenoma? Yes Yes established their menstrual cycles and ovulated could also suppose that the catecholaminergic (56.6%). None of the women in whom galactorrhea mechanism which controls gonadotropin secretion persisted ovulated. Six of the patients who did not via LH-RH could also be affected An argument ovulate (E. P., E. B., C. Ch., G. F., S. L., and S. B.) supporting this hypothesis is the abnormal posishowed PRL levels-under bromocriptine-above tive feedback effect of estradiol on LH release in the normal range or in the upper limit; on the other women with hyperprolactinemia.22 Therefore, the hand, patients who ovulated had PRL levels with- association of clomiphene, which promotes goin the normal range. Consequently, it seems nadotropin secretion by acting at the hypothanecessary to perform PRL determinations periodi- lamic level, with bromocriptine seems to cally during treatment to ascertain whether ini- be logical. tially high levels have been reduced and whether In this series, as in other reports, side effects they persist within the normal range. have not frequently been present; they were gen- Pregnancy was obtained in 7 of 18 infertile pa- erally transient and it was seldom necessary to tients (38.8%). Six of them had been previously stop treatment. A positive effect observed in two treated unsuccessfully with CC or CC plus LH- patients was an improvement of nervousness and a RH. Other authors have also reported good re- feeling of well-being. suits in the induction of ovulation and pregnancy A patient with nontumoral amenorrhea-galacusing bromocriptine in hyperprolactinemic torrhea must be periodically evaluated to detect women the possible eventual development of a micro- One patient became pregnant with the associa- adenoma. The physician must be very careful if the tion of clomiphene and bromocriptine; this finding patient becomes pregnant, for severe complicahas also been reported by others If we consider tions can appear if an undetected pituitary tumor that hyperprolactinemia could be the consequence is present. All of our pregnant patients have thus of a dysfunction of the hypothalamic-dopamin- far been free of the symptoms and signs of pituiergic system that controls PRL secretion, 19 we tary enlargement.

128 BADANO ET AL. One question that can be posed is: must patients with nontumoral hyperprolactinemia be chronically treated with bromocriptine?

5 128 BADANO ET AL. One question that can be posed is: must patients with nontumoral hyperprolactinemia be chronically treated with bromocriptine? Davies et ap3 found that male rats under continuous estrogenic stimulation had reduced PRL secretion and DNA synthesis by the pituitary if treated with bromocriptine. Lloyd et al. 24 showed that mitotic activity of lactotrophs was reduced by bromocriptine. One of our patients (B. R.) with radiologic evidence of a microadenoma is in the 9th month of treatment with 2.5 mg daily; she has re-established normal menstrual cycles, galactorrhea has disappeared, and no changes in radiologic and ophthalmologic studies have occurred. Thorner et a1. 25 have treated for 28 months two men with suspected pituitary tumor without side effects, although, they have no evidence that any underlying pathologic process might have been altered by bromocriptine. On the other hand, it is well known that hyperprolactinemia, amenorrhea, and galactorrhea reappear after bromocriptine withdrawal in almost all cases. With all of these findings in mind we can speculate that chronic treatment with bromocriptine could reduce the possibility of the development of a PRL-secreting tumor or prevent its eventual size increase. This possibility needs to be confirmed through a more prolonged follow-up of a larger number of cases. Aknowledgments. The authors would like to thank Dr. R. Vegensteen of Sandoz Argentina and Dr. A. Guitelman for kindly providing bromocriptine (ParlodeI2, 5), and Dr. A. &inchez for revision of the manuscript. ADDENDUM Following this study another eight hyperprolactinemic anovulatory women who failed to ovulate or to become pregnant with CC or bromocriptine alone received both drugs simultaneously, and four of them became pregnant. REFERENCES 1. Marshall JR, Wider JA: Results of human menopausal gonadotrophins (HMG) therapy for anovulatory infertility using a nonvariable treatment schedule: comparison with previous repol'tb. Fertil Steril 22:19, Garcia J, Jones GS, Wentz AC: The use of clomiphene citrate. Fertil SteriI28:707, Frantz AG: The regulation of prolactin secretion in humans. In Frontiers in Neuroendocrinology, Edited by WF Ganong, L Martini. New York, Oxford Press, 1973,p Bohnet HG, Dahlen HG, Wuttke W, Schneider HPG: Hyperprolactinemic anovulatory syndrome. J Clin Endocrinol,Metab 42:132,1976 February Fluckiger E,Doepfner W, Marko M, Niederer W: Effects of ergot alkaloids on the hypothalamic-pituitary axis. Postgrad Med J [Suppl1) 52:57, Thorner MO, Besser GM: Treatment of hypogonadism with bromocriptine. In Pharmacological and Clinical Aspects of Bromocriptine (ParlodeD. Symposium held at.the Royal College of Physicians, London, May 14, 1976, Edited by RIS Bayliss, P Turner, WP Maclay. Kent, MCS Consul~ tants, 1976, p Jacobs HS, Franks S: Diagnosis and treatment of hyperprolactinemic amenorrhea. In Pharmacological and Clinical Aspects of Bromocriptine (Parlodel). Symposium held at the Royal College of Physicians, London, May 14, Edited by RIS Bayliss, P Turner, WP Maclay. Kent, MCS Consultants, 1976, p Pepperell RJ, Evans JH, Brown JB, Bright MI, Smith MA, Burger HG, Healy D: A study of effects of bromocriptine on serum prolactin, follicle stimulating hormone and luteinizing hormone and ovarian responsiveness to exogenous gonadotrophin in anovulatory women. BR J Obstet Gynaecol 84:456, Yarkoni S, Polishuk WZ, Spitz 1M, Ben-David M: Inhibitory effect ofhyperprolactinemia on induction of ovulation by gonadotropins. Fertil Steril 28:772, Meites J: Neuroendocrine control of prolactin in experimental animals. Clin Endocrinol [Suppl) 6:9s, Figueroa Casas PR, Miechi HR, Badano A, Mirkin A, Aparicio N, Turner D, Nagle C, Rosner J: Clinical and gonadotropic response of amenorrheic patients treated with clomiphene and repeated injections ofluteinizing hormone-releasing hormone (abstr). Fertil Steril 28:293, Schwarzstein L, Laborde N, Aparicio A, Turner D, Mirkin A, Rodrlguez A, Rogrlguez Lhullier F, RosnerJ: Daily variations of FSH, LH and testosterone response to intravenous luteinizing hormone~releasing factor (LRF) in normal men. J Clin Endocrinol Metab 40:313, March CM,'Kletsky OA, Davajan V: Clinical response to CB-154 and the pituitary response to thyrotropin-releasing hormone-gonadotropin-releasing hormone in patients with galactorrhea-amenorrhea; Fertil SteriI28:521, Seppala M, Hirvlmen E, Ranta:r: Bromocriptine treatment of secondary amenorrhea. Lancet 1:1154, Friesen HG, Tolis G: The use of bromocriptine in the galactorrhea-amenorrhea syndromes: the Canadian Cooperative Study. ClinEndOcrinol6 [Suppl):915, Del Pozo E, VargaL, WissH, Tolis G, FriesenH, WennerR, Vetter L, Uttwiler A: Clinical and hormonal response to bromocriptine (CB-154) in the galactorrhea syndromes. J Clin Endocrinol Metab 39:18; Hirvonen E: Etiology, clinical features and prognosis in secondary amenorrhea. Int J Fertil22:69, de Leiderman SB:Simposio.sobre Bromocriptina, Buenos Aires,.27 Septiembre, Lachelin GeL, Leblanc H, Yen SSC: Functional delineation ofhyperprollrtinemic-amenorrhea. J Clin Endocrinol Metab 44:1163, Lachelin GeL, Leblanc H, Yen SSC: The inhibitory effect of dopamine agonists on LH release in women. JClin Endocrinol Metab 44:728, Badano AR, Nagle C, Figueroa Casas PR, Miechi H, Mirkin A, Turner Do, ApariciQ N, Rosner J: Plasmalevels of norepinephrine during the periovulatory period in normal

6 Vol. 31, No.2 BROMOCRIPTINE IN THE TREATMENT OF HYPERPROLACTINEMIC AMENORRHEA 129 women: further studies. Am J Obstet Gynecol 131:299, Glass MR, Shaw RW, Butt WR, Logan Edwards R, London DR: An abnormality of oestrogen feedback in amenorrhea galactorrhea. Br Med J 3:274, Davies C, Jacobs J, Lloyd HM, Meares JD: DNA synthesis and the secretion of prolactin and growth hormone by the pituitary gland of the male rat: effect of diethylstilboestrol and 2-bromo-alpha-ergocryptine methanesulfonate. J Endocrinol 61:411, Lloyd HM, Meares JD, Jacobs J: Effects of oestrogen and bromocriptine on the in vivo secretion and mitosis in prolactin cells. Nature 255:497, Thorner MO, Besser GM, Hagen G, Mc Neilly AS: Long term treatment of galactorrhea and hypogonadism with bromocriptine. Br Med J 2:419,1974

PROLACTIN-SECRETING PITUITARY MICROADENOMA: DETECTION AND EVALUATION*t

FERTILITY AND STERILITY Copyright 1978 The American Fertility Society Vol. 29, No.3, March 1978 PrinlRd in U.s.A. PROLACTIN-SECRETING PITUITARY MICROADENOMA: DETECTION AND EVALUATION*t R. HERBERT WIEBE,