Hyperprolactinemic response after bromocriptine withdrawal in women with prolactin-secreting pituitary tumors*

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1 FERTILITY AND STERILITY Copyright 1984 The American Fertility Society Vol. 41, No.2, February 1984 Printed in U.8A. Hyperprolactinemic response after bromocriptine withdrawal in women with prolactin-secreting pituitary tumors* Wayne S. Maxson, M.D.tt Michelle Dudinski, M.D. t Stuart H. Handwerger, M.D. Charles B. Hammond, M.D. t Duke University Medical Center, Durham, North Carolina In patients with prolactin (PRL)-secreting tumors, plasma PRL concentrations after discontinuation of bromocriptine therapy have been used clinically as an index of tumor activity. To investigate the pattern of PRL response under these conditions, seven women on chronic bromocriptine therapy for PRL-producing pituitary tumors were followed with serial PRL determinations for 2 months after bromocriptine withdrawal. In these patients, peak PRL concentrations were achieved 28.1 days (mean; range, 14 to 49 days) after bromocriptine discontinuation. However, PRL concentrations did not usually plateau until at least 40 days after cessation of therapy, and the pattern of PRL response was highly variable. Because of the inconsistent pattern of serum PRL response during the first 40 days after discontinuation of bromocriptine, decisions regarding tumor activity based on PRL concentrations should not be made until at least 6 weeks after withdrawal of the drug. Fertil Steril41:218, 1984 Bromocriptine has gained widespread clinical use in the treatment of women with prolactin (PRL)-producing pituitary tumors because of a possible antiproliferative effect on pituitary adenomas demonstrated in laboratory animals1 and because of numerous case reports of radiographic and symptomatic improvement in humans. 2, 3 In patients with pituitary tumors, the sie of the tumor frequently corresponds to the magnitude of the PRL elevation,4-6 and measurement of serial serum PRL concentrations has been suggested as Received July 19, 1983; revised and accepted September 28, *Supported by RR-30, General Clinical Research Centers Program Division of Research Resources, NIH. tdepartment of Obstetrics and Gynecology. :j:present address and reprint requests: Wayne S. Maxson, M.D., Division of Reproductive Endocrinology, Center for Fertility and Reproductive Research, D-3221, Vanderbilt University Medical Center North, Nashville, Tennessee Department of Pediatrics. a biochemical marker of tumor activity or progression. 7, 8 Once bromocriptine therapy has been instituted, however, the ability to monitor tumor activity with serial PRL determinations is lost, and documented progression of a tumor despite bromocriptine-induced euprolactinemia has occurred. 9 Some investigators lo have therefore recommended the measurement of PRL concentrations after diagnostic withdrawal of bromocriptine therapy as a potential index of tumor activity. Since only limited data are available regarding the pattern of PRL response after the discontinuation of chronic bromocriptine treatment,11-13 this study was designed to investigate systematically the pattern of return of hyperprolactinemia in seven women after bromocriptine withdrawal. Our data indicate a wide interpatient variability in PRL patterns and suggest that at least a 6-week drug-free interval must be maintained before a plateau in PRL concentrations is established. 218 Maxson et al. Prolactin after bromocriptine withdrawal Fertility and Sterility

2 Table 1. Clinical Profiles and Treatment Prior to Bromocriptine Patient Age Race Parity Diagnostic pro- Previous treatcedures4 Diagnosis ment 1 37 W G2P2 Tomography, PEG, Pituitary macroade- Transsphenoidal CAT scan noma with para- surgery, incofusellar extension plete resection 2 34 W GlP1 Tomography Pituitary microade- Transsphenoidal noma (recurrent) surgery 3 24 W GOPO Tomography, PEG, Pituitary microade- Transsphenoidal CAT scan noma (residual) surgery, incomplete resection 4 45 W GOPO Tomography Pituitary microade- Transsphenoidal noma (residual), surgery, incompartially empty plete resection sella 5 33 B G2P2 Tomography, PEG, Possible pituitary CAT scan microadenoma, partially empty sella 6 30 B GOPO Tomography, CAT Pituitary microadescan noma, hyperparathyroidism (MEN-I) 7 28 W GOPO Tomography, CAT Pituitary microadescan noma, partially empty sella 4PEG, pneumoencephalogram; CAT, computeried axial tomography. MATERIALS AND METHODS Seven hyperprolactinemic women, 24 to 45 years of age, on chronic bromocriptine (Parlodel, Sando Pharmaceuticals, East Hanover, NJ) therapy were studied. The clinical profiles of these women are shown in Table 1. All seven women had galactorrhea and amenorrhea prior to initial treatment. Four patients (1 through 4) had recurrent hyperprolactinemia following craniotomy or transsphenoidal surgery with histologic documentation of a pituitary adenoma. Three patients (5 through 7) had hyperprolactinemia with radiographic evidence of erosion of the sella turcica suggestive of a micro adenoma. Two of these women (5 and 6) had a concomitant partially empty sella documented by pneumoencephalography. Patient 7 had a diagnosis of multiple endocrine neoplasia type I (MEN-I) with a history of previous surgical resection of a parathyroid adenoma. All patients in this study had normal complete blood counts, urinalysis, serum electrolyte values, SMA-12, and serum thyroid-stimulating hormone. The study protocol is outlined in Table 2. Women were admitted to the Clinical Research Unit of Duke University Medical Center during maintenance of their usual dose of bromocriptine. All inpatient PRL samples were obtained from an indwelling intravenous heparin lock after 1 Vol. 41, No.2, February 1984 hour's rest in the recumbent position, at least 1 hour after eating. Bromocriptine was administered at 8:30 P.M. on day - 1 and at 8:00 A.M. on day 0 at a dose of 2.5 mg (patients 2 through 7) or 5 mg (patient 1). Serial serum samples for PRL determinations were obtained at 8:00 P.M. on day -1 and at 4-hour intervals for 2 days, beginning at 8:00 A.M. on day O. No further bromocriptine was given after the morning of day O. Patients were discharged on day 3. Outpatient blood samples were drawn after a 30-minute rest, in a chair, at least 1 hour after eating, and between 7:30 A.M. and 10:00 A.M. Over the following 2 months, outpatient samples were obtained every 1 to 3 days for the first month and then weekly thereafter. In three patients (1, 2, and 4), bromocriptine was withheld for clinical reasons for 71 to 199 days, and subsequent PRL determinations were obtained during this additional drug-free interval. Table 2. Protocol for Evaluation of PRL Responses After Bromocriptine Withdrawal Days Bromocriptine PRL determinations M 8:30 P.M. 8:00 A.M. 8:00 P.M. Every 4 Every 1- Every 7 hours 3 days days Maxson et ai. Prolactin after bromocriptine withdrawal 219

3 T Table 3. Response of PRL Concentrations to Bromocriptine Therapy and Withdrawal Dose of Duration of PRLpre Patient bromocriptine bromocriptine treatment treatment mglday mo nglml PRL during treatment Peak PRL Time to PRL at ter (mean, day after with- peak PRL mination of -1,0) drawal study nglml nglml days nglml PRL concentrations were determined by homologous radioimmunoassay.14, 15 This assay was sensitive at a PRL concentration of 1 ng/ml, and cross-reactivity with growth hormone or chorionic somatomammotropin was minimal. 14 The data were analyed by the Clinfo data analysis system of the Duke University Medical Center Clinical Research Unit. Statistical analyses were performed using linear regression analysis and Student's t-test. RESULTS PRL CONCENTRATIONS DURING BROMOCRIPTINE The subjects in this study had received bromocriptine at a dose of 5 to 20 mg/day for an average of 10.1 months (range, 4 to 16 months) prior to discontinuation (Table 3). Five of the seven patients had normal PRL concentrations «20 ng/ ml) while on bromocriptine therapy. The patient with the macro adenoma (1) had a PRL level of 76 ng/ml on 20 mg bromocriptine per day (from a pretreatment concentration of 2085 ng/ml). One of the women with a micro adenoma (7) had a PRL concentration slightly above normal, at 31.5 ng/ ml (from a pretreatment level of 178 ng/ml), on 7.5 mg bromocriptine daily. PRL CONCENTRATIONS FOLLOWING BROMOCRIPTINE DISCONTINUATION Serial PRL concentrations during the first 48 hours after discontinuation of bromocriptine are illustrated in Figures 1 and 2. Six of the seven subjects exhibited an increase in serum PRL concentrations over baseline (time 0) 48 hours after discontinuation of bromocriptine, although PRL levels in four subjects remained within the normal range during the first 2 days. The percentage of increase over baseline ofprl at 48 hours correlated significantly with the baseline PRL concentrations (r = 0.87,P < 0.005). Indeed, the earliest time at which PRL was significantly elevated over baseline occurred in the patient with the highest PRL concentration (patient 1, 16 hours). During the following 10 days after bromocriptine withdrawal, the PRL concentrations in all patients progressively increased (Fig. 3). However, a wide interpatient variation in the pattern ofprl response was apparent thereafter. Patient 1 reached a peak serum PRL level at 49 days (46% of her pretreatment value). In the five patients with normal PRL concentrations on bromocriptine therapy, plasma PRL levels did not rise> 25 ng/ml until an average of 4 days (range, 1 to 9 days) after discontinuation of bromocriptine. All six patients with documented or putative microadenomas had gradually rising PRL levels, peaking at a mean of 24.6 days (range, 16 to 35 days). These peak values varied from 53% to 528% of pretreatment PRL levels (Table 3). 600 ::: S '" 400 I- U a II: BROMOCRIPTINE -I ol lo HOURS Figure 1 PRL response during the first 48 hours after discontinuation of bromocriptine in patient 1 (macroadenoma). 220 Maxson et al. Prolactin after bromocriptine withdrawal Fertility and Sterility

4 60 50 E c 30 t- U «...J 20 0 a: a. 10 BROMOCRIPTINE,. A -10 o....ti p." HOURS Figure 2 PRL response during the first 48 hours after discontinuation of bromocriptine in patients 2 through 7 (microadenoma with or without partially empty sella) p.. ''6 A /.. \/ / ri The pattern of PRL response after bromocriptine withdrawal was unpredictable (Fig. 3). Four patients (1, 4, 5, and 7) exhibited a biphasic response in PRL with an initial rise and a subsequent nadir, which occurred between 16 and 56 days. In four women, PRL concentrations rebounded temporarily above pretreatment levels (patients 3,4,5, and 7). However, even by 60 days after bromocriptine withdrawal, six of the seven subjects exhibited PRL concentrations lower than pretreatment levels. 50 The observation of two patients (1 and 2) who were studied beyond the protocol interval indicated retrospectively that both had reached a plateau in PRL concentrations by 30 to 40 days following bromocriptine withdrawal. However, another patient (4) demonstrated a more prolonged suppression of PRL, with maintenance of a normal PRL concentration from days 56 to 71, with a subsequent rise undetected until remeasurement 101 days after bromocriptine discontinuation. This elevation was reconfirmed by a subsequent determination at 190 days. No significant correlation is observed between PRL concentrations obtained 1 month and those obtained 2 months after bromocriptine withdrawal (r = 0.54, P = 0.1). However, there is a highly significant positive correlation between PRL values at 2 months and pretreatment PRL concentrations (r = 0.94, P < 0.005). DISCUSSION Although the determination of PRL concentrations after the discontinuation of bromocriptine may provide a useful index of tumor activity, the pattern of the return of hyperprolactinemia has not been adequately elucidated, and hence the optimum time to measure a serum PRL level after bromocriptine withdrawal has not been established. While several studies have measured PRL concentrations after bromocriptine discontinuation, no conclusions regarding patterns of re Patient I 120 Patient IOO t t 0 g: = 1000! PRE_rx DAYS 500 i ;: 200 o f 100 = 400 l = 250 l.= J 100 o.. '" 50 Patient 7 PRE_TX DAYS PRE -TX b '0 60 DAYS Figure 3 PRL response in individual patients after discontinuation ofbromocriptine. Pretreatment (PRE-TXl indicates PRL concentration before bromocriptine therapy. Bromocriptine was discontinued on day 0 after 8:00 A.M. Vol. 41, No.2, February 1984 Maxson et ai. Prolactin after bromocriptine withdrawal 221

5 r sponse can be formulated because of infrequent sampling times. s, 11, 13 In one report utiliing more frequent sampling intervals, Sobrinho and colleagues12 stated that maximal values were generally reached 1 month after bromocriptine withdrawal. However, only a single PRL determination is reported, and the variability in PRL response is not addressed. Although the individual patterns of PRL response cannot be established from these reports, it is noteworthy that hyperprolactinemia recurred in all 66 women in these studies. In our series, all seven subjects demonstrated a return of hyperprolactinemia following bromocriptine discontinuation, with only one of the seven women demonstrating a PRL concentration that was higher than pretreatment concentrations 2 months after bromocriptine withdrawal. This finding was also noted by previous authors,s, with 93.2% of the women demonstrating PRL elevations after therapy that were lower than pretreatment levels following a study interval that ranged from 1 to 24 months. 13 With the frequent sampling intervals employed in the present study during the initial 2 months after bromocriptine withdrawal, variability in the pattern of PRL response between individual patients becomes apparent. During the initial 48 hours after bromocriptine discontinuation, PRL concentrations either remain stable or gradually increase. The degree of PRL increase has a significant positive correlation with the baseline PRL concentrations achieved on bromocriptine. During the first 10 days after bromocriptine withdrawal, PRL concentrations are increased in all patients in a fairly uniform fashion (Fig. 3). However, the patterns ofprl response thereafter vary markedly, without any predictable correlation with previous therapy, the dose or duration of bromocriptine treatment, pretreatment PRL concentrations, or diagnosis. The findings of abrupt nadirs (patients 1, and 4 through 7) and marked rebound (patients 3 through 7) illustrate the haards of attempting to use a single PRL determination as a tumor marker following bromocriptine withdrawal. The mechanism for the variability of response to bromocriptine withdrawal observed in this study has not been well elucidated. Despite the fact that chronic bromocriptine therapy almost invariably reduces circulating PRL concentration regardless of the cause, bromocriptine rarely induces permanent tumor regression and euprolac- tinemia in women with prolactinomas. Although several studies, including our own, have consistently indicated lower concentrations of PRL following chronic bromocriptine therapy, it is not clear whether these alterations represent an antitumor effect or prolonged inhibition of PRL synthesis or release. Continued follow-up may well indicate that PRL concentrations will gradually increase again during further observation. In animals, bromocriptine is antimitogenic for many prolactinomas. In humans, however, the relevance of these animal data has been questioned, since mitoses are not usually observed in human PRL-producing pituitary tumors.16 Histologic evidence of tumor degeneration has been reported in some surgically resected pituitary tumors after bromocriptine treatment in vi VO,16, 17 but this effect, when present, usually demonstrates focal involvement of only small areas of the sample.16 Bromocriptine induces a significant reduction in cytoplasmic, nuclear, and nucleolar areas, with a decrease in rough endoplasmic reticulum and Golgi complexes in PRLproducing pituitary tumors. This reduction in volume is reversible, with an increase in cell volume observed in pituitary tissue obtained 1 to 2 weeks after discontinuation of bromocriptine therapy in vivo. IS The prolonged suppression of PRL synthesis and release may reflect alterations in dopamine (and hence bromocriptine) receptors on the cell membrane surface of the pituitary lactotroph. However, the binding characteristics of dopamine receptors in PRL-producing pituitary tumors appear normal, although abnormalities in the number of receptors per cell cannot be ruled out.18 Indeed, dopamine inhibits not only PRL release but also the synthesis of PRL and its messenger ribonucleic acid in normal pituitary cells from rats,19 indicating a disorder in cell function that is reflected in the ultrastructural changes described by Tindall and colleagues. 18 Further studies are required to delineate the reasons for the rebound of PRL concentration after bromocriptine discontinuation in excess of pretreatment concentrations that was observed in four women in this study. Our data clearly demonstrate that PRL concentrations do appear to stabilie after bromocriptine withdrawal in women with pituitary tumors, but this apparent plateau does not generally occur until at least 40 to 50 days after bromocriptine discontinuation. Therefore, the measurement of a 222 Maxson et al. Prolactin after bromocriptine withdrawal Fertility and Sterility

6 PRL concentration within 2 months after bromocriptine withdrawal does not provide a reliable index of tumor progression or regression. Followup computeried axial tomography was not performed in our subjects during the initial 2 months after bromocriptine treatment, and correlations thus cannot be made between ultimate tumor sie and PRL concentrations in our series. It is clear, however, that the finding of a normal PRL concentration even 2 months after the discontinuation ofbromocriptine may not indicate a complete cure, since hyperprolactinemia in one patient required more than 77 days of observation before a persistent return of hyperprolactinemia could be detected. In light of the recent reports of a rapid increase in sie and a return of visual field defects in patients with pituitary macro adenomas following discontinuation of bromocriptine therapy,20 the diagnostic withdrawal of bromocriptine must be approached with caution, particularly in patients with large tumors. In the absence of tumor progression on serial radiographic assessment in the asymptomatic patient, diagnostic bromocriptine withdrawal may nevertheless be helpful in detecting residual tumor activity. As suggested by this study, the measurement of PRL concentrations during the first 2 months after bromocriptine withdrawal may be misleading. Acknowledgments. The authors would like to gratefully acknowledge the expert secretarial assistance of Ruth Robertson and Angela Sullivan and the technical support of Mattie Harris and Jerome Winegarden. REFERENCES 1. Lloyd HM, Meares JD, Jacobi J: Effects of oestrogen and bromocriptine on in vitro secretion and mitosis in prolactin cells. Nature 255:497, Thorner MO, Martin WH, Rogol AD: Rapid regression of pituitary prolactinomas during bromocriptine treatment. J Clin Endocrinol Metab 51:43, Wollesen F, Andersen T, Karle A: Sie reduction of extrasellar pituitary tumors during bromocriptine treatment. Ann Intern Med 96:281, Kleinberg DL, Noel GC, Frant AG: Galactorrhea: 235 cases including 48 with pituitary tumors. N Engl J Med 296:589, Child DF, Gordon H, Mashiter K, Joplin GF: Pregnancy, prolactin, and pituitary tumors. Br Med J 4:87, Fahlbusch R, Rjosk HK, von Werder K: In Treatment of Pituitary Adenomas, Edited by R Fahlbusch, K von Werder. Stuttgart, Thieme, 1978, p von Werder K, Fahlbusch R, Landgraf R, Pickardt CR, Rjosk HK, Scriba RC: Operative und medikamentose Behandlung jon Prolaktin-produierenden Hypophysentumoreno Verh Dtsch Ges Inn Med 82:1904, Bergh T, Nillius SJ, Wide L: Menstrual function and serum prolactin levels after long-term bromocriptine treatment of hyperprolactinemic amenorrhoea. Clin Endocrinol (OxO 16:587, Crosignani PG, Mattei A, Ferrari C, Giovanelli MA: Enlargement of a prolactin-secreting pituitary microadenorna during bromocriptine treatment-a case report. Br J Obstet Gynaecol 89:169, Thorner MO, Fluckiger E, Caine DB: Bromocriptine: A Clinical and Pharmacological Review. New York, Raven Press, 1980, p Evans WS, Schiebinger RJ, Kaiser DL, Nunley WC Jr, Loriaux DL, MacLeod RM, Thorner MO: Serum adrenal androgens in hyperprolactinemic women prior to, during, and after chronic treatment with bromocriptine. Acta Endocrinol (Copenh) 101:235, Sobrinho LG, Nunes MC, Calha-Jorge C, Mauricio JC, Santos MA: Effect oftreatment with bromocriptine on the sie and activity of prolactin-producing pituitary tumors. Acta Endocrinol (Copenh) 96:24, Eversmann T, Fahlbusch R, Rjosk HK, von Werder K: Persisting suppression of prolactin secretion after longterm treatment with bromocriptine in patients with prolactinomas. Acta Endocrinol (Copenh) 92:413, Sinha YN, Selby FW, Lewis UJ, Vanderlaan WP: A homologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab 36:509, Golander A, Hurley T, Barret J, Hii A, Handwerger S: Prolactin synthesis by human chorion-decidual tissue: a possible source of prolactin in the amniotic fluid. Science 202:311, Anniko M, Werner S, Wersall J: Bromocriptine-induced changes in hormone secretion and cell morphology in growth hormone and prolactin producing pituitary adenomas. Acta Otolaryngol (Stockh) 92:343, Tramu G, Beauvillain JC, Mauca M, Grenier JL, Fossati P, Christiaeurs JC: Time-dependent evolution of pituitary prolactin adenomas under bromocriptine therapy. Presented at the Second European Workshop on Pituitary Adenomas. Published by the Congress on Bromocriptine Therapy, Paris, 1979, p Tindall FT, Kovacs K, Horvath E, Thorner MO: Human prolactin-producing adenomas and bromocriptine: a histological, immunocytochemical, ultrastructural, and morphometric study. J Clin Endocrinol Metab 55:1178, Maurer RA: Dopaminergic inhibition of prolactin synthesis and prolactin messenger RNA accumulation in cultured pituitary cells. J Bioi Chern 255:8092, Thorner MO, Perryman RL, Rogol AD, Conway BP, Mac Leod RM, Login IS, Morris JC: Rapid changes of prolactinoma volume after withdrawal and reinstitution ofbromocriptine. J Clin Endocrinol Metab 53:480, 1981 Vol. 41, No.2, February 1984 Maxson et al. Prolactin after bromocriptine withdrawal 223

PRIMARY AMENORRHEA AND PITUITARY ADENOMAS

FERTIUTY AND STERILITY Copight c 1981 The American Fertility Society Vol. 35, No.6, June 1981 Printed in U.SA. PRIMARY AMENORRHEA AND PITUITARY ADENOMAS CAROLYN B. COULAM, M.D.* EDWARD R. LAWS, JR., M.D.t