FERTILITY AND STERILITY Copyright " 1978 The American Fertility Society

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Vol 30, No. 2, August 1978 Printed in U.S.A.

COMPARISON OF THE EFFECTS OF CONTRACEPTIVE STEROID FORMULATIONS CONTAINING TWO DOSES OF ESTROGEN ON PITUITARY FUNCTION*

JOSEF Z. SCOT!', M.D.t OSCAR A. KLETZKY, M.DJ PAUL F. BRENNER, M.D . DANIEL R. MISHELL, JR., M.D. Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles County-University of Southern California Medical Center, Women's Hospital, Los Angeles, California 90033

A pituitary stimulation test with gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) was undertaken to determine (1) whether pituitary responses to GnRH vary in individual women taking oral contraceptive steroids over time, (2) whether a less suppressive pituitary gonadotropin effect is produced by formulations containing less than 50 pg of estrogen, and (3) to obtain more information concerning prolactin secretion in users of oral contraceptive steroids. The same subjects who had had a suppressed luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response 6 to 9 months previously also had a suppressed response, indicating that this effect persists over time. Contraceptive formulations containing less than 50 pg of estrogen have a lesser suppressive effect on LH release than do formulations containing 50 pg of estrogen or more. The basal prolactin (PRL) response as well as the maximal PRL response to TRH were found to be significantly greater in subjects using oral contraceptives than in the control subjects. However, no difference in PRL response was found between the subjects using low or high doses of estrogen fomuliLtions. Fertil Steril30:141, 1978

It was recently reported that oral contraceptive steroids had a suppressive effect on pituitary gonadotropin release after stimulation with gonadotropin-releasing hormone (GnRH) in 80% of 50 women. 1 In this study the degree of suppression of pituitary gonadotropins was correlated with the type of formulation used, but not with the length of its use or the age of the woman. 1 The present study was undertaken to determine (1) whether pituitary responses to GnRH vary in indiviual women taking oral contraceptive steroids over time, (2) whether a less suppressive pituitary gonadotropin effect is produced

by a formulation containing less than 50 p..g of estrogen, and (3) to obtain more information concerning prolactin secretion in users of oral contraceptive steroids. For this purpose, a pituitary stimulation test with GnRH and thyrotropinreleasing hormone (TRH) was undertaken. MATERIALS AND METHODS

Eleven women between 23 and 38 years of age with regular menstrual cycles served as a control group. The GnRH-TRH stimulation test was carried out during days 3 to 5 of the menstrual cycle. Thirty-nine women receiving various oral contraceptive formulations received the GnRH-TRH between 15 and 18 days after daily ingestion of oral contraceptives was initiated. These study subjects were separated as follows: (1) Twentyseven women had been ingesting formulations of various combinations for 2 to 4 years and had had

Received March 20, 1978; accepted April 13, 1978. *Supported by a grant from The Ford Foundation. t Supported by a fellowship from the R. S. McLaughlin Travelling Fellowship, Canada. :j:Reprint requests: Oscar A. Kletzky, M.D., Women's Hospita, Room L-915, 1240 North Mission Road, Los Angeles, Calif. 90033.

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a GnRH-TRH stimulation test performed 6 to 9 months earlier. 1 Of these 27 subjects taking combined formulations, 20 were taking a combination of norethindrone 1 mg and either 50 or 80 p,g of mestranol; 7 were taking a combination of ethinylestradiol 50 p,g and d-norgestrel 50 p,g. 2 Twelve women had been ingesting contraceptive steroid formulations containing less than 50 p,g of estrogen for periods ranging from 6 months to 3 years. Of these 12 subjects, 4 were taking a combination of ethinylestradiol 30 p,g and d-norgestrel 0.3 mg, 6 were taking a combination of ethinyl estradiol 35 p,g and norethindrone 0.5 mg, and 2 were taking a combination of ethinylestradiol 20 p,g and norethindrone acetate 1 mg. Control and study subjects received an intravenous bolus of 50 p,g of GnRH and 250 p,g of TRH. Blood samples were obtained by venipuncture just prior to and 30 and 60 minutes following the GnRH-TRH in order to measure peak hormone values. 1 Blood samples were allowed to clot at room temperature for 2 hours and, after centrifugation, the serum was stored at -20° C until assayed. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) were measured in all samples by previously reported radioimmunoassay procedures. 2• 3 Estradiol was measured in the base line samples of all subjects. 4 Statistical significance of the results obtained in control subjects and in the two study groups for basal and peak response values was determined by the Mann-Whitney U-test for two independent samples. 5

RESULTS

Estradiol. The mean (± standard error of the mean) serum estradiol level in the control subjects at the time of the GnRH~TRH stimulation was 68.2 ± 7.8 pg/ml; in the subjects taking formulations of 50 p,g of estrogen or more, the mean level was 35.7 ± 3.0 pg/ml; and in the subjects using formulations of less than 50 p,g of estrogen, the mean level was 28.5 ± 5.7 pg/ml. The difference in serum estradiol between the higher and lower dose of estrogen was not significant. LH (Fig.l). Ofthe 27 subjects taking combined formulations containing 50 p,g of estrogen or more, 5 had basal serum LH levels similar to those of the controls. Three of these five women also had normal basal LH levels during their prior GnRH stim)llation. The other two had LH levels slightly below normal. The remaining 22 subjects (81%)

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had abnormally low basal LH levels, and all had lower basal levels prior to the previous test. Of the 12 subjects taking oral contraceptives with less than 50 p,g of estrogen, 5 normal basal LH levels whereas the remaining 7 subjects had abnormally low levels of LH. Although there was no statistical significance in basal LH levels between the two groups of oral contraceptive users

Comparison of the effects of contraceptive steroid formulations containing two doses of estrogen on pituitary function.

A comparison of the effects of contraceptive steroid formulations containing 2 doses of estrogen on pituitary function is reported. The gonadotropin-r...
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