Psychoneuroendocrinology,Vol. 16, No. 1-3, pp. 213 -278, 1991

0306-4530/91 $3.00 + 0.00 ©1991 Pergamon Press pk

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HORMONAL CONTRIBUTIONS TO SEXUALLY DIMORPHIC BEHAVIORAL DEVELOPMENT IN H U M A N S JUNE MACHOVER REINISCH,1 MARY ZIEMBA-DAVIS,1 and STEPHANIE A. SANDERS The Kinsey Institute for Research in Sex, Gender, and Reproduction, and 1Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A. (Received in final form 18 December 1989)

SUMMARY Nineteen studies on the behavioral effects of prenatal exposure to hormones administered for the treatment of at-risk human pregnancy are reviewed. Because the role of prenatal exposure to hormones in the development of human behavioral sex differences is potentially confounded by society's differential treatment of the sexes, comparisons between exposed and unexposed subjects were evaluated and summarized separately for male and female subjects. Therefore, this review focuses on data for individuals whose prenatal hormone environments were atypical relative to what is normal for their own sex. Overall, it appears that prenatal exposure to androgen-based synthetic progestin exerted a masculinizing and/or defeminizing influence on human behavioral development, whereas prenatal exposure to natural progesterone and progesterone-based synthetic progestin had a feminizing and/or demasculinizing influence, particularly among female subjects. The data on prenatal exposure to synthetic estrogen derive primarily from subjects exposed to diethylstilbestrol (DES). DES-exposed male subjects appeared to be feminized and/or demasculinized, and there is some evidence that exposed female subjects were masculinized. These findings are discussed in the context of prenatal hormonal contributions to sexually dimorphic behavioral development both within and between the sexes. Recommendations for the conduct of future research in developmental behavioral endocrinology are presented.

INTRODUCTION THE CONTEMI~R~RY scientific literature on human sex differences is rife with debate regarding the existence, magnitude, and origins of differences in behavior between male and female individuals. It is not basic biological parameters~ such as sexual dimorphism in size or muscle mass, about which we debate, but biological contributions to culturally meaningful behaviors, such as aggression, empathy, or intellectual ability (Gould, 1981). Many arguments postulating a preeminent role for social or environmental factors, without regard for biological influences, have been constructed in reaction to biologically deterministic or sociobiological views. Yet, it has long been recognized that biological potentiality is quite different from biological determinism. Thus, although biology clearly does not preordain human behavior, "Humans are animals, Address correspondence and reprint requests to: Dr. June M. Reinisch, Director, The Kinsey Institute for Research in Sex, Gender, and Reproduction, Mordson Hall, 3rd Hoot, Indiana University, Bloomington IN 47405, USA. 213

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and everything we do is constrained, in some sense, by our biology" (Gould, 1981, p. 328). Yet, even those who maintain that behavioral sex differences simply reflect the differential treatment of male and female individuals in the psychosocial environment will acknowledge the primary role of biology in determining physical differences between the sexes which, with few exceptions, serve as the basis for the classification of individuals as male or female and set the stage for their differential treatment. We have conceptualized the complex interaction between organismic and environmental factors in the development of sex differences in human behavior as the "multiplier effect" (Reinisch & Sanders, 1987). Figure 1 depicts the process by which sex differences are established, facilitated, augmented, and maintained by this ,multiplier effect. Although not depicted in Fig. 1, this model also can be applied to influences that reduce or reverse sex differences. It is a generally accepted principle of mammalian development that hormones, rather than genetic sex p e r se, play the principal and proximal role in the physical differentiation of the sexes. In humans, the first important era of hormonal impact occurs prenatally (in some species it occurs peri- or neonatally), and the second occurs at puberty. In addition to the impact on genital development, prenatal exposure to hormones affects the sexually dimorphic differentiation of the brain (see below). As a result of its role in organizing the brain, the prenatal hormone environment is hypothesized to exert a direct influence on behavior, thereby contributing to the development of sex differences. From birth through adulthood, interactions between the organism and its environment affect behavioral sex differences in two primary ways (Reinisch et al., 1979). First, male and female subjects perceive certain stimuli differently. Differences in perception, cognition, and temperament probably lead to differences in the interpretation of, and response to, one's environment. Second, most societies treat individuals differently from birth, based upon their sex of assignment (i.e., what they are labeled at birth, boy or girl). According to the model in Fig. 1, the initially small, societally-valued sex differences present at birth tend to be augmented by each successive interaction between the organism and its environment. In addition to the physical dimorphism established prenatally, differences in sensation, perception, and behavioral predisposition may lead boys and girls to behave and react in slightly different ways, thus, presenting their caretakers and others with somewhat different stimuli. In interaction with the divergent sex roles held by society, these organismic differences are likely to lead caretakers and others to reinforce, punish, or ignore different behaviors in boys and girls from a very early age. Such differential treatment serves to facilitate and maintain socially-valued distinctions between boys and girls in terms of how each behaves and responds to the world, which in rum leads others to treat the sexes even more differently. The secondary era of sexual differentiation at puberty serves to further augment differences between the sexes, resulting in maximum differences during the adult reproductive years. As humans age, perhaps because role expectations become less divergent, there appears to be a tendency for both sexes to become more androgynous and therefore more similar, resulting in the relative reduction of sex differences among older adults. In strongly gender-stereotyped cultures, traits or roles may be differentially attributed to the sexes in the absence of, or even contrary to, the existence of a biological basis. For example, despite the fact that women appear to be more suited for space travel, based upon such physiological sex differences as height and weight, oxygen and food consumption, and sensory and perceptual thresholds, almost all American astronauts have been male. Thus, sociocultural norms may not only augment biologically based sex differences, but may also diminish, distort, or even ignore them. Although prospective longitudinal data on the development of sex

PRENATALHORMONEEXPOSURE: E~r'ECTSON BEHAVIOR

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Fro. 1: Multiplier effect: role of the interaction between biological factors and the environment in the developm e n t of sex differences. Prior to birth, genetic and hormonal differences lead to sexual differentiation of the genitalia and brain. The relatively small behavioral differences between the sexes t h a t exist at birth are augmented by successive interactions between the individual and the social environment. Pubertal h o r m o n e s lead to further physical differentiation which in t u r n magnifies the differences in societal expectations and social interactions experienced by m e n a n d women, t h u s f u r t h e r e n h a n c i n g sex differences in behavior. (Modified from Reinisch & Sanders, 1987.}

differences in behavior throughout the lifespan are needed, it is from this interactional perspective represented by our concept of the multiplier effect that we present the following review on the role of prenatal exposure to hormones in human personality and behavioral development. This review represents studies of offspring born to mothers therapeutically treated with hormonal preparations during pregnancy who, as a consequence, experienced prenatal hormone environments that were atypical for their sex. These studies investigated the influence of prenatal exposure to several exogenous hormonal treatments, including natural progesterone, synthetic progestin, synthetic estrogen, and combinations of progestin and estrogen, on the development of eight categories of sexually dimorphic behavior. By studying the effects of prenatal exposure to these exogenous hormones, insight may be gained into the role of prenatal endogenous hormones in the development of behavioral differences both within and between the sexes. However, because the role of prenatal hormonal exposure in the development of human behavioral sex differences is potentially confounded by society's differential treatment of male and female individuals, this review focuses on making comparisons within a given sex. The demonstration of within-sex behavioral differences attenuates the confound between prenatal hormonal contributions and environmental influences on the development of sexually dimorphic behavior. In order to provide a context in which to evaluate and interpret these data, before presenting a summary of findings from the studies included in our review, we (1) describe the normal process of prenatal genital differentiation, (2) briefly review evidence of sexual dimorphism in the central nervous system, (3) identify three issues that qualify the evaluation and interpretation of research in this area, and (4) provide a brief overview of the major types and actions of hormones typically administered for the maintenance of at-risk human pregnancy.

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SEXUAL D E V E L O P M E N T A N D D I F F E R E N T I A T I O N

The process of sexual development begins with the sex difference of the chromosomes established at conception. In addition to the 22 pairs of autosomes shared by both sexes, male cells include one X and one Y sex chromosome, whereas female cells are characterized by a pair of X chromosomes. The presence of the Y chromosome induces the second sex difference in early embryogenesis, the commitment of the previously undifferentiated gonads into testes if H-Y antigen is present, or ovaries if it is not. The next difference between the sexes is hormonal. In the male fetus, the testes commence testosterone production between the postconception seventh and eighth weeks (Sitteri & Wilson, 1974). The presence of testosterone and its metabolites, particularly dihydrotestosterone, masculinizes first the internal, and then the external, genitalia. In the female fetus, it is the relative absence of hormones, specifically testosterone, that permits the expression of the female phenotype (Jost, 1972; Reinisch, 1974; George et al., 1981; Yahr, 1988). In summary, masculine differentiation occurs because the fetal testes, which are actively producing androgen and a substance that inhibits the development of the female anlagen (Mifllerian inhibiting substance), impose masculinity upon the basic feminine trend of the body, whereas female differentiation proceeds in the relative absence of these influences. Thus, although specific, and often complex, signals are essential for normal morphological sexual development in the male fetus, female development proceeds in the relative absence of these factors. This basic model has been applied to all sexually dimorphic differentiation, be it morphological, physiological, neurological, or behavioral. SEXUAL D I M O R P H I S M IN THE C E N T R A L N E R V O U S SYSTEM

Animals

The growing list of sex differences in the central nervous system (CNS) of hamsters, rats, and monkeys attributed to the early organizational influence of hormones includes dimorphisms in various nuclei of the hypothalamus, cerebellum, hippocampus, amygdala, cerebral cortex, and spinal cord (for reviews, see Goy & McEwen, 1980; MacLusky & Naftolin, 1981; Reinisch, 1983; DeVries et al., 1984; Gorski, 1987; Juraska, 1991). Sex differences have been identified (1) in biochemical and physiological parameters such as oxidative metabolism, protein content, serotonin levels, RNA metabolism, and cholinesterase activity; (2) in morphological dimensions including synaptic connections, dendritic field pattems, and the size of brain nuclei; and (3) at the cellular level, including cell number, size, and volume, and the proportion of hormone-sensitive target cells. Evidence that androgens contribute to the survival of sexually dimorphic spinal cord cell groups during early development (Nordeen et al., 1985) has strengthened confidence in the view that gonadal hormones play a vital role in molding, shaping, or modifying the central nervous systems of genetic males and females (see ToranAllerand, 1986, for a more complete discussion). Increasing attention also has been paid to the organizing actions of gonadal hormones beyond the perinatal period (Loy & Milner, 1980; Breedlove &Amold, 1981; Matsumoto & Arai, 1981; Milner & Loy, 1982; Arnold & Gorski, 1984; DeVoogd, 1991). There is little question that some structures in the CNS, especially late-developing ones such as the cerebral cortex and hippocampus, appear to remain plastic well into adulthood, modifiable not only as a result of learning and experience, but also in response to the influence of gonadal hormones (Greenough, 1986). Stewart (1988) has suggested that CNS plasticity beyond the perinatal

PRENATAL H O R M O N E EXPOSURE: EFFECTS ON BEHAVIOR

217

beyond the perinatal period may be mediated by the extent to which the brain was organized by gonadal hormones during earlier developmental periods. Several sexually dimorphic behaviors in nonhuman species have been correlated with sexually dimorphic areas of the CNS. These include, but are not limited to, the lordosis and copulatory reflexes of male and female rats and the elaborate song systems of several avian species (see Kelley, 1988, for a more detailed discussion). Although the behavior of nonhuman animals is more often hormonally controlled than is the case for humans, these data from animals provide a context in which to consider sex differences in the brain and behavior of male and female humans. Humans

Morphological sex differences also have been identified in the human brain. Swaab and Flier (1985) described a sexually dimorphic cell group in the preoptic area of the human hypothalamus, regarded as analogous to the sexually dimorphic nucleus of the preoptic area (SDN-POA) in rats (Gorski et al., 1978). The volume of this sexually dimorphic nucleus in humans, which appears to affect the sleep-wake and ovulation cycles, was found to be 2.5 times larger in male than in female subjects and contained 2.2 times as many cells. A sex difference in the shape of the suprachiasmatic nucleus of the human hypothalamus also has been observed (Swaab & Hofman, 1984). De Lacoste-Utamsing and Holloway (1982) reported that the posterior fifth of the human corpus callosum was was larger in female than male subjects. Although this finding has been replicated in adults (Holloway & De Lacoste, 1986) and has been supported by similar data from human fetuses (Baack et al., 1982; De Lacoste et al., 1986) and nonhuman primates (De Lacoste & Woodward, 1983), other investigators have not been able to confirm a simple sex difference in the corpus callosum (see Weis et al., 1988, for a review). Nevertheless, an anatomical difference in the corpus callosum is consistent with other reports of sex differences in brain organization and the degree of hemispheric laterality in male and female humans (Diamond, 1991; TaUal, 1991; Witelson, 1991). The relationship between morphological sex differences in the human CNS and sex differences in behavior has not yet been established. Nonetheless, given the assumption that the brain provides the biological foundation for behavior, it seems reasonable that structural sex differences in the brain will ultimately be related to functional differences in behavior. One outcome related to prenatal exposure to gonadal hormones appears to be the organization of sexually dimorphic neural substrates which, in interaction with contextual factors, leads to varying behavioral predispositions between, and perhaps within, the sexes. ISSUES RELEVANTTO THE EVALUATIONAND INTERPRETATION OF HUMAN RESEARCH Three issues that qualify research in the area of human behavioral endocrinology must be considered in order to appropriately interpret the findings (see Reinisch & Gandelman, 1978, for a more detailed discussion). The first qualifier relates to the inability to implement true experimental design (i.e., random assignment to treatment conditions) in research on human behavioral endocrinology. Because this area of human research is subject to strict ethical, moral, and legal constraints, true experimental design is precluded when studying potentially harmful interventions in humans. Consequently, interpretation of the relationship between prenatal hormones and human behav-

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ioral development is limited to correlative rather than causal explanation. It is only through thoughtful comparison of conclusions derived from human "experiments of nature" or of medical treatmems with those derived from carefully controlled experimems with laboratory animals that confidence in the former can be attained. The role of hormones in organizing the neural substrate for behavior in nonhuman animals has been clearly established with two basic experimental paradigms: perinatal androgen administration to genetic females, resulting in defeminization and/or masculinization, and perinatal androgen deprivation of genetic males, resulting in demasculinization and/or feminization, of sexually dimorphic behaviors and gonadotropin secretion in adolescence and adulthood. Extensive reviews of the nonhuman animal literature are provided by Ellis (1982), Hines (1982), and Reinisch (1974; 1983). The second qualifier relates to the fact that the behavioral repertoires of males and females are not mutually exclusive, but rather, are overlapping. It is rare for one sex to display a behavior that is never exhibited by the other sex (menstruation, gestation, lactation, and impregnation being the notable exceptions). Typically, differences between males and females occur in the average frequency with which particular behaviors are exhibited by each sex. Thus, behavioral sex differences reflect quantitative, not qualitative, differences (Goy, 1970). The third qualifier relates to the fact that masculinity and femininity are multidimensional. Masculinity and femininity are no longer conceptualized as opposite ends of a single, unidimensional, bipolar continuum (Fig. 2a), but MODELS OF MASCULINITY AND FEMININITY

are n o w u n d e r s t o o d to be a m u l t i d i m e n s i o n a l

matrix of independent or semi-independent factors. The orthogonal or independent model (Fig. 2b: Constantinople, 1973; Bem, 1974; Whalen, 1974; Spence & Helmreich, 1978; Heilbrun, 1976; FEMININE ~ MASCULINE Berzins et al., 1978) and the oblique or correlated model (Fig. 2c: Reinisch, 1976; Reinisch & Sanders, 1987) suggest that masculinity and femiB. ORTHOGONAL ninity are, with regard to many behavioral dimenFEMININE sions, relatively independent. 1 These models imply that an increase in the freNOT MASCULINE- ~ MASCULINE quency or strength of masculine behavior (masculinization) is not necessarily associated with a NOT FEMININE decrease in feminine behavior (defeminization). C. OBLIQUE Conversely, feminization is not necessarily concomitant with demasculinization. Thus, an individual may exhibit high frequencies of both masculine and feminine behavior (androgynous), low levels of both kinds of behavior (undifferentiated), or high levels of one type of behavior and low levels of the other (masculine or feminine). The difference between the orthogonal and Fla. 2: Modelsof masculinity and femininity, oblique models resides in the extent to which mas(ReprintedfromRelrtlsch&Sanders. 1987.1 culinity and femininity are considered to be independent. Whereas the orthogonal model proposes total independence, the oblique model suggests that there is some degree of correlation between masculinization and defeminization and between feminization and demasculinization. A. BIPOLAR

PRENATAL H O R M O N E EXPOSURE: Em~crs ON BEHAVIOR

219

HORMONES ADMINISTERED FOR THE MAINTENANCE OF AT-RISKHUMAN PREGNANCIES The study of offspring bom to mothers therapeutically treated with exogenous hormonal preparations for the maintenance of at-risk pregnancy is one of two approaches by which prenatal hormonal contributions to human behavioral development have been evaluated (see Reinisch, 1983; and Sanders & Reinisch, 1985 for reviews). The other is investigations of human patients with clinical endocrine syndromes. The comparability of both these approaches to normal sexual development is limited. Studies of offspring exposed to exogenous hormonal preparations are more similar to laboratory animal experiments than those involving patients with clinical endocrine syndromes, in that (1) no genetic/chromosomal anomalies are involved, (2) most individuals are born with normal-appearing genitalia and good health, and (3) the exposure to atypical hormones ends at birth. However, the hormones administered to treat atrisk pregnancies are typically not identical in structure, activity, or potency to those involved in normal sexual development, although their effects may be similar. Data from three major classes of prenatal exogenous hormone exposure, the administration of progestins (naturally occurring and synthetic progestins), synthetic estrogens, and mixed regimens of progestins and estrogens, are included in this review.

Progestins The synthetic progestins (see Meyer-Bahlburg & Ehrhardt, 1980, and Sanders & Reinisch, 1985, for reviews) include compounds of varying chemical structure which are either androgen- or progesterone-based. These progestogenic hormones may have androgenic, estrogenic, antiandrogenic, or antiestrogenic properties. Although a majority of offspring from progestin-treated pregnancies are born with normally appearing external genitalia, evidence for the virilizing potential of androgen-based synthetic progestins, such as 19-nor-17a-ethynyltestosterone (19-NET), includes reports of masculinization of female genitalia in 188% of cases (Jacobson, 1962). In contrast to these virilizing effects, some progesterone-based synthetic progestins, such as medroxyprogesterone acetate (MPA), have been shown to have antiandrogenic effects on male development (McEwen, 1983; Sanders & Reinisch, 1985). (Endogenous progesterone of placental or fetal adrenal origin also may have a protective effect against androgenization in developing female fetuses [Resko, 1974; Shapiro et al., 1976; see Sanders & Reinisch, 1985, for review].) Thus, whereas prenatal exposure to androgen-based synthetic progestin is predicted to masculinize or hypermasculinize the brain and behavior of genetic female and male humans, exposure to progesterone-based synthetic progestin may lead to complex feminizing and/or demasculinizing effects, dependent on the sex of the individual. Synthetic Estrogen and Mixed Regimens of Progestin and Estrogen Most hormonal treatments for at-risk human pregnancy do not involve the administration of estrogen alone, but include combinations of gestational steroids. Consequently, evaluations of the effects of estrogen are usually conducted on offspring of women treated with mixed regimens of estrogens and progestins. On the basis of laboratory experiments with animals, perinatal exogenous estrogens alone have been shown to have paradoxical effects, generally masculinizing and/or defeminizing the genital morphology and sexually dimorphic behavior of females (Harris, 1964; Dtimer et al., 1971; Hines et al., 1982) and feminizing and/or demasculinizing these dimensions in males (e.g., Gray et al., 1965; Diamond et al., 1973). The paradox of masculinization due to prenatal estrogen exposure, when this effect would only be

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expected of androgens, has been explained as follows: Testosterone can be converted to estradiol by an aromatizing enzyme within the brain cells of some infrahuman species, particularly the rat. It is believed that, in these species, estrogens (aromatized from testosterone) may act at the cellular level to masculinize neural and behavioral development (Plapinger & McEwen, 1978; Goy & McEwen, 1980). Aromatizable androgens and/or estrogens are necessary to organize masculine sexual behavior in rats, mice, and hamsters. However, it appears that dihydrotestosterone, a nonaromatizable androgen, is capable of organizing masculine behavior in monkeys, guinea pigs, and humans (Goy & McEwen, 1980). Thus, there is some question about the applicability of the "aromatization hypothesis" (i.e., that estrogen is the proximal masculinizing agent) in human sexual differentiation. In this review, we also consider the effects on human behavior of prenatal exposure to the non-steroidal synthetic estrogen, diethylstilbestrol (DES). DES was often administered in combination with progestins, thus rendering it difficult to determine the role of this estrogenic agent alone in human development. If prenatal exposure to estrogenic compounds acts in humans as it does in some animals (i.e., masculinizing and/or defeminizing females and feminizing and/or demasculinizing males), then we might expect mixed regimens of estrogens and progestins to produce demasculinization in men and various results in women, depending on the exact ratio of estrogens to progestins and the nature of the progestin involved (i.e., androgen- or progesterone-based). REVIEW OF STUDIES Nineteen studies are included in this review. These investigations reported data from 11 groups of male subjects, six groups of female subjects, and eight groups of male and female subjects combined. Given the limited number of studies on the behavioral effects of prenatal exposure to exogenous hormones, evaluating the literature by separating studies into those which, for example, only included subjects of a particular age (e.g., children vs. adolescents) or employed particular types of assessment procedures (e.g., interviews vs. questionnaires) was not possible. Moreover, drawing definitive or simple conclusions about the influence of prenatal exposure to exogenous hormones is not possible, given the substantial variations in the drug regimens to which subjects were exposed (see Reinisch & Gandelman, 1978, for a more detailed discussion) and the numerous methodological and procedural inconsistencies across studies. Table I presents, for each of the 19 studies, a list of 13 methodological characteristics including the (1) type of hormone exposure; (2) dosage, duration, and timing of exposure; (3) sex, number, and age of exposed subjects; (4) type (see below), number, and age of comparison or control subjects; (5) existence of physical abnormalities and/or mental disabilities in the subjects; and (6) conditions of testing (i.e., whether or not the investigators, testers, raters, and/or subjects were blind to the exposure status of the subjects). The type of comparison or control subjects ranged from normal siblings or matched controls to offspring whose non-hormonally treated mothers had toxemia during pregnancy (toxemic controls), individuals born to untreated mothers who had diabetes (diabetic controls), and women who had been referred to a physician because of an abnormal Papanicolaou (Pap) smear. Because all comparisons were made within each sex, we were able to consider the behavioral consequences of prenatal exposure to hormones without concern for the differential treatment of the sexes. It should be noted that same-sex sibling controls provide the best matches, in terms of partially controlling for the effects of genetics and environmental influences.

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Type of Hormone Exposure The findings which form the basis of our summaries are organized by the type of hormonal exposure and are presented separately for male and female subjects in Tables 11 and HI, respectively. Results from studies that combined male and female subjects for analysis, while still matching on sex, are presented in Table IV. The hormonal treatment regimens are subdivided as follows: (1) subjects primarily exposed to progestins, (2) subjects primarily exposed to synthetic estrogens, and (3) subjects exposed to a mixture of progestins and estrogens. The data from subjects exposed primarily to progestins are further subdivided based on the kind of progestogen administered. Our classification of the type of hormone exposure is generally in agreement with that of the studies' investigators, except in one case (Yalom et al., 1973), wherein data on the dosages of hormones administered during pregnancy led us to reclassify one of the two subject groups (i.e., the 16-year-old subjects) as "primarily exposed to a combination of progestins and estrogens" rather than "primarily exposed to synthetic estrogens." In another study (Kester et al., 1980), since the investigators did not report the specific synthetic progestin(s) administered, and our attempts to ascertain which synthetic progestins were administered were unsuccessful, the subjects were included in the mixed androgen- and progesterone-based synthetic progestin group.

Behavioral Categories Findings, presented by sex and the type of hormonal treatment, were classified into eight behavioral categories. These include: play behavior and recreational interests, peer relations, aggression/assertion, interest in marriage and matemalism, gender identity/role and personality, sexual maturation and behavior, cognitive abilities and academic achievement, and athletic ability and physical coordination. In general, our assignment of a finding to a particular behavioral category was based on the classifications employed by the studies' investigators. For example, findings pertaining to "interest in playing with dolls" were assigned to the behavior category reflecting interest in "marriage and matemalism."

Comparisons Between Exposed and Control Subjects To describe the effects of prenatal hormone exposure on behavior, we use the symbol "$" to denote increases, and "$" to denote decreases, in the behavior of exposed subjects relative to their same-sex control or comparison group. (Due to space limitations, the few findings related to the dosage, d~ration, and timing of hormone exposure were generally not included.) In light of the small sample sizes, to more fully describe the direction and strength of effects, we included both trends (p0.10). Three findings on play (one showing a trend) and one finding on gender identity/role (also showing a trend) suggest that prenatal exposure to natural progesterone may have a (text continues on page 262)

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J. M. R~NISCHet al. TABLE IIA. MALE SUBJECTSPRIMARILYEXPOSEDTO PROGESTINS

Study

Measures

Play/ Interests

1. Natural Progesterone Kester et al. (1980) a

Zussman et al. 8 (unpublished data)

Embedded Figures Test Bern Sex Role Inventory Masculine Scale Guilford Zimmerman Temperament Survey (GZTS) Strong Vocational Interest Blank (SVIB) Law and Politics Technical Supervisor (?) Medical Service Subject Interview Childhood: Preference for Stories with Aggressive Themes Adolescence: Age of First Nocturnal Emissions Adulthood: Participation in Sports Interest in Team, Competitive, Contact Sports Watching Individual, Competitive, Contact Sports Preference for Stories with Female Main Characters Frequency of Nocturnal Emissions Sexual Orientation

M

T

MC

DM $

MC

DM $** MC

Differential Aptitude Test Abstract Reasoning Bem Sex Role Inventory (BSRI)

California Psychological Inventory (M-F Scale) Subject Interview (Ages 5-10) Athletic Outdoor Play Activities and Interests

DM $* Tox Norm

Disciplinary Action in School

See page 236 for explanation of notes.

Peer Relations

PRENATALHORMONEExr'OSUI~: EFFECTS ON BEHAVIOa

Aggression/ Assertion

Marriage and Maternalism

Gender Identity/Role Personality

DM

? ? ?

M

$

MC

ns

MC

Sexual Maturation/ Behavior

231

Cognitive/ Academic Abilities

ns

MC

,L

Tox Norm

Athletic Ability/ Coordination

MC $* M C $ MC

I"

T* M C

--

I"

DEL 1"

MC

E N H 1" ns

MC MC

MC

ns "Tox Norm MC ns

M

Tox Norm MC

I"* Tox

Norm MC

Table Ila continues on the following p e p s .

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J. M. REINISCHet al. TABLE IIA (CONTINUED)

Study

Measures

Play/ Interests

Peer Relations

1. Natural Progesterone (continued) Zussman et al. 8 (unpublished data) (continued)

Subject Interview (Current) Dating Thoughts About Marriage and Family Going Steady

2, Primarily Progesterone-Based Synthetic Progestins

Meyer-Bahlburg et al. (1977)

Kester (1984)

Wechsler Intelligence Scale for Children-Revised (WISC-R) Full Scale IQ Subject Interview Athletic Skills Male Playmates Preferred Energy Expenditure Girls' Toys Preferred Interest in Marriage Interest in Children Interest in Infant Care Teased for Effeminacy Male Gender Role Preferred Bender Visual-Motor Gestalt Embedded Figures Test Draw-A-Person Test Forer Structured-Sentence Completion Test Masculine Rating Rosenzweig Picture-Frustration Study Group Conformity Type and Direction of Aggression Subject Interview Interest in Rough-and-Tumble Activities, Sports, and Games Interest in Watching Television or Reading Number of Hours Spent Reading Number of Hours Spent Watching Television

See page 236 for explanation of notes.

ns MC ns MC

ns MC ns MC ns MC --

1"*c MC

233

PRENATAL HORMONEEXPOSURE: EFFECTSO N BEHAVIOR

Aggression/ Assertion

Marriage and Maternalism

Gender Identity/Role Personality

D I M $*

DF

Sexual Maturation/ Behavior

Cognitive/ Academic Abilities

Athletic Ability/ Coordination

Tox Norm MC

~** Tox Norm MC D I M $** Tox Norm MC

ns

MC ns

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MC

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Table Ila continues on the following pages.

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J. M. REINISCHet al.

TABLE IIA (CONTINUED)

Study

Measures

Play/ Interests

Peer

Relations

2. Primarily Progesterone-Based Synthetic Progestins (continued) Ehrhardt et al. (1984)

Intelligence Scale Subject a n d / o r Mother Interview Athletic Ability Physical Activity Prefers Girls' Toys and Dolls Associates with Female vs. Male Friends, Current Associates with Female vs. Male Friends, Past Has Female vs. Male Best Friend Prefers Female vs. Male Peers (Group Situation) Prefers Female vs. Male Peer (Single) Prefers Mother Role in Playing House Interest in Infant Care Prefers Infants Over Toddlers an Preschoolers Wants to Have Children Interest in Stylish Clothes Interest in Cosmetics Interest in Hair Style Interest in Jewelry Incidents of Cross-Dressing Who Has More Fun in Life: Girls or Boys? If You Could Start All Over in Life: As a Girl Rather than a Boy If You Had a Choice Now, Would You Change Your Gender? Effeminacy Feels Closer to Mother

ns

3. Primarily Androgen-Based Synthetic Progestins Reinisch (1981)

Wechsler Intelligence Scales Leifer-Roberts Response Hierarchy Physical Aggression

4. Primarily Mixed Androgen and Progesterone-Based Synthetic Progestins Kester et al. (1980) A,D

Embedded Figures Test Bem Sex Role Inventory (BSRI) Feminine Scale Guilford Zimmerman Temperament Survey (GZTS)

See page 236 for explanatlon of notes.

MC

ns MC ns MC ns MC ns MC ns MC

235

PRENATALHORMONEEXPOSURE: EFFECTSON BEHAVIOR

Aggression/ Assertion

M a r r i a g e and

Gender Identity/Role

Sexual Maturation/

Cognitive/ Academic

Athletic Ability/

Matemalism

Personality

Behavior

Abilities

Coordination

ns

MC ns

ns

MC

ns ns

MC MC

ns ns

MC MC DF

ns MC ,1, M C ns MC ns MC n s MC ns

MC

ns

MC

ns ns ns

MC MC MC

ns M

MC

Sibs

3"* Sibs

MC F

?

MC

ns

MC Table Ila continues on the following pages.

236

J. M. REINISCHet al. TABLE IIA (CONTINUED)

Study

Measures

Play/ Interests

Peer

Relations

4. P r i m a r i l y M i x e d A n d r o g e n a n d P r o g e s t e r o n e - B a s e d S y n t h e t i c P r o g e s t i n s

Kester et al. (1980)A,D (continued)

S t r o n g V o c a t i o n a l I n t e r e s t B l a n k (SVIB) Social S e r v i c e Subject Interview Childhood: N u m b e r o f G i r l s as F r i e n d s Adolescence: I n t e r e s t in T e a m , C o m p e t i t i v e , Contact Sports I n t e r e s t in P a r t i c i p a t i o n in S p o r t s Age Learned About Masturbation Frequency of Masturbation Age Learned About Nocturnal Emissions Adulthood: I n t e r e s t in W a t c h i n g T e a m , Competitive, Contact Sports S a t i s f a c t i o n w i t h Sex Life Sexual Orientation

R e i n i s c h (1981)

F

M M

1"* M C 1"* M C

M

$*

1'

MC

MC

W e c h s l e r I n t e l l i g e n c e Scales Leifer-Roberts Response Hierarchy Physical Aggression Verbal A g g r e s s i o n

n s -- C o m p a r i s o n between exposed a n d u n e x p o s e d s u b j e c t s w a s not significant. I" = Scores of exposed s u b j e c t s were higher t h a n controls. $ = Scores of exposed s u b j e c t s were lower t h a n controls. No asterisk = p < O. 10 * = p < 0.05 ** = p < 0 . 0 1 M = Masculinized DF = Defeminized ? = May be sexually dimorphic b u t could n o t be a s s i g n e d a label F = Feminized DM = Demascullnized of M, DF, F, or DM in t h e a b s e n c e of additional data - - = Not typically regarded as sexually dirnorphic DEL = Delayed in exposed s u b j e c t s relative to controls. DIM = Diminished in exposed s u b j e c t s relative to controls. ENH = E n h a n c e d in exposed subjects relative to controls. Diab = Diabetic Control (offspring of n o n h o r m o n e - t r e a t e d diabetic mother. Non-Diab = Non-Diabetlc Controls (i.e., offspring of non-diabetic mothers). Sibs = Sibling Control MC = Matched Control Norm = Normal Control (i.e., n e x t - b o r n children in the hospital from normal, non-toxemic pregnancies). Tox = Toxemic Control (i.e., next-born children in t h e hospital from n o n - h o r m o n e - t r e a t e d toxemic pregnancies).

PRENATAL H O R M O N E EXInDSURE: EFFECTS ON BEHAVIOR

Aggression/ Assertion

Marriage and Matemalism

Gender Identity/Role Personality

F

T

Sexual Maturation/ Behavior

237

Cognitive/ Academic Abilities

Athletic Ability/ Coordination

MC

DEL T* MC DIM $ MC DEL T

MC

T* MC ns MC ns M

Sibs

T** Sibs n s Sibs

AOnly the results of 2-way ANCOVAs (comparing exposed to unexposed subjects), and not those based on 3way ANCOVAs or regression analyses, are presented. The covariate in the 2-way ANCOVAswas father's occupational status, which was included in analyses due to imperfect matching on this variable. 8Because the authors did not present data on overall group comparisons, in this one instance, we report findings related to the dosage, duration, and timing of hormone exposure. c One-tailed p value. DThe authors did not report the specific type(s} of synthetic progestin(s) to which subjects were exposed. Our attempts to ascertain which synthetic progestin(s) were administered were unsuccessful.

238

I. M. REINlSCH et al.

TABLE IIB. MALE SUBJECTSPRIMARILYEXPOSEDTO ESTROGENS Study

Measures

Yalom et al. (1973)

Embedded Figures Test

Play/ Interests

Peer Relations

Aggression Questionnaire: Anger Toward Another Male in Past Week Usually Wins Fights Likes to Fight Expression of Anger in Past Week Number of Fights Aggregate Aggression Score Rank Orderings Based on Subject and Mother Interviews: Heterosexual Experience Masculine Interests Aggression/Assertion Global Ratings of Masculinity Based on Subject and Mother Interviews Thematic Apperception Test (TAT): Extreme Scores (high and low) on Competition, Goal Attainment, Success, and Physical Prowess Behavioral Observations of Athletic Coordination Kester et al. (1980)8

Subjects Exposed to DES Only Embedded Figures Test Bern Sex Role Inventory (BSRI) Guilford Zimmerman Temperament Survey (GZTS) Strong Vocational Interest Blank (SVIB) Social Service Writing Academic Achievement Extraversion Subject Interview Childhood: Interest in Girls' Toys and Activities Number of Male Friends Cross-Dressing

See page 236 for explanation of standard notes and page 240 for notes spaclflc to this table.

M

1" M(

239

PRENATALHORMONEEXPOSURE: EFFECTSON BEHAVIOR

Aggression/ Assertion

Marriage and Matemalism

Gender Identity/Role Personality

Sexual

Maturation/ Behavior

Cognitive/ Academic Abilities ns

DM F F

~, ~, 4" ns ns

F

~

Athletic Ability/

Coordination

Diab Non-Diab

Diab Non-Diab Diab Diab Non-Diab Diab Non-Diab Diab Non-Diab

n s A Diab NonoDiab n s A Diab Non-Diab F

~,* Diab $* Diab

T* N o n - D i a b DM

ns

DF

ns

MC

ns

MC

F F ---

1'** 1' 1'* ?*

MC MC MC MC

M

~* M C

$

Diab

MC

$* M C

Table lib continues on the following pages.

240

J. M. RmNISCH et al.

TABLE IIB (CONTINUED)

Study

Kester et al. (1980) 8 (continued)

Reinisch & Sanders (unpublished data)

Measures

Play/ Interests

Peer Relations

Subjects Exposed to DES Only (continued) Subject Interview (continued) Adolescence: Interest in Sports M T MC Age at First Nocturnal Emission Adulthood: Prefers Television Shows with Aggressive Themes Prefers Reading Material with Male Main Characters Sexual Orientation Subjects Exposed Primarily to DES with Some Natural Progesterone Embedded Figures Test Bem Sex Role Inventory (BSRI) Feminine Scale Guilford Zimmerman Temperament Survey (GZTS) Reflective vs. Unreflective Scale Feminine Scale Strong Vocational Interest Blank (SVIB) Mathematics Subject Interview Childhood: Prefers Non-Contact Sports DM t MC Interest in Individual, Competitive, Non- Contact Sports -$* MC Interest in Individual, NonCompetitive, Non-Contact Sports -$ MC Participation in Sports DM ,L** MC Watching Sports M 1"* MC Adulthood: Participation in Sports DM $ MC Watching Individual, Competitive, Contact Sports M t MC Self-Rated Sex Drive Sexual Orientation Wechsler Intelligence Scales (WAIS and WISC-R) Full Scale IQ Spatial Ability Factor Witelson Dichhaptic Shapes Test Hemispheric Laterality

See page 236 for explanaUon of standard notes.

AThe authors did not report p values but described these findings as "trends." Thus. by convention these results were considered to be trends at the O. I0 level.

241

PRENATAL HORMONE EXPOSURE: EFFECTSON BEHAVIOR

Aggression/ Assertion

Marriage and Matemalism

Gender Identity/Role Personality

Sexual Maturation/ Behavior

ENH $

M

$

Cognitive/ Academic Abilities

Athletic Ability/ Coordination

MC

MC T

MC ns

MC ns

F

T

-F

T* MC 1" MC

M

T* MC

MC

MC

E N H 1"** MC ns MC

DM

ns Sibs J,* Sibs

F

$* Sibs

BOnly the results of 2-way ANCOVAs {comparing exposed to unexposed subjects), and not those based on 3way ANCOVAs or regression analyses, are presented. The covariate m the 2-way ANCOVAs was father's occupational status, which was included in analyses due to imperfect matching on this variable.

242

J.M. REINISCHet al.

TABLEIIc. MALE SUBJECTS EXPOSED TO MIXED REGIMENS OF PROGESTINS AND ESTROGENS Study

Measures

Ehrhardt et al. (1984)

Intelligence Scale Subject a n d / o r Mother Interview Athletic Ability Physical Activity Prefers Girls' Toys and Dolls Associates with Female vs. Male Friends, Current Associates with Female vs. Male Friends, Past Has Female vs. Male Best Friend Prefers Female vs. Male Peers (Group Situation) Prefers Female vs. Male Peer (Single) Prefers Mother Role in Playing House Interest in Infant Care Prefers Infants Over Toddlers and Preschoolers Wants to Have Children Interest in Stylish Clothes Interest in Cosmetics Interest in Hair Style Interest in Jewelry Incidents of Cross-Dressing Who Has More Fun in Life: Girls or Boys? If You Could Start All Over in Life: As a Girl Rather than a Boy If You Had a Choice Now, Would You Change Your Gender? Effeminacy Feels Closer to Mother Global Rating of Masculinity Based on Mother Interview and Behavioral Observation Draw-A-Person Test (DAP) IT Scale for Children Parent and Activity Preference Test Rank Orderings Based on Mother Interview Masculine Interests Aggressivity Teacher Ratings Assertiveness Toughness Disruptiveness Artistic Ability Athletic Ability

Yalom et al. (1973)

Sea page 236 for explanation of slandard notes.

Play/ Interests

ns

Peer Relations

MC

ns

MC

TA MC ns MC ns ns

AOne-tailed p value.

MC MC

PRENATALHORMONEEXPOSURE: EFFECTSON BEHAVIOR

Aggression/ Assertion

Marriage and Maternalism

Gender Identity/Role Personality

Sexual Maturation/ Behavior

243

Cognitive/ Academic Abilities ns

ns

MC

ns ns

MC MC

ns ns

MC MC ns ns ns ns ns

MC MC MC MC MC

ns

MC

Athletic Ability/ Coordination

MC DM

~A M C

DM

J,* M C

/'A M C

ns DM

ns ns ns

MC MC MC

ns ns ns ns

MC MC MC MC

ns

MC

MC

J,~ M C ns MC ns MC ns

MC

244

J. M. REINISCHet al.

TABLE IIIA. FEMALE SUBJECTS PRIMARILY EXPOSED TO PROGESTINS Study

Measures

Play/ Interests

Peer Relations

1. Natural Progesterone Lynch et al. (1978)

Zussman (unpublished data) A

Sixteen-Year-Olds Eysenck Personality Inventory (EPI) Neuroticism (N) Scale Extraversion (E) Scale Minnesota Multiphasic Personality Inventory (MMPI) Mf Interest Scale Bem Sex Role Inventory (BSRI)

California Psychological Inventory (M-F Scale) Subject Interview (Ages 5-10) Athletic Outdoor Play Activities and Interests

DM ,[,*

Tox

Norm MC Disciplinary Action in School

Concern for Appearance

Preference for Long Hair Tomboyism

2. Primarily Progesterone-Based Synthetic Progestins Ehrhardt et al. (1977)

Wechsler Intelligence Scale for ChildrenRevised (WISC-R): Full Scale IQ Subject Interview Energy Expenditure Female Playmates Preferred Athletic Skills Girls' Toys Preferred Interest in Marriage Interest in Children

See page 248 for explanation of notes.

ns

MC ns

MC

245

PRENATAL H O R M O N E EXPOSURE: E~'Ec'rsO N BEHAVIOR

Aggression/ Assertion

M a r r i a g e and

Matemalism

Gender Identity/Role Personality

F F

Sexual Maturation/ Behavior

Cognitive/ Academic Abilities

Athletic Ability/ Coordination

1" Tox $* Tox

ns

Tox

ns

Tox Norm MC

ns Tox Norm MC

$* Tox Norm MC T* Tox Norm MC T* Tox Norm MC $** Tox Norm MC

ns

MC

MC

ns ns ns

MC MC MC Table llla contlnuU on the following pages.

246

J. M. P~NxSCtl et al.

TABLE Ilia (CONTINUED) Study

Measures

Play/ Interests

Peer Relations

2. Primarily Progesterone-Based Synthetic Progestins (continued)

Ehrhardt et al. (1977) (continued)

Subject Interview (continued) Interest in Infant Care Tomboyism Female Gender Role Preferred Feminine Clothes Preferred

Ehrhardt et al. (1984)

Intelligence Scale Subject and/or Mother Interview Athletic Ability Physical Activity Prefers Girls' Toys and Dolls Associates with Female vs. Male Friends, Current Associates with Female vs. Male Friends, Past Has Female vs. Male Best Friend Prefers Female vs. Male Peers (Group Situation) Prefers Female vs. Male Peer (Single) Prefers Mother Role in Playing House Interest in Infant Care Prefers Infants Over Toddlers and Preschoolers Wants to Have Children Prioritizes Career Over Childrearing Interest in Stylish Clothes Interest in Cosmetics Interest in Hair Style Interest in Jewelry Incidents of Cross-Dressing Tomboyism Always a Complete Tomboy Feels Closer to Mother

DM $*B MC MC

ns

MC MC

r~

MC MC

3. Primarily Androgen-Based Synthetic Progestins

Money & Ehrhardt (1972) c

Subject Interview Energetic Athletic Interests and Skills Prefers Male Playmates Prefers Boys' Toys Childhood Fighting Interest in Infant Care

See page 248 for expianaUon of notes.

M

t* MC

M

7" MC

M

t* MC

PRENATALHORMONEEXPOSURE: EFFECTSON BEHAVIOR

Aggression/ Assertion

Marriage and Matemalism

ns

Gender Identity/Role Personality

Sexual Maturation/ Behavior

247

Cognitive/ Academic Abilities

Athletic Ability/ Coordination

MC F F

$ MC ns MC I"* MC ns

MC DM

F

J.~ MC

~s MC

ns MC ns MC ns ns ns

MC MC MC DF

F

.s

J,*" ns ns ns ns ns Ss ns

MC MC MC MC MC MC MC MC

MC ns

MC

Table Ilia continues on the following pages.

248

I. M. RFJNISCHet al.

TABLE IIIA (CONTINUED)

Study

Measures

Play/ Interests

Peer Relations

3. Primarily A n d r o g e n - B a s e d Synthetic Progestins (continued) Money & Ehrhardt (1972) (continued)

Subject I n t e r v i e w (continued) D a y d r e a m s / F a n t a s i e s of Pregnancy and Motherhood Play R e h e a r s a l / D a y d r e a m s of W e d d i n g a n d Marriage Prioritizes Career O v e r Marriage K n o w n to Self a n d M o t h e r as T o m b o y Satisfaction w i t h Female Role Prefers Slacks O v e r Dresses Interest in Jewelry, Perfume, a n d Hair Styles Frequency of M a s t u r b a t i o n Shared Sex P l a y / R e h e a r s a l Heterosexual R o m a n t i c i s m in Play and Daydreams D a y d r e a m s of Boyfriends a n d Dating H o m o s e x u a l Fantasies

Reinisch (1981)

Wechsler Intelligence Scales Leifer-Roberts R e s p o n s e H i e r a r c h y Physical Aggression

4. Primarily M i x e d A n d r o g e n a n d Progesterone-Based Synthetic Progestins Reinisch (1981)

Wechsler Intelligence Scales Leifer-Roberts Response H i e r a r c h y Physical Aggression Verbal Aggression

n s = Comparison between exposed and unexposed subjects was not significant. I' = Scores of exposed subjects were higher than controls, $ = Scores of exposed subjects were lower than controls. No asterisk= p< 0.10 * = p< 0.05 ** = p< 0.01 M = Masculinized DF = Defeminlzed ? = May be sexually dimorphic but could not be assigned a label F = Feminized DM = Demascullnized of M, DF, F, or DM in the absence of additional data - - = Not typically regarded as sexually dlmorphic B/H = Consistent with the development of a primarily bisexual/homosexual orientation. HEr = Consistent with the development of a primarily heterosexual orientation. Slbs = Sibling Control Me = Matched Control Pap = Controls referred to a physician because of an abnormal Pap (Papanicolaou) smear. Norm = Normal Control (i.e., next-born children in the hospital from normal, non-toxemic pregnancies). Tox = Toxemic Control (i.e., next-born children in the hospital from non-hormone-treated taxemlc pregnancies).

249

PRENATALHORMONE EXPOSURE: EFFECTSON BEHAVIOR

Aggression/ Assertion

Marriage and Maternalism

ns

M

Gender Identity/Role Personality

Sexual Maturation/ Behavior

Cognitive/ Academic Abilities

Athletic Ability/ Coordination

MC

ns M C "r* MC M M

T* MC ns MC T* MC its MC ns ns

MC MC

its MC Its M C Its MC

M

M

T

ns

Sibs

ns

Sibs

Sibs

1"*~ Sibs n s Sibs

ABecause the authors .did not present data on overall group comparisons, in this one instance, we report findings related to the dosage, duration, and timing of hormone exposure. 8One-tailed p value CReanalysis of Ehrhardt and Money (1967) with controls. A foUow-up study of subjects in these two reports. which also did not include control subjects, is presented in Money and Mathews (1982).

250

J. M. RE1NlSCHet al.

TABLE IIIB. FEMALE SUBJECTS PRIMARILY EXPOSED TO ESTROGENS Study

Measures

Hines & Shipley (1984)

Wonderlic Personnel Test (General Intelligence) Primary Mental Abilities (PMA) Battery Word Fluency Subtest (Verbal Ability) Spatial Relations Subtest (Visuospatial Ability) Dichotic ListenIng Task^ (Cerebral Lateralization) Negative Correlation Between Right- and Left-Ear Scores Right-Ear Scores Higher Than Left-Ear Scores Laterality Index "F" Menarche

Meyer-Bahlburg et al. (1984)

Wechsler Intelligence Scale (WAIS-R) Full Scale IQ Gender Role Assessment Schedule (GRAS-A) and Sexual Behavior Assessment Schedule (SEBAS-A) Breast Development Menarche First Masturbation First Holding Hands First Kissing First Necking First Breast PettIng First Genital Petting First Intercourse First Crush First Boyfriend First Steady Boyfriend First Love First Marriage

Ehrhardt et al. (1985)

Wechsler Intelligence Scale (WAIS-R) Full Scale IQ

Play/ Interests

Kinsey Scale RatingsBon the Sexual Behavior Assessment Schedule (SEBAS-A) Past 12 Months Masturbation Fantasies Masturbation Erotica Romantic/Sexual Daydreams/ Nightdreams See page 248 for explanaUon of standard notes and page 252 for notes specific to this table.

Peer Relations

PRENATALHORMONEEXPOSURE: EFFECTSON BEHAVIOR

Aggression/ Assertion

Marriage and

Gender Identity/Role

Sexual Maturation/

Matemalism

Personality

Behavior

ns

2~1

Cognitive/ Academic Abilities

ns

Sibs

ns

Sibs

ns

Sibs

M

.7** Sibs

M

1"* Sibs ns Sibs

--

T** Pap

--

ns Sibs ?** Pap

Athletic Ability/ Coordination

Sibs

ns Pap ns Pap ns Pap ns Pap ns Pap ns Pap ns Pap ns Pap ns Pap ns Pap ns Pap ns Pap ns Pap ns

Pap

B/H B/H B/H

ns 1"*c ns Tc ns Tc

Sibs Pap Sibs Pap Sibs Pap Table Bib continues on the fOllowing pages.

252

J. M. REINISCHet al.

TABLE IIIB (CONTINUED) Study

Play/

Measures

Interests

Ehrhardt et al. (1985) (continued)

Peer Relations

Kinsey Scale Ratings (continued) Sexual Attractions Sexual Imagery Sexual Relations Sexual Responsiveness Bisexual/Homosexual Responsiveness (Kinsey 2-6) Lifelong Sexual Relations Sexual Responsiveness Bisexual/Homosexual Responsiveness (Kinsey 2-6)

Meyer-Bahlburg et al. (1985)

Wechsler Intelligence Scale (WAIS-R) Full Scale IQ Sexual Behavior Assessment Schedule (SEBAS-A) Full Samvle° (Kinsey 0-6 B) Number of Heterosexual Coitus Partners Ever Number of Heterosexual Coitus Experiences Ever Number of Homosexual Coitus Partners Ever Number of Homosexual Coitus Experiences Ever Number of Disturbing Sexual Experiences (Rape, Sexual Abuse, etc.) Heterosexuals Only (Kinsey 0-18) Number of Heterosexual Coitus Partners Ever Number of Heterosexual Coitus Experiences in the Past 12 Months Frequency of Sexual Thoughts Frequency of Negative Feelings During Lovemaking Vaginismus or Dyspareunia Orgasm During Heterosexual Coitus Multiple Orgasms During Heterosexual Coitus

See page 248 for explanation of standard notes.

AOnly15 of the 25 sister pairs were tested on the Dlchotic Listening "Pask. 8The Kinsey Scale (Kinsey et oL, 1948. 1953) is a 7-point scale of sexual orientation anchored by "0" (indicatIng exclusive heterosexuality) and "6" (indicating exclusive homosexuality).

PRENATALHORMONEEXPOSURE:EFFECTSONBEHAVIOR

Aggression/ Assertion

Marriage and Maternalism

Gender Identity/Role Personality

Sexual Maturation/ Behavior

253

Cognitive/ Academic Abilities

Athletic Ability/ Coordination

B/H B/H

Tc Sibs T**cPap ns Sibs B / H 1"c Pap ns Sibs B / H T*e Pap B / H T*c Sibs B / H T*e Pap B / H Tc Sibs B / H T*e Pap ns

B/H B/H B/H B/H B/H

Sibs

T*c Pap $*c Sibs T**c Pap Tc Sibs T**c Pap --

B/H

$c

B/H

$c Pap

B/H

T*e Pap

B/H

T.e Pap ns

1"* Pap

Pap

Pap

B/H

$.c Pap

HEr __

T Pap $**cPap

-__

T**c Pap nsC Pap $,e Pap

__

~**cPap

COne-tailed p value DThe "Full-Sample" findings reflect the high proportion of bisexual a n d / o r homosexual women in this sample. Findings presented for *Heterosexuals Only" are those that remained significant after sexual orientation was statistically controlled. Due to the confound of sexual orientation, we do not present all the findings on the sexual behavior patterns of DES-exposed women reported in Meyer-Bahlburg et aL {1985).

254

J.M. REINISCHet al.

TABLE IIIc. FEMALE SUBJECTSEXPOSED TO MIXED REGIMENSOF PROGESTINSAND ESTROGENS

Study

Measures

Ehrhardt et al. (1984)

Intelligence Scale Subject a n d / o r Mother Interview Athletic Ability Physical Activity Prefers Girls' Toys and Dolls Associates with Female vs. Male Friends, Current Associates with Female vs. Male Friends, Past Has Female vs. Male Best Friend Prefers Female vs. Male Peers (Group Situation) Prefers Female vs. Male Peer (Single) Association With Female Company Based on Summary of All Social Contacts With Peers and Adults Prefers Mother Role in Playing House Interest in Infant Care Prefers Infants Over Toddlers and Preschoolers Wants to Have Children Prioritizes Career Over Childrearing Interest in Stylish Clothes Interest in Cosmetics Interest in Hair Style Interest in Jewelry Incidents of Cross-Dressing Who Has More Fun in Life: Girls or Boys? If You Could Start All Over in Life: As a Girl Rather than a Boy If You Had a Choice Now, Would You Change Your Gender? Tomboyism Feels Closer to Mother

See page 248 for explanation of standard notes.

Play/ Interests

Peer Relations

ns MC

ns MC ns MC ns MC TA MC ns MC

1"A MC

255

PRENATAL HORMONE EXPOSURE: EFFECTSON BEHAVIOR

Aggression/ Assertion

Marriage and Maternalism

Gender Identity/Role Personality

Sexual Maturation/ Behavior

Cognitive/ Academic Abilities ns

Athletic Ability/ Coordination

MC DM

F

ns

MC

ns ns

MC MC

ns MC ns MC $*A M C F F

--

AOne-tailed p value.

ns 1"A 1"A ns ns

MC MC MC MC MC

ns

MC

ns

MC

ns ns

MC MC MC

1"*^

$*A M C

256

J. M. REINXSCHet al.

TABLE IVA. COMBINED GROUPS OF MALE AND FEMALE SUBJECTS PRIMARILY EXPOSED TO PROGESTINS Study

Measures

1. Natural Progesterone Dalton (1968) a

Teacher Ratings of Academic Performance All Subjects Academic Subjects Verbal Reasoning English Arithmetic Craftwork Physical Education

Dalton (1976) ^

Educational Attainment Questionnaire Age of Leaving School Mean Number of "O" Level Passes per Subject Total Number of "O" Level Passes in Sciences and Art Mean Number of "A" Level Passes per Subject Total Number of "A" Level Passes in Sciences and Art Number of Subjects Entering University

Lynch et al. (1978)

Two-Year-Olds Bayley Scales of Infant Development Mental Development Index Sixteen-Year-Olds Wechsler Intelligence Scale (WAIS) Combined Social Classes Full Scale IQ Verbal IQ Performance IQ Embedded Figures Test Coltheart Test Verbal Test Visual-Spatial Task

See page 260 for explanation of notes.

Play/ Interests

Peer Relations

257

PRENATAL H O R M O N E EXPOSURE: EFFECTS ON BEHAVIOR

Aggression/

Marriage and

Assertion

Maternalism

Gender Identity/Role Personality

Cognitive/ Academic Abilities

Sexual Maturation/

Behavior

F F F F F F

Athletic Ability/

Coordination

T*e "fox Norm T*a Tox Norm I"*B Tox Norm ?.B Tox Norm T.B Tox Norm Tn'B TOX

Norm Tox

Norm ns

Tox Norm T* Tox ns

Tox Norm T* Tox Norm n s Tox Norm T* Tox Norm

Tox

ns ns ns

Tox Tox Tox

ns

Tox

n s Tox n s Tox Table IVa continues on the following pages.

258

J. M. REINISCHet al. TABLE IVA (CONTINUED)

Study

Play/

Measures

Peer Relations

Interests 1. Natural Progesterone (continued)

Lynch et al. (1978) (continued)

Teacher Ratings of Academic Performance Verbal Reasoning English Attainment Arithmetic Physical Sciences Natural/Biological Sciences Art (i.e., History, Geography) Foreign Language Craftwork Physical Education Eysenck Personality Inventory (EPI) Neuroticism (N) Scale Extraversion (E) Scale Minnesota Multiphasic Personality Inventory (MMPI) Mf Interest Scale

Zussman et alp (unpublished data)

Differential Aptitude Test Numerical Ability Spatial AbilityE Mechanical AbilityE Verbal Ability

Subject Interview (Ages 5-10) Playing in Large Groups Influence Over Peers

M

?* Tox Norm MC ._

$*

TOX Norm MC

Subject Interview (curren0 Daydreaming About the Opposite Sex

See page 260 for explanation of notes.

PRENATAL HORMONE EXPOSURE: E~'EC"rSON BEHAVIOR

Gender

Aggression/ Assertion

Marriage and Matemalism

Identity/Role Personality

F

Sexual Maturation/ Behavior

259

Cognitive/ Academic Abilities

ns ns ns ns ns

Tox Tox Tox Tox Tox

ns ns ns ns

Tox Tox Tox Tox

Athletic Ability/ Coordination

1" Tox ns

Tox

ns

Tox I"** TOX

M

1"

M

t

ns

DIM

Norm MC Tox Norm MC Tox Norm MC Tox Norm MC

$* Tox Norrn MC

Table IVa continues on the following pages.

J. M. REINISCHet

260

al.

TABLE I V A (CONTINUED)

Study

Measures

Play/ Interests

Peer Relations

2. P r i m a r i l y M i x e d A n d r o g e n a n d P r o g e s t e r o n e - B a s e d S y n t h e t i c P r o g e s t i n s R e i n i s c h (1977) F and Reinisch & Karow(1977)

W e c h s l e r I n t e l l i g e n c e Scales Full Scale IQ Cattell Personality Questionnaires (ESPQ, C P Q , H S P Q a n d 16 PF): I n d e p e n d e n t vs. S u b d u e d S e n s i t i v e vs. T o u g h - M i n d e d I n d i v i d u a l i s t i c vs. G r o u p - O r i e n t e d I n s e c u r e vs. S e l f - A s s u r e d Self-Sufficient vs. G r o u p - D e p e n d e n t D r y C o g n i t i v e Style vs. D e p e n d e n c e on Feeling

n s = C o m p a r i s o n between exposed a n d u n e x p o s e d s u b j e c t s w a s not significant. t = Scores of exposed s u b j e c t s were higher t h a n controls. $ = Scores of exposed s u b j e c t s were lower t h a n controls. No asterisk = p < O. 10 * = p < 0.05 ** = p < 0.01 M = Masculinized DF = Defeminized ? = May be sexually dimorphic b u t could not be a s s i g n e d a label F = Feminized DM = Demasculinlzed of M, DF, F, or DM in t h e a b s e n c e of additional d a t a - - = Not typically regarded as sexually dimorphic Sibs = Sibling Control MC = Matched Control Norm = Normal Control (i.e,, next-born children in the hospital from normal, non-toxemic pregnancies). Tox = Toxemic Control (i.e., n e x t - b o r n children in the hospital from n o n - h o r m o n e - t r e a t e d toxemic pregnancies).

TABLE IVB. C O M B I N E D GROUPS OF MALE A N D FEMALE SUBJECTS PRIMARILY EXPOSED TO ESTROGENS

Study

Measures

R e i n i s c h (1977) A and R e i n i s c h & K a r o w (1977)

W e c h s l e r I n t e l l i g e n c e Scales Full Scale IQ Cattell P e r s o n a l i t y Q u e s t i o n n a i r e s (ESPQ, C P Q , H S P Q a n d 16 PF): I n d e p e n d e n t vs. S u b d u e d S e n s i t i v e vs. T o u g h - M i n d e d I n d i v i d u a l i s t i c vs. G r o u p - O r i e n t e d I n s e c u r e vs. S e l f - A s s u r e d Self-Sufficient vs. G r o u p - D e p e n d e n t D r y C o g n i t i v e Style vs. D e p e n d e n c e on Feeling

See Table IVa above for explanation of standard notes.

Play/ Interests

Peer Relations

PRENATALHORMONEEXPOSURE:EFFECTSONBEHAVIOR

Gender Aggression/

Assertion

Marriage and Maternalism

Identity/Role

Sexual Maturation/

Personality

Behavior

261

Cognitive/ Academic Abilities

ns

M M M M

T* ns q'* $* T*

Sibs Sibs Sibs Sibs Sibs

ns

Sibs

Athletic Ability/ Coordination

Sibs

ABased on reanalyses of these data, Lynch and Mychalklw (1978) and Meyer-Bahlburg (1979) have questioned these findings. BThe authors did not report p values but described these findings as significant. Thus, by convention, these results were considered to be significant at the 0.05 level. CThe authors also presented data distributed by socioeconomic status, which are beyond the scope of the present report. DBecause the authors did not present data on overall group comparisons, in this one instance, we report findings related to the dosage, duration, and timing of hormone exposure. EThe authors did not report p values but described these findings as indicative of a "...marginally significant relationship showing borderline positive effects of progesterone exposure..." (p. 5). Thus, by convention, these results were considered to be trends at the 0. I0 level. ~ h e authors also presented results from comparisons of two hormone-exposed groups of subjects, which are beyond the scope of the present report.

Aggression/ Assertion

Marriage and Maternalism

Gender Identity/Role

Personality

Sexual Maturation/ Behavior

Cognitive/ Academic Abilities

ns

F F

Athletic Ability/ Coordination

Sibs

ns Sibs ns Sibs $* Sibs ns Sibs $* Sibs ns

Sibs

AThe authors also presented results from comparisons of two hormone-exposed groups of subjects, which axe beyond the scope of the present report.

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J. M. REINISCHet al. TABLE IVc. COMBINEDGROUPSOF MALEAND FEMALESUBJECTS EXPOSEDTO MIXEDREGIMENSOF PROGESTINSAND ESTROGENS

Study

Measures

Reinisch (1977)A and Reinisch & Karow(1977)

Wechsler Intelligence Scales Full Scale IQ Cattell Personality Questionnaires (ESPQ, CPQ, HSPQ and 16 PF): Independent vs. Subdued Sensitive vs. Tough-Minded Individualistic vs. Group-Oriented Insecure vs. Self-Assured Self-Sufficient vs. Group-Dependent Dry Cognitive Style vs. Dependence on Feeling

Play/ Interests

Peer Relations

See Table IVa on page 260 for explanallon of standard notes.

masculinizing effect on at least some aspects of these dimensions. There is one finding that is contradictory, which is increased participation in sports (showing a trend), suggesting masculinization. The two significant findings on aggression/assertion tentatively indicate that this hormonal treatment may increase, i.e. masculinize, interest and participation in aggressive activities during childhood. Although this may appear to be inconsistent with the generally demasculinizing effects of this hormone in male subjects, it should be noted that it is consistent with the observation that the synthetic progestins appear to enhance the potential for physical aggression in both male and female subjects (Reinisch, 1981). Five additional findings were not suited to interpretation as sexually dimorphic. Sexual maturation and behavior appear to be delayed in exposed subjects relative to controls. The age at which exposed subjects experienced their first nocturnal emission was delayed (showing a trend), and they reported significantly less dating and going steady. Although there was a delay in the age at which they began having nocturnal emissions, these men reported a slightly higher frequency of noctumal emissions in adulthood (showing a trend). These results tentatively suggest that exposure to natural progesterone may demasculinize play-related, athletic, and gender identity/role dimensions and delay sexual maturation and behavior, while perhaps masculinizing childhood aggression/assertion in boys. These findings are consistent with others indicating that progesterone may act as both an antiandrogen and a virilizing agent (see Sanders & Reinisch, 1985, for review). F e m a l e s Subjects

There are two reports on the behavioral effects of prenatal exposure to natural progesterone in female subjects compared to matched, toxemic, and normal controls (Lynch et al., 1978; Zussman et al., unpublished observations). Ten findings deriving from these two investigations of overlapping groups of subjects are presented in Table IIIa. 1. Three of the ten findings were not significant (p>0.10).

PRENATALHORMONEEXPOSURE: EFFECTSON BEHAVIOR

Aggression/ Assertion

Marriage and Maternalism

Gender Identity/Role Personality

Sexual Maturation/ Behavior

263

Cognitive/ Academic Abilities

Athletic Ability/ Coordination

ns Sibs

M

ns $* ns ns ns

Sibs Sibs Sibs Sibs Sibs

ns Sibs AThe a u t h o r s also presented results from comparisons of two hormone-exposed groups of subjects, which are beyond the scope of the present report.

Five findings on gender identity/role (one showing a trend) and one finding on aggression suggest that prenatal exposure to natural progesterone feminizes some aspects of female behavior. Concem for appearance and a preference for long hair were increased, and aggressive behavior and tomboyism were diminished. The observation that gender identity/role may be feminized among exposed female subjects is consistent with the demasculinizing effect noted among male subjects. Like progesterone-exposed male subjects, exposed female subjects also appear to be demasculinized with regard to at least one aspect of play behavior. They less often engaged in energetic outdoor play. Unlike boys, childhood aggression in progesteroneexposed girls appears to be feminized, not masculinized. In general, however, prenatal exposure to natural progesterone seems to have somewhat similar overall effects on male and female subjects - - feminizing and/or demasculinizing behavioral development. Combined Groups o f Male and Female Subjects

Four studies addressed the behavioral effects of prenatal exposure to natural progesterone in combined groups of male and female subjects compared to matched, toxemic, and normal controls (Dalton, 1968; 1976; Lynch et al., 1978; Zussman et al., unpublished observations). Given the overlap in some of the subjects included in these four reports, it appears that there are only three distinct groups of subjects prenatally exposed to natural progesterone: a group of two-year-old boys and girls studied by Lynch et al. (1978), a group of 17- to 20-year-olds studied by Dalton (1976), and a group studied at ages 9-10 by Dalton (1968), age 16 by Lynch et al. (1978), and ages 16-19 by Zussman et al. (unpublished observations). It appears that the study of Zussman et al. (unpublished observations) included a subgroup of progesteroneexposed subjects distinct from those studied by Dalton (1968) and Lynch et al. (1978). Collectively, these four investigations account for the 39 findings on the effects of prenatal exposure to natural progesterone in Table IVa. 1, 23 of which were not significant (p > 0.10). Teacher ratings of academic performance appear to have been enhanced or feminized (six findings). However, exposed subjects appear to have been slightly masculinized with respect to

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scores on two subtests of the Differential Aptitude Test (both showing trends). Also, exposed subjects played in large groups more often (generally more characteristic of male subjects) and scored higher on the Eysenck Neuroticism scale (generally higher in female subjects) than did controls. If these results are evaluated with respect to established or hypothesized sex differences, seven reflect feminization and three reflect masculinization. With regard to results that are less suited to interpretation as sexually dimorphic, four findings indicate that cognitive ability and academic achievement were enhanced. However, Lynch et al. (1978) failed to confirm some of these findings. Finally, influence over peers (one finding) and time spent daydreaming about the opposite sex (one finding) were diminished in progesterone-exposed subjects relative to their controls. These results from mixed groups of subjects are consistent with those noted for male and female subjects separately. In summary, Dalton (1968; 1976) and Zussman et al. (unpublished observations) concluded that prenatal progesterone exposure may enhance cognitive ability and academic achievement in both male and female subjects. However, based on reanalyses of these data, Lynch and Mychalkiw (1978) and Meyer-Bahlburg (1979) questioned this conclusion. Further investigation is required before definitive conclusions can be drawn. If viewed from a sex-differences perspective, the results summarized above suggest that, in general, prenatal progesterone exposure may demasculinize male and feminize female subjects. The few masculinizing effects reported reflect enhancement of some sexually differentiated dimensions of cognitive performance and increased aggression in childhood. Proeesterone-Based Synthetic Progestins Male Subjects Findings on the effects of prenatal exposure to progesterone-based synthetic progestin among male subjects derive from two groups of subjects studied in three investigations by two laboratories (Meyer-Bahlburg et al., 1977; Ehrhardt et al., 1984; Kester, 1984). Of the 43 comparisons to matched controls presented in Table na.2, 41 were not significant (p>0.10). Only one significant finding and one trend were noted. Thus, the available evidence does not support an effect of prenatal exposure to progesterone-based synthetic progestins on the development of sexually dimorphic behavior in male subjects. It is possible that (1) the dosage of synthetic progestin administered to the mothers of subjects in these studies was not high enough to produce demonstrable effects on behavior, (2) the assessment procedures employed in these investigations were not sufficiently sensitive, and/or (3) behavioral dimensions that might be affected have not been fully evaluated as yet. Female Subjects One group of girls prenatally exposed to progesterone-based synthetic progestins were evaluated in two investigations by the same laboratory (Ehrhardt et al., 1977; 1984). Twenty-six of the 33 findings presented in Table IIIa.2 indicate no differences between exposed subjects and their matched controls (p > 0.10). Three findings on gender identity/role (two of which were trends) and one related to interest in marriage and matemalism (also a trend) suggest that prenatal exposure to these hormones is feminizing. One finding on play behavior and another on athletic ability indicate demasculinization. Therefore, girls prenatally exposed to this hormonal treatment appear to be feminized and/or demasculinized. However, they were less interested in stylish clothes, a finding that can be interpreted as reflecting defeminization.

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In summary, based on the available data, it tentatively can be concluded that prenatal exposure to progesterone-based synthetic progestins has a feminizing or demasculinizing effect on female subjects. This effect is consistent with that noted for natural progesterone. In contrast to data on natural progesterone, any effect of exposure to progesterone-based synthetic progestins on male subjects has yet to be demonstrated.

Androgen-Based Synthetic Progestins Male Subjects Only one investigation assessed the behavior of men prenatally exposed to androgen-based synthetic progestins (Reinisch, 1981). These subjects represent a subgroup of a larger sample exposed to both androgen- and progesterone-based synthetic progestins (see below). The projective instrument used to assess aggression has been shown to be highly discriminating in studies of sex differences (Reinisch & Sanders, 1986). As shown in Table IIa.3, physical aggression scores were significantly higher, that is, more masculine, in a group of five male subjects as compared to their same-sex sibling controls. Although this finding requires replication, confidence in this observation is enhanced by these facts: (1) statistical significance was achieved even in this small sample; (2) subjects received high dosages of this hormone; (3) unexposed siblings were used as controls; and (4) a double-blind design was employed. Moreover, this finding is consistent with data on nonhuman animals indicating that aggression is influenced by exposure to androgenic hormones early in ontogeny.

Female Subjects Data on the behavioral effects of prenatal exposure to androgen-based synthetic progestins in female subjects were reported in two studies (Money & Ehrhardt, 1972; Reinisch, 1981). However, the majority of results listed in Table IIIa.3 are based on data from one sample (Money & Ehrhardt, 1972). The subjects investigated by Reinisch (1981) are a subgroup of a larger sample exposed to both androgen- and progesterone-based synthetic progestins (see below). Twelve of 19 comparisons between exposed subjects and matched or sibling controls in these two studies were not significant (p>0.10). Exposure to androgen-based synthetic progestins appears to masculinize play behavior (two findings), peer relations (one finding), aggression (one finding), interest in marriage and maternalism (one finding), and gender identity/role (two findings) in female subjects. These data are consistent with both the nonhuman animal literature and studies of human females with the adrenogenital syndrome, which demonstrate that prenatal exposure to excess androgens can masculinize behavior. In summary, as with endogenous androgens in normal prenatal differentiation, exogenous androgen-based synthetic progestins appear to masculinize behavioral development in humans.

Mixed Androgen- and Progesterone-Based Synthetic Progestins Male Subjects There were 16 findings on the behavioral effects of prenatal exposure to mixed androgenand progesterone-based synthetic progestins among male subjects compared to sibling and matched controls (Table IIa.4). These data derive from two groups of subjects studied by two laboratories (Kester et al., 1980; Reinisch, 1981). Five findings were not significant (p0.10). Subjects exposed to mixed synthetic progestins appear to be masculinized relative to their unexposed siblings on four of six sexually differentiated personality factors. On the basis of these data, subjects prenatally exposed to mixed androgen- and progesterone-based synthetic progestins were described as more independent, more individualistic, more self-assured, and more self-sufficient. These findings suggest that prenatal exposure to this type of hormonal treatment masculinizes some aspects of gender identity/role and personality in both male and female subjects. In summary, as with offspring exposed to androgen-based synthetic progestins, male and female subjects exposed to mixed regimens of androgen- and progesterone-based synthetic progestins appear to be masculinized. It is possible that this virilizing effect on behavioral

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267

development reflects a stronger influence of the androgenic, compared to the progestogenie, component of these treatment regimens. Synthetic Estrogens Male Subjects

There are three studies investigating four groups of male subjects exposed to synthetic estrogens, primarily DES (Yalom et al., 1973; Kester et al., 1980; Reinisch & Sanders, unpublished observations). Collectively, they report 45 findings from prenatally estrogen-exposed male subjects compared to various groups, including diabetic, non-diabetic, sibling, and matched controls (Table llb). Twelve of the findings were not significant (/9> 0.10). Three (two showing trends) of the six sexually differentiated findings on play reflect masculinization, while three (two showing trends) indicate demasculinization. Interestingly, masculinized dimensions appear to reflect an increased passive interest in watching sports (particularly watching competitive contact sports), while the demasculinized dimensions reflect a decreased interest in actively participating in sports. This latter finding is consistent with the demasculinization indicated by behavioral observations of athletic ability (one finding). With regard to gender identity/role, five of the seven sexually differentiated findings (three showing trends) indicate feminization. With reference to aggression/assertion (five findings, three showing trends), all of the findings reported by Yalom et al. (1973) suggest demaseulinization and/or feminization with respect to actively behaving aggressively. Similar to those findings related to sports, the one finding (showing a trend) suggesting masculinization on the aggression/assertion dimension has to do with the more passive behavior of watching aggressive television shows (Kester et al., 1980). Lower spatial ability and less hemispheric laterality among exposed subjects compared to sibling controls suggests that cognitive abilities also may be demasculinized and/or feminized. These results are consistent with two of three findings from the Strong Vocational Interest Blank indicating greater interest in social service and writing. However, they conflict somewhat with an increased interest in mathematics. Sexual maturation and behavior may be enhanced in subjects prenatally exposed to estrogen, as indicated by their having reported a somewhat earlier age at first nocturnal emission and higher self-rated sex drive in adulthood. However, it should be noted that all of the findings suggesting that prenatal exposure to DES masculinizes or defeminizes behavior in men derive from one group of investigators (Kester et al., 1980) who studied two groups of subjects interviewed by an interviewer not blind to their treatment status. Those findings suggesting that DES feminizes or demasculinizes behavior were reported from three laboratories representing four groups of subjects, two of which were evaluated in a double-blind design (Yalom et al., 1973; Reinisch & Sanders, unpublished observations). Although they were not interpreted in terms of sex differences, some findings in Table IIb support those indicating that prenatal exposure to synthetic estrogens feminizes or demasculinizes behavior in male subjects. For example, exposed subjects were more interested in individual non-contact sports, either competitive or noncompetitive (showing a trend) and were rated as more reflective in comparison to their controls. Overall, the picture that emerges from these findings suggests that prenatal exposure to synthetic estrogens, particularly DES, demasculinizes and/or feminizes behavior in male subjects. In general, the findings suggesting masculinization have to do with passive interests rather than active behavior.

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Female Subjects Table IIIb presents 59 findings related to the effects on female subjects of prenatal exposure to the synthetic estrogen, DES. However, the majority of results derive from three reports from one laboratory on sexual maturation and behavior in a single sample of female subjects (MeyerBahlburg et al., 1984; 1985; Ehrhardt et al., 1985). The remaining seven findings derive from a study of cognitive functioning (Hines & Shipley, 1984). Twenty-eight findings were not significant (p > 0.10). In one of the three reports on a single sample of DES-exposed women, 13 comparisons of sexual maturation (e.g., age at menarche) and behavior (e.g., first intercourse) between DESexposed women and Pap controls were not significant. In the second report, DES subjects were more likely than the Pap controls, and in some instances their sibling controls, to obtain bisexual or homosexual ratings on a number of dimensions including sexual attraction, fantasy, and behavior. However, results from the third report on these women, indicated that, when sexual orientation was statistically controlled, DES-exposed women were not different from controls on a number of these variables (Meyer-Bahlburg et al., 1985; see subgroup labeled "Heterosexuals Only" in Table IIIb). Although heterosexual DES-exposed women had had fewer male coital partners in their lifetimes, they tended to have more heterosexual coital experiences in the past 12 months than did the Pap control subjects. Differences not related to sexual orientation also were observed. For example, heterosexual DES-exposed women reported having fewer sexual thoughts, fewer single and multiple orgasms during heterosexual coitus, and more negative feelings during lovemaking. There were no differences in the incidence of vaginismus or dyspareunia or disturbing sexual experiences (e.g., rape and sexual abuse). Although these data provide some support for the investigators' suggestion that prenatal exposure to DES is associated with increased bisexuality and/or homosexuality in women, this conclusion should be regarded as tentative, since these studies represent the only reports of a relationship between prenatal exposure to exogenous hormones and human sexual orientation. However, there is some evidence that exposure to excess androgens as a result of the clinical endocrine disorder, adrenogenital syndrome, also may result in increased bisexual imagery or orientation in women (Money & Schwartz, 1977). With regard to cognitive functioning and hemispheric laterality, two of three findings on a dichotic listening task paradoxically suggest that prenatal exposure to estrogen may masculinize and/or defeminize women. However, there were no reported differences between exposed and unexposed subjects on the verbal and visuospatial subtests of the Primary Mental Abilities Test. Combined Groups of Male and Female Subjects The effects of prenatal exposure to synthetic estrogens on the behavior of a single sample of male and female subjects has been investigated by Reinisch (1977) and Reinisch & Karow (1977). Five of seven findings were not significant (p>0.10). As shown in Table IVb, the scores of estrogen-exposed subjects on two personality factors were labeled as feminized relative to their unexposed brothers and sisters. Exposed subjects were found to be less individualistic and more group oriented, and less self-sufficient and more group dependent. These observations are generally consistent with those reported for estrogen-exposed male subjects alone, insofar as it appears that prenatal exposure to these hormones is feminizing and/or demasculinizing.

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In summary, consistent with the animal literature, prenatal exposure to synthetic estrogens appears to have a feminizing and/or demasculinizing effect on male subjects while perhaps paradoxically masculinizing and/or defeminizing female subjects.

Mixed Regimens of Progestin and Estrogen Male Subjects Table IIc lists 34 findings on the behavioral effects of prenatal exposure to mixed regimens of progestin and estrogen in boys compared to matched controls. These data were reported from two laboratories on two groups of subjects (Yalom et al., 1973; Ehrhardt et al., 1984). Although 29 of the 34 findings showed no difference between groups (p>0.10), the five significant findings were all in the direction of feminization and/or demasculinization. Both studies reported decreased athletic ability (one showing a trend) among exposed subjects as assessed by teacher, mother, and subject ratings. Hormone-exposed subjects also were rated as less assertive by teachers. It is interesting to note that these subjects had tended to associate more with girls than with boys in the past and were somewhat more likely to choose to be a girl if they could start life over again. In light of the fact that the majority of findings from these two studies were not significant, it can be concluded only tentatively that prenatal exposure to progestin/estrogen combinations may result in the demasculinization or feminization of male behavior and interests. However, the consistency of the few significant findings, in spite of mixed treatment regimens, a lack of sibling controls, and the possibility that the evaluation procedures were not sufficiently sensitive, is noteworthy. Moreover, one study (Ehrhardt et al., 1984) did not provide information on the dosages of progestin and estrogen. Consequently, it is not possible to ascertain whether these subjects were exposed to treatment regimens sufficient to affect human behavioral development. Female Subjects Only one study (Table IIIc) investigated the behavior of girls subsequent to prenatal exposure to mixed regimens of progestin and estrogen (Ehrhardt et al., 1984). Eighteen of the 25 comparisons between exposed subjects and matched controls were not significant (p > 0.10). However, six findings suggest that prenatal exposure to this hormonal treatment feminized gender identity/role (two showing trends), peer relations (two showing trends) and interest in marriage and maternalism (one significant finding), as well as having demasculinized athletic ability (one significant finding). Although four of the findings were only marginally significant, in general it appears that, as for male subjects, prenatal exposure to combinations of progestin and estrogen may feminize some aspects of behavioral development in female subjects. Combined Groups of Male and Female Subjects Two studies, representing one group of hormone-exposed subjects, reported on the effects of prenatal exposure to mixed regimens of progestin and estrogen in combined groups of male and female subjects (Reinisch, 1977; Reinisch & Karow, 1977). As indicated in Table IVc, these subjects were compared to their unexposed siblings. Six of seven comparisons between subjects exposed to mixed regimens of progestin and estrogen and their unexposed brothers and sisters on a sexually differentiated personality measure and standardized intelligence scale were not significant (p > 0.10). However, hormoneexposed subjects were masculinized on one factor, reflecting the fact that they were less sensi-

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tive and more tough-minded than their same-sex controls. These findings are generally not consistent with those presented separately for male and female subjects. In summary, whereas findings for each of the sexes alone suggest that exposure to progestin-estrogen combinations resulted primarily in the feminization and/or demasculinization of gender identity/role, the one study evaluating combined groups of male and female subjects reported that one aspect of this dimension was masculinized. This inconsistency may be due to combining data from male and female subjects for analysis, which may have distorted any effects, and/or differences in the ratio of androgenic, progestogenic, and estrogenic compounds in the treatment regimens to which male, female, and the combined group of male and female subjects were exposed. CONCLUSIONS Despite methodological inconsistencies across the 19 studies reviewed, it is nonetheless possible to derive tentative conclusions about the long-term behavioral effects in humans of prenatal exposure to the hormones under consideration. The picture that emerges is generally consistent with the scientific literature based on animal experimentation and clinical endocrine syndromes discussed below. It appears that prenatal exposure to androgen-based synthetic progestins exerted a masculinizing and/or defeminizing influence on human behavioral development, whereas exposure to natural progesterone and progesterone-based synthetic progestins had a feminizing and/or demasculinizing influence, particularly in female subjects. The data on prenatal exposure to synthetic estrogen primarily derive from subjects exposed to diethylstilbestrol (DES). DESexposed male subjects appear to have been feminized and/or demasculinized, while there is some evidence that exposed female subjects may have been masculinized. There are several methodological problems inherent to research in this area of human behavioral endocrinology in which true experimental design is precluded. For example, the use of small samples raises questions about the representativeness, and therefore the generalizability, of these findings. And, larger treatment effects are required with small samples in order to attain statistical significance. Thus, more subtle effects of prenatal exposure to hormones may go unrecognized. Unfortunately, it is difficult to locate large groups of subjects exposed to particular hormones of interest because (1) treatment regimens commonly involve a mixture of hormones with variable dosages and timing and duration of administration; (2) medical records often do not provide sufficient documentation of treatment, thereby limiting the number of potential subjects that can be considered for evaluation; (3) the high rate of mobility in the United States makes it difficult to locate subjects based on antenatal records; and (4) there is limited financial support for human research in this area, which is quite costly, in terms of both money and time. However, even given these limitations, scientific progress in this area would be considerably enhanced if research clearly addressed the issues of the specific hormones administered and the specific parameters of dosage, duration, and timing of treatment, and whether prepregnancy conditions, pregnancy complications, and maternal complaints were controlled for by matching or statistical adjustment. It also would be helpful if researchers utilized double-blind designs, a standardized assessment battery, siblings or controls matched on a wide range of variables beyond age, sex, IQ, and socioeconomic status, and post hoc statistical adjustments for biases between index and control groups.

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DISCUSSION We have reviewed findings from 19 studies on the behavioral effects of prenatal exposure to hormones used in the treatment of at-risk human pregnancy. These exogenous hormones are similar, but not identical, to the endogenous hormones present in the normal prenatal environment. Data regarding the role of exposure to natural progesterone, synthetic progestin, synthetic estrogen, and combinations of progestin and estrogen in the development of eight categories of sexually dimorphic behavior were evaluated separately for male and female subjects. Whenever possible, effects were interpreted in terms of whether or not they reflected increased masculinization, defeminization, feminization, or demasculinization among prenatally hormone exposed subjects compared to same-sex controls. The examination of within-sex behavioral differences obviates the confound between prenatal factors and differential socialization, thereby clarifying the processes by which behavioral differences develop between and within the sexes. Our review suggests that endogenous hormones present prenatally influence at least some aspects of sexually dimorphic behavioral development in normal male and female subjects, perhaps by establishing particular behavioral predispositions. In general, play-related activities and interests, aggression/assertion, and gender identity/role emerged as the behavioral categories most often affected by prenatal exposure to exogenous hormones. These effects are not simple, however. For example, although prenatally DES-exposed male subjects appear to have been demasculinized in terms of interest in active participation in sports, they were masculinized with regard to interest in passive viewing of sports. Prenatal exposure to some of these hormonal treatments was associated with delayed or diminished sexual maturation and behavior, while in other instances these dimensions were enhanced. Data from these exogenous hormone studies are generally consistent with those based on female and male subjects with the clinical endocrine disorders, adrenogenital syndrome (AGS) and androgen insensitivity syndrome (AIS) (see Money & Ehrhardt, 1972, for review). AGS results from the genetically induced absence of, or deficiency in, an essential enzyme needed for the synthesis of cortisol. The inability to synthesize cortisol leads to an abnormal buildup of adrenal androgens. Thus, AGS in human females is analogous to laboratory animal experiments in which nonhuman genetic females are administered androgens during the period critical for the sexual differentiation of brain and behavior. The available data suggest that even early-treated females with AGS are masculinized and/or defeminized with respect to sexually dimorphic play behavior, interest in marriage and maternalism, and gender identity/role (Ehrhardt et al., 1968; Masica et al., 1971; Ehrhardt & Baker, 1974; Money & Schwartz, 1977). The limited available data on the behavior of male subjectsn with this syndrome are inconsistent, with some suggesting increased masculinization (Ehrhardt & Baker, 1974) and some indicating no differences between these male subjects and their controls (McGuire et al., 1975). Evidence that androgenic hormones present prenatally may masculinize and/or defeminize behavior in patients with AGS supports the findings reported herein on androgenic synthetic progestins. AIS is the result of a genetically-induced insensitivity to androgens, due to the lack of the normal complement of androgen receptors at the cellular level. Although genetically male subjects with this disorder usually produce normal amounts of testosterone, they are not able to utilize this androgen. Boys with total AIS are virtually indistinguishable from girls at birth and experience a feminizing puberty. AIS in human male subjects is analogous to laboratory animal experiments in which nonhuman genetic males are either chemically or surgically

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deprived of androgenic stimulation during the period critical for the sexual differentiation of brain and behavior. Although there are only a few studies of males with total AIS, the available data indicate that they are feminized and/or demasculinized with regard to interest in marriage and matemalism and gender identity/role (Money et al., 1968). Exogenous exposure to natural progesterone, progesterone-based synthetic progestin (for female subjects), estrogen (for male subjects), and mixed regimens of progestin and estrogen in general show a similar effect. These findings reflect the antiandrogenic properties of these exogenous hormones. In general, data gathered on subjects prenatally exposed to exogenous hormones, supported by studies on clinical endocrine syndromes, indicate that gonadal hormones influence the human brain and behavior in a manner consistent with data from animal experiments and established principles of sexual development and differentiation. Despite this consistency, the relationship between endogenous prenatal hormones and sexually dimorphic behavioral development has been questioned, largely because evidence for its existence is based on findings from atypical populations (Quadagno et al., 1977; Fausto-Sterling, 1985; Bleier, 1986). Importantly, however, some data deriving from normal populations also indicate that sex differences in behavioral development may be influenced by the prenatal hormonal milieu. Several studies have confirmed a sex difference in fetal levels of testosterone during the period of morphological differentiation of the genitalia (i.e., the 14th to 18th week), although the higher male levels begin to decline around week 17 (Abramovich, 1974; Reyes et al., 1974; Robinson et al., 1977). Significantly higher levels of unbound plasma testosterone in peripheral blood samples drawn from women carrying male fetuses, compared to those carrying female fetuses, also have been observed (Drmer et al., 1975). Although inconsistencies exist in the literature, sex differences in concentrations of hormones in the umbilical cord blood of male and female newborns at delivery have been observed in both humans and rhesus monkeys (e.g., Abramovich & Rowe, 1973; Abramovich, 1974; Resko, 1974; Forest & Cathiard, 1978; Maccoby et al., 1979). In general, circulating testosterone levels appear to be higher in male than in female infants at birth, whereas estrogen concentrations appear to be comparable between the sexes. Data regarding sex differences in progesterone levels at birth are contradictory (Hagemenas & Kittinger, 1972; McDonald et al., 1973; Laatikainen & Peltonen, 1974; Resko, 1975; Forest & Cathiard, 1978; Maccoby et al., 1979). Nonetheless, sex differences in the relationships among several hormones in cord blood samples and early postnatal behaviors, including timidity, muscle strength, and mood, have been noted in normal human neonates (Jacklin et al., 1983; 1984; Marcus et al., 1985). These data suggest that differences in perinatal levels of endogenous hormones may be related to sex differences in behavior, personality, and temperament in later life. In addition to serum assays, amniocentesis has been employed in investigations of the concentrations of hormones present prenatally in normal male and female fetuses. Significant sex differences in midgestation levels of fetal testosterone (male levels being higher) have been observed among fetuses of normal, healthy pregnancies (e.g., Finegan e t a L , 1989). Additionally, individual within-sex differences in plasma testosterone during the same period of gestation have been noted among rhesus (Resko, 1974) and human (Wame et al., 1977) males. These sophisticated diagnostic procedures open the door to future research wherein it will be possible to prospectively correlate variability in fetal hormone levels both between and within the sexes with behavioral variability later in life among offspring from normal pregnancies. The potential for investigating the relationship between the normal prenatal hormone environment and postnatal behavior holds promise for a better understanding of the ontogeny of sexually dimorphic aspects of neurological and behavioral development.

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Acknowledgements: We express our gratitude to Dr. Craig A. Hill for his assistance in evaluating sex-typing of behavioral dimensions, in compiling tables, and for providing editorial comments. We also thank Sandra Stewart Ham for typing drafts of the tables and Janet Rowland, Petra Miskus and Kim Sare for clerical and reference assistance. Supported in part by Public Health Service grants HD20263 (to JMR) and DA05056 (to JMR and SAS). REFERENCES Abmmovich DR (1974) Human sexual differentiation - - in utcro influences. J Obst Gynaecol Brit Commonwealth 81: 448-453, Abramovich DR, Rowe P (1973) Foetal plasma testosterone levels at mid-pregnancy and at term: relationship to foetal sex. J Endocrino156: 621-622. Arnold AP, Gorski R (1984) Gonadal steroid induction of structural sex differences in the CNS. Annu Rev Neurosci 7: 413- 442. Baack J, De Lacoste-Utamsing MC, Woodward DJ (1982) Sexual dimorphism in the human fetal corpora caUosa. Neurosci Abstr 8: 18. Beatty WW (1984) Hormonal organization of sex differences in play fighting and spatial behavior. Prog Brain Res 61: 315-330. Bern SL (1974) The measurement of psychological androgyny. J Consult Clin Psycho142: 155-162. Benbow CP (1988) Sex differences in mathematical reasoning ability in intellectually talented preadolescents: their nature, effects, and possible causes. Behav Brain Sci 11: 169-232. Berzins JI, Welling MA, Wetter RE (1978) A new measure of psychological androgyny based on the Personality Research Form. J Consult Clin Psycho146: 126-138. Bleier R (1986) Sex differences research: science or belief. In: Bleier R (Ed) Feminist Approaches to Science. Pergamon Press, Elmsford NY, pp 147-164. Breedlove M, Arnold A (1981) Sexually dimorphic motor nucleus in rat spinal cord: response to adult hormone manipulation, absence in androgen insensitive rats. Brain Res 225: 297-307. Burstein B, Bank L, Jarvik LF (1980) Sex differences in cognitive functioning: evidence, determinants, implications. Hum Deve123: 289-313. Constantinople A (1973) Masculinity-femininity:an exception to a famous dictum? Psychol Bull 80: 389407. Dalton K (1968) Ante-natal progesterone and intelligence. J Psychiat 114: 1377-1382. Dalton K (1976) Prenatal progesterone and educational attainments. Br J Psychiatry 129: 438-442. Daly M, Wilson M (1983) Sex, Evolution, and Behavior. PWS, Boston. De Lacoste MC, Woodward DJ (1983) Neocortical commissural size and sex differences in primate brain. Soc Neurosci Abstr 9: 45. De Lacoste-Utamsing MC, Holloway RL (1982) Sexual dimorphism in the human corpus caUosum. Science 216: 1431-1432. De Lacoste MC, Holloway RL, Woodward DJ (1986) Sex differences in the fetal human corpus callosum. Hum Neurobiol 5: 93-96. DeVoogd TJ (1991) Endocrine modulation of the development and adult function of the avian song system. Psychoneuroendocrinology 16: 41-66. DeVries GJ, DeBruin JCP, Uylings HBM, Corner MA (Eds) (1984) Sex differences in the brain. Progr Brain Res 61. Diamond MC (1991) Hormonal effects on the development of cerebral lateralization. Psychoneuroendocrinology 16: 121-129. Diamond M, Llacuna A, Wong CL (1973) Sex behavior after neonatal progesterone, testosterone, estrogen, or antiandrogens. Horm Behav 4: 73-88. Di Pietro JA (1981) Rough and tumble play: a function of gender. Dev Psychol 17: 50-58. Dtrner G, Dtcke F, Hinz G (1971) Paradoxical effects of estrogen on brain differentiation. Neuroendocrinology, 7: 146-155. Dtirner G, Stahl F, Rhode W, Robner P, Halle H, Schott G (1975) Elevated free testosterone in the plasma of early pregnant women bearing male fetuses and of hypersexual men. Endokrinologie 65: 224.

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Hormonal contributions to sexually dimorphic behavioral development in humans.

Nineteen studies on the behavioral effects of prenatal exposure to hormones administered for the treatment of at-risk human pregnancy are reviewed. Be...
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