Chlorpromazine-Induced Changes in Serum Prolactin in Women with Oligomenorrhea, Amenorrhea, and Pituitary Adenoma

Vol. 28, No. 11, November 1977 Printed in U.S.A.

FERTILITY AND STERILITY Copyright' 1977 The American Fertility Society

CHLORPROMAZINE-INDUCED CHANGES IN SERUM PROLACTIN IN WOMEN WITH OLIGOMENORRHEA, AMENORRHEA, AND PITUITARY ADENOMA

DAYID F. ARCHER, M.D.* JOHN B. JOSIMOVICH, M.D. JOSEPH C. MAROON, M.D. Departments of Obstetrics and Gynecology and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

Chlorpromazine (CPZ, Thorazine) administration has been found to result in an increase in peripheral serum levels of prolactin (hPRL) in both men and women. Normal menstruating women were found to have at least a doubling of serum hPRL (100% increase) over basal values within 150 minutes of the intramuscular administration ofCPZ (0.7 mg/kg). Thirty-nine women with oligomenorrhea or amenorrhea with normal or elevated basal levels of serum hPRL were evaluated by this testing modality. Their responses were compared with those of normal women as well as those of 18 women with elevated serum hPRL levels and roentgenographic evidence ofpituitary microaderwma. Women with oligomenorrhea or amerwrrhea and normal serum hPRL levels generally had a rwrmal response to CPZ (9 of 16 [56.3%V. A smaller percentage of normal responses was found in women with elevated hPRL levels but no overt evidence of pituitary microadenoma (7 of21 [33%V. Women with elevated hPRL levels and evidence of pituitary microadenoma uniformly failed to have a rwrmal hPRL response following CPZ administration. Although the group with microadenomas did not show a significant hPRL response to CPZ, this test does not unequivocally differentiate between women who have evidence of pituitary adenoma and those who do not. Suggestive, but not conclusive, evidence of hypothalamic dysfunction as the cause of the oligomerwrrhea or amenorrhea is presented.

Chlorpromazine (Thorazine) has been known to cause amenorrhea and galactorrhea when administered to women. 1. 2 The administration of chlorpromazine (CPZ) either orally or intramuscularly results in an increase in serum prolactin (hPRL) levels in normal men and women. 2•7 The mechanism of action of CPZ appears to be via the hypothalamic catecholaminergic mechanisms, resulting in a decrease of prolactin-inhibiting factor and a subsequent increase in peripheral levels of hPRL.l. 7. 8 For these reasons, CPZ-induced hPRL release

Received May 20, 1977; accepted June 20, 1977. *Reprint requests: David F. Archer, M.D., Department of Obstetrics and Gynecology, Magee-Womens Hospital, Forbes Avenue and Halket Street, Pittsburgh, Pa. 15213.

has been utilized to evaluate the hypothalamicpituitary axis in women with galactorrhea. and elevated serum hPRL levels with and without overt evidence of pituitary adenoma. 5. 6. 9 These reports have also documented that women with pituitary adenoma do not have an increase in peripheral hPRL levels following CPZ administration, which suggests that the adenoma is autonomous, and without the normal hypothalamic control. However, patients with elevated hPRL levels without evidence of pituitary adenoma by roentgenographic means also fail to show a response of hPRL to CPZ, making it difficult to utilize the testing modality to discriminate women with adenoma from those without microadenoma.5. 6. 9 The present study was initiated to determine the hPRL response to CPZ in women with oligo-

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CHLORPROMAZINE-INDUCED CHANGES IN SERUM PROLACTIN

menorrhea or amenorrhea whose serum hPRL levels were normal or elevated. The rationale behind this testing was to determine whether the hPRL response to CPZ could be utilized as a means of documenting hypothalamic-pituitary dysfunction in these individuals as a cause of their oligomenorrhea or amenorrhea. The hPRL response.was also assessed in women with roentgenographic evidence of pituitary microadenoma and elevated serum hPRL levels and compared with that of other women with hyperprolactinemia only, in order to determine whether this testing modality could be used to discriminate between individuals with and without pituitary adenoma.

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Clinical Study. All patients and normal volunteers were apprised of the efficacy of CPZ to alter serum hPRL levels, as well as its potential side effects. Informed consent was obtained in all instances, and the testing modality had been approved by the Human Experimentation Committee of Magee-Womens Hospital. All testing was performed with the subject in a supine position in a nonfasting condition. Administration of Chlorpromazine. An indwelling venous catheter was inserted into a vein in . the forearm, attached to a three-way stopcock, and patency was maintained with a slow infusion of normal saline containing heparin (1.0 IU/mI). Chlorpromazine in a dose ofO. 7 mg/kg was injected intramuscularly into the deltoid muscle immediately after obtaining the zero-time blood sample. Samples were obtained at 15, 30, 45, 60, 90, 120, and 150 minutes after the injection ofCPZ. Blood pressure and pulse were monitored every 30 minutes during the study period. Other known side effects, such as drowsiness and postural hypotension, were looked for and noted by the nurse in attendance if they occurred. Prolactin Assay. All blood samples for each study were stored at 20° C until the study was completed. At that time they were centrifuged at 4° C and the serum was removed and stored at -12° C until analyzed. A double-antibody radioimmunoassay for hPRL was performed as previously described, using the kit for hPRUo provided by the National Institute of Arthritis, Metabolism and Digestive Diseases. The normal hPRL value for menstruating women in our laboratory was <35 ng/ml at the beginning of the study; currently it is <25 ng/ml.

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FIG. 1. Response of hPRL to intramuscular chlorpromazine in normal women. 0, Chlorpromazine, 25 mg intramuscularly; ., chlorpromazine, 0.7 mg/kg intramuscularly.

RESULTS

Normal Subjects. Initial testing of the hPRL response to CPZ was carried out with 25 mg ofCPZ, administered intramuscularly. The response to this dose was variable in three normal volunteers, a marked response being found in one woman who weighed 40 kg, but a minimal response in a second volunteer whose weight was 70 kg (Fig. 1). Since this discrepancy was believed to be due to body weight, all subsequent studies were performed with 0.7 mg/kg of CPZ. The response of hPRL to this dose in another three normal women indicated a more consistent response curve of hPRL (Fig. 1; Table 1). A normal response was defined as a doubling of the basal serum hPRL value within 150 minutes after administration of CPZ. Women with Oligomenorrhea or Amenorrhea and Normal Serum hPRL Levels. Eighteen women with either oligomenorrhea or amenorrhea who had normal serum hPRL levels were evaluated (Table 1). No specific etiology of either the oligomenorrhea or amenorrhea was found for the majority of the patients under investigation. Two patients were diagnosed by other parameters as having Sheehan's syndrome and were found to have low basal hPRL levels and a minimal hPRL response to CPZ. The remainder of the women had variable hPRL responses (Table 1).

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ARCHER ET AL.

TABLE 1. Response of hPRL to Chlorpromazine (0.7 mglkg) in Normal Women and Women with Oligomenorrhea or Amenorrhea and Normal Basal hPRL Levels Patient

~hPRL

Basal hPRL'

% Change

inhPRL

nglml

Normal women J.H. J.M. S. S.

Mean ± SD

94 400 186

53.3 ± 19.3

Mean ± SD Oligomenorrheic or amenorrheic women with normal basal hPRL N. K. F.P. M.N. H.W. S. B. M.Cr. T.H. K. W. L.Mo. J.H. A. K. M. S.b C.Z. J. F. M.M. U. K. L.Me. B. C.b

31 64 64

33 16 35

125 2 16 60 8 20 42 38 28 15 122 2 8 97 5 9 35 7

15 16 18 19 10 10 28 29 25 22 28 3 5 19 23 22 17 12

833 13 89 316 80 200 150 131 112 68 436 67 60 511 22 53 206 58

35.5 ± 40.0

aNormal hPRL < 35 ng/ml; see text. bSheehan's syndrome,

Maximal responses occurred at various times following CPZ injection, buthPRL changes had· definitely occurred within 150 minutes after administration of CPZ to all individuals. Seven of the sixteen women had a poor response «100% change in serum hPRL levels). Women with Oligomenorrhea or Amenorrhea and Elevated Serum hPRL Levels. Basal serum hPRL levels were greater than 35 ng/ml in all of the women in this category (Table 2). There was no roentgenographic evidence of pituitary adenoma in any women in this group at the time of testing. Of the 21 women in this group, 7 manifested a normal hPRL response to CPZ as defined by a change over basal values greater than 100%. However, one patient (J. D. ), on retesting after a I-year interval, had no change in basal hPRL but a marked reduction in the percentage change in hPRL. The follow-up period for the remaining 14 women has been 6 months to 3 years. At present only one of these patients has evidence of a pituitary micro adenoma (Table 2). Serum hPRL levels remained elevated in these women on repeated testing.

Women with Oligomenorrhea or Amenorrhea, Elevated Serum hPRL Levels and Evidence of Pituitary Adenoma. Nineteen patients were evaluated in this group, and ten subsequently have had neurosurgical removal of a pituitary adenoma (Table 3). The remaining eight patients have definite evidence of pituitary adenoma by hypocycloidal poly tomography, and the ninth has an empty sella syndrome (Table 3). The percentage increase in. hPRL over the basal values ranged from 0% to 70%, with a mean of 22.7%. The absolute changes in hPRL were minimal in most cases as compared with basal values, with the exception of two patients, A. L. and E. H. (Table 3); in both of these women there was a marked change in hPRL which was approximately 70% of the basal value. DISCUSSION

The data support previous findings that chlor" promazine resultsin.an increase in serum hPRL levels in normal females. 3 • 5 - 7 The maximal change in hPRL from basal values in normal women occurs 15 to 150 minutes following the administration of chlorpromazine intramuscularly. A normal response should be considered as a doubling of the basal hPRL value, i.e., a 100% or greater increase in the peripheral values. 9 TABLE 2. Response of hPRL to Chlorpromazine (0.7 mglkg) in Women with Oligomenorrhea or Amenorrhea and Elevated Serum hPRL Patient

Basal hPRL

~hPRL

% Change

40 152 48 45 200 19 17 124 30 164 7 32 19 7 60 82 11 8 24 112 56 32

89 249 34 83 308 23 38 295 37 364 10 57 45 11 50 121 17 7 33 200 144 27

in hPRL

nglml

Me. K. V.A. D.M. E. R. F.R. M.B. E.C. D.N. R. B. V.G. G.H." G.L. S.W. P.W. N.B. J. D.b C. J. M.K. C. P. J. T. L. R. Mean ±SD

45 61 140 54 65 82 45 42 81 45 67 56 42 65 120 68 64 108 72 56 39 118

58.6 ± 56.3

"Currently has evidence of pituitary adenoma by hypocycloidal polytomography. bTwo tests performed with 12-month interval.

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TABLE 3. Response of hPRL to Chlorpromazine (0.7 mg/kg) in Women with Elevated Serum hPRL and Pituitary Adenoma Patient

Basal hPRL

.lhPRL

% Change in hPRL

30 15 276 89 2 30 320 28 40 175 28 0 37 80 30 30 17 43 2

19 8 70 24 13 40 67 14 12 7 23 0 12 44 10 54 4 5 2

ng/ml

S. F." H.G." A. L." D.M." R. P." A.W. E. H.n E. K.n J. F.a P. S.n A. C.b L. McC. J. J. B.J." D.J. J. B. L. K. M.Ch. Mean ±SD

162 195 396 368 16 75 480 200 340 2425 120 25 303 180 288 56 410 893 100

59.2 ± 86.5

nTranssphenoidal removal of a pituitary microadenoma. bEvidence of empty sella by pneumoencephalography. "Testing carried out twice with 12-month interval.

The present findings suggest that there may be a dysfunction of hypothalamic catecholamine biosynthesis in amenorrheic or oligomenorrheic women. Ifone assumes that normal hypothalamicpituitary control of prolactin results in a normal or nearly normal response to CPZ, the group of women with oligomenorrhea or amenorrhea and normal serum hPRL levels generally had normal responses (9 of 16 [56.3%]) (Table 1). In those women in whom the oligomenorrhea or amenorrhea was associated with elevated serum hPRL levels, only 7 of 21 patients (33%) had a normal response. Finally, none of the group with elevated serum hPRL levels and evidence ofpituitary adenoma had a normal response. Although the majority of patients with elevated hPRL levels and oligomenorrhea or amenorrhea failed to respond to CPZ (14 patients), as of this date only one has been found to have evidence of pituitary adenoma. However, the follow-up period has been less than 2 years for most of these women. At present the hPRL response to CPZ does not allow for accurate discrimination between women with evidence of pituitary adenoma and those without roentgenographic evidence of adenoma. Failure to elicit a normal hPRL response is highly suggestive of pituitary adenoma, but should be confirmed by roentgenographic examination of the sella turcica. Conversely, a normal response (doubling of basal values) of hPRL to CPZ does not exclude absolutely the presence of

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pituitary adenoma, especially in the group of women with elevated basal hPRL values. Consequently, it is apparent that this modality of testing the hypothalamic-pituitary axis is of little or no value in the diagnostic evaluation of women with oligomenorrhea or amenorrhea with normal or elevated levels of serum hPRL. The two women who had Sheehan's syndrome failed to respond to CPZ and had low-normal levels of hPRL (Table 1). These data confirm the previous report of prolactin deficiency postpartum in two patients who were unable to nurse their children. 4 This finding, taken with the clinical setting, may allow CPZ to aid in determining the extent of pituitary reserve in postpartum women with persistent amenorrhea and normal to low levels of hPRL. However, our two patients were found to have low-normal levels of hPRL, and these values should be contrasted to the peripheral levels of hPRL which were undetectable (below the assay sensitivity) in previously reported cases. 4 Acknowledgments. The authors would like to thank the house staff and nurses of Magee-Womens Hospital who have generously aided us in this investigation. Our special thanks to Ms. June Imhoff, R.N., and Ms. Linda J. Hough, B.S., for their continued support over the past several years in patient management and laboratory assistance. REFERENCES 1. DeWeid D: Chlorpromazine and endocrine function.

Pharmacol Rev 19:251, 1967 2. Archer DF: Current concepts of prolactin physiology in normal and abnormal conditions. Fertil Steril 28:125, 1977 3. Kleinberg DL, Noel GL, Frantz AG:Chlorpromazine stimulation and L-dopa suppression of plasma prolactin in man. J Clin Endocrinol Metab 33:873, 1971 4. Turkington RW: Phenothiazine stimulation test for prolactin reserve: the syndrome of isolated prolactin deficiency. J Clin Endocrinol Metab 34:247, 1972 5. Friesen H, Guyda H, Hwang P, TysonJE, Barbeau A: Function evaluation of prolactin secretion: a guide to therapy. J Clin Invest 51:706, 1972 6. Zarate A, Jacobs LS, Canales ES, Schally AV, De La Cruz A, Soria J, Daughaday WH: Functional evaluation ofpituitary reserve in patients with the amenorrhea-galactorrhea syndrome utilizing luteinizing hormone-releasing hormone (LH-RH), L-dopa and chlorpromazine. J Clin Endocrinol Metab 37:85;;, 1973 7. LeBlanc H, Yen sse: The effect of L-dopa and chlorpromazine on prolactin and gTowth hormone secretion in normal women, Am J Obstet Gynecol 126:162, 1976 8. Frohman LA: Neurotransmitters as regulators of endocrine function. Hosp Practice 10:54, 1975 9. Kleinberg DL, Noel GL, Frantz AG: Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 296:589, 1977 10. Archer DF, Nankin HR, Gabos PF, Maroon J, Nosetz S, Wadwha SR, Josimovich JB: Serum prolactin in patients with inappropriate lactation. Am J Obstet Gynecol 119: 466, 1974