Oxytocin enhances thyrotropin-releasing hormone-induced prolactin release in normal menstruating women*

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1 Printed in U.8A. F'ERTlJTY AND STERJTY Copyright" 1987 The American Fertility Society Oxytocin enhances thyrotropin-releasing hormone-induced prolactin release in normal menstruating women* Vittorio Coiro, M.D.t+ Angelo Gnudi, M.D. Riccardo Volpi, M.D.t Carlo Marchesi, M.D. Giacomo Salati, M.D.t Paolo Caffarra, M.D.~ Paolo Chiodera, M.D. University of Parma, School of Medicine, Parma, and Hospital of Fidenza, Fidenza, taly The effects of oxytocin (OT) on basal thyrotropin-releasing hormone (TRH)stimulated thyrotropin (TSH) and prolactin (PRL) secretion were evaluated in normal menstruating women during follicular, periovulatory, and luteal phases. Two different studies were performed. n one study, 15 subjects were treated with OT or saline; in the other study, 20 women were tested with TRH alone or in combination with ~T. Results during follicular, periovulatory, and luteal phases were similar. OT did not produce any effect on basal serum TSH and PRL levels and on the TRHstimulated TSH secretion, whereas it significantly enhanced the PRL response to TRH. At all examined phases during the menstrual cycle,the mean peak PRL response was reached within 20 minutes after TRH injection, and the peak was about three times higher than basal value when TRH was given alone and about fourtimes when OT was present. These data suggest that in normal women OT is not involved in the control of basal and TRH -stimulated TSH secretion and of basal PRL release. n contrast, the enhancement of the TRH -induced PRL release suggests that OT plays a role in the control of the acutely stimulated PRL secretion. Because results were similar regardless of the phase of the menstrual cycle,estrogen and/or progesterone do not appear to be involved in the effect ofot on the TRH-induced PRL release. Fertil Steril 47:565, 1987 High concentrations of oxytocin (OT) have been found in the portal blood supplying the anterior pituitary gland,, 2 where OT is thought to act as Received October 10, 1986; revised and accepted December 9,1986. *Supported in part by a grant from Ministero Pubblica Struzione and by grant CT from Consiglio Naziona Le Ricerche, Rome, taly. tchair of Medical Clinic, University of Parma. :j:reprint requests: Vittorio Coiro, M.D., Chair of Medical Clinic, University of Parma, via Gramsci 14, Parma, taly. Chair of Endocrinology, University of Parma. Chair of Psychiatry, University of Parma. ~Division of Neurology, Hospital of Fidenza. modulator of various hormonal secretions. Current knowledge of the effect ofot on the thyrotropin-stimulating hormone (TSH) and prolactin (PRL) secretory systems is both confused and controversial, because conflicting data concerning OT action have been reported. 3-8 Furthermore, it is not clear whether OT interferes with the basal secretion of these hormones or affects their response to provocative stimuli. This problem is of particular interest. Both TSH and PRL are released in response to suckling in lactating rats 9,10 and in women during early puerperium,l1 perhaps as a consequence of the sucklingstimulated thyrotropin-releasing hormone (TRH) Coiro et a. Oxytocin and PRL response to TRH 565

2 increase in hypophyseal stalk blood.12 t has been hypothesized that in rat the simultaneous secretion of OT would partially block TSH response to endogenous TRH, without affecting PRL secretion. 8 The current study was undertaken to gain a better insight of the effect of OT on basal and TRH-stimulated TSH and PRL secretion in human beings. For this purpose, normal women were treated with OT, TRH, and a combination of OT and TRH. TSH and PRL responses in these various experimental conditions were evaluated and compared. Experiments were carried out in the follicular, periovulatory, and luteal phases to evaluate the possible role of estrogen and progesterone (P) in modulating OT action. MATERALS AND METHODS Thirty-five normal women volunteers, 22 to 33 years of age, without clinical or laboratory evidence of endocrine, hepatic, or renal diseases, participated in the study. All of the volunteers were informed of the purpose of the study and gave their written consent. All subjects were within 10% of their ideal body weight and had a history of regular menstrual cycles of normal duration (26 to 30 days). None of them took any drug for at least 2 weeks before the experimental days. Basal body temperature and plasma levels of ovarian steroids were evaluated daily and served as criteria to determine the precise period of the cycle. The women were divided into two groups, which participated in two different studies. EFFECT OF OT ON BASAL TSH AND PRL SECRETON Fifteen women were randomly chosen for this study. Five women were tested in the follicular phase (days 6 to 8), five in the periovulatory phase (days 12 to 16), and five in the luteal phase (days 21 to 23). Two tests were carried out in random order and in the same subject on corresponding days of two consecutive menstrual cycles. OTTEST At 9:00 A.M., after an overnight fast, the subjects.were placed in the supine position, and two intravenous cannulas were inserted into veins, one in each forearm. One of them was kept patent by a slow saline infusion and was used for blood sampling; the other was used for OT administration. Basal blood samples were collected at -10 and 0 minutes. At time 0 blood sampling was followed by the injection of 2 U OT (Syntocinon, Sandoz, Basel, Switzerland), which lasted about 3 minutes and was followed by the infusion of 4 U OT in 100 ml normal saline in 60 minutes. The solution was infused at a constant rate. Further blood specimens were taken 10, 20, 30, 45, and 60 minutes after the beginning of the infusion. CONTROL TEST This test was performed as previously described, except that an equal volume of saline was given instead of ~T. EFFECT OF OT ON TRH-STMVLATED TSH AND PRL SECRETON The remaining 20 women participated in this study. Six women were.studied in the follicular phase, six in the periovulatory phase, and eight in the luteal phase. Two tests were carried out in random order and in the same subject on corresponding days of two consecutive menstrual cycles. The preliminary experimental conditions were similar to those described previously. TRH PLUS OT TEST A blood sample was taken at time -10 minutes and followed by the injection of 2 U synthetic OT. At time 0 minutes, TRH (Biodata, Rome, taly) (200 f-lg) was rapidly injected intravenously and followed by the infusion of OT (4 U in 100 ml saline) in 60 minutes. Further blood specimens were withdrawn at the same times as in the tests previously described. TRHTEST This test was performed in order to measure the effect of TRH on serum TSH and PRL levels in our subjects. TRH was given as described previously; an equal volume of saline was administered instead of ~T. At each sampling time, during all tests, blood pressure and heart rate were monitored. Subjects were also asked if they were suffering subjective symptoms, such as nausea and abdominal cramps. Serum samples from all experiments were stored at - 20 C until they were used for TSH, PRL, 17~-estradiol (E2), and P assay. Measurements were carried out by specific radioimmunoassays,13-16 with the reagents supplied by Biodata. Results are reported as the mean ± standard error (SE); analysis of variance followed by specific means comparison test has been used for data evaluation. 566 Coiro et al. Oxytocin and PRL response to TRH Fertility and Sterility

3 OTTEST RESULTS The administration of OT did not modify the serum TSH and PRL concentrations at any time during the menstrual cycle (Figs. 1 and 2). TBH.. u/... A e----etan+ot ~TA'" o <l at O----O... L~ TRH PLUS OT TEST The administration of OT did not alter the TSH response to TRH in the follicular, periovulatory, and luteal phases (Fig. 2). n contrast, OT significantly enhanced the TRH-induced PRL release (Fig. 1). Results were similar regardless of the phase of the menstrual cycle. n the TRH test, PRL levels rose by about threefold, whereas in presence of OT the mean peak level was about four times higher than basal value. The increase 1 PRL NG/ML A / ~..,,'... /'....TAM+DT TAM c.---o at ALN. C Figure 2 Effects of OT on basal TSH levels and on TRH-stimulated TSH release during follicular (A), periovulatory (B), and luteal (C) phases. Each point represents the mean ± SE of at least five observations. b 80MN. Figure 1 Effects ofot on basal PRL levels and on TRH-stimulated PRL release during follicular (A), periovulatory (B), and luteal (C) phases. Each point represents the mean ± SE of at least five observations. TRH + OT versus TRH: *p < 0.001; **p < 0.005; ***P < 0.01; ****p < of serum PRL levels after TRH plus OT was significantly higher than after TRH alone (F = , P < 0.01 in the follicular phase; F = , P < 0.01 in the periovulatory phase; F = , P < 0.01 in the luteal phase). The mean serum levels of E2 were 63.9 ± 3.0 pg/ml in the follicular phase, ± 4.2 pg/ml in the periovulatory phase, and 85.6 ± 3.5 pg/ml in the luteal phase; Pconcentrations in the serum were 1.6 ± 0.7 ng/ml in the follicular phase, 3.2 ± 0.5 ng/ml in the peri ovulatory phase and 10.5 ± 0.9 ng/ml in the luteal phase. These values were observed during the menstrual cycle in which the TRH test was performed. Similar values were obtained during the menstrual cycle in which the effect of OT on the TRH test was studied. The administration of OT and/or TRH did not produce any subjective or objective side effects. Coiro et al. Oxytocin and PRL response to TRH 567

4 f' DSCUSSON These data fail to show an effect of OT on basal TSH and PRL secretion, although OT was given in a dose (intravenous bolus of2 U = 4.4 fj-g) that diluted in a normal plasma volume of about 3 leads to circulating plasma levels of about 1500 pg/ml. This concentration is in the range of values found in the hypophyseal portal blood by Gibbs.1 Trials with higher doses of OT (intravenous bolus of 4, 6, or 10 U) were equally ineffective in modifying serum TSH and PRL levels in man (unpublished data). OT did not modify the TRH-induced TSH secretion, whereas it induced a marked enhancement of the PRL-releasing activity of TRH. Because changes in the estrogens and P milieus during the menstrual cycle did not alter OT action, this effect appears to be independent of physiologic blood sex steroid concentrations. These findings might indicate that OT does not control PRL release in basal conditions, whereas it acts as a primer for the release of PRL induced by the acute stimulation of hypothalamic hypophysiotropic factors. This hypothesis agrees with the fact that OT is secreted in a pulsatile manner under circumstances that induce the synchronized secretion of PRL-releasing factorsy TRH is an important PRL-releasing factor. Even though its physiologic role in the control ofprl secretion has not been fully established, increased amounts of TRH are released in the hypophyseal portal blood during lactation,12 when TSH and PRL are simultaneously secreted. 9, 11, 17 The demonstration of a modest rise in TSH in comparison with that of PRL speaks against the possibility that TRH is the mediator of the suckling-induced PRL and TSH release. Frawley et al 8 have proposed a convincing explanation for this abnormal finding by demonstrating that in a complete in vitro system OT attenuates the TRH-induced TSH release from rat pituitary cells, whereas it does not modify the PRL response to TRH. Our data fail to support this hypothesis for the human species. n man, OT was found to have quite opposite effects in vivo, enhancing the PRL response to TRH without affecting the TRH-stimulated TSH secretion. This suggests that during suckling OT might sensitize the PRL, but not the TSH, secretory system to TRH stimulation. This could explain why TRH induces a modest TSH rise in comparison with that of PRL. OT given in vivo might act at various levels. 7 Besides a direct in- 568 Coiro et al. Oxytocin and PRL response to TRH fluence on the lactotropes of the anterior pituitary, OT might stimulate the release from the hypothalamus of one or more hypophysiotropic factors, which could modulate PRL, but not TSH, response to exogenously administered TRH. However, the possibility that OT decreases the metabolic clearance rate of PRL must be excluded, because the administration of OT alone did not modify serum PRL concentrations. REFERENCES 1. Gibbs DM: High concentrations of oxytocin in hypophysial portal plasma. Endocrinology 124:1216, Horn AM, Robinson AF, Fink G: Oxytocin and vasopressin in rat hypophysial portal blood: experimental studies in normal and Brattleboro rats. J Endocrinol 104:211, Kuhn ER, McCann 8M: An inhibitory action of large doses of oxytocin on milk yield in the lactating rat. Endocrinology 87:1266, Vaughan MK, Blask DE, Johnson LY, Reiter RJ: The effect of subcutaneous injections of melatonin, arginine vasotocin and related peptides on pituitary and plasma levels of luteinizing hormone, follicle-stimulating hormone, and prolactin in castrated adult male rats. Endocrinology 104:212, Del Pozo E, Kleinstein J, Brun del Re R, Derre F, Martin Perez J: Failure of oxytocin and lysine-vasopressin to stimulate prolactin release in humans. Horm Metab Res 12:26, Salisbury RL, Kreig RJ, Seibel HT: Effects of arginine vasotocin, oxytocin and arginine vasopressin on steroidinduced surges of luteinizing hormone and prolactin in ovariectomized rats. Acta Endocrinol (Copenh) 94:166, Lumpkin MD, Samson WK, McCann SM: Hypothalamic and pituitary sites of action of oxytocin to alter prolactin secretion in the rat. Endocrinology 112:1711, Frawley LS, Leong DA, Neill JD: Oxytocin attenuates TRH-induced TSH release from rat pituitary cells. Neuroendocrinology 40:201, Blake CA: Stimulation of pituitary prolactin and TSH release in lactating and proestrous rats. Endocrinology 94:503, Burnet FR, Wakerley JB: Plasma concentrations of prolactin and thyrotropin during suckling in urethane-anaesthetized rat. J Endocrinol 70:429, Dawood MY, Khan-Dawood FS, Wahi RS, Fuchs F: Oxytocin release and plasma anterior pitui :try and gonadal hormones in women during lactation. J Clin Endocrinol Metab 52:678, de Greef WJ, Visser TJ: Evidence for the involvement of hypothalamic dopamine and c:,yrotropin-releasing hormone in suckling-induced release of prolactin. J Endocrinol 91:213, 1981 Fertility and Sterility

5 13. Odell WD, Rayford PL, Ross GT: Simplified, partially automated method for radioimmunoassay of human thyroid-stimulating, growth, luteinizing and follicle-stimulating hormones. J Lab Clin Med 70:973, Sinha YN, Selby FW, Lewis UJ, Van der Laan WP: A homologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab 36:509, De Hertog R, Thomas K, Bietlot Y, Vanderheyden, Ferin J: Plasma levels of unconjugated estrone, estradiol and estriol and HCS throughout pregnancy in normal women. J Clin Endocrinol Metab 40:93, De Villa 0, Roberts K, Wiest WG, Mikhail G, Flickinger G: A specific radioimmunoassay of plasma progesterone. J Clin Endocrinol Metab 35:458, Neill JD, Frawley LS, Mulchahey JJ, Leong DA: Hypothalamic control of prolactin secretion. n Prolactin, Neurotransmission et Fertilite, Edited by JP Gautry. Paris, Masson, 1982, p 157 Coiro et al. Oxytocin and PRL response to TRH 569