Are Any Animals Attracted Sexually To Female Humans

1. Introduction

Sexual reproduction implies a specialization of the 2 sexes, and so that one produces large gametes usually in limited numbers (female eggs), whereas the other produces a much larger number of smaller gametes (male sperm). This specialization is by necessity accompanied by major sex differences in reproductive morphology and physiology, such as the presence in vertebrates of ovaries secreting big amounts of oestrogens and progesterone in females and the presence of testes secreting testosterone in males. The activeness of these sex steroids is, even so, non limited to reproduction, and these steroids have now been shown to bear upon a vast array of physiological and behavioural responses, including, for instance, neuronal plasticity, neuroprotection, tumour growth, memory formation and retentiveness, to cite a few [1,two]. Based on the prominent sexual practice differences in production and thus circulating concentrations of sexual practice steroids, it follows that many of the processes influenced by these steroids are themselves associated with sex activity differences.

Sex activity differences in brain, behaviour and physiology are thus widespread and not the exception which actually led Larry Cahill (University of California, Irvine) to write that 'the burden of proof regarding the issue (of sex differences) has shifted from those examining the event in their investigations more often than not having to justify why, to those not doing and so having to justify why not' [3,4]. Information technology has also go articulate recently that the analysis of the functional significance of these sex differences has become a priority in neurosciences [5].

Another consequence of sexual reproduction is that males are every bit a rule sexually attracted by females and vice versa. This behavioural departure is ordinarily referred to every bit the sexual partner preference (for concision, partner preference in the following) or also sexual orientation in humans. Partner preference can be considered as one of the multiple sex differences in behaviour, considering males and females present a different target for their sexual attraction. Any divergence from this heterosexual attraction, that is an allure for the same sex or homosexual attraction, is and then considered every bit a reversed sex divergence (run into also [6] on this topic). Accepting the idea that partner preference is a sexual activity difference begs the question of the mechanisms that command its development. All behavioural differences in animals and humans develop nether 2 major types of influence: biological factors including mostly genes, their expression and hormones, and ecology factors recovering multiple forms of influences of parents, peers and congeners, in general, associated with diverse forms of learning.

Nosotros shall focus hither on the biological aspects that are the topic of this special issue. It must exist noted, however, that some scientists, usually with a psychological or sociological background, consider that all behavioural and possibly neural sex differences in humans are culturally constructed [7] and negate biological influences on sex differences [6], a concept known as the gender theory. In §2 we shall first review the mechanisms that control sex differences in encephalon and behaviour, drawing largely on the literature dedicated to the sexual differentiation of reproductive behaviour in rodents. In §3 we shall then review how these same mechanisms were shown to apply, at to the lowest degree in part, to the sexual differentiation of partner preference in a few animal species in which this process has been studied. Finally, in §four, nosotros shall summarize clinical and epidemiological evidence strongly suggesting that these same biological mechanisms are still at play in the command of human being sexual orientation even if information here are nonetheless almost exclusively correlational and thus conclusions cannot be presented with the same level of confidence.

2. Sexual differentiation: how exercise sex differences emerge?

Although multiple forms of sexual activity conclusion are nowadays in animals (meet [eight] for a contempo review), this process in mammals including humans is controlled most exclusively by a specialized set of chromosomes, the sex chromosomes, XX in females and XY in males. Schematically, the Y chromosome of males contains a gene chosen SRY that determines the development of the initially undifferentiated gonad into a testis, whereas in females (XX complement), the absence of SRY will lead to differentiation of the gonadal anlage into an ovary [9,x] (figure ane).

Figure 1. Schematic of the hormonal, genetic and epigenetic mechanisms controlling sexual differentiation in mammals based mainly on studies of sexual behaviour in rodents. See text §2 for boosted explanations.

(a) The organizational effects of hormones

Studies of sex differences in primary sexual characteristics (e.g. penis versus clitoris and vagina, the presence of a uterus in females but) initially led to the formulation of a theory of sexual differentiation explained past the embryonic hormonal secretions of the gonads (for review, meet [11]). It was initially believed that differences in reproductive behaviour betwixt males and females resulted from the presence of different hormones in adults of the two sexes: testosterone in males and oestradiol (plus progesterone) in females [12]. However, the seminal work of Young and co-workers [13] in guinea pigs demonstrated that these differences mostly result from the early exposure of embryos to a high concentration of testosterone for males and a much lower (lack of?) exposure to sex steroid in females. These investigators demonstrated that only males exposed to loftier levels of testosterone in utero exhibit male sexual behaviour in adulthood when they once more feel high levels of testosterone. Females artificially exposed to testosterone during development to the aforementioned degree and at the same time as males too showroom male person-like sexual behaviours towards other females if supplied with male levels of testosterone when adults. At the aforementioned time, these females treated with exogenous testosterone lose the capacity to reply to ovarian hormones in adulthood and thereby lack female person sexual behaviour. This interplay between early life hormonal profile and adult responsiveness is referred to as the organizational/activational hypothesis of sexual differentiation and has been shown to utilize to a variety of other species including rats, equally illustrated in figure 1.

These organizing furnishings occur early in life, during the embryonic period or just subsequently nascence, and are irreversible. Early exposure to testosterone produces a male phenotype: the behavioural characteristics of the male are strengthened (masculinization), and the power of males to evidence behaviour typical of females is reduced or lost (defeminization). The female phenotype develops in the apparent absence of hormone action during the embryonic period (or in the presence of very low oestrogen). More recent studies signal, withal, that development of the full female person behavioural phenotype requires exposure to oestrogens during ontogeny, only this exposure takes place much later, during the pre-pubertal menstruum rather than in utero [14].

These studies indicated that the type of sexual behaviour (male person- or female person-typical) displayed past an adult individual is determined by exposure to steroids during the early stages of life. More recent work, however, shows that genes tin produce behavioural or physiological differences between males and females in a more direct fashion that apparently does non involve sex steroid action.

(b) Factor effects that are not hormone-mediated

The notion of a sexual differentiation that would be independent of early on steroid action largely originated in the analysis of a single zebra finch (Taeniopygia guttata) individual that was male person on the left side and female person on the right side, the well-known gynadromorphic zebra finch [xv]. Genetic markers confirmed that this bird had male person cells on the right side merely female cells on the left side of its brain. Correlatively, the volume of its song control nucleus HVC was much larger on the male than on the female side, despite the fact that both sides had plain been exposed to the same concentrations of circulating sex steroids. Sexual practice differences in birds are, like in mammals, largely under the control of organizational effects of sex steroids, although modalities of these controls differ markedly (see [16] for review). The morphological divergence between left- and right-side HVC in the gynandromorphic subject indicated, yet, that this characteristic was controlled, at least in office, by an activity of genes somewhat contained from the organizational action of steroids [15]. Some reframing of the original organizational/activation hypothesis was therefore needed. A few studies had already demonstrated that some phenotypic sex differences [17,18] and sex differences in gene expression [nineteen–21] are observed before the gonads develop and start secreting substantial amounts of sexual practice steroids. These sex differences thus cannot exist induced past exposure to a differential hormonal milieu.

To accost this question, it is obviously impossible to follow up in the single gynandromorphic zebra finch. Therefore, researchers took reward of a mutated mouse model in which the SRY factor was no longer functional, so that it could no longer induce the formation of testes (the XY^SRY− mouse). In another mouse line, they additionally translocated the SRY gene to an autosome, so that XX females would develop testes during the early embryonic life (Xx^SRY mouse). Together with control mice (XX and XY), these mice provided four separate genotypes in which the presence of testes (in XY and XX^SRY subjects) or ovaries (in XX and XY^SRY−subjects) could exist disentangled from the presence of an XY or XX genotype; the so-chosen four core genotype model [22]. In this model, behavioural and neuroanatomical traits directly related to reproduction were commonly confirmed to differentiate mostly nether the organizing influence of gonadal steroids, but a growing number of other sex differences not straight tied to reproduction have now exist shown to differentiate equally a function of the chromosome complement independently of the presence of testes or ovaries [23–27]. Interactions between these two processes have likewise been detected (e.chiliad. in the control of torso weight [27,28]).

(c) Epigenetics

Recent studies have added yet another layer of complexity to our understanding of the procedure of sexual differentiation. It has go clear that a multifariousness of modifications of the Deoxyribonucleic acid itself (mostly methylations) or of the associated histones (acetylations, methylations, etc.) that practice not modify the master structure of the Dna markedly bear on its transcription. These caused modifications of Dna and histones, called as a whole epigenetic marks, can even exist transmitted to the offspring and in this style influence phenotypic traits in multiple generations [29]. Information technology is, for example, now well established that early stress or early exposure to a high calories/high-fatty diet affects stress physiology and energy rest, respectively, in a permanent style in the exposed individual, and also in her offspring (see [29] for review).

These epigenetic effects also extend to the control of behaviour every bit illustrated past the elegant work of Michael Meaney and co-workers showing that rat mothers providing poor maternal care will transmit this phenotype to their offspring via changes in the methylation of a few key genes, including the gene coding for a glucocorticoid receptor in the hippocampus and the gene of one oestrogen receptor in the medial preoptic surface area [30,31].

It was besides demonstrated that organizing furnishings of sex steroids on encephalon and sex behaviour are mediated, to a big extent, by epigenetic mechanisms. Oestradiol, for example, affects the enzymes that control these epigenetic marks such as DNA methyltransferases and histone deacetylases in the encephalon of neonate rodents, and pharmacological manipulations of these enzymes in neonate rats have been shown to affect very significantly the sexual differentiation of brain and behaviour [32–34]. Oestradiol derived from testosterone aromatization in the brain reduces the activity of Dna methyltransferases in the preoptic area in males. This consequently decreases Deoxyribonucleic acid methylation in subjects exposed to testosterone (males or testosterone-treated females) and releases masculinizing genes from epigenetic repression. Almost importantly, experimental manipulation of the Deoxyribonucleic acid methyltransferases (with pharmacological or molecular biology tools) mimicked the furnishings of testosterone on cistron expression and adult behaviour. These data thus quite surprisingly show that the female brain and behaviour are actively maintained by an active suppression of masculinization via Deoxyribonucleic acid methylation, a procedure that is inhibited by testosterone in males [34]. Recent work as well indicates that some of these organizing effects of testosterone on the methylome do not necessarily appear immediately during or after exposure to the steroid simply are eventually more pronounced later in life (up to a 20-fold increment) [35]. This observation certainly contributes to explaining the long-lasting (permanent) organizational effects of sexual activity steroids.

Note, however, that non all epigenetic marks that control gene expression are necessarily the issue of a differential exposure to steroids, because the expression of many genes is already sexually differentiated on solar day ten.5 mail service-coitum of embryonic mice, in accelerate of gonadal development and differential steroid secretion in males and females [19,20]. The origins of such a differential early on expression are not clearly identified at this fourth dimension but presumably reflect direct genetic effects such as those discussed in §ii(a), with a few sex chromosome genes inducing the differential expression of other genes located on autosomes.

In summary, the sexual phenotype of an private can exist afflicted in a permanent manner by three different types of mechanisms: endocrine, genetic and epigenetic. Importantly, these three types of influences are only partly independent and multiple interactions have been described. In detail, sex steroids practice alter epigenetic marks and thus cistron expression, and a variety of genes deeply affect hormone secretion and activity. Identifying the primary factor(due south) responsible for a sex difference is thus often not piece of cake.

3. Sexual differentiation of partner preference in animals

The organizational activity of steroids on sexual behaviour patterns (§2a) seems to apply also to the sexual differentiation of partner preference in animals. In most cases, sexual differentiation of different traits is coordinated, and a subject displaying male person sexual behaviour patterns will correlatively exhibit a sexual preference for females and vice versa. Sometimes, nonetheless, disassociations can occur, presumably nether the influence of subtle alterations during limited periods of ontogeny of circulating hormones or of their local hormone action. A genetic male expressing male sexual behaviour can so develop a sexual preference for other males (for review, encounter [36,37]). This conclusion is supported by studies manipulating the endocrine perinatal environment in a few species and assessing the effects on adult partner preference, and as well by the analysis of sexual partner preferences in sheep, a species in which a spontaneous exclusive male homosexual preference is observed in approximately 8% of the rams.

(a) Experimental manipulations of the perinatal endocrine environment

In rats and mice, perinatal manipulations of sexual activity steroid concentrations modify in a permanent style the partner preferences of the treated subjects. Exposure to testosterone (or its metabolite oestradiol) induces a preference for female person over male sexual practice partners (male-typical orientation), whereas in the absence of loftier concentrations of these steroids, a female pattern of sexual orientation will develop (preference for male partner).

The first set of studies establishing this conclusion were performed in rats at the University of Rotterdam equally part of the PhD thesis of Julie Bakker performed under the supervision of Dr Kos Slob. They showed that pharmacological inhibition of aromatase activity during the week before and the week after nativity in male person rat pups/embryos reverses their adult partner preference, so that the subjects will at present adopt to spend fourth dimension with other males than with sexually receptive females. They will also brandish female person receptive behaviour (lordosis) in the presence of another male person and allow these males to mount them [38]. These males with a sex-reversed partner preference also display a neuronal activation, every bit revealed past expression of the c-fos gene, in nuclei controlling sexual behaviour in response to male urine, whereas control males testify such an activation in response to female, but non male person, urine [39]. Their sexual orientation and the related neural circuits have thus been profoundly and permanently affected past these neonatal endocrine manipulations.

The same type of endocrine control was demonstrated in females. Treatment of young females during their outset three weeks of postnatal life with oestradiol benzoate, a long-acting oestrogen, reversed their adult sexual partner preference, so that afterward treatment they preferred to interact sexually with other females instead of males [40].

Similar organizational effects of sex steroids on partner preference have been observed in mice, although in this species androgens themselves seem to play a more important role in the sexual differentiation of partner preference than their oestrogenic metabolites produced by aromatization. Specifically, sexual differentiation of partner preference was shown to be affected in testicular feminized mice (tfm) that deport a mutation of the androgen receptor making it non-functional. When adult, males in these mice prefer, like control females, to investigate odours from bedding soiled by control male urine as opposed to female urine [41]. Furthermore, tfm males, like females, testify no preference for a partner of one sex or the other, in contrast to control males that show a strong preference for females. As well, at that place is a strong activation of the preoptic area and nucleus of the stria terminalis of tfm male and of command female mice exposed to bedding soiled past male person urine that is not observed in control males. Together, these data show that lack of androgen action in tfm males blocks the masculinization of their partner preference. Additional work in mice also shows that this masculinization tin can be induced by an early on treatment with the not-aromatizable androgen dihydrotestosterone, even if oestrogens are additionally implicated in this process to some extent [42] equally they are in rats [43,44].

(b) Homosexual sheep

The studies described in §3(a) business concern experimentally induced same-sex partner preference. Spontaneous homosexual behaviour, divers as exclusive aforementioned-sex sexual preference, appears to be rare in fauna species despite the fact homosexual behaviours (mounting or being mounted past a field of study of the same sex) are often seen in hundreds of species [45,46] when congeners of the opposite sex are non (easily) available.

I case of spontaneous homosexual preference has, yet, been documented in a population of male sheep living in the western function of the USA (Idaho). In this population, an estimated 8% of the rams show footling or no sexual reaction to females, but contrary to what had been originally assumed, they are not asexual and they brandish agile mounting behaviour towards other males even if provided with a choice between male and female person partners [47].

This behaviour of male-oriented rams (MOR) equally termed past the authors of the report is non explained past differences in their rearing weather or adult endocrine status when compared with female-oriented rams (FOR) (come across [48] for review). Assay of their encephalon indicates, even so, that the ovine sexually dimorphic nucleus (oSDN) of the preoptic surface area, a structure that is normally three times more voluminous in males than in females, in MOR has the same book as in females and contains fewer neurons than in FOR. The oSDN of FOR too expresses two to three times more aromatase mRNA than females and MOR as quantified by in situ hybridization [48].

This correlation betwixt the volume of the oSDN and sexual orientation (larger in subjects attracted to females, the FOR, than in subjects attracted to males, the females and the MOR) appears to be the result of a differential exposure to testosterone during embryonic life. Indeed, the book of the oSDN is already larger in males than in females effectually twenty-four hours 135 of embryonic life, and treatment of female person embryos with testosterone between 30 and ninety days of gestation markedly increases the oSDN volume in these females [49]. These information thus strongly suggest that the volume of the oSDN is determined before nascency under the influence of testosterone, in whatever case well before subjects had an opportunity to limited their sexual orientation. The volume of this nucleus is additionally no longer sensitive to changes in testosterone concentrations during adult life. The smaller oSDN of MOR when compared with FOR is thus likely to reflect a lower exposure to androgens during gestation and could, in plough, be responsible for the same-sex activity attraction characterizing these subjects. It must, indeed, exist recalled here that the medial preoptic area is non just a fundamental site of steroid action for the activation of male copulatory behaviour in all vertebrate species investigated so far from fishes to mammals [50], but it besides seems to control male sexual orientation. Lesions of this nucleus reverse sexual partner preference in males of several species, including ferrets [51] and rats [52].

In summary, the sex of the preferred sexual partner is markedly influenced if not determined by the early hormonal environment in a manner reminiscent of the early organizational furnishings of steroids on the sex-specific patterns of reproductive behaviour. In that location is, notwithstanding, no experimental cloth allowing us to appraise the possible contribution to this attribute of the developed phenotype of more direct steroid-contained genetic or epigenetic mechanisms, with the exception of studies in fruitflies (Drosophila melanogaster) showing that mutation of the fruitless (fru) gene produces adult males who volition court males and females equally [53–55]. These findings practice not, nonetheless, easily transfer to mammals given the profound differences between vertebrate and insect physiology (see [56] for additional discussion).

4. Sexual orientation in humans

Converging bear witness indicates that the 3 types of mechanism (hormonal, genetic and epigenetic) described in animals are implicated, to some degree at least, in the control of human sexual orientation. However, given the about complete impossibility of performing truly causal experiments in humans, this conclusion rests generally on correlative studies, just these all point in the same management.

(a) Endocrine influences

It is clear that the sex steroids (testosterone and oestradiol) that organize behaviour in animals are still present in homo embryos and adults, and this is besides the case for their receptors in the brain. Embryonic testosterone also clearly determines sex differences in human being genital morphology [57]. Two types of data, clinical cases and the phenotypic distribution of sexually differentiated characteristics, so suggest that modulations of this early exposure to testosterone influence human sexual orientation. Exposure to a high concentration of testosterone during a critical period of development would predispose to a male-typical allure to women, whereas a lower embryonic exposure to steroids would lead to a female-typical orientation.

(i) Sexually differentiated characteristics are affected in gays and lesbians

Although information technology is nearly impossible, for applied reasons, to determine the hormonal milieu to which an individual was exposed during his/her embryonic life, it is possible to gather indirect data nearly this milieu by studying in adults phenotypic traits that are known to exist influenced in a permanent manner by embryonic testosterone. A large number of studies have compared such traits in homo- versus heterosexual populations and found statistically meaning differences that strongly suggest that homosexual populations were on average exposed to slightly unlike endocrine weather during their early life. These differences business organization morphological, physiological and behavioural traits that are too numerous to be reviewed hither in detail (see [36,37,56,58,59] for item and references).

These indicators of exposure to singular endocrine conditions during early life in homosexual subjects include at the morphological level: (i) the relative length of the index (D2) to the ring finger (D4) (shorter, masculinized ratio in lesbians compared with heterosexual women), (ii) the relative length of long bones in the legs, artillery and hands (shorter bones in gays and women who are attracted to men compared with men and lesbians who are attracted by women), and the size of several brain structures including, (iii) the surprachiasmatic nucleus (larger in gays than in heterosexual men), (iv) the inductive commissure (larger in gays than in heterosexual men) and finally (5) the interstitial nucleus of the anterior hypothalamus number three (INAH3; two to 3 times larger in heterosexual men than in gays [threescore] (figure ii) and having a lower density of neurons in gays than in heterosexual men [61]).

Figure 2. — Figure ii. Schematic of the human hypothalamus showing the position of the third interstitial nucleus of the inductive hypothalamus (INAH3; elevation) and volume of this nucleus (average shown by bars and individual points) measured by histological techniques in a sample of women, men and homosexual (gay) men who had died from AIDS (filled circles) or from another unrelated crusade (open circles). Results in heterosexual men do not seem to be affected by whether they died from AIDS or another cause, suggesting that the lower average values in gay men was not a result of their expiry from AIDS-related factors. Adjusted from [threescore].

Several physiological differences also indicate to similar modifications of the embryonic exposure to testosterone in homosexual when compared with heterosexual subjects. This is namely the case for (i) aspects of the inner ear physiology, in detail the minor noises presumably produced by movements of the tympanic membrane, the and then-called otoacoustic emissions (less frequent and of lower amplitude in lesbians compared with heterosexual women; effigy iii), (2) the feedback of steroids on the secretion of luteinizing hormone (presence of a weak positive feedback after injection of a large dose of oestrogens in gays but non in heterosexual men), and (iii) the brain activation as detected by magnetic resonance imaging (MRI) or positron emission tomography (PET) in response to male person- or female-typical odours (reaction of gay men to male person odours contrary to heterosexual men and lack of reaction of lesbians to male odours contrary to heterosexual women).

Figure 3. — Figure three. The average amplitude of click-evoked otoacoustic emissions (CEOAE) is larger in women than in men and in female person sheep compared with males. In sheep and other animals, the amplitude in females is reduced past a perinatal treatment with testosterone (+T). In homosexual women (lesbians), this amplitude is besides significantly lower than in heterosexual women, suggesting that lesbians were exposed to college concentrations of testosterone during their early life. Adapted from information in [62,63].

In that location are, in addition, studies reporting average cerebral/behavioural differences betwixt homo- and heterosexual populations in a given sexual activity. Amongst the most reliably established differences of this type one can cite those concerning: (i) aggressive behaviour (gays less aggressive than heterosexual men), (ii) visuospatial tasks (gay performing poorly compared with heterosexual men), (three) verbal fluency (gays more fluent than heterosexual men), and (iv) the memorization of object location (gays performing better than heterosexual men).

Interestingly, in all these cases but one (the volume of the suprachismatic nucleus), the modification seen in gays or lesbians makes them more like to heterosexual subjects of the reverse sexual activity, suggesting that they were exposed to endocrine influences that were typical of the other sex activity. This approach is, nevertheless, bound past sure limitations:

— some of these effects have been reproduced, but others have not and the origin of the discrepancies has not always been identified (dissimilar recruitment of study subjects?),
— although statistically pregnant, the differences observed only explicate a part of the variance, and information technology is conspicuously incommunicable to predict the sexual orientation of a bailiwick based on any of these criteria,
— it is sometimes unclear whether the difference observed reflects the signature of a differential early exposure to steroids and is potentially a cause of homosexuality or if it is a consequence of this sexual orientation. This limitation is particularly critical for cognitive/behavioural differences but much less so for morphological or physiological traits. The case of the smaller INAH3 of homosexual men is particularly interesting, because (i) the equivalent (homologous?) sexually dimorphic nucleus of the preoptic expanse is known to differentiate irreversibly between males and females in response to early on endocrine conditions in rats and sheep [64,65], (two) the book of INAH3 does not seem to depend significantly on the hormonal status of a man in machismo [66], (iii) lesions of this nucleus opposite sexual orientation in male rats and ferrets [51,52], and (iv) in sheep, the book of this nucleus correlates with sexual orientation in rams [48]. The smaller INAH3 of gay men could thus exist at the same fourth dimension the signature of their lower exposure to testosterone in early on life and the (fractional) crusade of their sexual orientation. Attributable to the limitations mentioned higher up, this conclusion remains, all the same, tentative.

(two) Clinical studies

A number of homo pathologies are associated with significant modifications of the embryonic endocrine environs. Many studies have therefore asked whether these endocrine changes are associated with changes in the incidence of homosexual orientation, and a positive response has been obtained in several cases. 3 such clinical weather condition are important to mention in this context. First, girls suffering from built adrenal hyperplasia are exposed in utero to abnormally high levels of androgens that masculinize their genital structures and a variety of behavioural traits (e.thousand. aggressive play and toy selection). These girls also display a significantly increased incidence of homosexual (or at least not strictly heterosexual) orientation (up to 40% compared with less than 10% in command populations; [67–69]). Second, girls built-in from mothers who had been treated with the synthetic oestrogen diethylstilboestrol in the hope of preventing undesired abortions were shown to display a pregnant increase in non-heterosexual (bi- or homosexual) fantasies and sexual activities [lxx].

Thirdly, it is also interesting to notation here that the sex in which a kid is reared does not seem to be able to completely counter the endocrine influences experienced prenatally. This is of course illustrated by the case of John/Joan a young boy who had his penis destroyed during circumcision and was therefore raised equally a girl. It turned out that in adulthood he reverted to a male identity and male sexual orientation [71]. This anecdotal story is additionally supported by the systematic study of patients afflicted by cloacal dystrophy, a rare genitourinary malformation resulting in the birth of XY males who, in addition to various malformations of the pelvis, have no penis. These subjects have normal testes and were thus presumably exposed to a male-typical design of androgen secretions before birth. Very oft, these subjects were submitted to vaginoplasty and raised equally girls. Follow-upwards studies take shown that in about half of the cases, these subjects when adults adopt a male identity, gender role and male-typical sexual orientation, again suggesting a significant influence of their embryonic exposure to androgens [72,73].

Even if alternative explanations can and have been proposed for some of these observations, then the well-nigh parsimonious explanation remains that embryonic hormones play a substantial office in the control of developed sexual orientation. Note, however, that changes in sexual orientation as a result of endocrine embryonic disruption always business concern a fraction of affected individuals (usually a maximum of thirty–40%) so that at to the lowest degree 60–lxx% of subjects in these atmospheric condition still brandish a heterosexual orientation. Other factors must therefore be involved every bit described in §4(b,c) following.

(b) Genetic influences

Because hormones obviously influence merely do not seem to fully explain sexual orientation, at least in the current stage of knowledge, researchers take considered an alternative group of explanations based on genetic influences. Furthermore, even if embryonic testosterone determines sexual orientation, this raises the question of why testosterone secretion or action was inverse during the development of gays and lesbians. A genetic influence would appear in this context as the virtually likely candidate.

Multiple epidemiological studies take shown that the presence of a gay homo in a family is correlated with an increased probability of finding other homosexual men in this family, and in addition this probability is directly correlated with genetic relatedness. For instance, if a son is gay, between 20% and 25% of his brothers will share this orientation, compared with 4–6% in the whole population. Similarly, lesbians take a greater probability than heterosexual women of having a homosexual sister [74,75].

Twins studies propose that this correlation does non reflect the similarity of postnatal experiences (psychosocial factors) but rather genetic similarity. There is indeed a much college concordance of male sexual orientation in identical (50–65%) than in dizygotic (about 15%) twins who shared the same postnatal environment, only differ in genetic relatedness [74]. Overall, data suggest that in social conditions typical of Western societies, most 50% of the variance in man sexual orientation has a genetic origin.

Although this notion was established many years ago, the genes that might support the phenomenon have so far remained somewhat elusive. Family lineage studies indicate that male homosexuality tends to be transmitted through matriarchal lineage: a gay human being has a higher probability of having gay men among his relatives on the maternal side, merely not the paternal side. This was originally interpreted as a sign of inheritance through gene(due south) located on the 10 chromosome and one study indeed identified a linkage with markers located in the subtelomeric region of the long arm of the 10 chromosome, a region called Xq28 [76]. A genomewide scan too identified linkage of male homosexuality to regions of chromosome 7 (7q36) and 8 (8q12) also equally a linkage to chromosome 10 (10q26) resulting from a sharing of maternal alleles only [77].

The association with Xq28 originally detected by Hamer et al. in 1993 [76] was replicated three times by the aforementioned and other authors (encounter [78] for detail), and very recently this association with Xq28 was confirmed in a study based on a much larger sample of over 400 gay brothers [79]. This last report additionally confirmed a significant linkage with a region on chromosome 8 (8q12).

Taken together, these studies go out no doubt most the existence of genetic controls on sexual orientation, but at the same time they show that these controls are probable to exist polygenic and very complex. The specific genes implicated in this process remain unknown even if candidate genes located at Xq28, such as the arginine–vasopressin receptor 2, appear every bit interesting candidates (see [79] for discussion). Whether or not these genes affect sexual orientation by modifying steroid action during ontogeny also remains unknown.

(c) Epigenetic modulation of androgen sensitivity

Although endocrine and genetic factors clearly seem to bear upon sexual orientation in humans (§4a,b), a meaning part of the variance in this trait remains unexplained and a number of of import questions remain. Why, for example, is there only 50–60% similarity in orientation of monozygotic twins when they share the aforementioned genetic material (see §4b)? It was likewise noted that even in rats [78] and humans [80,81] which are the best studied, at that place is during most if not all of the embryonic life some overlap between circulating concentrations of testosterone of males and females, even if males have on boilerplate higher concentrations. The sex activity divergence in plasma testosterone concentration is thus an ambiguous bespeak that cannot by itself explain why there is essentially no overlap between male and female phenotypes. The differentiation of the external genitalia into a male phallus or female vulva takes place, for example, in rats and humans during a period of embryonic life when testosterone concentrations overlap between the sexes [80,82–84]. Yet discordance between genetic sex and sexual activity of the genitalia is extremely rare, clearly indicating that some additional factors are needed to produce this sexually differentiated phenotype. Information technology has been postulated that additional factors upregulate the sensitivity to testosterone in males or downregulate it in females, and multiple mechanisms that mediate such a differential sensitivity have been identified (reviewed in [85]).

This so raises the question of what controls these mechanisms, and bear witness has recently accumulated indicating that sexual practice chromosomes independently of sex hormones epigenetically regulate expression of a diverseness of autosomal genes that may be responsible for the control of sensitivity to sex steroids [86]. There is also evidence that gene expression is sexually differentiated even before the gonads develop [19,20,87] (see also §2b). Actually, Xx and XY embryos are differentiated at the stem cell stage of the blastocyst [88] far in advance of androgen production, and epigenetic marks are likely the causal agents of this differentiation.

Importantly, these controls are gene-specific and therefore preferentially modulate item functional responses. It has, for example, been shown that expression of the 5α-reductase factor coding for the enzyme that catalyses the transformation of testosterone into vα-dihydrotestosterone is three times college in the genital structures of male than in female fetuses, and this difference would not exist a outcome of sexual practice steroid action [89]. This transformation critically mediates effects of testosterone on the sexual differentiation of the phallus and probably explains why the sexual activity of the ballocks is usually in agreement with the genetic sex even in the presence of a large overlap between circulating testosterone concentrations in male and female embryos.

Because androgen signalling differs betwixt organs and tissues, namely because the androgen receptors employ dissimilar co-activators and co-repressors to command transcription, it is conceivable that different epigenetic marks transmitted beyond generations might touch on subsets of sexually dimorphic traits. The androgen-dependent sexual orientation could, for example, be afflicted in the absence of whatever effect of the genitalia. A statistical model has been presented demonstrating the feasibility, over a wide range of values for the critical parameters of the model, of a command of sexual orientation based on the inheritance of sexually antagonistic (protecting XX subjects from androgen action) epigenetic marks conditioning androgen sensitivity in a tissue-specific manner (see [85] for a full presentation). Based on whether these marks escape erasure or not in the primordial stem cells and zygote, this model would explain the observed heritability of homosexuality, the failure so far to place clear genetic markers explaining homosexuality (reviewed in [84,90]), the different degree of concordance of sexual orientation betwixt mono- and dizygotic twins, and besides the absence of consummate cyclopedia in monozygotic twins.

Note, finally, that the incidence of male homosexuality in a given male person discipline increases by 33% for each older full brother (born to the same mother) he has. The effect is not related to differences in teaching or family background and is currently interpreted as the result of accumulation in the female parent during successive pregnancies of antibodies against i or more proteins expressed specifically by the male person brain. [91]. An epigenetic command of gene expression related to the early interaction of the male fetus with his mother could obviously contribute to explicate this phenomenon.

5. Conclusion

Sexual differentiation is clearly the result of an interaction between endocrine, genetic and epigenetic mechanisms, and this conclusion largely applies to the differentiation of sexual orientation in animals and humans. Human sexual orientation, and in particular its less mutual form homosexuality, is thus not mainly the result of postnatal pedagogy but is, to a large extent, adamant before birth by multiple biological mechanisms that go out piffling to no space for personal choice or effects of social interactions.

Our electric current agreement of these biological mechanisms decision-making sexual orientation is admittedly incomplete and will likely remain so, because we are dealing here with a complex behavioural trait and additionally nearly of the critical experiments that would be needed to achieve firm conclusions are evidently unethical. Each of the biological factors identified so far seems to explain homosexuality in only a fraction of individuals, and three not-mutually exclusive reasons potentially explain this limitation. Either different forms of homosexuality (butch/femme in women, hyper-masculine versus feminized in men, whatsoever other differential feature) have different origins (endocrine, genetic, epigenetic) or the different biological factors but produce a homosexual phenotype when acting in combination or, finally, the action of these biological factors that predispose to homosexuality must be combined with specific, so far unidentified, psychosocial influences during postnatal life playing an of import permissive function. It appears, indeed, likely that genes or hormones do not human activity specifically on sexual orientation. They rather change more full general behavioural traits, such as cross-gender identification [92,93] or the propensity to exist sexually attracted by individuals who are similar or dissimilar to yourself [94], which indirectly predispose or lead to homosexuality.

In addition, relatively contempo research in juvenile rats indicates that some aspects of sexual behaviour, including a preference for a same-sex partner, can be conditioned by early experience associated or not with pharmacological manipulations. For example, young female person rats allowed to express juvenile play with artificially scented males will in adulthood show a sexual preference for males bearing the same odour over other males [95]. More directly related to the present topic, male rats that were allowed to conjugate iii times during 24 h with some other almond-scented male person immediately afterwards beingness treated with quinpirole, a D2 dopaminergic agonist, developed a social and sexual preference during subsequently drug-complimentary tests for this scented male over a novel unscented male partner [96] and over a sexually receptive female, but such a preference did not develop if males were injected with saline before the cohabitation periods [97]. Too such preferences do not develop in females even if they are exposed to quinpirole before the cohabitation periods [96]. A similar same-sex activity socio-sexual preference developed in male rats who cohabitated with an almond-scented male person under the influence of oxytocin lone or combined with quinpirole [98].

In another experiment, male rats were first allowed to copulate with a sexually receptive female and were immediately removed from the female person compartment to be placed for one h during the mail service-ejaculatory interval (PEI) with some other almond-scented male that served as conditioned stimulus. Although this procedure was repeated daily for ten days in the absence of pharmacological handling, this cohabitation with a male partner during the PEI that was likely associated with enhanced dopaminergic and oxytocinergic receptor activation in the brain did not induce a same-sex activity partner preference [99].

Together, these information demonstrate that same-sexual activity partner preference in male rats tin, to some extent, be manipulated by cohabitation with another male, provided cohabitation is experienced during pharmacological activation of D2 or oxytocin receptors which presumably enhances the salience of the stimuli or the attention/expectation/reward in experimental subjects [98], merely this feel effect does not take place in females or in the absenteeism of pharmacological treatment. These pharmacological treatments facilitate the formation of stimulus–response associations, simply it remains to be demonstrated whether the preference for the scented familiar male person partner would generalize to other unfamiliar males as opposed to unfamiliar sexually receptive females.

Postnatal effects on sexual partner preference thus seem to be present, simply accept a limited magnitude in rodents. If these data tin can exist extrapolated, then the aforementioned blazon of limited effects might exist in humans, merely presumably exercise not fully explicate the development of exclusive same-sex activity preference. It seems, therefore, that most if non all human being beings do not choose to get homo- or heterosexual. This sexually differentiated behavioural feature is largely controlled past the aforementioned biological factors as other sexually differentiated traits, and this makes sense in evolutionary terms given the critical importance of sexual orientation for reproductive fitness.

Competing interests

I declare I have no competing interests

Funding

Writing of this review was partially supported by the NIMH grant no. RO1 MH50388 to Gregory F. Ball.

Acknowledgements

I thank Margaret K. McCarthy for her disquisitional reading of an earlier version of this manuscript and for a number of useful comments.

Footnotes

1 contribution of 16 to a theme outcome 'Multifaceted origins of sex differences in the brain'.

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Source: https://royalsocietypublishing.org/doi/10.1098/rstb.2015.0118

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