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Effects of hyperprolactinemia and bromocriptine on the human endometrium
Vol. 35, No.4, April 1981 Printed in U.SA.
FERTILITY AND STERILITY Copyright c 1981 The Am~rican Fertility Society
EFFECTS OF HYPERPROLACTINEMIA AND BROMOCRIPTINE ON THE HUMAN ENDOMETRIUM
WALLACE C. NUNLEY, JR., M.D., F.A.C.O.G.*t JAMES D. KITCHIN, III, M.D., F.A.C.O.G.t MICHAEL O. THORNER, M.B.B.S., M.R.C.P.:!: WILLIAM S. EVANS, M.D.:!: PHILIP S. FELDMAN, M.D.§ Departments of Obstetrics and Gynecology, Internal Medicine, and Pathology, University of Virginia Hospital, Charlottesville, Virginia 22908
operatively. Fifteen subjects had secondary amenorrhea of 3 to 156 months' duration (longer than 6 months in thirteen women). Two women had oligomenorrhea. All patients were euthyroid, including three on thyroid replacement, and all had normal adrenal reserve documented by insulin-induced hypoglycemia. Renal and hepatic function were normal in all subjects, and none was taking any medications known to alter serum prolactin. All were requested to use mechanical contraception during the study. Each patient was admitted to the clinical research center on five occasions (before therapy; at 3, 6, and 12 months during therapy; and 2 months after bromocriptine was stopped). Informed consent was obtained. Fourteen women were treated with bromocriptine, 2.5 mg orally three times daily. Three women required 5 mg three times daily, as the initial dosage regimen did not successfully lower their serum prolactin levels to normal. Gynecologic assessment included a pelvic examination, an evaluation of the cervical mucus, and an endometrial biopsy. The endometrial biopsies were obtained with a Novak curette, fixed in formalin, stained with hematoxylin-eosin, and examined and graded by the same pathologist (P. S. F.) according to the criteria set forth by Noyes et al. 3 Serum prolactin levels were measured by radioimmunoassay as described elsewhere. 4
Hyperprolactinemia is a common condition, and the diagnosis is being made more frequently with increasing physician awareness. Bromocriptine, a dopamine agonist, is effective in lowering elevated prolactin levels in serum. Prolonged administration of high dosages of bromocriptine to rats has been associated with the subsequent development of uterine neoplasia. 1 However, there has not been any documented evidence in the human of an adverse effect of this drug on the endometrium. 2 In this prospective study, 17 women were examined for a relationship between elevated prolactin levels, bromocriptine therapy, and histologic changes in the endometrium. With the lowering of elevated serum prolactin by bromocriptine, ovarian and menstrual function were restored in these women. There was no evidence of an adverse effect of this drug on the endometrium during therapy. MATERIALS AND METHODS
Seventeen hyperprolactinemic women (mean age 26.8 years; range 19 to 41) were studied. Fourteen patients had hyperprolactinemia secondary to a presumed pituitary microadenoma. Three women had had pituitary surgery (confirming tumor) but remained hyperprolactinemic postReceived September 12, 1980; revised and accepted December 9,1980. *Reprint requests: Wallace C. Nunley, Jr., M.D., Department of Obstetrics and Gynecology, Box 387, University of Virginia Hospital, Charlottesville, Virginia 22908. tDepartment of Obstetrics and Gynecology. :!:Department of Internal Medicine. §Department of Pathology.
RESULTS (TABLE 1)
Before Treatment. Serum prolactin levels were elevated in all subjects (mean 206 ng/rill; range 45 to 451 ng/ml). Endometrial biopsies demonstrated 479
atrophy in ten patients, proliferative tissue in five, and dyssynchronous histology in one. No biopsy was performed initially in patient 1. During Treatment. Serum prolactin levels decreased to normal after the institution of bromocriptine therapy in thirteen women (mean 8 ng/ml; range 2 to 24 ng/ml). In four patients the prolactin levels declined but not to normal (mean 77.8 ng/ml; range 34 to 128 ng/ml). Twenty-five endometrial biopsies were performed during various stages of the menstrual cycle. Sixteen specimens were secretory, five were proliferative, two were inactive, one was dyssynchronous, and one was menstrual. All revealed a normal histologic pattern with no abnormal architectural features noted. After Treatment. Five women had conceived during treatment and one discontinued the study at her request. Eleven patients were evaluated, and in all of these patients serum prolactin levels rose, reaching pretreatment values in nine women. Five women consented to an endometrial biopsy. Three biopsies exhibited secretory endometrium, whereas two had a proliferative pattern. No abnormal histologic features were noted. DISCUSSION
Serum prolactin levels should be measured in all women with infertility, menstrual irregularities, or abnormal luteal phase function, regardless of the presence or absence of galac-
torrhea. Hyperprolactinemia may be treated effectively with bromocriptine with restoration of normal ovulatory function. Bromocriptine therapy has to be continued on a chronic basis to maintain suppression of increased prolactin levels. In studies on rats, suppression of prolactin by life-long high-dose bromocriptine administration has resulted in an increase in endometrial hyperplasia and uterine tumors.1, 2 This prospective study, involving multiple endometrial biopsies in women over a 14-month period, did not reveal any abnormalities of the endometrium during treatment. Although the duration of this study to date does not rule out the possibility of a long-term adverse effect on endometrial histology, the lack of any detectable abnormalities during serial histologic examinations for more than 1 year is reassuring. REFERENCES 1. Griffith RW: Toxicity studies with 2-bromo-a-ergocryptine mesylate (CB 154): effect of prolonged oral administration in rats. IRCS 2:1661, 1974 2. Besser GM, Thorner MO, Wass JAH, Doniach I, Canti G, Curling M, Grudziniskas JG, Setchell ME: Absence of uterine neoplasia in patients on bromocriptine. Br Med J 2:868,1977 3. Noyes RW, Hertig AT, Rock J: Dating of the endometrial biopsy. Fertil Steril 1:3, 1950 4. Thorner MO, Sehran lIF, Evans WS, Rogol AD, Morris JL, MacLeod RM: A broad spectrum of prolactin suppression by bromocriptine in hyperprolactinemic women. J Clin Endocrinol Metab 50:1026,1980
FERTILITY AND STERILITY Copyright c 1981 The Am~rican Fertility Society
EFFECTS OF HYPERPROLACTINEMIA AND BROMOCRIPTINE ON THE HUMAN ENDOMETRIUM
WALLACE C. NUNLEY, JR., M.D., F.A.C.O.G.*t JAMES D. KITCHIN, III, M.D., F.A.C.O.G.t MICHAEL O. THORNER, M.B.B.S., M.R.C.P.:!: WILLIAM S. EVANS, M.D.:!: PHILIP S. FELDMAN, M.D.§ Departments of Obstetrics and Gynecology, Internal Medicine, and Pathology, University of Virginia Hospital, Charlottesville, Virginia 22908
operatively. Fifteen subjects had secondary amenorrhea of 3 to 156 months' duration (longer than 6 months in thirteen women). Two women had oligomenorrhea. All patients were euthyroid, including three on thyroid replacement, and all had normal adrenal reserve documented by insulin-induced hypoglycemia. Renal and hepatic function were normal in all subjects, and none was taking any medications known to alter serum prolactin. All were requested to use mechanical contraception during the study. Each patient was admitted to the clinical research center on five occasions (before therapy; at 3, 6, and 12 months during therapy; and 2 months after bromocriptine was stopped). Informed consent was obtained. Fourteen women were treated with bromocriptine, 2.5 mg orally three times daily. Three women required 5 mg three times daily, as the initial dosage regimen did not successfully lower their serum prolactin levels to normal. Gynecologic assessment included a pelvic examination, an evaluation of the cervical mucus, and an endometrial biopsy. The endometrial biopsies were obtained with a Novak curette, fixed in formalin, stained with hematoxylin-eosin, and examined and graded by the same pathologist (P. S. F.) according to the criteria set forth by Noyes et al. 3 Serum prolactin levels were measured by radioimmunoassay as described elsewhere. 4
Hyperprolactinemia is a common condition, and the diagnosis is being made more frequently with increasing physician awareness. Bromocriptine, a dopamine agonist, is effective in lowering elevated prolactin levels in serum. Prolonged administration of high dosages of bromocriptine to rats has been associated with the subsequent development of uterine neoplasia. 1 However, there has not been any documented evidence in the human of an adverse effect of this drug on the endometrium. 2 In this prospective study, 17 women were examined for a relationship between elevated prolactin levels, bromocriptine therapy, and histologic changes in the endometrium. With the lowering of elevated serum prolactin by bromocriptine, ovarian and menstrual function were restored in these women. There was no evidence of an adverse effect of this drug on the endometrium during therapy. MATERIALS AND METHODS
Seventeen hyperprolactinemic women (mean age 26.8 years; range 19 to 41) were studied. Fourteen patients had hyperprolactinemia secondary to a presumed pituitary microadenoma. Three women had had pituitary surgery (confirming tumor) but remained hyperprolactinemic postReceived September 12, 1980; revised and accepted December 9,1980. *Reprint requests: Wallace C. Nunley, Jr., M.D., Department of Obstetrics and Gynecology, Box 387, University of Virginia Hospital, Charlottesville, Virginia 22908. tDepartment of Obstetrics and Gynecology. :!:Department of Internal Medicine. §Department of Pathology.
RESULTS (TABLE 1)
Before Treatment. Serum prolactin levels were elevated in all subjects (mean 206 ng/rill; range 45 to 451 ng/ml). Endometrial biopsies demonstrated 479
atrophy in ten patients, proliferative tissue in five, and dyssynchronous histology in one. No biopsy was performed initially in patient 1. During Treatment. Serum prolactin levels decreased to normal after the institution of bromocriptine therapy in thirteen women (mean 8 ng/ml; range 2 to 24 ng/ml). In four patients the prolactin levels declined but not to normal (mean 77.8 ng/ml; range 34 to 128 ng/ml). Twenty-five endometrial biopsies were performed during various stages of the menstrual cycle. Sixteen specimens were secretory, five were proliferative, two were inactive, one was dyssynchronous, and one was menstrual. All revealed a normal histologic pattern with no abnormal architectural features noted. After Treatment. Five women had conceived during treatment and one discontinued the study at her request. Eleven patients were evaluated, and in all of these patients serum prolactin levels rose, reaching pretreatment values in nine women. Five women consented to an endometrial biopsy. Three biopsies exhibited secretory endometrium, whereas two had a proliferative pattern. No abnormal histologic features were noted. DISCUSSION
Serum prolactin levels should be measured in all women with infertility, menstrual irregularities, or abnormal luteal phase function, regardless of the presence or absence of galac-
torrhea. Hyperprolactinemia may be treated effectively with bromocriptine with restoration of normal ovulatory function. Bromocriptine therapy has to be continued on a chronic basis to maintain suppression of increased prolactin levels. In studies on rats, suppression of prolactin by life-long high-dose bromocriptine administration has resulted in an increase in endometrial hyperplasia and uterine tumors.1, 2 This prospective study, involving multiple endometrial biopsies in women over a 14-month period, did not reveal any abnormalities of the endometrium during treatment. Although the duration of this study to date does not rule out the possibility of a long-term adverse effect on endometrial histology, the lack of any detectable abnormalities during serial histologic examinations for more than 1 year is reassuring. REFERENCES 1. Griffith RW: Toxicity studies with 2-bromo-a-ergocryptine mesylate (CB 154): effect of prolonged oral administration in rats. IRCS 2:1661, 1974 2. Besser GM, Thorner MO, Wass JAH, Doniach I, Canti G, Curling M, Grudziniskas JG, Setchell ME: Absence of uterine neoplasia in patients on bromocriptine. Br Med J 2:868,1977 3. Noyes RW, Hertig AT, Rock J: Dating of the endometrial biopsy. Fertil Steril 1:3, 1950 4. Thorner MO, Sehran lIF, Evans WS, Rogol AD, Morris JL, MacLeod RM: A broad spectrum of prolactin suppression by bromocriptine in hyperprolactinemic women. J Clin Endocrinol Metab 50:1026,1980