Differential prolactin response to oral metoclopramide in nulliparous versus parous women throughout the menstrual cycle

Vol. 55, No.5, May 1991

FERTILITY AND STERILITY

Printed on acid-free paper in U.S.A.

Copyright © 1991 The American Fertility Society

Differential prolactin response to oral metoclopramide in nulliparous versus parous women throughout the menstrual cycle

Antonio Espinosa de los Monteros, M.D. Judith Cornejo, M.D. Adalberto Parra, M.D. Department of Endocrinology, Instituto Nacional de Perinatologia, Mexico City, Mexico

Objective: To analyze if serum prolactin (PRL) changed throughout the menstrual cycle and if parous women have lower PRL than nulliparous women. Design: A prospective study of PRL was performed in basal conditions and during oral metoclopramide stimulation on days 7, 14, and 21 of menstrual cycle. Setting: Instituto Nacional de Perinatologia, third level medical institution. Patients: Four parous (group A) and seven nulliparous (group B) healthy volunteer women entered and finished the study. Interventions: Women were studied each day before and every 30 minutes during 2 hours after oral metoclopramide (10 mg). Main Outcome Measure: Duplicate PRL determinations were performed by radioimmunoanalysis. Hypothesis was formulated before data collection. Results: Group A and B had similar basal PRL levels and no within group differences existed in response to metoclopramide, regardless of the day studied. Group A had lower PRL increments than group B from 60 to 120 minutes on days 14 and 21 (P < 0.05); the peak increments also were lower on days 7, 14, and 21 (P < 0.05). Conclusions: Parous women had a diminished PRL response. Although the dopaminergic tone was similar throughout the menstrual cycle within each group, two distinct levels of dopaminergic tone existed in parous and nulliparous women. Fertil Steril 55:885, 1991

Because there is a circadian variation in the blood concentrations of prolactin (PRL),l the study of this hormone under basal conditions may only give a partial vision of any possible change; thus, the analysis of the PRL response to a given stimulus may provide a better way to disclose differences among different groups of women, inasmuch as it would reflect the PRL pituitary secretory capacity. In this respect, a single oral dose of metoclopramide has

Received March 29, 1990; revised and accepted January 25, 1991. * Reprint requests: Antonio Espinosa de los Monteros, M.D., Instituto Nacional de Perinatologia, Departamento de Endocrinologia, Montes Urales No. 800, 11000 Mexico, D.F., Mexico.

Vol. 55, No.5, May 1991

been used as stimulus for PRL release because of its antidopaminergic properties. 2 On the other hand, some authors have described significant changes in plasma PRL levels in women during the follicular or lutheal phase of their menstrual cycle, both, in basal conditions and after thyrotropinreleasing hormone administration. 3,4 However, this issue remains controversial because other investigators have not confirmed such findings. 5,6 Finally, there is a recent report describing lower PRL levels (both in the basal state and postperphenazine stimulation) in parous versus nulliparous women 7 who were studied only once during their menstrual cycle. Based on the above information, the present study was undertaken to explore the basal and metoclopramide-stimulated serum PRL

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levels in a small group of nulliparous and parous women during three different stages of their menstrual cycle. MATERIALS AND METHODS Subjects

Eleven clinically healthy volunteer women, 23 to 36 years of age, with a history of regular menses (cycle length 28 to 30 X 4 to 6 days) were studied. None had been regularly taking any medication, including oral contraceptives, nor have had an intrauterine device during the last 6 months before the study. Sexual intercourse was not allowed during the period of study. All subjects were included after giving written informed consent, and the protocol was accepted by the Investigation Committee of the Instituto Nacional de Perinatologia. The women were further divided into two groups: Group A

Four women, age ranging from 23 to 34 years, who have had only one previous uneventual full-term pregnancy, delivery occurring 20 to 74 months before the study were in group A. They have nursed their newborns up to 4 months after delivery, and two of the four women had previously received hormonal contraceptives for a period of 5 and 12 months before their pregnancies. GroupB

Seven women, age ranging from 26 to 36 years, who have never been pregnant nor have initiated their sexual activity were in group B. None had ever taken oral or parenteral contraceptives.

All hormonal determinations were carried out in duplicate using commercially available kits (PRL and P, Amersham International, Amersham, United Kingdom; E 2, Diagnostic Products Corporation, Los Angeles, CA). The intra-assay and interassay coefficients of variations, respectively, were: PRL 2.4 % to 4.3% and 4.6% to 5.8%; P, 2.0% to 5.1 % and 3.6% to 9.4%; and E 2, 3.2% to 6.2% and 2.7% to 7.4%. Statistical Analysis

The Student's paired t-test and one-way ANOVA were used for within- and between-groups comparison. A value of P < 0.05 was indicative of statistical significance. RESULTS

The values described represent the mean ± SEM unless otherwise stated. There were no significant differences between both groups in age, weight, or percent overweight for height. In group A, the age at first delivery ranged from 21 to 27 years, and the interval between delivery and the present study varied from 20 to 74 months (Table 1). Basal serum E2 levels in group A were 99.2 ± 12.2, 176.2 ± 29.1, and 199.2 ± 57.9 pgjmL on days 7, 14, and 21, respectively, and in group B 62.4 ± 16.0, 129.4 ± 19.0, and 250.7 ± 62.1 pgjmL on the same days studied. These values were not statistically different. In both groups, all women had serum P levels above 4.0 ngjmL on day 21, and the values ranged from 12.5 to 16.5 ngjmL in group A and from 6.8 to 18.0 ngjmL in group B. Basal serum PRL levels (ngjmL) in group A and B, respectively, were: 7.8 ± 2.8 and 5.7 ± 1.4 (day 7), 8.5 ± 2.1 and 9.9 ± 1.4 (day 14), and 6.1 ± 1.6 and 10.8 ± 1.5 (day 21). There were no statistical differences within a group com-

Experimental Protocol

Both groups of women were identically studied. On days 7, 14, and 21 of their menstrual cycle, and after a 10 to 12 hour overnight fasting, an indwelling peripheral venous catheter was placed in the antecubital region. A basal blood sample (time 0) was obtained between 8:00 and 8:30 A.M. (after 1 hour rest), and thereafter at 30-minute intervals for 2 hours after a single 10 mg oral dose of metoclopramide. Serum concentrations of PRL were measured in all samples, serum estradiol (E 2) only in the basal state on each day and serum progesterone (P) only on the basal sample of day 21.

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Table 1

General Clinical Data"

Age (y) Weight (kg) Overweight for height (%) Age at delivery (y) Time elapsed from delivery to study (mo)

Group A

Group B

(n = 4)

(n = 7)

27.5 ± 1.3 53.7 ± 2.2

28.7 ± 1.3 55.5 ± 1.1

5.4 ± 2.0 24.2 ± 1.3

10.4 ± 2.2

39.7 ± 12.2

" Values are means ± SEM.

PRL in nulliparous and parous women

Fertility and Sterility

A was 92.5 ± 18.0 and 156.7 ± 16.3 ngjmL in group B (P < 0.005, Fig. 2). The individual peak increments in serum PRL levels observed on each one of the 3 different days of the menstrual cycle, for women in groups A and B, are shown in Figure 3.

paring the three different days nor between groups when comparing a similar day. The increments in serum PRL above basal levels in response to oral metoclopramide on the 3 different days of the menstrual cycle are shown in Figure l. There was a significant sustained increment in serum PRL in group A at 60, 90, and 120 minutes (P < 0.025 to <0.005) on each ofthe 3 days studied. A similar finding was observed in group B at the same sampling times (P < 0.005 to <0.001). However, within each group no significant differences were disclosed among the 3 different days of the menstrual cycle. On day 7, group A had lower serum PRL increments at 60 minutes and thereafter when compared with group B, but the differences did not reach statistical significance; the peak increment in group A was 88.2 ± 12.7 and in group B was 154.9 ± 25.4 ngjmL (P < 0.05, Fig. 2). On day 14, significantly lower PRL increments were observed in group A than in group B at 60 (P < 0.01), 90 (P < 0.05), and 120 minutes (P < 0.025); the peak increment in group A was 77.0 ± 10.7 and in group B was 156.9 ± 15.4 ngjmL (P < 0.01, Fig. 2). On day 21, again group A had lower increments in serum PRL than group B at 60 (P < 0.025), 90 (P < 0.05), and 120 minutes (P < 0.025); the peak increment in group

200-

DISCUSSION

Our results obtained in a small group of women clearly demonstrated a different serum PRL response to a single oral dose of metoclopramide in parous as compared with nulliparous women. The former group had consistently lower increments above basal levels in serum PRL than the latter group, especially during the 2nd hour of the test, and this difference was more noticeable on days 14 and 21 of their menstrual cycle. This difference was also significant when the serum PRL peak increments were analyzed as a group or as individual values, especially on days 14 and 21 of the menstrual cycle; however, the present study did not disclose statistical differences in basal serum PRL levels between both groups of women regardless of the day of the cycle, possibly because of the small number of women studied as well as their individual variability. It must be pointed out that the cycle days studied are related to the 1st day 200

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Figure 1 Mean (±SEM) increments above basal levels in serum PRL in response to oral metoclopramide during 3 days of the menstrual cycle in parous (. ---.) and nulliparous (0···0) women.

Vol. 55, No.5, May 1991

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of the menstrual bleeding but not strictly correlated with the day of ovulation. The possible participation of other known PRL stimuli, such as stress, sleep, exercise, and even sexual intercourse8 in the observed differential PRL response to oral metoclopramide, can be readily excluded because stress should have affected in a similar fashion both groups; also, the patients had been awake for at least 2 hours and at rest 1 hour before the study. In group A, none had sexual activity during the period of study, and in group B, none had even initiated their sexual activity. Other factors, such as age, body weight, and percent overweight, were not significantly different between both groups. Furthermore, the PRL response to oral metoclopramide, as to any other provocative stimulus, explores the pituitary secretory capacity for this hormone 7 , and in all likelihood, its effects are not dependent of the pulsatile secretion of PRL. However, we cannot exclude the theoretical possibility that metoclopramide might be absorbed differently in parous than in nonparous women, which could also account for the observed differences in PRL response. Therefore, in the small group of women studied, the only difference present thus far was whether or

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not they had had a previous pregnancy. In this regard, our data are in accordance with previous reports 7,9,10 and also suggest that pregnancy may very well have a long-term lowering effect on serum PRL levels, both in the basal as well as in the post-stimulated state. 7 Because in our study parous women had had only one previous pregnancy, we cannot speculate if the type of PRL response is associated to parity.1O In a previous study, 7 the diminished pituitary PRL response to perphenazine in parous women lasted at least 19 months, and in our study, the decreased pituitary PRL response to metoclopramide was still seen in parous women 20 to 74 months after their only parturition. An interesting finding was that within each group, the PRL response to oral metoclopramide was similar, both from a qualitative and quantitative viewpoint, regardless of the day of the menstrual cycle studied; however, there were significant betweengroups differences, at least on days 14 and 21. This could be of some relevance, first in terms of indicating a lack of change in dopaminergic tone throughout the menstrual cycle within each group, and second, suggesting that there are two distinct

PRL in nulliparous and parous women

Fertility and Sterility

levels of dopaminergic tone between groups. In group A, parous women, the dopaminergic-induced inhibition of PRL seems to be more effective or pronounced than in group B (nulliparous women). Whether or not the existence of previous sexual activity but not pregnancies has some implication, cannot be disclosed from the present study. In brief, we have found in a small number of healthy women that: (I) parous women had a significantly lower PRL response to oral metoclopramide than nulliparous women on days 14 and 21 of their menstrual cycle, suggesting a diminished pituitary secretory capacity for PRL in the former group; (2) this effect may be present up to 74 months after the first parturition; and (3) it seems likely that the dopaminergic tone did not change throughout the menstrual cycle within each group, but there may be two distinct levels of dopaminergic tone in parous and nulliparous women.

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2.

3.

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Acknowledgments. We are indebted to Eduardo Ortigosa, M.D., for assistance in the statistical analysis of the data and to Miss Maria Rodriguez Rios for the secretarial assistance.

Vol. 55, No.5, May 1991

on the circadian periodicity of circulating prolactin in women. J Clin Endocrinol Metab 40:886, 1975 McCallum RW, Sowers RJ, Hershman MJ, Sturdevant ALR: Metoclopramide stimulates prolactin secretion in man. J Clin Endocrinol Metab 42:1148,1976 Vekemans M, Delvoye P, L'Hermite M, Robyn C: Serum prolactin levels during the menstrual cycle. J Clin Endocrinol Metab 44:989, 1977 Boyd EA III, Sanchez-Franco F: Changes in the prolactin response to thyrotropin-releasing hormone (TRH) during the menstrual cycle of normal women. J Clin Endocrinol Metab 44:985, 1977 Hwang P, Guyda H, Friessen HG: A radioimmunoassay for human prolactin. Proc Nat! Acad Sci USA 68:1902, 1968 Tyson J, Friessen HG: Factors influencing the secretion of human prolactin and growth hormone in menstrual and gestational women. Am J Obstet GynecoI116:377, 1973 Musey VC, Collins DC, Musey PI, Martino-Saltzman D, Preedy JRK: Long-term effect of a first pregnancy on the secretion of prolactin. N Engl J Med 316:229, 1987 Frantz AG: Prolactin. N Engl J Med 298:201, 1978 Yu MC, Gerkins VR, Henderson BE, Brown JB, Pike MC: Elevated levels of prolactin in nulliparous women. Br J Cancer 43:826, 1981 Kwa HG, Cleton F, Bulbrook RD, Wang DY, Hayward JL: Plasma prolactin levels and breast cancer: relation to parity, weight and height, and age at first birth. Int J Cancer 28:31, 1981

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