Effect of estrogen on the growth hormone response to the alpha-adrenergic agonist clonidine in women with menopausal flushing

Abstract

The serum GH response to the «2-adrenergic receptor agonist clonidine (0.15 mg, iv) was measured in 8 postmenopausal women with hot flushes before and during treatment with the conjugated estrogen premarin (1.25 mg, orally daily for 4 weeks), 9 normal premenopausal women, and 12 normal men. The men had a significantly greater GH response than did the age-matched premenopausal women (P < 0.05). The mean individual peak GH response was significantly higher in the premenopausal compared with the postmenopausal women (P < 0.05). Premarin decreased the number of hot flushes (P < 0.01), but had no effect on the GH response to clonidine. These results suggest that estrogens do not enhance a2-adrenergic mechanisms that regulate GH secretion and that improvement in menopausal flushing after estrogen therapy is not mediated by an effect on central a2-adrenergic function. (J Clin Endocrinol Metab 65: 6,1987) HOT FLUSHES are associated with a decline in circulating estrogen levels (1). Administration of estrogens improves the condition. The mechanism by which this amelioration takes place is unknown, although functional changes in estrogen-sensitive neurons linked to LHRH pulsatile release are believed to play a role (2). Improvement in menopausal flushing also occurs during treatment with the «2-adrenergic receptor agonist clonidine and a-methyldopa, a precursor of the a-adrenergic agonist a-methylnorepinephrine (1, 3, 4). These observations together with data that estrogens affect hypothalamic adrenergic mechanisms in animals (5-9) suggest that estrogens may improve menopausal flushing by enhancing a-adrenergic function (1). Clonidine, which binds to a2-receptors in the hypothalamus (10), increases GH secretion in animals (11) and man (12) by stimulating hypothalamic postsynaptic «2-adrenergic receptors (13, 14), but it has no effect on LH secretion in humans (3, 12). Several investigators have used this GH response to investigate a-adrenergic function in patients with various disorders (15, 16). The effect of estrogens on the GH response to clonidine in man is unknown. In this study we investigated the effect Received October 10,1986. Address all correspondence and requests for reprints to: Dr. T. Tulandi, M.D., Department of Obstetrics and Gynecology, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. * This work was supported in part by the MRC of Canada. of estrogen on a-adrenergic function in women with menopausal flushes by evaluating the effect of premarin, a conjugated estrogen, on the GH response to clonidine. As gender is an important variable affecting the GH response to various stimuli of GH secretion (17), we also examined the effect of this variable on clonidine-induced GH secretion. Materials and Methods The GH response to clonidine was determined in 8 women, aged 27-57 yr, with menopausal flushing (6 spontaneous menopause, 1 surgical menopause, and 1 premature menopause) before and during treatment with the conjugated estrogen premarin (Ayerst Laboratories, Rouses Point, NY; 1.25 mg/day, orally, at 2000 h for 4 weeks). In addition, the GH response to clonidine was determined in 9 normal premenopausal women, aged 21-32 yr, in the follicular phase of their cycle and 12 agematched men, aged 21-33 yr. All subjects were healthy nonobese volunteers taking no medication. After an overnight fast a 19-gauge scalp vein needle was inserted into an arm vein at 0800 h and kept open with heparin-saline. Blood samples were taken at -30, 0,15, 30 45, 60, and 90 min commencing at 0900 h. Clonidine (Boehringer Ingelheim, Canada Ltd, Burlington, Ontario, Canada; 0.15 mg in 10 mL 0.15 M saline) was given iv in 10 min starting at 0 min. The last dose of premarin was administered at 2000 h the night before clonidine administration. The blood samples were centriruged, and the serum was stored at -20 C until assayed for GH (18). All samples from an individual subject were analyzed in the same assay. Specimens ESTROGEN-CLONIDINE-GH INTERACTION for RIA of serum LH (NIDDK anti-hLH-2), FSH (NIDDK anti-hFSH-6), estrone (Ei), and estradiol (E2) were taken at 0 min before and after 4 weeks of premarin treatment. The antisera for Ei and E2 were obtained from Endocrine Sciences (Tarzana, CA). The women used a diary to record the number of daily flushes for 8 weeks before and 4 weeks during premarin treatment. The interassay and intraassay variations for GH were both 10%. The minimal detectable level of GH was 1.0 ng/ml. The data were analyzed by repeated measures analysis of variance. The areas under the GH concentration-time curve (AUC) for the period 0-90 min were calculated by the trapezoidal method. Mean individual peaks, AUCs, changes in estrogen and gonadotropin levels, and number of flushes were compared using Student's t test (unpaired for independent groups and paired for dependent groups).