The effect of gonadotropin-releasing hormone agonist on thyroid-stimulating hormone and prolactin secretion in adult premenopausal women

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1 FERTILITY AND STERILITY Vol. 64, No.4, October 1995 Copyright 1995 American Society for Reproductive Medicine Printed on acid-free paper in U. S. A. The effect of gonadotropin-releasing hormone agonist on thyroid-stimulating hormone and prolactin secretion in adult premenopausal women Samuel J. Chantilis, M.D. * Cathy Barnett-Hamm, R.N.C. William E. Byrd, Ph.D. Bruce R. Carr, M.D. Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, Texas Objective: To investigate the effects of chronic administration of GnRH agonists (GnRH-a) on pituitary TSH and PRL secretion in adult women. Design: Prospective case-controlled study. Setting: Academic division of Reproductive Endocrinology, Department of Obstetrics and Gynecology. Patients: Ten ovulatory women and 10 women treated with monthly depot injections of leuprolide acetate (3.75 mg) were studied. Interventions: All subjects underwent pituitary stimulation with human thyrotropin-releasing hormone (TRH), 500 j-lg IV. Main Outcome Measures: Basal and post-trh-stimulated serum levels of TSH and PRL at 15, 30, 45, 60, 90, 120, and 180 minutes were compared among the two groups. Also, basal oft4, triiodothyronine, and triiodothyronine resin uptake studies were obtained and compared among the GnRH-a-treated and control groups. Results: No statistically significant difference between baseline or TRH-stimulated serum TSH and PRL could be detected between control and GnRH-a-treated groups of women. Furthermore, these groups were similar with respect to routine thyroid function assays. Conclusion: Gonadotropin-releasing hormone agonist does not significantly affect baseline or TRH-stimulated TSH and PRL levels nor basal serum T4 and triiodothyronine levels or triiodothyronine resin uptake in adult women. Fertil SterilI995;64: Key Words: Gonadotropin-releasing hormone agonist, thyroid-stimulating hormone, prolactin, pituitary Gonadotropin-releasing hormone agonists (GnRH -a) have been used extensively for the treatment of a variety of endocrine-related disorders due to the suppressive effects on serum FSH, LH, and subsequently gonadal sex steroids, that is, E2 and T. The use of these agents to treat uterine leiomyomata, endometriosis, and premenstrual syndrome in adult women via suppression of gonadal steroid production is well documented (1). Gonadotropin-releasing Received January 31,1995; revised and accepted May 23,1995. * Reprint requests: Samuel J. Chantilis, M.D., Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas (FAX: ). hormone agonists are also used to delay the effects of the premature awakening of the hypothalamicpituitary-gonadal axis in children with precocious puberty by inhibition of gonadotropin suppression (2). Gonadotropin-releasing hormone agonists may affect aspects of pituitary function other than gonadotropins, that is, GH and PRL secretion. Our group (3) previously demonstrated a reduction in GH-releasing hormone (RH)-stimulated release of GH in women, whereas basal GH and insulin-like growth factor levels were not affected. We suggested that the reduction in GH release may be due to decreased E2 levels (3). We hypothesized that thyrotropin-releasing hormone (TRH)-stimulated PRL release 698 Chantilis et al. Effect of GnRH-a on TSH and PRL secretion Fertility and Sterility

2 might also be simultaneously affected. Golan and co-workers (4) suggested that GnRH-a may reduce serum PRL in patients with hyperprolactinemia, although GnRH-a treatment did not lower PRL levels in individuals who were euprolactinemic. Alteration of TSH secretion with chronic administration of GnRH-a, however, has not been reported. The purpose of our study was to investigate what effects GnRH -a administered chronically may have on basal and TRH-stimulated pituitary TSH and PRL secretion in adult women. Dynamic testing with TRH was performed to assess pituitary TSH and PRL secretion in the event that GnRH-a may affect stimulated, but not basal, serum levels of these hormones. Basal thyroid function studies from GnRH-a-treated women are also reported. MATERIALS AND METHODS Ten ovulatory women (group 1) served as control subjects and were recruited from the medical school and community at large. Ten GnRH-a-treated women (group 2) who had received at least two (but <4) monthly depot injections of depot leuprolide acetate (LA, 3.75 mg; TAP Pharmaceuticals, Chicago, IL) were recruited to serve as the experimental subjects. All women were between the ages of 21 and 38 years with a body weight of 47 to 85 kg (100 to 180 lbs). Subjects who had a recent (l-year) history of irregular menses, chronic anovulation, luteal phase defect, or any history of hyperprolactinemia, galactorrhea, thyroid disease, central nervous system disease, or cardiopulmonary disease were excluded from the study. Leuprolide acetate for depot suspension was prescribed for all subjects for the indications of either endometriosis or uterine leiomyomas. All subjects agreed to participate in this study and signed an informed consent approved by the Institutional Review Board of The University of Texas Southwestern Medical Center at Dallas. Human TRH (5-0xY-L-propyl-L-histidyl-L-proline amide) was obtained from Abbott Laboratories-Diagnostic Division (Abbott Park, IL). All subjects were studied beginning at 7:00 to 9:00 A.M. after a 7- to 9-hour fasting state. Control women (group 1) were studied during the follicular phase of their ovarian cycle. Experimental subjects (group 2) had been receiving monthly GnRH-a therapy for a minimum of 6 weeks but for <3 months. Down-regulation of the pituitary gland was confirmed by observation of suppressed baseline E2 levels in all experimental subjects. All subjects were in the sitting position and remained awake during the study. Blood pressure and pulse were recorded every 15 minutes during the 1st hour ofthe study and every 30 minutes thereafter, until the completion of the study. An 18-gauge IV catheter was placed in the subjects' forearms and connected to a heparin lock to maintain patency. Basal blood samples were collected 0.25 hours after catheter placement, which served as the initial time point. TRH (500 f.lg) was administered over 1 minute as a bolus injection. Blood samples were subsequently collected at 15, 30, 45, 90, 120, and 180 minutes after TRH administration. Blood samples for all studies were collected in serum tubes and were immediately centrifuged at 300 X g (2,800 rpm) at 5 C for 10 minutes. Supernatant serum was stored at -20 C until assayed. Assays Estradiol, FSH, LH, TSH, PRL, total and unbound T4 serum levels, triiodothyronine resin uptake, and total and unbound triiodothyronine serum levels were quantified by immunoassays obtained from Diagnostic Products Corporation (Los Angeles, CA). All samples from each subject were analyzed in a single assay. Statistical Analysis Comparison of hormone concentrations between the two groups at baseline and given time periods were analyzed using an unpaired two-tailed Student's t-test. The level of significance was P $ RESULTS Upon completion of the study, the results from 20 subjects were available for analysis with 10 subjects each in the control and study groups. Group 1 consisted of four black and six white women; group 2 consisted ofthree black and seven white women. The means ± SE with respect to age and weight for group 1 (32.1 ± 1.50 years, 68.4 ± 3.27 kg) were similar to group 2 (31.7 ± 2.01 years, 65.8 ± 4.06 kg) (Table 1). The groups were similar with respect to transient side effects experienced by all subjects upon administration of TRH. Side effects included transient nausea (19 subjects), facial flushing (3 subjects), lightheadedness (6 subjects), urgency (4 subjects), headaches (3 subjects), and palpitations or chest pressure (2 subjects). None ofthese side effects were endured longer than 5 minutes, and no significant changes in pulse or blood pressure were detected. The mean basal serum E2 and LH levels were significantly higher (P < 0.05) in group 1 subjects (129.9 pg/ml [conversion factor to SI unit, 3.671] and miu/ml [conversion factor to SI unit, 1.00], respectively) than group 2 subjects (22.1 pgl ml and 0.7 miu/ml, respectively). An LH surge (57 Vol. 64, No.4, October 1995 Chantilis et a1. Effect of GnRH a on TSH and PRL secretion 699

3 Table 1 Comparison of Age, Weight, and Basal Serum Hormone Levels Between Control (Group 1) and GnRH-a-Treated (Group 2) Subjects* Assay Group 1t Age (y) 32.1 :!: 1.50 Weight (kg) 68.4 :!: 3.27 Ez (pg/ml) :!: 86.1 FSH (miu/ml) 5.8 :!: 1.0 LH (miu/ml) :!: 5.3 TSH (miuil) 1.5 :!: 0.7 PRL (ng/ml) 7.7 :!: 2.7 T4, total (flg/dl) 7.0 :!: 0.9 T4, unbound (flg/dl) 1.1 :!: 0.2 Triiodothyronine resin uptake (%) 29 :!: 2 Triiodothyronine, total (ng/dl) :!: 24.9 Triiodothyronine, unbound (ng/dl) 2.6 :!: 0.6 Group 2t 31.7 :!: :!: :!: :!: :!: :!: :!: :!: :!: :!: :!: :!: 1.0 * Both groups contained 10 subjects. t Values are means:!: SEM. :j: Significance level is <0.05;, not significant. Conversion factors to SI units are as follows: E 2, 3.671; FSH, LH, TSH, and PRL, 1.00; total T4 and unbound T4, 12.87; total triiodothyronine and unbound triiodothyronine, II n = 9; one subject in group 1 with an LH surge was excluded. p:j: <0.05 <0.05 miu/ml) was detected in one subject in group 1, but when excluded, the control group mean serum LH (5.6 miu/ml) remained significantly higher (P < 0.05) than that of group 2. The mean basal serum F8H was higher in group 1 (5.8 miu/ml [conversion factor to 81 unit, 1.00]) than group 2 (2.8 miu/ml) but did not reach statistical significance (P = 0.178). The suppressed levels of E2 and gonadotropins in group 2 patients confirm GnRH-a suppression of the hypothalamic-pituitary-ovarian axis. The mean ± 8E basal T8H level in group 1 (1.5 ± 0.7 miu/l [conversion factor to 81 unit, 1.00]) was similar (P = 0.628) to group 2 (1.3 ± 0.7 miu/l). The effects of GnRH-a on T8H secretion in response to TRH stimulation is presented in Figure 1. Mter an IV bolus infusion of TRH (500 p,g), mean ± 8E peak T8H secretion was achieved at 30 minutes, reaching levels of 16.6 ± 1.8 miuil in group 1 and 12.9 ± 2.2 miu/l in group 2. Although GnRH-a appear to suppress T8H secretion, the differences are not statistically significant at any time point assayed. There was no difference (P = 0.367) between the basal serum PRL levels of group 1 (7.7 ± 0.9 ng/ml [conversion factor to 81 unit, 1.00]) and group 2 (6.7 ± 0.7 ng/ml). The effect of GnRH-a on PRL secretion after TRH stimulation is shown in Figure 2. The mean ± 8E peak PRL levels were obtained 30 minutes after TRH administration and were 53.9 ± 16.4 ng/ml in group 1 and 57.5 ± 28.3 ng/ml in group 2. Gonadotropin-releasing hormone agonist administration had no demonstrable effect on PRL secretion after TRH stimulation of the pituitary ~! 10 5 ol l l---'------" o TIME (MINUTES) Figure 1 Effect of GnRH-a on TRH-stimulated TSH release. D, mean::+:: SE serum TSH values for the control women (n = 10); e, mean::+:: SE serum TSH values for the experimental women receiving GnRH-a for a minimum of 6 weeks. Time points are relative to TRH bolus infusion. gland in the subjects in group 2. Prolactin levels from all time points measured were similar between the two groups. The effect of GnRH-a administration on basal thyroid function was evaluated with comparison of thyroid hormone levels and the triiodothyronine resin uptake assay between the groups. There was no significant difference among the two groups with respect to total or unbound free T 4, triiodothyronine ::r, a 80 z i= u... C 0 a: a TIME (MINUTES) Figure 2 Effect of GnRH-a on TRH-stimulated PRL release. D, mean::+:: SE serum PRL values for the control women (n = 10); e, mean::+:: SE serum PRL values for the experimental women receiving GnRH-a for a minimum of 6 weeks. Time points are relative to TRH bolus infusion. 700 Chantilis et al. Effect of GnRH-a on TSH and PRL secretion Fertility and Sterility

4 resin uptake, and total or unbound triiodothyronine (Table 1). DISCUSSION The use of GnRH-a for long-term suppression of gonadal steroid production is widely accepted for the treatment of a wide variety of endocrine-related diseases. These agents may also affect the secretion of pituitary hormones other than gonadotropins and may affect stimulated but not basal values. By way of example, Word and colleagues (3) demonstrated suppression of GH release after stimulation by GH RH in premenopausal women compared with control women, although basal serum levels of neither GH nor insulin-like growth factor-i were affected. In contrast, GnRH-a do not affect basal nor corticotropinreleasing hormone-stimulated ACTH release in adult women (5). The specific mechanism by which GnRH-a may affect nongonadotropin pituitary hormonal secretion is unknown. We found no significant effect on basal or TRHstimulated secretion of TSH, although GnRH-atreated group 2 subjects had a diminished response. Our thyroid function testing of unchanged total or unbound T 4, total or unbound triiodothyronine, and the triiodothyronine resin uptake levels were similar in GnRH-a-treated and control women, which is consistent with our findings of unaltered basal and TRH-stimulated TSH levels. These data are in agreement with those of Cedars and colleagues (6), who found no change in the free thyroxin index in women receiving chronic GnRH-a. We found GnRH-a had no significant effect on TSH secretion, whereas the serum E 2 1evel in group 2 subjects clearly demonstrated suppression of the hypothalamic-pituitarygonadal axis. Based on our previous study of the effects of GnRH-a to suppress GnRH-stimulated GH release, possibly due to lowered estrogen, we hypothesized that TRH-stimulated PRL release might also be suppressed by GnRH-a. This seemed plausible because PRL levels increase in response to estrogen. However, the two study groups were similar with respect to basal and TRH-stimulated PRL levels. Our findings of similar basal PRL levels among the two groups are consistent with those of several investigators who also found no significant differences of basal PRL levels in women exposed to chronic GnRH-a therapy (4, 7, 8). Venturini and colleagues (7) followed 32 adult women diagnosed with endometriosis who were treated for 6 months with GnRH-a goserelin acetate depot and found no significant change in basal serum PRL levels when compared with pretreatment levels. Sklar and co-workers (8) found no difference in unstimulated PRL secretion before and after LA treatment of 11 children with central precocious puberty. Fifteen adult euprolactinemic women with uterine leiomyomata treated with GnRH-a by Golan and colleagues (4) failed to demonstrate a significant change in PRL secretion, although one woman with hyperprolactinemia had significant suppression of serum PRL. None of these investigators (4,7,8), however, evaluated stimulated PRL levels, viz., all of these studies compared basal, that is, unstimulated pretreatment to post-treatment, levels of PRL. Other investigators (9, 10) reported chronic GnRH-a treatment results in diminished serum PRL levels (unstimulated), but these results may be secondary to the markedly higher E2 levels in the control groups as estrogens are believed to augment PRL secretion in women (11, 12). In summary, we analyzed the effect of GnRH-a on the secretion of TSH and PRL before and after IV infusion of TRH. We found no alteration in the basal or stimulated patterns of TSH and PRL secretion in reproductive-aged women treated chronically with GnRH-a. Additionally, we performed common thyroid function tests and found no significant differences between normal and GnRH-a-treated reproductive-aged women. The effects of short-term, that is, <6 weeks, administration of GnRH-a on pituitary TSH and PRL secretion, particularly during ovulation induction, remain unknown and deserve further study. Acknowledgments. We gratefully acknowledge the expert technical assistance of John O. Ritter, B.S., Stacy Tran, B.S., Y. Dong, B.S., and Amy Marshall, B.S., The University of Texas Southwestern Medical Center, Dallas, Texas. REFERENCES 1. Forti G. Clinical applications of GnRH analogs. J Endocrinol Invest 1988; 11: Boepple PA, Mansfield MJ, Wierman ME, Rudlin CR, Bode HH, Crigler JF Jr, et al. Use of a potent, long acting agonist of gonadotropin releasing hormone in the treatment of precocious puberty. Endocr Rev 1986;7: Word RA, Odom MJ, Byrd W, Carr BR. The effect of gonadotropin-releasing hormone agonists on growth hormone secretion in adult premenopausal women. Fertil Steril 1990; 54: Golan A, Bukovsky I, Weinraub Z, Ron-EI R, Herman A, Raziel A, et al. The effect of chronic gonadotropin-releasing hormone analogue (D-Trp6) treatment on elevated and normal serum prolactin levels. Fertil SteriI1989;51: Wilson EE, Little BB, Byrd W, McGee E, Carr BR. The effect of gonadotropin-releasing hormone agonists on adrenocorticotropin and cortisol secretion in adult premenopausal women. J Clin Endocrinol Metab 1993;76: Vol. 64, No.4, October 1995 Chantilis et ai. Effect of GnRH-a on TSH and PRL secretion 701

5 6. Cefcdars MI, Steingold KA, Lu JHL, Judd HJ, Meldrum DR. Pituitary function before, during, and after chronic gonadotropin-releasing hormone agonist therapy. Fertil Sterill992; 58: Venturini PL, Fasce V, Costantini S, Anserini P, Cucuccio S, de Cecco L. Treatment of endometriosis with goserelin depot, a long-acting gonadotropin-releasing hormone agonist analogue: endocrine and clinical results. Fertil Steril 1990; 54: Sklar CA, Rothenberg S, Blumberg D, Oberfield SE, Levine LS, David R. Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth hormone, insulin-like growth factor-i, and prolactin secretion. J Clin Endocrinol Metab 1991;73: Mettler L, Steinmiiller H, Schachner-Wiinschmann E. Experience with a depot GnRH-agonist (Zoladex) in the treatment of genital endometriosis. Hum Reprod 1991;6: Fraser IS, Shearman RP, Jansen RPS, Sutherland PD. A comparative treatment trial of endometriosis using the gonadotrophin-releasing hormone agonist, nafarelin, and the synthetic steroid, danazol. Aust N Z J Obstet Gynaecol 1991;31:2: Yen SSC, Ehara Y, Siler TM. Augmentation of prolactin secretion by estrogen in hypogonadal women. J Clin Invest 1974; 53: Carr BR, Wilson JD. Disorders of the ovary and female reproductive tract. In: Isselbacher KJ, Braunwald E, Wilson JD, Marin JB, Fauci AS, Kasper DL, editors. Harrison's principles of internal medicine. 13th ed. New York: McGraw-Hill, 1995: Chantilis et al. Effect of GnRH-a on TSH and PRL secretion Fertility and Sterility

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