Influence of corpus lute urn age on the steroidogenic response to exogenous human chorionic gonadotropin in normal cycling women Lt Col Marc A. Fritz, MC, USAF: David L. Hess, PhD: and Phillip E. Patton, MDc Bethesda, Maryland, and Beaverton and Portland, Orgeon OBJECTIVE: The null hypothesis of this study is that the patterns of steroid secretion exhibited by the human corpus luteum in response to exogenous human chorionic gonadotropin stimulation are independent of corpus luteum age at the time of treatment. STUDY DESIGN: Twenty-five normally cycling women in whom the midcycle urinary luteinizing hormone surge (luteal day 0) was identified and from whom blood samples were obtained daily from cycle day 11 until menses were prospectively randomized to receive no treatment (group I, n = 5) or exogenous human chorionic gonadotropin 5000 IU administered intramuscularly on luteal day 0 (group II, n = 5), + 4 (group III, n = 5), +8 (group IV, n = 5), or + 12 (group V, n = 5). Serum concentrations of estrone, estradiol, progesterone, 17-hydroxyprogesterone, and androstenedione were measured by specific radioimmunoassays in all subjects; serum human chorionic gonadotropin concentrations were determined by immunoradiometric assay in treated subjects. RESULTS: Serum human chorionic gonadotropin levels (mean ± SEM) were virtually identical among treatment groups (p > 0.05). Luteal phase duration (mean ± SEM) was prolonged (p < 0.05) only in group V (18.4 ± 0.5 days) compared with untreated subjects (group 113.8 ± 0.7 days). In all groups estrone and 17-hydroxyprogesterone concentrations closely paralleled those of estradiol and progesterone, respectively. Steroid data and progesterone/estradiol ratios (mean ± SEM) in groups I and II were indistinguishable and were combined (control, n = 10). Group III subjects exhibited patterns of steroid secretion similar to groups I and II, although progesterone was moderately increased after human chorionic gonadotropin treatment. In groups IV and V, progesterone increased (p < 0.05) 1 day after human chorionic gonadotropin and remained elevated for 5 to 6 days; a 4-day rise (p < 0.05) in estradiol began 3 days after treatment, and androstenedione rose modestly in parallel. Progesterone/estradiol ratios in groups III through V increased (p < 0.05) approximately twofold after human chorionic gonadotropin treatment and remained elevated for 4 to 5 days. CONCLUSION: The human corpus luteum exhibits distinct age-dependent patterns of steroid secretion in response to exogenous human chorionic gonadotropin stimulation, an observation that may have clinical implications regarding the empirical use of exogenous human chorionic gonadotropin in support of luteal function. (AM J OBSTET GVNECOL 1992;167:709-16.)

Key words: Human chorionic gonadotropin, human corpus luteum, luteal phase deficiency

From the Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences: the Division of Reproductive Biology and Behavior, Oregon Regional Primate Research Center,' and the Department of Obstetrics and Gynecology, Oregon Health Sciences University.' Supported in part by a grant from the Office of the Surgeon General, United States Air Force (M.A.F.), and National Institutes of Health grant HD-18185. Presented at the Forty-seventh Annual Meeting of the American Fertility Society, Orlando, Florida, October 21-24, 1991. The opinions expressed in this article are those of the authors and not necessarily those of the United States Air Force or the Department of Defense. Received for publication November 26, 1991; revised February 25, 1992; accepted February 28,1992. Reprint requests: Marc A. Fritz, MD, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814. 611137558

Exogenous human chorionic gonadotropin (heG) is commonly administered on one or more occasions to stimulate or prolong corpus luteum steroidogenesis in clinical settings in which luteal function is known or suspected to be inadequate. In spite of widespread application, heG treatment schedules are empiric and widely varied because the optimal dose, timing, and frequency of administration remains unexamined. Observations of the steroidogenic response to exogenous heG in midcycle monkeys' and during experimental pseudopregnancy in both nonhuman primates 2 • 3 and women: together with experience gained through development of steroid replacement regimens for donor oocyte recipients 5 suggest that the effects of empiric

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September 1992 Am J Obstet Gynecol

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and androgen secretion were compared with those patterns observed in untreated women.

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DAYS AFTER hCG INJECTION Fig. 1. Serum concentrations (mean ± SEM) of heG standardized to day of exogenous heG administration in four groups of normally cycling women who received exogenous heG 5000 IV intramuscularly on luteal day 0 (day of midcycle urinary LH surge; group II, n = 5), +4 (group III, n = 5), +8 (group IV, n = 5), or + 12 (group V, n = 5).

exogenous hCG treatment on human luteal function deserve more careful examination. In the nonhuman primate the patterns of both estrogen and progesterone secretion that accompany a 5_ 2 or IO-day' course of incremental exogenous hCG stimulation vary with the postovulatory age of the corpus luteum. Similarly, in women an alternate-day exogenous hCG treatment regimen yields different patterns of progesterone secretion in the early and midluteal phase! Evidence that even subtle changes in the steroid milieu may influence the rate and extent of endometrial development and that implantation can succeed only within a relatively narrow "window of endometrial receptivity"5. 6 suggests that such hCG-induced alterations in the pattern of corpus luteum steroidogenesis may have important clinical implications. The available human data are limited in scope and are inadequate to define the steroidogenic response to exogenous hCG as it is administered in clinical practice. The effects of exogenous hCG on corpus luteum estrogen and androgen secretion remain unexamined, and the clinical relevance of results obtained during experimental pseudopregnancy is uncertain. To define the spectrum of steroidogenic response to exogenous hCG stimulation and the influence of corpus luteum age, we studied a group of healthy ovulatory women. Subjects were randomly assigned to receive exogenous hCG at precisely defined times during the luteal phase, and the patterns of estrogen, progestin,

Material and methods

Study subjects. Twenty-five women aged 18 to 35 years were recruited and gave informed consent for our study, which was approved by the Institutional Review Boards at our institutions. Each subject had regular, spontaneous menstrual cycles with an intermenstrual interval between 24 and 35 days and had not used steroid contraception in the 6 months before the study. All subjects were within 20% of ideal body weight, and none were involved in a program of regular strenuous exercise. A biphasic basal body temperature (BBT) pattern and midluteal phase (5 to 8 days before menses) serum progesterone ~ 10 ng / ml in a screening cycle were required as evidence of ovulatory function. Experimental design. Beginning on cycle day 11, venous blood samples (10 ml) were drawn daily until menses. Voided urine samples were obtained twice daily, the first between 11 :00 AM and 3:00 PM and the second between 5:00 PM and 10:00 PM, until the midcycle urinary luteinizing hormone (LH) surge (luteal day 0) was identified with a rapid commercial enzyme immunoassay kit (Ovuquick, Monoclonal Antibodies, Inc., Mountain View, Calif.). Group assignment was determined at entry by the subject's random selection of a sealed envelope containing a specific assignment. Subjects received no treatment (group I, n = 5) or exogenous hCG (A.P.L., lot no. 3890359, Wyeth-Ayerst Laboratories, Philadelphia, Pa.) 5000 IU administered intramuscularly on luteal day 0 (group II, n = 5), + 4 (group III, n = 5), + 8 (group IV, n = 5), or + 12 (group V, n = 5). Assays. Blood samples were allowed to clot, and separated serum was stored at - 20° C until assayed. All samples from each individual were assayed together for each hormone. Serum concentrations of estrone, estradiol, progesterone, and I7-hydroxyprogesterone were measured in duplicate by specific radioimmunoassays after diethyl

Steroidogenic response to exogenous hCG in women

Volume 167 Number 3

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400

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0'-CI Co. ·, the response we observed in women was only slightly reduced compared with that seen at midluteal phase. Differences between the human and nonhuman primate response to late luteal phase exogenous hCG stimulation may be the result of our use of a single, large, exogenous hCG stimulus as opposed to the pseudopregnancy regimen used in the primate model!' 3 The results of our study in normally cycling women do not necessarily predict the outcome of similar treatment in the clinical management of luteal phase deficiency or in cycles induced with exogenous menotropins, because corpora lutea derived from follicles subjected to abnormal patterns of gonadotropin secretion·' or exogenous gonadotropin administration 24 frequently have altered steroidogenic, biochemical, and physical properties that may influence their response to exogenous hCG. Therefore in spite of evidence that an abnormal, mOre profoundly progestational environment (like that that accompanied early, mid, and late luteal phase hCG treatment) may adversely affect endometrial development,s. 6 .•5 the clinical relevance of the normal corpus luteum's age-dependent steroidogenic response to exogenous hCG is uncertain. In summary, the patterns of exogenous hCG-induced estrogen, progestin, and androstenedione secretion varied with the postovulatory age of the corpus luteum

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in normally cycling women. Our data suggest that exogenous heG has no effect on sex steroid concentrations when administered coincident with the endogenous midcycle LH surge, but otherwise consistently stimulates human luteal function in a manner that favors progesterone secretion over that of estradiol.

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