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. 2008 Feb 28;149(6):2743–2749. doi: 10.1210/en.2008-0049

Progesterone Receptors and Neural Development: A Gap between Bench and Bedside?

Christine K Wagner 1
PMCID: PMC2408811  PMID: 18308849

Abstract

Despite a recent increase in the clinical use of progesterone in pregnant women and premature neonates, very little is understood about the potential role of this hormone and its receptors in neural development. Findings from rodent models indicate that the brain is indeed sensitive to progesterone during critical periods of development and maturation. Dramatic sex differences in progesterone receptor (PR) expression, in which males express higher levels of PR than females in specific regions, suggest that PR may play an important role in the sexual differentiation of brain and behavior and that the expression of PR may be one mechanism by which testicular hormones masculinize the brain. PR is also transiently expressed during fetal and neonatal development in areas of the brain associated with cognitive behaviors. PR protein and mRNA are expressed in pyramidal cell layers of perinatal cortex in an anatomically and developmentally specific manner, generating the intriguing hypothesis that progesterone is essential for normal cortical development. Basic research elucidating a potential role for progesterone and PR in developing brain is reviewed in light of the clinical use of this hormone. The necessity for future research integrating findings from the bench and the bedside is evident.

THE ADMINISTRATION OF progesterone to pregnant women for the prevention of premature birth is becoming increasingly common in the United States (1). In addition, breast-fed neonates may be exposed to progestins from maternal contraceptive use (2,3,4), and clinical trials in which premature infants are treated with progesterone and estradiol are underway in Europe (5). Yet very little is known about the effects of progestin exposure on the developing brain. In contrast to the traditional notion of progesterone (P) as a female hormone, a role for progesterone and progesterone receptors (PR) in the development of the male brain is beginning to emerge. Numerous regions of the developing male rodent brain express PR (6), and dramatic sex differences in PR expression during critical windows of development suggest that PR plays an important role in sexual differentiation of the brain. In addition, the developmentally transient expression of PR in brain regions linked to cognition, and not directly related to reproductive function, implies that the effects of P on brain development are more extensive than previously thought. This review discusses evidence implicating PR in the development of the male brain and highlights the critical need for future research in this area in light of the rising clinical use of progestins.

P Use in Humans

As the rate of premature birth (<37 wk) in the United States increases at alarming rates [an increase of about 30% over the past two decades; (1)], the administration of P to pregnant women to prevent premature delivery has significantly increased (7,8). In a study published in the American Journal of Obstetrics and Gynecology in 2006 (1), two thirds of board-certified maternal-fetal medicine specialists reported using P to prevent preterm birth, compared with only 38% in 2003, a 76% increase in just a few years. Yet in several recent comprehensive papers on the use of progestins, little attention is given to the need for follow-up on the children exposed to P in utero (e.g. Refs. 9,10,11).

In ongoing clinical trials in Germany, premature infants have been treated with a continuous infusion of P and estradiol for the initial few weeks of life (5,12,13,14). The rationale behind this treatment is that premature infants are deprived of the maternal hormonal environment to which they would normally be exposed at the end of gestation. Premature female infants receiving this hormonal treatment demonstrated increased uterine growth and changes in vaginal cytology, indicating that hormonal exposure alters neonatal physiology (14). Interestingly, premature infants treated with hormones achieved normal psychomotor development earlier than untreated premature infants (13). Whereas this suggests some beneficial effects of hormonal treatment, the long-term consequences of this relatively new practice are not completely understood.

Progestin-only contraceptives are routinely prescribed to lactating women as a safe alternative to contraceptive methods containing estrogen, which can interfere with milk production. Recent evidence suggests that progestins in contraceptives can enter mother’s milk, can be detected in the serum of breast-fed infants (2,3,4,15), and may influence the infant hypothalamo-pituitary-thyroid axis (16). Yet a recently published meta-analysis of clinical reports concluded that evidence regarding the use of hormonal contraceptive during lactation is limited and of poor quality and stressed the urgent need for a properly conducted clinical trial in this field (17).

In each of these examples, the timing of progestin exposure in fetuses and neonates closely corresponds to important periods of brain maturation. Existing evidence from rodent models suggests that many regions of the developing brain, particularly the male brain, are sensitive to P. Although P treatment in women and infants may potentially produce immediate beneficial results, very little is known about the role of progestins and PR in neural development and the possible long-term effects of such exposure.

Progestin Receptor Expression in Developing Brain

Steroid hormones exert their effects on target tissues through the activation of specific nuclear receptors, which as transcription factors, can exert powerful effects on gene expression and thereby cell function. Therefore, the sensitivity of the developing brain to P is conferred, at least in large part, by the expression of nuclear PR in specific brain regions during critical developmental periods. Previous studies have demonstrated both progestin binding and PR mRNA in homogenized whole hypothalamus of neonatal rats (18,19) and have suggested developmental regulation of PR. Using the cellular level resolution of immunocytochemistry to detect PR protein, our laboratory has reported that specific subpopulations of neurons within numerous regions of both the fetal and neonatal rat forebrain express high levels of PR immunoreactivity (PRir) as early as embryonic d (E) 17–18 (6). PR was expressed in regions with known reproductive and/or neuroendocrine function, such as the anteroventral periventricular nucleus (AVPv), the medial preoptic nucleus (MPN), the arcuate nucleus, and the ventromedial nucleus of the hypothalamus. However, PRir was also expressed in regions not typically associated with reproduction, but rather, associated with cognitive, motor, and visual function, such as neocortex, hippocampus, caudate putamen, and lateral geniculate nucleus (6). PR expression was transient during perinatal life in these regions, suggesting an exclusively developmental function for progesterone. These findings are consistent with the emerging idea that progesterone and its receptors may play a critical role in specific and fundamental mechanisms of neural development.

Sex differences in PR expression

Circulating levels of progesterone are similar in perinatal male and female rodents (20,21). However, dramatic sex differences in PR expression exist within specific regions of fetal and neonatal brain in which PR expression is high in males and is virtually absent in females (Fig. 1). For example, from E19 until postnatal d 10, the MPN of the male expresses high levels of PRir and PR mRNA, whereas the female MPN expresses very little PRir until the second postnatal week (22,23,24), thereby reducing, but not eliminating the sex difference. These findings suggest that there are developmental windows during which the male brain may be more sensitive to progesterone than the female brain. The prenatal surge in testosterone secretion from the testes at approximately E18 is responsible for the fetal expression of PR in males (23), whereas the onset of estradiol synthesis by the ovary after Postnatal d 10 is responsible for the later expression of PR in females (22). Treatment of female fetuses with testosterone or with the aromatized metabolite of testosterone, estradiol, induced PR expression in the MPN to levels seen in males (22,23). Similarly, castration on the day of birth, treatment with an aromatase enzyme inhibitor, or administration of the selective estrogen receptor modulator, tamoxifen, virtually abolished PR expression in the MPN of perinatal males (22,23,25). Furthermore, PR expression is dependent on estrogen receptor (ER)-α activity because males that lack a functional ERα gene do not express PR in the MPN (26). A similar sex difference in PR expression (males more than females) has also been documented in the arcuate nucleus and the AVPv (Fig. 1) (22), both of which are sexually differentiated structures that regulate critical neuroendocrine functions in adulthood.

Figure 1.

Figure 1

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PR activity may be one mechanism by which testicular hormones masculinize neural development and subsequent adult behavior. A, Neonatal treatment of females with the PR antagonist, RU486, attenuated the masculinizing effects of testosterone propionate (TP) on the volume of the SDN-POA (27). *, Significantly different from vehicle group (P < 0.05; **, significantly different from oil-treated females (P < 0.01). B, Neonatal treatment of males with RU486 significantly reduced the percent of males displaying mounting behavior in adulthood (34). *, Significantly different from untreated and vehicle.

PR and sexual differentiation of the brain and behavior

Sex differences in PR expression suggest a differential sensitivity of developing male and female brains to progesterone and implicate PR in the sexual differentiation of the brain. The induction of PR expression by testicular hormones suggests that the expression of PR during development may be one mechanism by which testosterone and its metabolite, estradiol, masculinize neural development and subsequent adult behavior. Consistent with this idea, Quadros et al. (27) demonstrated that neonatal treatment of females with the PR antagonist, RU486, attenuated the masculinizing effects of testosterone on the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) (Fig. 2A). Interestingly, the effects of neonatal RU486 treatment were dependent on sex because the same doses of RU486 and testosterone given to males castrated on the day of birth hypermasculinized SDN-POA volume, suggesting that prenatal exposure to endogenous testosterone alters the postnatal response to PR activity (27). This raises the intriguing idea that natural fluctuations in the timing and level of testosterone and P exposure, in concert with tightly regulated nuclear receptor expression, produce dynamic and complex hormonal interactions that are important for normal sexual differentiation of the MPN (28).

Figure 2.

Figure 2

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There are striking sex differences in PR expression, in which males express much higher levels of PR than females within specific regions of the perinatal rat brain associated with reproductive and/or neuroendocrine function in adulthood. For example, A, PRir in the MPN and the periventricular (PeN) of male and female rats on the day of birth (24). B, PRir in the arcuate nucleus of male and female rats on postnatal d 7. C, PR mRNA, detected by in situ hybridization, in the AVPv of male and female rats on the day of birth. 3V, Third ventricle; AC, anterior commissure.

In addition to effects on morphology, PR appears to play a role in the sexual differentiation of MPN-dependent adult male sexual behavior. The idea that perinatal progesterone exposure and PR activity in brain might influence the development of sexual behavior goes back as early as the 1970s (e.g. Refs. 29,30,31,32,33). However, variability in the doses and timing of P treatment across reports produce disparate results that are difficult to synthesize into a unified conclusion (28). More recently Lonstein et al. (34) demonstrated that neonatal treatment of males with RU486 reduced subsequent sexual behavior in adult males (Fig. 2B). To date, only two papers have examined sexual behavior in transgenic mice lacking a functional PR gene (PR knockout mice), and although results differ between the two reports, both suggest that PR expression influences normal male sexual behavior (35,36). As in all studies using transgenic mice, it is difficult to determine from these experiments whether PR exerts its effects on behavior through its actions during development, during adulthood (e.g. Refs. 37 and 38), or during puberty (39). However, sex differences in the expression of PR in the developing MPN and behavioral effects of neonatal RU486 in rats suggest that PR expression in MPN during development is critical for normal reproductive behavior in males.

Expression of PR in nonreproductive areas of developing male brain

It is becoming increasingly evident that steroid hormones and their receptors not only exert effects on brain regions with reproductive and/or neuroendocrine function but also influence the development and function of brain areas more commonly associated with cognitive function. Since 1980 evidence existed that PR was expressed within the cortex of developing rats and mice (18,19,40,41). Our laboratory has recently demonstrated that PR is transiently expressed in specific lamina of fetal and neonatal cortex (Fig. 3). PR is first expressed in the cortical subplate (Fig. 3A) beginning a few days before birth and continuing through at least the first postnatal week. Subplate neurons mature earlier than other cortical plate neurons and play a pivotal role in pioneering corticothamalic and corticofugal connections (42,43). PR is later expressed in neurons of the pyramidal cell layers of cortex beginning on approximately postnatal d 1 in layer 5 and approximately postnatal d 7 in layers 2 and 3 (Fig. 3B) (6,44). This developmental pattern of PRir expression comes to an end sometime between postnatal d 14 and 28. There are no striking sex differences in PR expression in neocortex, in contrast to those in preoptic and hypothalamic regions (Lopez, V., and C. K. Wagner, unpublished observations), nor is PR in cortex altered by testosterone or estradiol exposure (45). Rather, preliminary work from our laboratory suggests that PR expression in cortex is regulated by maternal thyroid hormone levels (46), consistent with an earlier report by Hirata et al. (47). In addition to the expression of PR in developing neocortex, Quadros et al. (6) demonstrated that PRir is also transiently expressed within the dentate gyrus of the hippocampus beginning shortly before birth and continuing through the second week of life. Developmentally transient PR expression in the cortex and hippocampus suggest that PR may play a fundamental role in the development of these regions and thereby influence later cognitive behaviors. For example, work from Hull and colleagues in the 1980s demonstrated that perinatal P exposure facilitated active avoidance behavior, but impaired maze performance (29,48), suggesting that P exerts a more complex effect on the developing brain than a simple inhibition or facilitation of learning.

Figure 3.

Figure 3

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PR is transiently expressed within specific lamina of perinatal neocortex. PRir nuclei in the subplate of neocortex in a male rat on postnatal d 1 (A) and in cortical layer V (B) in a male rat on postnatal d 7. cc, Corpus callosum; sp, subplate.

Possible sources of endogenous P in developing male brain

The source of endogenous ligand for PR in developing male brain is currently unknown, but several possibilities exist. Potential sources include the adrenal gland, the maternal ovary, the placenta, and/or de novo synthesis of P within the developing brain itself. Circulating P levels are extremely high in females during pregnancy and lactation (49,50). Preliminary studies from our laboratory demonstrate that plasma P levels in mothers and fetuses are positively correlated at the end of gestation and suggest that P from maternal circulation can bind to nuclear PR within the fetal male rat MPN (20). In humans, progesterone has been isolated and quantified in mother’s milk (51), and it has been demonstrated that progestins in milk can pass to breast-fed neonates (2,3,4). In addition to potential maternal sources of P, the perinatal rodent brain expresses all the enzymes necessary for the de novo synthesis of P from cholesterol (52,53,54,55), potentially producing locally high concentrations of P within specific brain regions. Thus, it is likely that both the fetal and neonatal brain may be exposed to significant concentrations of endogenous P.

Progesterone and Human Development

Role of P exposure in human sexual development

The practice of treating women with progestins early in pregnancy to prevent miscarriage was abolished in the 1970s when some girls born to treated women had masculinized genitalia requiring corrective surgery due to the androgenic effects of the synthetic progestins prescribed (56). Although the incidence of tomboyism was increased in exposed female offspring (57,58), it is unclear whether to attribute these behavioral changes to progesterone receptor or androgen receptor action during development. However, other studies in boys suggest that in utero exposure to nonandrogenic progestins was negatively correlated with physical activity in childhood and heterosexual activity in adolescence (58). Although provocative, these early studies were wrought with methodological limitations and cross-study inconsistencies, making it difficult to draw a simple conclusion. However, these findings suggest the importance of monitoring psychosocial and psychosexual development in children exposed to progesterone in recent years (1).

Prenatal exposure to progestins and cognition in humans

The idea that exposure to P during perinatal life plays a role in cortical development and/or cognitive behavior is not unique to the rodent literature. It was initially reported that girls exposed to progestins prenatally had higher than average IQ scores (59). The observation was also made that children whose mothers received P during pregnancy were more likely to be standing and walking on their first birthday and had greater academic achievement at 9–10 yr of age, compared with controls (60). Interestingly, it was reported that academic success showed a dose-dependent effect, with academic performance being highest in children whose mothers had received more than 8 g of P during pregnancy (61). Whereas several studies failed to replicate the original findings (57,62,63), these studies were only pseudoreplications, in that they examined synthetic progestins, rather than natural P and, in general, mothers had received lower doses of progestins than in the original study. It is perhaps noteworthy that recent studies demonstrated that premature infants given P and estradiol treatment neonatally scores on the Psychomotor Developmental Index at 15 months (corrected age) fell within the normal range, whereas the Psychomotor Developmental Index of untreated premature infants indicated mildly delayed performance (13). Although this may be attributable to general effects on overall health, the possibility exists that hormonal treatment had a beneficial effect on brain development. Clearly the unresolved question of whether prenatal progestin exposure influences cognitive ability remains clinically important and in need of more rigorous assessment.

A Working Model of PR and the Development of the Male Rodent Brain

Existing evidence can be used to create a working model of P and PR action in the developing male brain (Fig. 4). In the MPN, in which PR expression is dependent on testicular hormone secretion and ERα function (22,23,26), exposure to P during critical periods of development may exert profound effects on the male but exert very little effect on females, who express very little PR in this region (22,24). In this manner, P and PR may play a critical role in sexual differentiation and the normal development of the male brain and reproductive behavior. Evidence spanning several decades of research suggests that exposure to exogenous P or changes in PR activity during neural development can alter the function of the MPN in the form of altered sexual behavior.

Figure 4.

Figure 4

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Differential regulation and activation of PR across brain regions creates a working model for the actions of P and PR within the MPN and cortex of fetal and neonatal rats. In the MPN of males, testosterone (T), secreted by the fetal and neonatal testes, readily enters the brain, in which it can be aromatized to estradiol (E) or reduced to dihydrotestosterone (DHT). Estradiol activates ERα, which increases the transcription of the PR gene. This results in a developmental period between E18 and approximately postnatal d 10 when PR expression is high in males but not females. P may arise from one or more potential sources creating brain concentrations of P that are dynamic and perhaps locally quite high. P presumably activates PR, which as a transcription factor can initiate a cascade of molecular and cellular events, which, because they occur in the male brain only, lead to sexual differentiation of MPN structure and function. In contrast, PR is expressed in an anatomically and developmentally specific manner in both male and female fetuses and neonates. PR expression in cortex is not regulated by either androgens or estradiol but rather appears to be dependent on maternal thyroid status; expression of PR in developing cortex is reduced by maternal hypothyroidism. P, likely arising from de novo synthesis in cortex, activates PR. Because PR is expressed in cortical subplate neurons and pyramidal cell layers 5 and 2 and 3, it is possible that PR plays an important role in establishing normal thalamocortical connectivity. AR, Androgen receptor; TH, thyroid hormone; THR, thyroid hormone receptor.

In cortex, a nonreproductive area of the brain, PR expression is similar in males and females and is not regulated by either estradiol or androgen exposure (45). Rather, PR in cortex appears to be regulated maternal thyroid hormone levels (46,47). PR activity during late fetal and early postnatal life may play a critical role in the proper development of specific cortical lamina in both males and females. In addition, P exposure may alter normal cortical function manifested in the form of altered learning and memory (29,48).

From this hypothetical model it can be proposed that P and PR exert temporally and anatomically specific effects on fundamental developmental processes. Exogenous P exposure, at abnormally high levels or during inappropriate periods of development, could produce consequential and long lasting effects on brain function and behavior. Surely this model requires more extensive research before its complexity and implications can be elucidated fully.

Conclusions

Clearly P cannot be regarded as simply a female hormone. Evidence from rodent models adds to the growing notion that PR may contribute to the normal maturation of the male brain and may influence the development of neuroendocrine and reproductive capacities. However, PR may also guide fundamental developmental processes within brain regions more closely associated with cognitive function in both males and females. In light of the dramatic rise in the use of P in women to prevent premature birth, the use of progestin contraceptives in lactating women and the potential treatment of premature infants with progesterone, our lack of knowledge regarding PR and neural development is disconcerting. Future research in this area must strive to bridge the gap between the potentially beneficial effects of clinical P use and the implications for neural development from basic research in rodent models.

Acknowledgments

We give special thanks to Princy S. Quadros and Veronica Lopez for their contributions.

Footnotes

This research was supported by National Science Foundation Grant IOB447492 and a grant from the March of Dimes Foundation for Birth Defects (to C.K.W.).

Disclosure Statement: The author has nothing to disclose.

First Published Online February 28, 2008

Abbreviations: AVPv, Anteroventral periventricular nucleus; E, embryonic day; ER, estrogen receptor; MPN, medial preoptic nucleus; P, progesterone; PR, progesterone receptor; PRir, PR immunoreactivity; SDN-POA, sexually dimorphic nucleus of the preoptic area.

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