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Neuroscience and Biobehavioral Reviews
journal homepage: www.elsevier.com/locate/neubiorev
Anorexia nervosa and estrogen: Current status of the hypothesis
John K. Young *
Dept. Anatomy, Howard University College of Medicine, 520 W St., NW, Washington, DC 20059, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 November 2009 Received in revised form 28 January 2010 Accepted 29 January 2010 Keywords: Anorexia Estrogen Hypothalamus Genetics Estrogen receptors Neonatal Feeding
Anorexia nervosa occurs predominantly in young women. Also, recent data suggest that a heritable, genetic defect may contribute to this feeding disorder. These observations support the hypothesis that an inherited, abnormal response of the brain to rising levels of estrogens at puberty may contribute to the symptoms of weight loss in anorexia. To evaluate the merits of this hypothesis, the current literature on feeding depression by estrogens in anorexic patients and possible genetic or developmental mechanisms that could alter brain responsiveness to estrogens are reviewed. It is concluded that a number of speciﬁc biochemical or developmental pathways—abnormalities in the classical or membrane-bound forms of estrogen receptors, in co-activators for estrogen, in thyroxine receptors, in steroid metabolizing enzymes, in quantitative trait loci, in perinatal androgenization, and in processes of puberty—could converge to produce an abnormal response to estrogen and the onset of anorexia nervosa. ß 2010 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. Evidence for abnormal effects of steroids in feeding disorders . Anorexic effects of estrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular mechanisms of estrogen action . . . . . . . . . . . . . . . . . Developmental events that affect responsiveness to estrogen . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1196 1196 1197 1198 1198 1199
One feature of anorexia nervosa (AN) that distinguishes it from many other neuropsychiatric disorders is that it occurs mainly in young women at or about the time of puberty. Therefore, a major goal of research on AN should be to explain this unusual sex difference in incidence. Traditional approaches examined the psychosocial characteristics of women in attempts to reach this goal. More recently, data showing that AN is highly heritable and has a strong genetic component have lead to searches for inherited, neurochemical features of females that might predispose women towards the development of AN (Bulik et al., 2007; Kaye et al., 2008). One straightforward explanation is that an abnormal response of the brain to increasing blood levels of estrogens during puberty could be involved in AN (Butera, 2010; Eastwood et al., 2002; Klump et al., 2006; Qiu et al., 2006; Rosenkranz et al., 1998; Young, 1975, 1991). This hypothesis is one among many of theories
* Tel.: +1 202 806 7723; fax: +1 202 265 7055. E-mail address: firstname.lastname@example.org. 0149-7634/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2010.01.015
proposing that an abnormal function of feeding-regulating circuits in the hypothalamus and elsewhere could underlie AN (RaskAndersen et al., 2010). Ovarian steroids such as 17b estradiol have long been known to exert effects upon feeding in experimental animals and humans (see below). Molecules with estrogenic activity also include estrone and estriol, which are present in substantial amounts in human serum; hence, it is more appropriate to refer to ovarian ‘‘estrogens’’ rather than to ‘‘estrogen’’ in discussing effects of ovarian steroids upon eating (Blaustein, 2008; Eliassen et al., 2006). ¨ Sodersten et al. (2008) have criticized these neurochemical types of approaches on the grounds that, while theoretically interesting, they have not led to effective psychopharmaceutical treatments for AN. He has argued that AN begins when a patient initially ﬁnds a condition of low body weight and reduced intake to be rewarding. This leads to a disordered pattern of eating, lowered body fat, and other symptoms of starvation like amenorrhea. According to this view, many of the psychological features of anorexics, like compulsivity, perfectionism, preoccupation with
administration of steroids was closely correlated temporally with the subsequent development of AN. Butera. 2008. These sites abound in feeding-regulating neurotransmitters and neuropeptides that have been implicated in the genesis of AN (Rask-Andersen et al... 2001. even when treatments are aimed at ameliorating them. which restores ovarian function and menstruation in anorexics.. Thus. Evidence for abnormal effects of steroids in feeding disorders Direct evidence that an abnormal response to estrogens may be present in AN is sparse and mainly comes from clinical studies that could be criticized as anecdotal in nature. an abnormal function of many possible targets of estrogens could result in AN. However. Young et al. a selective estrogen receptor agonist... some degree of intervention in the free behavior of an AN patient seems justiﬁable (Agras. 1989. 2007. Clariﬁcation of this issue would be helpful. low.. Finally. 2008). Similar effects in humans have been suggested by a decreased caloric intake (by about 10%) that occurs during the days of the menstrual cycle when levels of estrogen are elevated (Asarian and Geary. Estrogens increase the sensitivity of the brain to satiety factors such as leptin. In any event. Differences between these two studies may be related to differences in the types of estrogenic compounds utilized. additional functional alterations are likely also induced by classical estrogen receptors that directly affect gene transcription (Roepke et al. 4-day cycles in food intake that take place prior to vaginal opening can be observed. 2007). Cell populations affected by estrogens appear to include feedingregulating neurons that utilize neuropeptide Y and proopiomelanocortin as neurotransmitters..K. are simple consequences ¨ of starvation. However. 2. 1996).. This suggests that at least one feature of AN—rewarding aspects of dieting—is not present in most individuals to the same degree as in anorexics.. however.. Gao et al. Other types of studies of effects of steroids in feeding disorders are also available. reported an improvement of symptoms of depression but no changes in other psychological or behavioral symptoms (Yokoyama et al.. 1977).. treatment of bulimic women with an anti-androgen decreased episodes of bulimia (Naessen et al.. a study of ﬁve anorexics treated with raloxifene. if anorexics are otherwise normal individuals who are simply adapting to starvation. which according to Sodersten can also be found in certain victims of starvation.. and hyperactivity. Anorexics typically defend their patterns of behavior. Skalba et al. 2010).. leading to circulating levels of estradiol that are about one-fourth that of normal levels (Audi et al. Muhs and Liberrz (1993) reviewed a total of 21 such cases and concluded that. 2007). increases in blood levels of estrogens beyond these minimal amounts need not further alter food intake. in spite of lowered body weight (Wade and Gray. 1989). or if some other subjective phenomena such as an aversion to tastes occur in the estrogenic (periovulatory or follicular) phase of the human menstrual cycle. Weizman et al. In pre-pubertal rats. 1978a. Young / Neuroscience and Biobehavioral Reviews 34 (2010) 1195–1200 body image and size. Anorexic effects of estrogen The ability of estrogens to depress feeding in ovariectomized rodents is well known and has been summarized in a number of excellent reviews (Asarian and Geary. All of these clinical reports suggest that sudden alterations in the steroid milieu of the brain can be associated with alterations in eating. does not worsen their patterns of eating or weight gain (Nillius et al.. in a majority of patients. In this context. Such patients show signs of sexual immaturity and are consequently treated with sex steroids to induce the secondary sexual characteristics of puberty. pre-pubertal levels of estrogens that do not affect the function of reproductive organs nevertheless seem to affect feeding. Thus. in view of the fact that AN is associated with a mortality rate higher than for any other psychiatric disorder. Ohzeki et al. Clegg et al. 1996. Also. Thammacharoen et al.. One objection to the general proposal that estrogens could heighten the risk for developing AN is that many anorexics have amenorrhea and a lowered ovarian production of estrogens.. 2010). 2006.. Cheng et al. Musatov et al. 2002. The sudden introduction of sex steroids to immature girls can be followed by symptoms of AN that often cease soon after the steroid replacement therapy is stopped (Kauli et al. and cholecystokinin (Butera et al. since a decline in appetite per se is not generally believed to occur in AN.. Estrogen-induced taste aversions have been demonstrated in rats (Ossenkopp et al. Thammacharoen et al. 1996). 2006). On the other hand. These 4-day cycles are in synchrony with post-pubertal cycles in food intake that are clearly linked to vaginal estrus and to a more dramatic post-pubertal variability in circulating levels of estrogens (Sieck et al. 2008). 1. 2008). They suggested that anxieties related to the hormone-induced development of sexual maturation led to symptoms of AN. Also. One critical component of this hypothesis is that a lowered caloric intake initially becomes reinforcing to anorexics by activating reward circuits of the mesolimbic dopaminergic system. 2002). Sodersten has accumulated a convincing body of evidence supporting this viewpoint. Administration of ethinyl estradiol to anorexic patients reportedly produced symptoms of malaise and diminished food intake (Gustavson et al. 2006.. efforts to ﬁnd an effective treatment for AN must be viewed with caution from the viewpoint that any type of treatment of AN contains an element of coercion. food intake falls for only about a week and then recovers to normal values. This would appear to be unlike the long-lasting decline in food .1196 J. since weight loss by dieters is poorly maintained over several years (Grodstein et al. The brain sites essential for this appetite-depressing effect of estrogens have not be identiﬁed with clarity: some experiments have shown that activation of estrogen receptors in the mediobasal hypothalamus are sufﬁcient. as well as hypothalamic astrocytes (Blutstein et al. Most of these clinical studies describe a sub-population of anorexics who also have Turner’s syndrome of gonadal dysgenesis. 1982). evidence from many studies of dieting suggests that lowered caloric intake is not sufﬁciently rewarding for most of the population to continue a diet.. Roepke et al. 1979). studies in rats suggest that very low levels of estrogens that do not affect the uterus or vagina may yet be sufﬁcient to alter the regulation of feeding by the brain. glucose. 2007. 1982. ¨ This leads to a reluctance to eat. it is of interest that estrogens appear to activate mesolimbic dopaminergic reward systems in women (Dreher et al. 1975). However.. 2007. 2009.. The subjective explanation for this decline in caloric intake has not been clariﬁed: it is not known whether an actual decline in appetite takes place. whereas other studies have indicated that the dorsal medulla is an important site of action (Musatov et al.. an effect of a sudden introduction of estrogens upon feeding-regulating neuronal systems is an equally plausible explanation. 2008). 2001). why is there such clear evidence that genetic factors promote anorexia? The unique ability of anorexics to voluntarily maintain very low body weights over many years suggests that at least this feature distinguishes them from the rest of the population. Stimulation of a membrane-associated form of estrogen receptor alters the expression of at least 241 genes in the hypothalamus.b). administration of luteinizing hormone–releasing hormone (LH–RH).. Another objection to an involvement of estrogens in AN is that when rats are given continuous administration of estradiol.
The abundance and interactions of these co-activators with ERs varies from cell type to cell type. the authors concluded that it might have no functional signiﬁcance (Rosenkranz et al.. The authors concluded that this ﬁnding may have represented a false positive. the authors concluded that these non-functional alterations might be in linkage disequilibrium with other. 1998). 2003. At least 19 co-activators of the ERa protein alone have been identiﬁed.. 2004). data from rats do support the proposal that ovarian estrogens could produce a long-term decrease in food intake in humans. hypothalamic neurons possess both types of ER (Shughrue et al. 1992). 22 women and no men reported a episode of AN over their lifetimes (Preti et al. Young. An initial study suggested that the ERb might be important for feeding regulation. 2010). presumably because they alter the processing of the mRNA for the ER and thus alter the abundance of the ER protein (Herynk and Fuqua. In addition to mutations in either form of classical ER.. Young / Neuroscience and Biobehavioral Reviews 34 (2010) 1195–1200 1197 intake seen in anorexics. as well as women.. A plausible means of examining this question would be to transfect cells in vitro with the genes for the mutated forms of these ER’s and determine if the mutations have any effect upon the expression of ER proteins (Cheng et al. 2001).K. One study found no signiﬁcant association between polymorphisms in the ERa and AN. It is not then intention of this article. Curiously. This would clarify whether or not the ER mutations observed in AN might be of functional and clinical signiﬁcance. called co-activators. However. however. Liang et al. excessive levels of thyroid hormones have been reported to produce overeating and bulimia in young women (Schmidt and O’Donoghue.. lowered levels or an impaired functionality of the ERb protein could lead to enhanced activity of the ERa protein and increased anorexic effects of estrogens. and binge eating. Eliassen et al. has been reported (Kelly et al. 2009). 1998). to propose that estrogens represent the only or even the most important risk factor for AN. food intake and meal size appear to remain depressed indeﬁnitely (Asarian and Geary. 2006. It is possible that an abnormal response to estrogens could also contribute to the development of AN in men as well as in women. another polymorphism associated with AN was found at the same site (position 1082) in the ERb gene. since each receptor forms a dimer following the binding of estrogen.. Thus. 2007). more consequential mutations (Nilsson et al. a fact that is probably related to the differing effects of estrogen on different types of cells (Jaber et al. This controversy is still not completely resolved (Butera. 2003).. .. 1997). On the other hand.. some of these selectively augment the transcriptional activity of ERa but not of ERb (Klinge. are 3–8-fold more common in women than in men. For example. the ERa and the ERb. it is undeniable that men. Thus. 2000). 2001). Thyroid hormone receptors are commonly expressed in neurons that possess estrogen receptors (Kia et al. Thus. which is a complex human behavior that will not likely be explained as solely a simple response to a hormone or to another genetic risk factor. 2006). even mutations in non-coding intronic regions of these classical ER genes or ‘‘silent’’ mutations that fail to affect amino acid identity in the ﬁnal protein can have phenotypic effects.. Mutations in ERs are by no means the only types of genetic errors that could affect responsiveness to estrogen. mimicking the physiological patterns of serum estrogens seen in normal rats... 2009. non-genomic effects of estrogen upon cells and which are important for effects of estrogen upon body weight (Qiu et al. (2) levels of ERb can affect the functionality of the ERa (which mediates anorexic effects of estrogen). 2004). However. though not all. There exists a large literature on the effects of such mutations in various tissues (Herynk and Fuqua.... the presence of the ERb in a cell diminishes the transcriptional activity of the ERa (Matthews and Gustafsson.. Mutations in thyroid hormone receptors that reduce effects of thyroxine could thus also enhance anorexic effects of estrogen. can develop AN. Agouti-related protein appears to play a role in both the control of feeding and in the control of responsiveness of the hypothalamus to estrogen (Schioth et al. The goal of this paper is to examine a possible explanation for the sex difference in the incidence of AN. 2008). estrogeninduced regulation of transcription (genomic mechanism) has received the most attention. Santollo et al. Heterodimers composed of both forms of ER have different biological activity than that of homodimers of single forms of ER. out of 4139 respondents to a survey. agoutirelated protein. In another study. Once again. Suen et al. 2004. 1996. but did ﬁnd a statistically signiﬁcant polymorphism associated with AN in exon 5 (position 1082) of the ERb gene (Eastwood et al. Mutations in such enzymes could result in altered circulating levels of estrogens or in alterations in the synthesis of neurosteroids within the brain itself (Dunning et al. 3. A third study of ERb mutations found an association between bulimia and different polymorphisms (position 1730 in exon 8 and another polymorphism in an alternatively spliced exon 9) in the ERb gene. 2002). these did not alter the structure of the ER protein. Mutations in any of these estrogen receptors could conceivably result in an abnormal response to estrogens. 2001). even these lesser amounts of estrogens appear to exert signiﬁcant metabolic effects in the male body (Ohlsson and Vandenput. 2001).. however... bulimia. 2000.. The mechanism of this ability of thyroxine to reduce effects of estrogens appears to involve interactions between thyroid hormone receptor proteins and co-activator proteins required for ER function (Vasudevan et al. 2002). Finally.. Monroe et al. 1998)..J. 2007). when rats are given only a single small dose of estradiol every 4 days. 1994).. Vink et al. 2002. 2004.. the incidence of AN in men has been thought to amount to only 5–10% of that seen in women (Sharp et al. Thyroxine diminishes the effects of estrogen upon cells and reduces the anorexic potency of estrogen (Zhu et al. 2009).. It is of interest that a signiﬁcant association between AN and polymorphisms in the gene for a hypothalamic peptide. Roepke et al. 1980.. Traditionally. 2007). which have steroidbinding domains and DNA-binding domains. In addition to the classical nuclear estrogen receptors. membrane-bound estrogen receptors have recently been identiﬁed that mediate more rapid. The ability of ERs to stimulate transcription is also dependent upon numerous other proteins. 2001. These co-activators are important modiﬁers of estrogen action upon hypothalamic neurons and could also be related to the etiology of AN (Tetel et al. 1986). the degree of coexpression of the ERa and ERb in a cell could inﬂuence the response to estrogens. However. including AN. 2008).. which modify the binding of ERs to DNA. 2004. and (3) many. Micevych et al. Molecular mechanisms of estrogen action For many years it has been thought that estrogens affect cell function mainly by binding to one of two forms of estrogen receptor protein (ERs). More recent epidemiological studies have conﬁrmed that all eating disorders. Heritable alterations in steroid-synthesizing enzymes could also be a signiﬁcant factor in AN. Levenson et al. Since this polymorphism was a ‘‘silent’’ mutation that would not affect the corresponding identity of the amino acid at that site. Two studies have examined AN patients for polymorphisms in ER proteins. three pieces of information suggest that such conclusions might be premature: (1) even ‘‘silent’’ polymorphisms may affect the stability and translation of the mRNA for ERs.. later studies have contradicted this conclusion and have shown that the ERa alone mediates the anorexic effects of estrogens (Geary et al. Hoshino et al. Blood levels of estrogens in men amount to about one-fourth of the values seen in women (Brambilla et al.
In humans. 2008).1198 J. 1998). The detailed structures and mechanisms of action of these gene loci are not yet known. readily replicated explanation for the syndrome.. Ryan and Vandenbergh. Varied. Sex differences in the incidence of a wide range of psychiatric disorders (autism. but broader indices of masculinization (body weight.. in quantitative trait loci. White blood cells possess both forms of ER. for unknown reasons (Neal-Perry et al. This sexual dimorphism appears in human fetuses early in gestation. Consistent with this hypothesis. AN is not the only neuropsychiatric disorder that may encompass a variety of interrelated neurochemical abnormalities. may exert a protective effect upon the development of schizophrenia by modulating retinoic acid metabolism (Palha and Goodman. 1986. favor the viewpoint that the 2D:4D ratio is a reliable measure of androgenization. anxiety disorders) may also be related to effects of sex steroids on the brain (Westberg and Eriksson.. The reasons for a puberty-related decrease in reactivity to estrogens.. Hiney et al.. Developmental events that affect responsiveness to estrogen If a hypersensitivity to estrogens is present in AN.. Terasawa and Fernandez. the ﬁnding of Klump.. thyroxine metabolism and action) that affect the activity of dopaminergic neurons. The ability of estrogens to provoke this increase in kisspeptin declines with aging in rats. caution may be appropriate in utilizing this ratio as such. Conclusions All of the above data show that the existence of an abnormal response to estrogen is a plausible explanation for the sex difference in incidence of AN. Furthermore. are uncertain. Wilson et al. grip strength) show few differences between same-sex and opposite-sex female humans (Cohen-Bendahan et al. that women with a slightly androgenized 2D:4D ratio are less likely to develop feeding disorders may support the proposition that an abnormality in responsiveness to steroids may be present in AN. for example. If the normal puberty-associated desensitization of the brain to estrogens were not to occur. which is stimulated by estrogens (Clarkson et al. 2010). 2006). Another approach to this hypothesis is to examine the incidence of feeding disorders in same-sex female twins vs. 2001). this could conceivably result in an estrogen-stimulated anorexia as secretion of ovarian estrogens increases during puberty. 2000). presumably contain steroid co-activators. This more indirect approach is based upon the presumption that androgens produced by male twins might have a masculinizing effect upon female twins in utero. 1979).. Nutrition-regulated peptides such as insulin-like growth factor-1 have been implicated in these alterations in responsiveness to estrogen (Grinspoon et al. Culbert et al. This hypothesis indicates the possibility that anorexics may represent a genetically very heterogeneous population that nevertheless suffers from the same common feature. plus others cited by Klump. it has been hypothesized that abnormalities in dopaminergic systems in schizophrenia may arise from a complex interaction of many neurochemical pathways (retinoic acid metabolism and action. and in processes of puberty— could all conceivably result in a common endpoint. An early event in puberty is an increase in the synthesis of a hypothalamic neurotransmitter. in perinatal androgenization. Young / Neuroscience and Biobehavioral Reviews 34 (2010) 1195–1200 Finally. The sexual dimorphism in the 2D:4D ratio increases from the fetal stage through childhood and adulthood (Galis et al. Yet another factor involved in biological effects of estrogens is the presence in the blood of a carrier protein for steroids called sex hormone binding globulin. Schmidt et al. 2009). in co-activators for estrogen. then any event that depresses responsiveness to estrogens should have a protective inﬂuence upon the development of AN. Estrogen. multiple mechanisms— abnormalities in the classical or membrane-bound forms of estrogen receptors. an early puberty seems associated with an increased risk for feeding disorders (Zehr et al.. 2006. 2008). a recently published report by Raevuori et al. Also. which reduces the ability of estrogens to reduce feeding later in adulthood (at least in rodents) (Asarian and Geary. Mechanisms of puberty seem to involve functional changes in a variety of stimulatory and inhibitory neurons. in steroid metabolizing enzymes. as well as in hypothalamic astrocytes (Terasawa and Fernandez. Puberty is another developmental event associated with dramatic changes in responsiveness to estrogen. (2008) found a protective effect of opposite-sex development upon the rates of eating disorders. 2002). has been to measure the ratio of the lengths of the second digit and fourth digit (2D:4D ratio) in a patient population (Culbert et al.. 2007).. kisspeptin. 2009).. in thyroxine receptors. a recent study of men with androgen insensitivity did detect a modest feminization of digit ratios. One such event is exposure to androgens during embryonic or neonatal periods.. fertility.K. Wilson.. 2008). an abnormal response to estrogen. 2004). contiguity of female fetuses with males does seem to have small masculinizing effects upon indices such as tooth size and hearing acuity. This concept is based upon research in rodents and other mammals showing that the intrauterine position of a female fetus next to male fetuses has a permanent.. 2008). 1996. which may involve both the hypothalamus and pituitary. masculinizing effect upon body weight... 2005. 2007). opposite-sex female twins (Culbert et al. Gaist et al. The general concept that an abnormal responsiveness of the brain to sex steroids may induce behavioral or mood disorders has been supported by studies showing that women who suffer from premenstrual syndrome show abnormal behavioral and endocrine responses to estrogens (Roca et al. 1995). With these admonitions in mind. 2008). Methodological difﬁculties in obtaining accurate digit ratios and the possible inﬂuences of deformable soft tissues upon digital dimensions complicate the utilization of digit ratios in all studies (Berenbaum et al. alternatively. namely. 2009).. (2008) failed to replicate these results. Polymorphisms in the sequence of this protein affect its synthesis and binding of estrogens and can alter tissue responses to estrogens (Napoli et al. In contrast. However. 5. and sexual behaviors (Kinsley et al. 4.. 2001. These data. This 2D:4D ratio is sexually dimorphic in humans and other animals. the ability of estrogens to suppress the secretion of luteinizing hormone in experimental animals decreases during and after the onset of puberty (Gasser et al. How can this inﬂuence be examined in humans? One approach. and may react to the same circulating signals of . suggesting that it is inﬂuenced by androgens during early development. This may undermine the hypothesis of an involvement of steroids in AN. Which of the many mechanisms should be tested in a sample population of anorexics? How would such tests be conducted? Perhaps one approach would be to measure the effectiveness of estrogens in suppressing the secretion of interleukin-1 from white blood cells isolated from control and AN patients (Rogers et al. 2004. For example. Young et al. a number of uncharacterized genetic loci in rats have been found to mediate strain-speciﬁc differences in responsiveness to estrogen (Kurz et al. 2009).. 2006. may simply be evidence that perinatal androgenization of females by contiguous male fetuses is less important in humans relative to other mammals. adopted by Klump et al. or. et al. but found wide within-group variability of this parameter and concluded that digit ratios are not a reliable index of individual exposure to androgens in utero.. since it is not always sexually dimorphic in some strains of mice (Manno. The variety of mechanisms that could produce an abnormal response to estrogen may make it difﬁcult to conﬁrm a single. 2003.
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