Gender identity and sexual orientation are permanently programmed in the fetal brain
During the intrauterine period a testosterone surge masculinizes the fetal brain, whereas the absence of such a surge results in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other. Sex differences in cognition, gender identity (an individual’s perception of their own sexual identity), sexual orientation (heterosexuality, homosexuality or bisexuality), and the risks of developing neuropsychiatric disorders are programmed into our brain during early development. There is no evidence that one’s postnatal social environment plays a crucial role in gender identity or sexual orientation. We discuss the relationships between structural and functional sex differences of various brain areas and the way they change along with any changes in the supply of sex hormones on the one hand and sex differences in behavior in health and disease on the other.
Gender identity and sexual orientation are permanently programmed in the fetal brain.
Testosterone in the fetal stage determines sexual differentiation of the human brain.
The degree of genital masculinization does not necessarily reflect that of the brain.
No evidence indicates social environment affect gender identity or sexual orientation.
Sex differences in the brain determine sex-specific prevalence of brain disorders.
Sources and more information
Sexual differentiation of the human brain: Relation to gender identity, sexual orientation and neuropsychiatric disorders, Sciencedirect, pii/S0091302211000252, doi:10.1016/j.yfrne.2011.02.007, 2011.
Gynecol Endocrinol 2004;19:301–312, full PDF, DOI: 10.1080/09513590400018231, 2004.
Things NOT to say to a trans person | Breaking the mould
BBC Free Speech asked Paris Lees, Fox Fisher, Veronica Blades, Adeleh Sasansara, Munroe Bergdorf, Dani Gibbison and Harry Taylor to pick out questions they often hear. BBC Three asked, so you don’t have to! Video published on 21 May 2015.
The number of children aged 10 or under who have been referred to the NHS because of transgender feelings has more than quadrupled in five years, according to new figures.
The Tavistock and Portman NHS Trust said referrals over the period included 47 children aged five or under, and two children just three years old.
The trust – UK’s only centre specialising in gender issues in under 18s – said that in total, the number of under 11s referred to the unit has risen from 19 in 2009-10 to 77 in 2014-15.
Parents said they had sought help after children became deeply distressed about their gender.
Sources and more information
Rise in child transgender referrals, telegraph, 07 Apr 2015.
Referrals for young transgender people increase, bbc, 5 February 2015.
Transgender people do not face higher breast cancer risk
2015 Study Conclusions
Breast cancer in transgender patients is rarely reported, and when it is, it is often in association with the receipt of CSH and mentioned as a potential adverse effect of cross-sex hormones (CSH). This report expands the number of reported cases from 15 (10 in male-to-female (MtF), 5 in female-to-male (FtM)) to 25 (13 in MtF, 12 in FtM) in the English literature. Maglione and colleagues, reporting on two cases, concluded that breast cancer occurs in MtF transsexuals who receive “high doses of exogenous estrogens,” which results in an increased risk of breast cancer. Researchers using large cohorts of transgender/transsexual patients followed prospectively have not detected an increased incidence relative to the general population. However, breast cancer can occur, in theory, in the absence of known CSH treatment, in persons with a diagnosis of gender dysphoria, or in a way that is associated with, but unrelated, to gender dysphoria. Given that it is well known that patients who seek CSH treatment from medical sources may also obtain CSH from nonmedical sources in unknown quantities, it is difficult to conduct dose–response studies linking CSH dose/exposure to breast cancer outcomes. It should be noted that this case series derives only from transgender veterans who were identified based on a clinical, psychiatric diagnosis. It is likely that there are many more veterans who self-identify as transgender who did not receive one of the four qualifying psychiatric diagnoses. The number of breast cancer cases in those veterans cannot be determined.
These 10 case reports do not attempt to link CSH to outcome, especially given the fact that provision of CSH treatment was not openly available to gender dysphoric veterans until 2011. Therefore, the VHA EHR for these cases include only information about CSH provided by VHA clinicians. All three birth sex male cases in this series presented with late-stage disease and died from metastatic cancer, whereas the birth sex female patients with gender dysphoria had all been treated and, in all but one case, had survived at least 2 and as long as 25 years after initial diagnosis or at the end of the observation period.
Although apparently rare, breast cancer does occur in transgender people of both birth sexes, and screening methods generally in place for nontransgender persons should be sensitively discussed and applied by clinicians providing transgender healthcare, whether or not CSH medications are utilized. In addition, family histories of breast cancer should be elicited from all transgender persons as part of their routine medical care.
Study finds hormone therapy in transgender adults safe
In the most comprehensive review to date addressing the relative safety of hormone therapy for transgender persons, researchers from Boston University School of Medicine (BUSM) have found that hormone therapy in transgender adults is safe.
2015 Study Abstract
Some providers report concern for the safety of transgender hormone therapy (HT).
This is a systematic literature review of HT safety for transgender adults.
Current literature suggests HT is safe when followed carefully for certain risks.
The greatest health concern for HT in transgender women is venous thromboembolism; increase risk of thrombosis..
HT among transgender men appears to cause polycythemia.
Both groups experienced elevated fasting glucose.
There is no increase in cancer prevalence or mortality due to transgender HT.
Although current data support the safety of transgender HT with physician supervision, larger, long-term studies are needed in transgender medicine.
Sources and more information
Study finds hormone therapy in transgender adults safe, BostonUNews, February 24, 2015.
Prenatal and childhood exposure to EDCs may be responsible for a variety of abnormalities in human sexuality, gender development and behaviors, reproductive capabilities, and sex ratios
Although scientists have postulated a wide range of adverse human health effects of exposure to endocrine-disrupting chemicals (EDCs), the nexus of the debate is the concern that prenatal and childhood exposure to EDCs may be responsible for a variety of abnormalities in human sexuality, gender development and behaviors, reproductive capabilities, and sex ratios. Scientists today are asking hard questions about potential human effects: Do EDC exposures impair fertility in men or women? Can they cause sexual organ malformations, stunted reproductive development, or testicular or breast cancer? Do fetal exposures to EDCs alter sex phenotypes? Do they change later gender-related neurobiological characteristics and behaviors such as play activity and spatial ability? Could such exposures even be involved in the etiology of children born with ambiguous gender?
EDCs include a spectrum of substances that can be loosely classified according to their known or suspected activity in relation to sex hormone receptors and pathways. The most-studied and best known are the environmental estrogens, which mimic estradiol and bind to estrogen receptors (ERs). ER agonists include the pesticide methoxychlor, certain polychlorinated biphenyls (PCBs), bisphenol A (BPA; a high production volume chemical used to make polycarbonate plastic), pharmaceutical estrogens such as diethylstilbestrol (DES) and ethinyl estradiol, and phytoestrogens, which occur naturally in many plants, most notably in soybeans in the form of genistein and related substances. There are a few known ER antagonists, or antiestrogens. Antiandrogens, or androgen receptor (AR) antagonists, include the fungicide vinclozolin, the DDT metabolite p,p′-DDE, certain phthalates (a group of chemicals used to soften polyvinyl chloride plastics), and certain other PCBs. And there are other types of EDCs that affect particular endocrine targets. The various EDCs differ greatly in their potencies relative to natural hormones, and in their affinity for target receptors. Some have been shown to act via non–receptor-mediated mechanisms, for example by interfering with hormone synthesis.
In many well-documented cases of high-level fetal exposures to known EDCs such as DES, certain PCBs, and DDT, the answer to the question of whether exposure is associated with gender-related effects is clearly yes. But high-level exposures such as these are relatively rare and isolated. The debate today centers on low-dose exposures—generally defined as doses that approximate environmentally relevant levels—and the idea that low-dose intrauterine exposure to some EDCs during certain critical windows of development can have profound, permanent impacts on subsequent fetal development and adult outcomes.
Critics of this idea maintain that thus far there is no credible evidence to suggest that low-dose exposures cause any adverse human health effects. But if low-dose exposures were confirmed to be the threat that proponents of the concept insist they are, public health would clearly be at risk, regulatory agencies’ risk assessment approach would need to be revised, and certain common chemicals—including some that are massively produced and economically important—would likely disappear from the marketplace.
In a June 2000 EHP review article on human health problems associated with EDCs, Stephen Safe, director of the Center for Environmental and Genetic Medicine at Texas A&M University, concluded that “the role of endocrine disruptors in human disease has not been fully resolved; however, at present the evidence is not compelling.” Frederick vom Saal, a developmental biologist at the University of Missouri–Columbia, disagrees, particularly in light of the research that’s been presented in the years since that review. “The jury is not out on human effects,” he says. “In terms of the amount of information we have in animals and the amount of information we have in humans, clearly there is a huge difference, but that’s a lot different than saying the jury is out on whether EDCs influence humans.” One thing both scientists might agree on, though, is that right now there are still more questions than answers.
A Delicate Process
Evidence of Effects
The Phthalate Connection
EDCs and Sex Ratios
How Low Do They Go?
Connecting the Gender Dots
The Road Ahead
Continue reading: Are EDCs Blurring Issues of Gender?, Environ Health Perspect. Oct 2005; 113(10): A670–A677., PMCID: PMC1281309.
These data suggest that DES-induced SV toxicity and feminization are primarily mediated by Estrogen Receptor-α; however, some aspects of androgen response may require the action of ERβ
Studies have shown that perinatal exposure to the synthetic estrogen diethylstilbestrol (DES) leads to feminization of the seminal vesicle (SV) in male mice, as illustrated by tissue hyperplasia, ectopic expression of the major estrogen-inducible uterine secretory protein lactoferrin (LF), and reduced expression of SV secretory protein IV (SVS IV).
The present study was designed to evaluate the role of the estrogen receptor (ER) in this action by using ER-knockout (ERKO) mice.
Wild-type (WT), ERα-null (αERKO), and ERβ-null (βERKO) male mice were treated with either vehicle or DES (2 μg/day) on neonatal days 1-5. These mice were divided into two groups: In the first group, intact mice were sacrificed at 10 weeks of age; in the second group, mice were castrated at 10 weeks of age, allowed to recover for 10 days, treated with dihydrotestosterone (DHT) or placebo, and sacrificed 2 weeks later. Body weights and SV weights were recorded, and mRNA expression levels of Ltf (lactoferrin), Svs4, and androgen receptor (Ar) were assessed.
In DES-treated intact mice, SV weights were reduced in WT and βERKO mice but not in αERKO mice. DES-treated WT and βERKO males, but not αERKO males, exhibited ectopic expression of LF in the SV. DES treatment resulted in decreased SVS IV protein and mRNA expression in WT males, but no effect was seen in αERKO mice. In addition, DES-treated βERKO mice exhibited reduced Svs4 mRNA expression but maintained control levels of SVS IV protein. In DES-treated castrated mice, DHT implants restored SV weights to normal levels in αERKO mice but not in WT mice, suggesting full androgen responsiveness in αERKO mice.
These data suggest that DES-induced SV toxicity and feminization are primarily mediated by ERα; however, some aspects of androgen response may require the action of ERβ.
Estrogen receptor-α mediates diethylstilbestrol-induced feminization of the seminal vesicle in male mice, NCBI, PMID: 22275727, 2012 Apr;120(4):560-5. doi: 10.1289/ehp.1103678. Epub 2012 Jan 24.
Feminization of the male mouse reproductive tract after prenatal exposure to DES
1994 Study Abstract
Exposure to estrogens during critical stages of development has been reported to cause irreversible changes in estrogen target tissues such as the reproductive tract. In fact, recent studies using mice describe prenatal estrogen exposure resulting in the expression of the major estrogen-inducible uterine secretory protein, lactoferrin (LF), by the seminal vesicles of the male offspring. Thus, we have studied the role of estrogens in abnormal and normal gene expression in the developing male reproductive tract using LF and seminal vesicle secretory protein IV (SVS IV), an androgen-regulated murine seminal vesicle secretory protein, as markers. Lactoferrin and SVS IV protein and mRNA expression were studied in histological samples by using the techniques of in situ hybridization (ISH) and immunohistochemistry (IHC). Seminal vesicle secretory protein IV was expressed in all (100%) epithelial cells of the control seminal vesicle, but this protein was decreased by castration. However, LF expression was undetectable by ISH or IHC in control seminal vesicle epithelium. Lactoferrin was inducible in 2% of the seminal vesicle epithelial cells from adult castrated mice treated with estradiol 17 beta (E2; 20 micrograms/kg/day for 3 days), indicating that a small percentage of the seminal vesicle cells could be induced to secrete LF after modification of the endocrine environment. Prenatal DES treatment (100 micrograms./kg. maternal body weight on days 9 through 16 of gestation) resulted in the male offspring exhibiting constitutive expression of LF in 5% of the seminal vesicle epithelial cells, while expression of the androgen-regulated protein SVS IV was slightly decreased. The maximal contrast between LF and SVS IV expression was observed in prenatally DES-treated mice that were subsequently castrated as adults and further treated with E2; LF was detected in 40% of the epithelial cells in these mice. Double immunostaining techniques revealed that epithelial cells which were making LF had ceased production of SVS IV. Since a large percentage of the epithelial cells in the intact prenatal DES exposed male was capable of expressing the normal gene product, SVS IV, it was concluded that DES treatment during prenatal development appears to imprint or induce estrogenic sensitivity in the adult seminal vesicle, causing increased production of LF. The results suggest that this altered protein response may be an example of atypical gene expression in male reproductive tract tissues following hormonal manipulation early in development.
Molecular feminization of mouse seminal vesicle by prenatal exposure to diethylstilbestrol: altered expression of messenger RNA, NCBI, PMID: 8158792, 1994 May;151(5):1370-8.
The seminal vesicle of prenatally DES-exposed male mice acquired two key characteristics of female tissues
Previous studies from our laboratory on the feminization of the male mouse reproductive tract after prenatal exposure to Diethylstilbestrol (DES) showed that the mRNA for the major estrogen-inducible uterine secretory protein, lactoferrin (LF), was constitutively expressed in the seminal vesicle of male mice exposed prenatally to DES, but not in the seminal vesicle of control mice. After castration, treatment with 17 beta-estradiol (20 micrograms/kg.day) for 3 days induced the LF mRNA in the seminal vesicle of both control and prenatally DES-exposed mice; however, the levels in DES-treated tissues were approximately 6-fold higher than those in control tissue. This report describes the presence of LF in seminal vesicle tissues and secretions of prenatally DES-exposed mice, as determined by immunohistochemistry and Western blot analysis. Further, these data are correlated with immunolocalization of the estrogen receptor in the seminal vesicle tissue. We conclude that the seminal vesicle of prenatally DES-exposed male mice has acquired two key characteristics of female tissues, namely LF production/regulation and estrogen receptor localization/distribution similar to that in uterine tissues.
Female gene expression in the seminal vesicle of mice after prenatal exposure to diethylstilbestrol, NCBI, PMID: 2707167, 1989 May;124(5):2568-76.