Successful Outcome of Ergocryptine-Induced Pregnancies in Twenty-One Women with Prolactin-Secreting Pituitary Adenomas

FERTILITY AND STERILITY Copyright © 1979 The American Fertility Society

Vol. 32, No, 2, August 1979 Prinred in U.S.A.

SUCCESSFUL OUTCOME OF ERGOCRYPTINE-INDUCED PREGNANCIES IN TWENTY-ONE WOMEN WITH PROLACTIN-SECRETING PITUITARY ADENOMAS

BERNARD CORENBLUM, M.D., F.R.C.P.(C) Department of Medicine, University of Calgary, Calgary, Alberta, Canada

The natural history of prolactin-secreting adenomas is not known. For this reason, optimal therapy for women harboring these adenomas who desire to conceive is also unknown. Argument can be found to favor surgical excision, radiation therapy, prolactin-suppressing chemotherapy, and clinical observation. In a large series of women with prolactin-secreting pituitary adenomas, 21 have conceived and delivered healthy infants, all of whom had ergocryptine-induced prolactin suppression as the sole form of therapy. Endocrinologic, neurologic, biochemical, and radiologic assessment failed to demonstrate any obvious growth of the pituitary adenoma, except for slight enlargement of the sella turcica in one patient who delivered twins. The failure to demonstrate any worsening of the clinical state may reflect the fact that no large tumors were included in this series, only small but definite microadenomas found on sellar tomography. All of the various modalities of therapy must be considered with each patient, but this series suggests that ergocryptine treatment with careful clinical follow-up is relatively safe in patients with small pituitary tumors. Fertil Steril32:183, 1979

Infertility resulting from prolactin-secreting pituitary adenomas is becoming a more easily recognizable entity. With greater utilization of the serum prolactin assay and hypocycloidal polytomography of the sella turcica, women with suggestive clinical features may be identified. Upon making this diagnosis, the clinician must now select the most appropriate therapy for the patient. If fertility is desired, then the choice of therapy should be nondestructive to the otherwise normal nonadenomatous pituitary, yet bring normalization of serum prolactin levels with restoration of normal ovulatory function. Furthermore, it is feared that any remaining adenomatous tissue may increase in size during the hyperestrogenized state of pregnancy.1 The choices of therapy are controversial and vary from center to center depending on local clinical experience and abilities. There are advocates of pituitary microsurgery2.3 or radiation therapy4 before conception is allowed, whereas others5 • 6 believe that the use of prolactin-lowering drugs with careful observation is the treatment of choice. 5.6 The natural history of these

prolactin-secreting adenomas is not known, nor the effects of pregnancy on these adenomas. Thus, no choice of therapy has become universally accepted. Because of these deficiencies in knowledge, many patients are merely being followed clinically without any intervention. 7• 8 In view of this controversy surrounding the women desiring fertility, I report a series of 21 women with probable prolactin-secreting pituitary adenomas who were initially treated with ergocryptine, conceived, delivered, and have been subsequently followed. MATERIALS AND METHODS

From a large personal series of patients presumed to have prolactin-secreting adenomas (hyperprolactinemia and abnormal sella turcica tomography), there have been in total 21 women who have completed a pregnancy to term and have been subsequently followed. These 21 women, who delivered 22 infants, form the reference group for this report. All women had amenorrhea, most had galactorrhea (17 of21), and all were infertile. Nine had onset of symptoms upon discontinuation of

Received January 22,1979; revised March 19,1979; accepted March 21, 1979.

183

CORENBLUM

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oral contraceptives, and three after a previous pregnancy. All had elevated basal serum prolactin concentrations, were clinically and biochemically hypoestrogenized, and all had definite features of micro adenomas on sellar tomography. 9 Results of neurologic and visual field examinations were normal in all women, as well as pneumoencephalography in 2 and computerized axial tomography (CAT) scanning in 19. All 21 patients had normal anterior pituitary function according to reserve testing with insulin-induced hypoglycemia, thyrotropin-releasing hormone, and luteinizing hormone-releasing hormone lO before treatment. No previous therapy had been directed at the prolactin-secreting adenomas. After giving informed consent, all patients responded to the administration of ergocryptine, 2.5 mg twice daily, with return of menses and/or conception, as predicted. 10 All were followed throughout gestation by visual field examinations (Goldman) every 1 to 2 months, repeat sellar tomography if headache recurred (in 2 cases) or if the visual fields had changed, and by clinical assessment. After delivery, breast-feeding was discouraged, sellar tomography was performed at 6 weeks, and blood samples for repeat serum prolactin determinations were obtained at 6 and 12 weeks postpartum. All of the baseline and postpartum sellar tomograms were reviewed at one sitting by two radiologists. Repeat pituitary reserve testing was performed at 12 weeks postpartum in 16 patients. RESULTS

In this group of 21 women, all had return of reproductive function and conceived in 2 to 7 months (Table 1). In three women, spontaneous abortions occurred at 6 to 9 weeks, but all three women again conceived and delivered. Of the 22 infants (1 set of twins), 10 were males. All women had uncomplicated deliveries, all infants were healthy, and all are developing normally (follow-up 2 months to 3 years). No women in this series developed any visual field changes, any neurologic deficit, or any clinical pituitary dysfunction. Comparison of the postpartum examination with the pretreatment examination revealed that all but one patient failed to demonstrate any change on sellar tomography. Patient 4, who delivered twins, had a 2-mm increase in the depression of the lateral half of the sella turcica. Results of postpartum pituitary reserve testing were unchanged from those of pretreatment reserve testing. All postpartum women demon-

August 1979 TABLE 1. Course of Pregnancy in Twenty-One Women with Prolactin-Secreting Adenomas Serum prolactin

Patient

1

Age

23

Time to

Before treatment

After deliveryll

conception

nglml

nglml

mo

150

2 3 4 5 6 7 8 9 10 11 12 13

24 34 24 38 27 25 24 28 31 24 22 29

170 162 125 102 200 43 91 69 107 79 63 200

14 15 16

38 23 30

70 275 240

17 18 19 20 21

28 30 28 26 27

60 213 68 81 116

162 198 206 184 111 181 62 98 76 129 98 66 229 51 314 268 67 258 69 74 139

4 2 4 2 2 2 4 2 5 7 4 3 3 4 3 3 4 4 6 3 3 4 3 5

Comments

Abortion NDb ND ND Twins ND ND ND ND ND ND ND ND Abortion ND ND ND Abortion ND ND ND ND ND ND

aAverage of 6 and 12 weeks postpartum. bND, Normal delivery.

strated return of the amenorrhea-galactorrhea state and required reinstitution of ergocryptine therapy. The postpartum serum prolactin level tended to be higher than the pretreatment values (Table 1) but this was not invariably so, and no dramatic increase occurred in any patient. DISCUSSION

Even though the natural history of prolactinsecreting pituitary adenomas is unknown, estrogen may increase the size of these adenomas in a manner similar to the estrogen-induced hyperplasia in nonadenomatous prolactin cellsY' 12 Clinical experience repeatedly finds that a large percentage of these adenomas become clinically evident after discontinuation of birth control pills or termination of a pregnancy .13 There are now many reports that these adenomas enlarge during pregnancy to produce local neurologic and endocrinologic symptomatology.3 Animal studies have demonstrated that estrogen directly produces prolactin cell hyperplasia, increased mitotic activity,t4 and adenoma formation. 15 It is relevant that this estrogen-induced proliferation is inhibited by ergocryptine,16 and this drug may actually reduce the size of adenomasY There is now suggestive

Vol. 32, No.2

OUTCOME OF ERGOCRYPTINE-INDUCED PREGNANCIES

clinical evidence that ergocryptine may reduce the size of adenomas in some women,18, 19 and may even be used during pregnancy to alleviate new symptoms arising from growth of an adenoma. 5 In an attempt to prevent pregnancy-induced tumor growth, prior radiation has been recommended,4 presumably extrapolating from the prevention of pituitary tumor growth in patients with Cushing's disease treated with bilateral adrenalectomy. Unfortunately, with prolactinsecreting adenomas such treatment has not proven to be adequate in the prophylaxis of pregnancy-induced tumor growth,3 and to date there is no evidence that radiotherapy plus ergocryptine is superior to ergocryptine alone. Surgical removal of the adenoma is the traditional therapy of choice. Certainly with widespread use of transsphenoidal adenectomy, this possibility must be considered in every patient. Clinical experience is beginning to suggest that the smaller the tumor, the more likely the successful surgical reversal of amenorrhea-galactorrhea. 20 As low as they are, surgical mortality and morbidity rates are still prominent factors. Furthermore, the failure to normalize adequately the serum prolactin in many patients is also a deterrent. On the other hand, in some patients with abnormal sellar tomography an adenoma is not found during surgical exploration. 2I have seen two patients with amenorrhea-galactorrheahyperprolactinemia who had surgical excision with complete reversal of the syndrome, yet who returned 3 and 4 years later with amenorrhea, hyperprolactinemia, and another change on sellar tomography.21 This latter observation may reflect the fact that, in some patients, the lesion is not a discrete autonomous adenoma but rather is associated with more widespread hyperplasia of prolactin cells. In one series, 11 of 15 pituitary glands demonstrated prolactin cell hyperplasia in the pituitary tissue adjacent to a discrete adenoma. 22 If short-loop feedback inhibition was active,23 then involution of the adjacent nonadenomatous prolactin cells would be expected. One may speculate that in these patients the underlying problem is more diffuse, probably hypothalamic in origin, and that the prolactin cells respond first with hyperplasia and secondarily with adenoma formation. It would not be surprising to find that surgical removal ofthese adenomas is not permanently curative. The 21 women reported here were treated with ergocryptine alone, with careful observation throughout the course of each gestation. The ab-

185

sence of any major tumor-induced complication may reflect the prior ergocryptine therapy (with its possible antimitotic effect) or else the fact that this group of women had relatively small adenomas, as judged by the localized changes in sellar tomography and only moderate elevations of the serum prolactin levels. If any tumor-induced complication had arisen, then delivery (if possible), surgical resection, or reinstitution of ergocryptine may have been considered. 5 The failure to document any tumor-induced complication or any evidence of tumor growth should suggest that ergocriptine be considered as therapy for women with amenorrhea-galactorrhea who wish to conceive. Careful repeated clinical reassessment is mandatory and necessitates good patient compliance. Therapy must be individualized for any given patient, and one therapeutic choice should not be used to the exclusion of the others. It would be ideal to discuss the different therapeutic approaches with each patient and then obtain informed consent after coming to a decision. ADDENDUM

Since submission of the manuscript, one complication has occurred in a patient not included in this series. A 30-year-old woman with 10 years of amenorrhea, elevated serum prolactin levels (210 ng/mI), but normal sella turcica tomography, conceived after ergocryptine treatment. At 3 months' gestation, the visual field examination was normal. At 4 months' gestation, she had sudden onset of headaches, and a visual field examination now demonstrated bilateral upper quadratic temporal defects. Repeat sellar tomography was still normal, but a repeat CAT scan demonstrated a sellar mass with suprasellar extension. After discussion with the patient, she again began taking ergocryptine, 2.4 mg twice daily, and within 2 days the headaches had disappeared; within 1 week the visual fields were close to normal. She is now entering the 6th month of pregnancy quite normally and is asymptomatic. A repeat CAT scan failed to demonstrate any sellar mass or suprasellar extension. Acknowledgments. The author would like to thank the many gynecologists and radiologists who have contributed to this study, as well as to Mrs. Jinny Boyack for her able assistance and for typing the manuscript.

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2. Chang RJ, Keye WR, Young JR, Wilson CB, Jaffe RB: Detection, evaluation, and treatment of pitutiary microadenomas in patients with galactorrhea and amenorrhea. Am J Obstet Gynecol 128:356, 1977 3. Husami N, Jewelewicz R, Vande Wiele RL: Pregnancy in patients with pituitary tumors. Fertil Steril 28:920, 1977 4. Thorner MO: Prolactin. J Clin Endocrinol Metab 6:201, 1977 5. Bergh T, Nillius SJ, Wide L: Clinical course and outcome of pregnancies in amenorrhoeic women with hyperprolactinaemia and pituitary tumours. Br Med J 1:875, 1978 6. Hancock KW, Scott JS, Gibson RM, Lamb JT: Pituitary tumours and pregnancy. Br Med J 1:1487, 1978 7. Davajan V, Kletzky 0, March CM, Roy S, Mischell DR: The significance of galactorrhea in patients with normal menses, oligomenorrhea, and secondary amenorrhea. Am J Obstet Gynecol 130:894, 1978 8. Magyar DM, Marshall JR: Pituitary tumors and pregnancy. Am J Obstet GynecoI132:739, 1978 9. Vezina JL, Sutton TJ: Prolactin-secreting pituitary adenomas. Am J Roentgenol 120:46, 1974 10. Corenblum B, Taylor PJ: Prediction of reE\ponse to ergocryptine in the galactorrhea-amenorrhea syndrome. Fertil Steril 30:388, 1978 11. EI Etreby MF, Gunzel P: Sex hormones-effects on prolactin cells. Acta Endocrinol [Suppl] (Kbh) 189:3, 1974 12. Goluboff LG, Ezrin C: Effect of pregnancy on the somatotroph and the prolactin cell of the human adenohypophysis. J Clin Endocrinol Metab 29:1533,1969 13. Sherman BM, Schlechte J, Halmi NS, Chapler FK, Harris CE, Duello TM, Van Bilder J, Granner DK: Pathogenesis of prolactin-secreting pituitary adenomas. Lancet 2:1091, 1978 14. Lloyd HM, Meares JD, Jacobi J: Early effects of stilboestrol on growth hormone and prolactin secretion and on pitu-

August 1979 itary mitotic activity in the male rate. J EndocrinoI58:227, 1973 15. Jacobi J, Lloyd HM, Meares JD: Induction of pituitary tumors in male rats by a single dose of estrogen. Horm Metab Res 7:228, 1975 16. Davies C, Jacobi J, Lloyd GM, Meares JD: DNA synthesis and the secretion of prolactin and growth hormone by the pituitary gland of the male rat: effects of diethylstilboestrol and 2-bromo-ergocryptine methanesulphonate. J Endocrinol 61:411, 1974 17. MacLeod RM, Lehmeyer JE: Suppression of pituitary tumor growth and function by ergot alkaloids. Cancer Res 33:849, 1973 18. Corenblum B, Webster BR, Mortimer CB, Ezrin C: Possible anti-tumor effect of 2-bromo-ergocryptine (CB-154 Sandoz) in 2 patients with large prolactin-secreting pituitary adenomas. Clin Res 33:614A, 1975 19. Sobrinho LG, Nunes MCP, Santos MA, Mauricio JC: Radiological evidence for regression of prolactinoma after treatment with bromocriptine. Lancet 2:257,1978 20. Hardy J, Beauregard H, Robert F: Prolactin secreting pituitary adenomas: transsphenoidal microsurgical treatment. In Progress in Prolactin Physiology and Pathology, Edited by C Robert, M Hatter. Amsterdam, Elsevier Publishing Co, 1978, p 361 21. Corenblum B: Unpublished data 22. Kovacs K, Ryan N, Horvath E, Ezrin C, Penz G: Abundance of prolactin cells in the nontumerous parts of human pituitaries harboring prolactin cell adenomas. IRCS 5:37, 1977 23. Motta M, Fraschini F, Martini L: Short feedback mechanism in control of anterior pituitary function. In Frontiers in Neuroendocrinology, Edited by WF Ganong, L Martini. New York, Oxford University Press, 1969, p 211