Prenatal exposure to medroxyprogesterone acetate (MPA) in girls

Psychoneuroendocrinology, 1977, Vol. 2, pp. 391-398. Pergamon Press. Printed in Grcat Britain

PRENATAL

EXPOSURE

TO MEDROXYPROGESTERONE

ACETATE (MPA) IN GIRLS ANKE A . EHRHARDT, GUDRUN C. GRISANTI a n d HEINe F. L. MEYER-BAHLBURG Departments of Psychiatry and Pediatrics, School of Medicine, State University of New York at Buffalo, Children's Hospital of Buffalo, New York 14222, U.S.A.*

(Received 30 August 1976) SUMMARY (1) Studies on the long-team effects of progesterone administration during gestation have suggested that it has a mild influence on postnatal female behavior causing even greater femininity than expected in normal controls. (2) However, it has been difficult to distinguish the effects of the prenatal hormone from those of the maternal disease state (toxeania). O) In a new study, girls (n= 15) with prenatal exogenous hormonal exposure due to maternal intake of medroxyprogesterone acetate (MPA) were compared with a closely matched control group. (4) The results suggested that MPA was not associated with genital abnormalities in genetic females. (5) Behavior effects of prenatal MPA appeared to be subtle and included a lower incidence of being labeled a tomboy during childhood and a more constant preference for feminine clothing styles. (6) We conclude that prenatal MPA may have an enhancing effect on female sexually dimorphic behavior.

Key Words---medroxyprogesterone acetate; prenatal; psychosexual differentiation; prenatal hormone effects; human; prenatal progesterone; female behavior.

INTRODUCTION

Tins paper is part of a series on the possible effects of maternal intake of various hormones during pregnancy on postnatal childhood behavior of the offspring. We focus here on some of the findings on the behavior of females whose mothers took medroxyprogesterone acetate (Provera) during pregnancy. Animal experiments have shown that progesterone can antagonize androgen action under certain conditions. For instance, Kind & Maqueo 0965) showed that administration of progesterone simultaneously with injection of testosterone (TP) in 5 day-old rats prevented the androgenizing effect of TP in the female, so that subsequently ovulation occurred. As Resko (1975) pointed out, no one has shown in the nonhuman primate fetus that progesterone can interfere with the action of androgen, but neither has anyone shown that it cannot have a similar effect to that in lower mammals. For a discussion of the effects in the female, it is important to remember that androgen has been shown to alter reproductive differentiation of the genitalia in rhesus monkeys and to have masculinizing effects on some aspects of sexually dimorphic behavior (Goy, 1968). Findings on human beings which are compatible * Current address: Psychiatric Institute, Columbia University, 722W 168 Fth Street, New York, N.Y. 10032. 391

392

Arcr~ A. EHRHARDT,GUDRUNC. GRISANTIand H~INOF. L. MEY~R-BAm~BURO

with animal experimental evidence on the action of prenatal androgens have been suggested by several clinical studies on females with congenital adrenal hyperplasia (Money & Ehrhardt, 1972; Ehrhardt & Baker, 1974). In the normal female fetus, androgen levels are low, since the ovary and the adrenal produce relatively small amounts of androgen. Progesterone levels have been shown to be significantly higher in females than in males which may well antagonize the action of even small amounts of androgen. If the progesterone level is increased by maternal drug intake of additional progesterone, the possible antiandrogenizing effect of progesterone may be enhanced. In the area of human behavior, Katharina Dalton has been working for several years on the effects of prenatal progesterone on subsequent behavior in males and females. Recently, Zussman, Zussman & Dalton (1975) presented data on 12 girls whose mothers had been administered progesterone for a toxemic pregnancy between the 6th and 39th week of gestation. Total dosage was at least 500 mg and maximally 9400mg. All patients had been managed in a general medical practice or in a hospital setting in London and were matched with a control group from the same medical practice or hospital ward on the basis of socioeconomic-status, mother's age, blood group, birth weight and family size. Age at follow-up was 16-19 yr. Behavior assessment included a battery of tests and a short semistructured interview. The groups showed little difference in their behavior, except for a few behavior aspects during childhood. Some of the questions centered around being labelled a tomboy between the ages of 5 and 10, physical energy level, toy preference and interest in appearance. Those females who had received larger, longer and earlier doses of progesterone were less likely to report having been a tomboy during childhood. The progesterone group was also less active in play and sports than the controls and was more concerned about their appearance, such as clothes and hairdo. The authors suggested that prenatal progesterone seemed to have a feminizing effect on girls. A disadvantage of the study by Zussman et al. (1975) was that the control group was from two groups of mothers, some with toxemic and some with normal pregnancies. Therefore, the possible hormonal effect was difficult to separate from the confounding variable of maternal pregnancy condition. In our new project on progestational agents, we attempted to match experimental subjects and controls as closely as possible. Overall, the experimental subjects in our study had less severe pregnancy conditions and were exposed to smaller amounts of progesterone than previously described. The investigation was approved by the Human Investigation Committee of the Children's Hospital of Buffalo. The Code of Ethics of the World Medical Association was adhered to and there has been no infringement of Human Rights.

SUBJECTS AND METHODS Subjects

The subsample of this study is part of the larger Buffalo project, as described by Meyer-Bahlburg, Grisanti & Ehrhardt 0977). It is comprised of a group of 15 girls with prenatal exogenous hormone exposure to MPA exclusivelyand a control group of 15 girls with documented lack of hormonal drug exposure before birth (Table I). Mean age is approximately 11 yr with a range from 8 yr 7 months to 12 yr 11 months at the

PRENATAL MPA: EFFECTSON FEMALEB~AVlOR

TABL~I.

393

GIRI.~ WIT H PRENATAL EXPOSURE TO M P A : SAMPLECHARACTERISTICS

Exp. subjects

Control subjects

15 10; 8 8; 7-12; 1 Caucasian 80.6 40-93 114.6 96--132

15 11; 4 9; 3-12; 11 Caucasian 81.7 47-93 112.1 90--141

n

Age (yr; months): mean range

Race Socioeconomic status: mean FulI-IQ(WISC-R): TABLE II.

range mean range

MPA:

GIRLS WITH PRENATAL EXPOSURE TO

PREGNANCY DATA

Exp. subjects

Control subjects

15

15

17.1 2-34

u --

1086 140--2020

---

38; 3 30; 5--42; 3

39; 2 33; 6-41; 4

6; 9 3; 10-8; 10

6; 15 4; 14-8; 8

n

Duration o f MPA.admin. (weeks) mean range

Total MPA dosage (nag) mean range

Gestation (weeks; ds Post-LMP) mean range

Birth weight (lb; oz) mean range MPA-exposure

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1530

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1930

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FXG. 1. Girls with prenatal exposure to MPA: total dosage and duration of administration in weeks after last menstrual period (LMP). The solid bars indicate the time span of hormone administration during gestation. The extension of the hatched bars to the right marks the length of gestation in weeks after LMP.

394

ANKBA. EHRHARDT,GUDRUNC. GRISANTIand H~NO F. L. MBYER-BAHLRURG

time of the study. All subjects are white and come predominantlyfrom middle and upper-middle class homes. Mean IQ is in the high average range. All the experimental subjects were exposed to MPA during gestation (Table II). Maternal dosage ranged from 140 to 2020 mg with a mean of 1086 rag. Average duration of the drug administration was 17.1 weeks, ranging from 2 to 34 weeks during pregnancy. The average gestation period was normal for both groups. The distribution of treatment weeks during the gestation period is shown in Fig. 1. For most subjects, the main part of the treatment period fell into the time of presumably high sensitivity of brain differentiation. Both experimental and control groups were selected by computer-matchingfrom the same large population of the Buffalo sample of the Collaborative Perinatal Study of the National Inst itutc of Neurological Diseases and Stroke (1972). As a second step, study records of several suitable controls wore screened in an attempt to match closely for a history of vaginal bleeding during pregnancy (for further details, see Meyer-Bahlburg et al., 1977). Considering all sample characteristics, we were confident that we were comparing two groups which did not differ significantly from each other except for prenatal hormone exposure to MPA. Pro cedure

The follow-up study on these female children included the same battery (or an appropriately modified version) of psychological tests, questionnaires, school reports and interviews with both mother and child as previously described (Mcyer-Bahlburg et aL, 1977). Interviews were half-structured and covered various aspects of sexually dimorphic behavior. They lasted several hours and were conducted separately with the girl and her mother by a female interviewer who rated the interview material during the interview sessions on previously established behavior rating scales. The interviews were tape-recorded and a second independent interviewer repeated the ratings. The disagroemems between raters that did occur were subsequently resolved by discussion. The whole study was done in a double-blindfashion. The cooperation of the families was high. With a few exceptions, everybody who was contacted and asked to participate in the study agreed to do so. For the subjects, this follow-up was nothing unusual, since they had come in for similar psychological examinations several times before as part of the larger Perinatal Study. For the investigators who tested and interviewed the families, the particular pregnancy history was unknown at the time of the follow-up and data scoring.

RESULTS We report here some preliminary findings from our interviews with the children. The areas of childhood behavior are the same as those which were previously assessed in other groups of females with abnormal prenatal hormone exposure (Ehrhardt, 1975). The Activity

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females (n : 1 5 )

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Fie. 2. Girls with prenatal exposure to MPA: comparison of subjects and controls on aspects of energy expenditure, athletic skills and peer preference. The bars represent the percentage of subjects from each group who were reported to exhibit the behavior specified by the category adjacent to the bars.

PRENATAL M P A : EFFECTSON FEMALEB ~ V Z O R

395

behavior data are summarized on rating scales. Group differences have been statistically tested with the Sign Test for matched pair comparisons. Because of the relatively small sample size, we report p values up to the 10% level. The results are shown in bar graphs although the data were not dichotomous.

Physical energy expenditure Figure 2 represents a cluster of data on activity levels in play and sports and choice of playmates during childhood. The MPA females were more frequently described as falling into the categories of "low" or "average" in physical energy expenditure rather than into "above average" or "intense" in outdoor active play. The difference was not significant. The same tendency is true for athletic skills. More girls in the MPA group were average or below than in the control group. In both groups, most girls clearly preferred other females as friends and playmates.

Maternal role rehearsal The next cluster of behavior data concerns toy preference and role rehearsal of becoming a mother in adulthood (Fig. 3). In both samples, most of the girls clearly preferred dolls MATERNAL ROLE REHEARSAL % 0

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Fza. 3. Girls with prenatal exposure to MPA: comparison of subjects and controls on aspects of maternal role rehearsal. The bars represent the percentage of subjects from each group who were reported to exhibit the behavior specified by the category adjacent to the bars. or other traditional girls' toys exclusively or almost all of the time throughout childhood, while only a few played with boys' toys predominantly. The majority in both samples wanted to get married in adulthood, although more MPA females were less concerned about this aspect of their adulthood. Both groups showed a strong interest in infant care as becomes obvious in paying attention to small babies, liking to babysit and taking care o f small siblings. P.N.~.C. 2/4--F

396

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A.. EHRHARDT,GUDRUNC. GRISANTIand HEINOF. L. MI~YER-BAHLBURG Gender 0 I Tomboyis m : none or little

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Control females (n =15)

FIG. 4. Girls with prenatal exposure to MPA: comparison of subjects and controls on tomboylsm, gender role and clothing preference. The bars represent the percentage of subjects from each group who were reported to exhibit the behavior specifiedby the category adjacent to the bars.

Tomboyism, gender role and clothingpreference We had several questions on being labeled and identifying oneself as a tomboy. Many girls are tomboyish some time during their childhood, some are complete tomboys, some have only tomboyish traits and some consider themselves tomboys throughout the ages of 5-10. Our data show a tendency for the MPA girls to be less frequently tomboys on a longterm basis than the control girls, for whom this was true in about half of the sample (Fig. 4). We also asked the children about their gender role preference, e.g. what wasmore fun, tobea girl or a boy; or, what would they have liked to be if they could start all over again; or, how many would want to change over to the male sex if that were possible. In Fig. 4, we see the answers to the questions about what the girls would prefer to be, a girl or a boy, if they could magically start all over again. Most girls in both groups clearly and without ambivalence wanted to be born a girl again. The children were rated as to their preference for feminine, stylish clothes vs no preference vs a preference for unisex, functional rather than attractive clothing. Statistically significantly more girls of the experimental group had a clear preference for attractive, stylish clothes, while most of the control group had either no preference or clearly preferred jeans, pants and other comfortable unisex-type clothing. DISCUSSION Our results suggested a difference between experimental and control groups with respect to being labelled, and having identified, as a tomboy during childhood. The MPA group showed less tomboyism on a long-term basis than the control group. There was a significant difference in the same direction in the area of preference for feminine clothing. The control group showed a relatively higher number of girls who identified themselves as tomboys, although not ambivalent in their gender role preference. One has to keep in mind, though, that the age group between 8 and 10 yr is the childhood phase for girls in normative studies

I~ENATALMPA: ErFEc'rsONFEMALEBEHAVIOR

397

during which the highest frequency of tomboyism occurs. Also, brighter girls have been reported to be tomboys more often, and our sample was of relatively higher intelligence compared with the norm. However, behavior differences between the two groups in our study could not be attributed to age and IQ, since the MPA group was closely matched in those criteria. The majority of girls in both groups were stereotypically femininewith respect to rehearsal of maternalism in doll play and baby care and, also, in their preference for female friends. It appeared as if the exposure to prenatal MPA by maternal drug intake had no negative effect on females in their physical or psychological development. Their behavior was hardly different from other girls of the same age and family background. If anything, additional progesterone exposure mayhave enhanced traditional patternsof femininitywitha relatively low level of physical energy expenditure in play and sports, an absence of long-term tomboyism and a strong preference for feminine clothing styles. Our findings agree with previously reported data (Zussman et al., 1975) with respect to the lower incidence of long-term tomboyism in children with exposure to prenatal progesterone treatment including a tendency to a lower level of physical energy expenditure and a stronger preference for feminine clothing styles than in the control group. This behavior pattern is in contrast to the one exhibited by females with prenatal exposure to androgenizing substances. A high level of prenatal androgens in genetic females was found to be associated with intense physical energy expenditure in rough play and sports, a preference for boys as playmates, and a low interest in doll play and baby care (Ehrhardt, 1975). Androgens also masculinize the differentiation of the external genitalia, while medroxyprogesterone has no visible effect on the sex organs in females (Pincus, 1965). To speculate on the action of MPA, it could be that progestogen intake by the mother during pregnancy may antagonize the small amounts of androgen produced by the adrenal and the ovary during fetal life in the female fetus. The implications for subsequent behavior development in females may be a proneness to be somewhat less active, having a greater interest in feminine clothing and therefore being less often identified as a tomboy. In contrast, MPA did not affect significantly the behavior development in boys in our study (Meyer-Bahlburg et al., 1977). The difference in findings between the female and male samples does not necessarily preclude the possibility of an effect by prenatal MPA on the CNS. Two possible explanations should be considered. One is that the male fetus is exposed to much higher levels of androgens produced by his own testes. It may take a much higher dosage of medroxyprogesterone to antagonize the masculinizing effects of androgens. This would be consistent with the difference in results between the sample described by MeyerBahlburg et aL (1977) and previous studies. Zussman et al. (1975) reported relatively high dosages of progesterone in their sample and subtle but significant effects of demasculinization on some aspects of sexually dimorphic behavior in genetic males. By contrast, MeyerBahlburg et aL (1977) found weak tendencies in the same direction in a sample exposed to considerably lower dosages of MPA before birth. As an alternative explanation, the difference between the findings on females and males may be explained by a social-environmental theory. Boys are exposed to much more pressure toward stereotypically masculine behavior in our culture and the range of permissible variation in sexually dimorphie behavior is much more narrow than for girls. Therefore,

398

A t a ~ A. EHRHARDT, GUDRUN C. G~sA~'rt and HE~o F. L. MEYER-BAHLBURO

subtle tendencies o f deviating f r o m the n o r m o f a p p r o p r i a t e m a l e b e h a v i o r p o s s i b l y intiuencod b y p r e n a t a l p r o g e s t o g e n s m a y be strongly c o u n t e r a c t e d b y c u l t u r a l influences and, thus, be less obvious. I n females m o r e v a r i a t i o n within the s p e c t r u m o f permissible b e h a v i o r is t o l e r a t e d , so t h a t subtle b e h a v i o r changes associated with p r e n a t a l M P A m a y be m o r e r e a d i l y noticeable. This work was supported b y a grant from the Spencer Foundation. We also wish to thank the children and parents who participated in the study; Dr. J. S. Drage, NINDS in Bethesda, Md., Dr. H. M. Beirne and Mrs. M. Housler, Child Development Program of the Children's Hospital of Buffalo, who helped us initiate this study; and Dr. D. Slone, Boston Collaborative Drug Surveillance Program, who supplied us with the initial computer selection of subjects and controls. Michelle Smith and Susan Gillies provided valuable technical assistance. REFERENCES The Collaborative Perinatal Study of the National Institute of Neurological Diseases and Stroke (1972) The Women and their Pregnancies. W. B. Saunders, Philadelphia, London, Toronto. Em~HARDT, A. A. (1975) Prenatal hormone exposure and psychosexual differentiation. In Topics in Psychoendocrinology, E. J. Sachar (Ed.). Seminars in Psychiatry Series. Grune & Stratton, New York. EHRHAaDT, A. A. & BAKER, S. W. (1974) Fetal androgen, human CNS differentiation and behavior sex differences. In Sex Differences in Behavior, R. C. Friedman, R. M. Richart & R. L. Vande Wiele (Eds.). Wiley, New York. GoY, R. W. (1968) Organizing effects of androgen on the behavior of rhesus monkeys. In Endocrinology and Human Behavior, R. P. Michael (Ed.). Oxford University Press, London. KINCL, F. A. &. MAQUEO, M. (1965) Prevention of steroid-induced sterility in neonatal male and female rats. Endocrinology 77, 859-862. MEYER-BAHLBURO,H. F. L., GRISANTI,G. C. & EHRHAm)T, A. A. (1977) Prenatal effects of sex hormones on human male behavior: medroxyprogesterone acetate (MPA). Psychoneuroendocrinology 2, 383-390. MONEY, J. & EHRHARDT,A. A. (1972) Man and Woman. Boy and Girl. The Johns Hopkins University Press, Baltimore, London. I~NCUS,G. (1965) The ControlofFertility. Academic Press, New York. R~SKO, J. A. (1975) Fetal hormones and their effect on the differentiation of the central nervous system in primates. Federation Proceedings 34,1650-I 655. ZUSSMAN,J. U., Zus.w~u, P. P. & DALTOU,K. (1975) Post-pubertal effects of prenatal administration of progesterone. (Paper presented at the meeting of the Society for Research in Child Development, Denver, Colorado, April 1975.)