Cognitive Ability and Cerebral Lateralisation in Transsexuals

image of transsexual

1998 Study Abstracts

It is still unclear to what extent cross-gender identity is due to pre- and perinatal organising effects of sex hormones on the brain. Empirical evidence for a relationship between prenatal hormonal influences and certain aspects of gender typical (cognitive) functioning comes from pre- and postpubertal clinical samples, such as women suffering from congenital adrenal hyperplasia and studies in normal children.

In order to further investigate the hypothesis that cross-gender identity is influenced by prenatal exposure to (atypical) sex steroid levels we conducted a study with early onset, adult male-to-female and female-to-male transsexuals, who were not yet hormonally treated, and nontranssexual adult female and male controls. The aim of the study was to find out whether early onset transsexuals performed in congruence with their biological sex or their gender identity.

The results on different tests show that gender differences were pronounced, and that the two transsexual groups occupied a position in between these two groups, thus showing a pattern of performance away from their biological sex. The findings provide evidence that organisational hormonal influences may have an effect on the development of cross-gender identity.

… … For this reason, DES-exposed males and females provide a valuable opportunity for investigating possible influences of a synthetic estrogen on hemispheric specialization. In a study of cognitive abilities and functional asymmetry in DES-exposed women and their unexposed sisters, the influence of DES on verbal, visuospatial and dichotic listening tasks was investigated. Subjects for this study included 25 right-handed women exposed to DES for at least 5 months prenatally (with 3 of those months occurring during the second trimester when human sexual differentiation is believed to occur), and their unexposed sisters who served as controls. … …



Transgenerational transmission of environmental effects through epigenetic modifications

The history of Distilbène® (Diethylstilbestrol) told to grandchildren – the transgenerational effect

2015 Study Abstract

The Distilbène® story is a dramatic episode which belongs to the history of medicine. It provided several useful lessons such as the importance of evidence-based medicine and the hazard to develop treatments during pregnancy without careful animal verifications. However, this experience has also provided unexpected progress by suggesting new pathophysiological concepts: fetal programming of adult diseases and/or transgenerational transmission of environmental effects through epigenetic modifications.


  • Introduction
  • History
  • Diseases reported in second generation after foetal exposure to DES
    • Developmental and reproductive anomalies
    • Non-reproductive anomalies
  • Diseases reported in the third generation after the grandmother was treated with DES during pregnancy
    • Human abnormalities
    • Concordance with rodent model
  • Which molecular mechanisms?
    • Exposure window
    • Chemical nature of estrogens
    • The mechanisms involved in foetal programming of adult diseases – epigenetic modifications
    • Transgenerational transmission mechanisms
  • Conclusion
  • Disclosure of interest


  • Full paper (free access) : The history of Distilbène® (Diethylstilbestrol) told to grandchildren–the transgenerational effect, ANNALES D’ENDOCRINOLOGIE, EM Consulte, article/990390, 22/07/15.
  • Featured image Isaiah Rustad.

Medical Conditions among Adult Offspring prenatally exposed to DES

DES Follow-up Study Summary

Concern about the possible impact of estrogen-like substances found in the environment on a range of health conditions has spurred research in this area. Diethylstilbestrol (DES) is an example of an endocrine-disruptor i.e., chemicals that interfere with the body’s hormone system. While prenatal exposure to DES is known to increase risks of vaginal or cervical cancer and poor reproductive outcomes in women, and abnormalities in the urinary and genital tracts in men information on non-reproductive medical conditions are lacking.

We studied the associations between prenatal DES exposure and the occurrence of cardiovascular disease, diabetes, osteoporosis and related conditions among 5,590 exposed and unexposed daughters and 2,657 exposed and unexposed sons in the NCI Combined DES Follow-up Study. The associations took into account the participants’ birth year, sex, weight adjusted for height, smoking status, alcohol use, educational status, number of general physical examinations in the past 5 years, and study site.

Comparing participants exposed prenatally to DES with those who were not exposed, there were increases in the risk of developing cardiovascular disease (27%), heart attacks (28%), hypertension (14%), and high cholesterol (12%). In addition, the risks of developing diabetes, coronary artery disease, osteoporosis and fractures were elevated, but these findings were possibly due to chance. The associations of DES and the medical conditions did not differ by dose and timing of DES exposure, nor, in the women, by presence or absence of vaginal epithelial changes (a marker of DES host susceptibility).

This study raises the possibility that prenatal DES exposure is associated with several common medical conditions in adulthood, although there is the possibility that our results are explained by differences in the reporting of conditions by the exposed and unexposed participants, or by other factors related to both the conditions and DES exposure status that were not accounted for in the study, such as dietary intake and physical activity. We plan to continue to study these associations by obtaining medical records to confirm the diagnoses in the current round of the study.

” DES Exposure estimated hazard ratios and their associated 95% confidence intervals for the associations between prenatal DES exposure and the occurrence of cardiovascular disease, diabetes, osteoporosis, and related conditions among 5590 female and 2657 male offspring followed from 1994 through 2006, adjusted for birth year, cohort, sex, body mass index, smoking status, alcohol use, education, and number of general physical examinations in the past 5 years “.

commented DES Info.


Diethylstilbestrol (DES), a synthetic estrogen that was used in pregnancy, is a prototype endocrine-disrupting chemical. Although prenatal exposure to DES is known to increase risks of vaginal/cervical adenocarcinoma and adverse reproductive outcomes in women, and urogenital anomalies in men, data on nonreproductive medical conditions are lacking.

We estimated hazard ratios and their associated 95% confidence intervals for the associations between prenatal DES exposure and the occurrence of cardiovascular disease, diabetes, osteoporosis, and related conditions among 5590 female and 2657 male offspring followed from 1994 through 2006, adjusted for birth year, cohort, sex, body mass index, smoking status, alcohol use, education, and number of general physical examinations in the past 5 years.

Comparing persons exposed prenatally to DES with those who were not exposed, the hazard ratios were 1.21 (95% confidence interval = 0.96-1.54) for diabetes, 1.27 (1.00-1.62) for all cardiovascular disease, 1.18 (0.88-1.59) for coronary artery disease, 1.28 (0.88-1.86) for myocardial infarction, 1.12 (1.02-1.22) for high cholesterol, 1.14 (1.02-1.28) for hypertension, 1.24 (0.99-1.54) for osteoporosis, and 1.30 (0.95-1.79) for fractures. The associations did not differ by dose and timing of DES exposure, nor, in the women, by the presence or absence of vaginal epithelial changes (a marker of DES host susceptibility).

These data raise the possibility that prenatal exposure to DES is associated with several common medical conditions in adulthood, although differential reporting by DES status and residual confounding cannot be ruled out. Further follow-up should assess these findings with validated outcomes and seek to understand the biological mechanisms.


  • Medical conditions among adult offspring prenatally exposed to diethylstilbestrol, Epidemiology, PMID: 23474687, 2013 May.
  • Featured image rawpixel.

Evidence for decreasing quality of semen during past 50 years

In a 1981 study, 80% of the DES-exposed males qualified as infertile

1992 Study Abstract

To investigate whether semen quality has changed during the past 50 years.

Review of publications on semen quality in men without a history of infertility selected by means of Cumulated Index Medicus and Current List (1930-1965) and MEDLINE Silver Platter database (1966-August 1991).

14,947 men included in a total of 61 papers published between 1938 and 1991.

Mean sperm density and mean seminal volume.

Linear regression of data weighted by number of men in each study showed a significant decrease in mean sperm count from 113 x 10(6)/ml in 1940 to 66 x 10(6)/ml in 1990 (p < 0.0001) and in seminal volume from 3.40 ml to 2.75 ml (p = 0.027), indicating an even more pronounced decrease in sperm production than expressed by the decline in sperm density.

There has been a genuine decline in semen quality over the past 50 years. As male fertility is to some extent correlated with sperm count the results may reflect an overall reduction in male fertility. The biological significance of these changes is emphasised by a concomitant increase in the incidence of genitourinary abnormalities such as testicular cancer and possibly also cryptorchidism and hypospadias, suggesting a growing impact of factors with serious effects on male gonadal function.

Such remarkable changes in semen quality and the occurrence of genitourinary abnormalities over a relatively short period is more probably due to environmental rather than genetic factors. Some common prenatal influences could be responsible both for the decline in sperm density and for the increase in cancer of the testis, hypospadias, and cryptorchidism. Whether oestrogens or compounds with oestrogen-like activity or other environmental or endogenous factors damage testicular function remains to be determined.


  • Full text (free access) : Evidence for decreasing quality of semen during past 50 years, The International journal of risk & safety in medicine, The BMJ, bmj00091-0019, PMCID: PMC1883354, 1992 Sep 12.
  • Featured image credit freemalaysiatoday.

DES and Nuclear Receptors

image of Nuclear Receptors

Nuclear receptors and endocrine disruptors in fetal and neonatal testes: a gapped landscape

2014 Study Abstract

During the last decades, many studies reported that male reproductive disorders are increasing among humans. It is currently acknowledged that these abnormalities can result from fetal exposure to environmental chemicals that are progressively becoming more concentrated and widespread in our environment.

Among the chemicals present in the environment (air, water, food, and many consumer products), several can act as endocrine disrupting compounds (EDCs), thus interfering with the endocrine system. Phthalates, bisphenol A (BPA), and diethylstilbestrol (DES) have been largely incriminated, particularly during the fetal and neonatal period, due to their estrogenic and/or anti-androgenic properties. Indeed, many epidemiological and experimental studies have highlighted their deleterious impact on fetal and neonatal testis development.

As EDCs can affect many different genomic and non-genomic pathways, the mechanisms underlying the adverse effects of EDC exposure are difficult to elucidate. Using literature data and results from our laboratory, in the present review, we discuss the role of classical nuclear receptors (genomic pathway) in the fetal and neonatal testis response to EDC exposure, particularly to phthalates, BPA, and DES.

Among the nuclear receptors, we focused on some of the most likely candidates, such as peroxisome-proliferator activated receptor (PPAR), androgen receptor (AR), estrogen receptors (ERα and β), liver X receptors (LXR), and small heterodimer partner (SHP).

First, we describe the expression and potential functions (based on data from studies using receptor agonists and mouse knockout models) of these nuclear receptors in the developing testis. Then, for each EDC studied, we summarize the main evidences indicating that the reprotoxic effect of each EDC under study is mediated through a specific nuclear receptor(s). We also point-out the involvement of other receptors and nuclear receptor-independent pathways.

DES and Nuclear Receptors

DES and ERs

Diethylstilbestrol exerts its anti-androgen effects mainly through classical ER signaling, particularly via ERα. In an organ culture system of mouse fetal testes, the reduction in testosterone production observed following DES exposure in wild type testes does not occur in ERα-deficient mice. Similarly, INSL3 gene expression and testis descent are not affected by in utero exposure to DES in ERαKO mice, whereas ERβ invalidation does not protect from DES effect.

DES and ARs and PPARs

To our knowledge, there is no data showing the direct involvement of AR or PPARs in DES testis effects. However, an indirect action of DES cannot be excluded in relation with the reduction of testosterone secretion observed in vitro in rodent testes incubated with DES.

DES and LXRs

Some studies have linked estrogens and LXRs in breast and in mouse adipose tissue. In the testis, LXRs could partially interfere with DES effects. Daily treatment with DES from day 1 to day 5 after birth induces an important increase in cell apoptosis in LXR-deficient mice at day 10 compared to wild type animals. Likewise, LXRs modify the neonatal effects of DES on the expression of Leydig and Sertoli cell markers. However, whether LXRs have a protective effect against or contribute to DES effects remains unclear.


Treatment with DES promotes SHP mRNA accumulation in the testes of wild type SHP male mice (NR0B2+/+) at postnatal day 10 (P10). Moreover, neonatal DES exposure induces apoptosis, in P10 NR0B2+/+ mice, without any effect on cell proliferation. Conversely, DES does not have any effect on apoptosis in the testes of NR0B2L−/L− males, suggesting that SHP inactivation protects against DES effects. This seems to be germ cell-specific because DES treatment drastically decreases intratesticular testosterone in both NR0B2L−/L− and NR0B2L−/L− males. Interestingly, SHP, mediating the deleterious effects of DES in mice, is not detectable in human fetal testes, and incubation with DES does not modify testosterone production by human fetal testes in culture. SHP absence in human fetal testes could be an additional explanation for their lack of sensitivity to DES.

Sources and more information
  • Full study (free access) : Nuclear receptors and endocrine disruptors in fetal and neonatal testes: a gapped landscape, Frontiers in endocrinology, NCBI PubMed PMC4423451, 2014 Apr.
  • Structural Organization of Nuclear Receptors featured image credit wikipedia.

The ‘oestrogen hypothesis’- where do we stand now ?

oestrogen hypothesis image

In utero, rodents exposed to DES during development have abnormal testicular histology and altered adult male fertility

2003 Study Abstract

The original ‘oestrogen hypothesis‘ postulated that the apparent increase in human male reproductive developmental disorders (testis cancer, cryptorchidism, hypospadias, low sperm counts) might have occurred because of increased oestrogen exposure of the human foetus/neonate; five potential routes of exposure were considered.

This review revisits this hypothesis in the light of the data to have emerged since 1993. It addresses whether there is a secular increasing trend in the listed disorders and highlights the limitations of available data and how these are being addressed. It considers whether new data has emerged to support the suggestion that increased oestrogen exposure could cause these abnormalities and reviews new data on potential routes via which such increased exposure could have occurred.

Secular trends
The disorders listed above are now considered to represent a syndrome of disorders (testicular dysgenesis syndrome, TDS) with a common origin in foetal life. Testicular cancer has increased in incidence in Caucasian men worldwide and lifetime risk is 0.3-0.8%. Secular trends in cryptorchidism are unclear but it is by far the commonest (2-4% at birth) congenital abnormality in either sex. Secular trends for hypospadias are not robust, although most studies suggest a progressive increase; registry data probably under-estimates incidence, but based on this data hypospadias is the second most common (0.3-0.7% at birth) congenital malformation. Retrospective analyses of sperm count data show a global downward trend but this is inconclusive – prospective studies using standardized methodology show significant differences between countries and very low sperm counts in the youngest cohort of men. For all disorders, other then testis cancer, standardized prospective studies are the best way forward and are in progress across Europe.

Oestrogen effects
Evidence that foetal exposure to oestrogens can induce the above disorders has strengthened. New pathways via which such changes could be induced have been identified, including suppression of testosterone production by the foetal testis, suppression of androgen receptor expression and suppression of insulin-like factor-3 (InsL3) production by foetal Leydig cells. Other evidence suggests that the balance between androgen and oestrogen action may be important in induction of reproductive tract abnormalities.

Oestrogen exposure
Although many new environmental oestrogens have been identified, their uniformly weak oestrogenicity excludes the possibility that they could induce the above disorders. However, emerging data implicates various environmental chemicals in being able to alter endogenous levels of androgens (certain phthalates) and oestrogens (polychlorinated biphenyls, polyhalogenated hydrocarbons), and the former have been shown to induce a similar collection of disorders to TDS.

Other mechanisms via which increased fetal exposure to pregnancy oestrogens might occur (increasing trend in obesity, dietary changes) are also discussed.

Sources and more information

Was DES involved in falling sperm counts and disorders of the male reproductive tract ?

image of falling sperm counts

Male sexual development in “a sea of oestrogen” during in-utero DES exposure

1993 Study Abstract

The incidence of disorders of development of the male reproductive tract has more than doubled in the past 30-50 years while sperm counts have declined by about half.

Similar abnormalities occur in the sons of women exposed to diethylstilbestrol (DES) during pregnancy and can be induced in animals by brief exposure to exogenous oestrogen/DES during pregnancy.

We argue that the increasing incidence of reproductive abnormalities in the human male may be related to increased oestrogen exposure in utero, and identify mechanisms by which this exposure could occur.

Sources and more information
  • Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract?, The Lancet, NCBI PubMed PMID: 8098802, 1993.

Impaired immune function (infectious illness, allergic, autoimmune conditions) in the DES-exposed

Long-term Effects of Exposure to Diethylstilbestrol

1988 Study Abstract

The present survey represents a preliminary look at possible health effects of prenatal exposure to DES in humans beyond those already known. As such, it should be considered as a guide to areas needing further investigation in less biased samples. The findings, however, are consistent with those of experimental studies in animals and indicate a need for follow-up in the human cohort. Of particular note are conditions that suggest impaired immune function, such as infectious illness, allergic and autoimmune conditions, and malignant tumors.

Studies of certain genetic strains of mice with exposure to DES during the critical neonatal period of immune system ontogeny-analogous to the first trimester of human pregnancy-show persistent, lifelong immunosuppression. The main DES effect is a reduced number of Thelper cells, important for the induction and regulation of many immune responses. B-cell response is impaired in assays requiring T-cell mediation but is normal if corrected for T-helper numbers. Experiments with varying combinations of B and T cells in vitro show that the defect is in T-cell number but not function.

Mice with neonatal exposure also have a reduced number of natural killer cells thought to recognize and kill certain tumor cells. Following injection with a classic carcinogen (3-methylcholanthrene [MCA]), DES-exposed mice show a reduced ability to resist tumors; MCA-induced sarcomas appear in greater numbers and at a faster rate.

Our findings regarding asthma, arthritis, and lupus are also consistent with those of a small study of human peripheral blood lymphocytes suggesting a hyperreactive immune response in women with in utero exposure to DES. Another small study of the daughters suggested possible functional alterations of natural killer cells. Even more suggestive, our findings are consistent with those of a recent preliminary report from the largest ongoing follow-up of DES daughters, the federally funded Diethylstilbestrol Adenosis Project. This report indicates about a twofold increase in autoimmune conditions in women with prenatal exposure compared with controls. One small study of daughters who had had DES associated cancer or reproductive problems showed no consistent increase in the rates of infectious disease but a suggestive increase in the rates of autoimmune disease compared with controls.

Evaluating immunologic consequences in women and men with DES exposure will be complicated by possible genetic contributions and by varying dosage and timing of the prenatal exposure. Furthermore, health consequences might become detectable only as the population ages, when the immune system generally declines in competence.

Possible pathologic disorders of the prostate, as noted in our survey, were also noted in experimental models of DES effects in rodents.In preliminary studies of mice with neonatal DES exposure, evidence of cytologic malignancy in the area of the prostate appeared only in the experimentally treated animals. Recent experiments in which human fetal prostate tissue was grafted into DES-treated and untreated athymic nude mice and then allowed to continue growing revealed ductal dilation and persistent distortion of ductal architecture; these conditions could contribute to early or increased development of prostatic neoplasms (S. Mee, G.R. Cunha, C.V. Yonemura, et al, “The Effects of Diethylstilbestrol on Human Prostate Development,” unpublished data, 1987).

Further inquiry should also focus on a possible increased prevalence of elevated prolactin levels among DES daughters. Substantial endocrine alterations occur in rodents; more specifically, experimental studies show that perinatal DES exposure results in a disruption of hypothalamic-pituitary feedback systems, including the regulation and production of prolactin. While endocrine effects of a similar magnitude are not apparent within the human cohort, there could be an increase of more subtle functional alterations in daughters or sons (or both) with exposure to DES. Although difficult to measure, abnormal endocrine function could be contributing to a diminished reproductive capacity in ways beyond the more apparent and well-documented structural anomalies. Two small studies of plasma hormones in the daughters suggest abnormalities that may reflect a disturbance of hypothalamic-pituitary-ovarian function. An additional study suggests that hyperprolactinemia may be a significant factor in infertility in daughters with DES exposure.

Comprehensive follow-up of DES-exposed daughters and sons is required to answer questions about the long-term consequences of prenatal exposure. As the cohort ages and reaches new “milestones” of increased health risks, such follow-up can contribute to a more adequate assessment of this population’s risks and to the early detection of various health conditions that may be affected by prenatal DES exposure and be responsive to treatment. In addition, an increased knowledge of the health consequences associatedwith DES exposure addresses a broader scientific need to examine fully the results of this reproductive exposure. Women and men with in utero exposure to DES constitute a unique, identified cohort from which much can be learned about the hormonal effects on both normal and abnormal human development. This cohort can provide a greater understanding of developmental biology, sex differentiation, and pathologic processes in humans. Beyond the basic knowledge to be gained are implications for therapeutic substances in use currently or considered for the future.

Sources and more information
  • Full study (free download) : Long-term Effects of Exposure to Diethylstilbestrol, Clinical Medicine, NCBI PubMed PMC1026532, 1988 Nov.
  • Prevalence Rates (%) of Selected Conditions Among Adults With Diethylstilbestrol (DES) Exposure featured image credit ncbi.

DES effects on T-cell differentiation in the thymus

image of T-cell differentiation

Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery

2006 Study Abstract

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans.

In the current study, we investigated the effects of DES on T-cell differentiation in the thymus using the HY-TCR transgenic (Tg) mouse model in which the female mice exhibit positive selection of T cells bearing the Tg TCR, while the male mice show negative selection of such T cells.

In female HY-TCR-Tg mice, exposure to DES showed more pronounced decrease in thymic cellularity when compared to male mice. Additionally, female mice also showed a significant decrease in the proportion of double-positive (DP) T cells in the thymus and HY-TCR-specific CD8+ T cells in the periphery. Male mice exhibiting negative selection also showed decreased thymic cellularity following DES exposure. Moreover, the male mice showed increased proportion of double-negative (DN) T cells in the thymus and decreased proportion of CD8+ T cells. The density of expression of HY-TCR on CD8+ cells was increased following DES exposure in both females and males. Finally, the proliferative response of thymocytes to mitogens and peripheral lymph node T cells to male H-Y antigen was significantly altered in female and male mice following DES treatment.

Taken together, these data suggest that DES alters T-cell differentiation in the thymus by interfering with positive and negative selection processes, which in turn modulates the T-cell repertoire in the periphery.

Sources and more information
  • Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery, Toxicology and applied pharmacology, NCBI PubMed PMID: 16122773, 2006 Apr.
  • T-cell differentiation featured image credit researchgate.

Neonatal DES exposure caused the differential expression of 900 genes

EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals


“Synthetic estrogens are well known disruptors of uterine structure and function in humans and animals. Consistent with previous studies, recent data indicate that neonatal DES exposure caused endometrial hyperplasia/dysplasia in hamsters and increased uterine adenocarcinoma and uterine abnormalities in Donryu rats. Neonatal DES exposure also caused the differential expression of 900 genes in one or both layers of the uterus. Specifically, DES altered multiple factors in the PPARγ pathway that regulate adipogenesis and lipid metabolism, and it perturbed glucose homeostasis, suggesting that DES affects energy metabolism in the uterus. In the mouse uterus, DES altered the expression of chromatin-modifying proteins and Wnt signaling pathway members caused epigenetic changes in the sine oculis homeobox 1 gene, and decreased the expression of angiogenic factors. DES also altered the expression of genes commonly involved in metabolism or endometrial cancer in mice, and it activated nongenomic signaling in uterine myometrial cells  and increased the incidence of cystic glands in rats.” …

… “The epidemiological data on potential links between EDCs and neurodevelopmental disorders have grown in the past 5 years; although we will focus on recent studies, we will also present results (briefly) from older studies for an historical perspective. The nature of this work generally involves measurements of body burden from maternal media (urine, blood, milk), umbilical cord blood, infant urine, and ultimately, a correlation with some neurodevelopmental measure in the child such as tests of cognitive function.” …

… “What is still very controversial is whether there are direct links among environmental EDCs and specific disorders such as autism spectrum disorders, attention deficit hyperactivity disorders, and others, although the hypothesis has been postulated that EDCs may contribute to the increasing prevalence of these disorders. A recent review has covered the subject of how aberrant prenatal steroid hormone levels produced by the mother, placenta, or fetal adrenal or gonad, along with pharmaceuticals and to a lesser extent EDCs, could affect the developing brain of the fetus in humans.” …

  • Read and download the full study (free access) EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, on the NCBI, PubMed, Endocrine Reviews, PMC4702494, 2015 Dec.
  • Image credit NCBI PubMedPMC4702494/figure/F4.