Etiology of obesity : Environmental Estrogen DES

DES exposure effects in mouse models replicate human findings

Abstract from “EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals”, 2015

Obesity requires eating more food and/or consuming less energy. To date, most of the obesity studies in animals are based in the observation that EDC exposures induce weight increases and changes in adiposity, as well as affecting hormones and adipokines involved in the regulation of food intake and energy expenditure. There are fewer studies related to how EDCs disrupt energy balance. Therefore, more studies are necessary to gain mechanistic insights into the role that EDCs play in the etiology of obesity.

Studies of rodents that were prenatally, neonatally, or perinatally exposed to EDCs support the obesogen hypothesis. For example, DES exposure effects in mouse models replicate human findings. DES is an estrogenic chemical that binds with high affinity to the ERs, ERα and ERβ, which play an important role in adiposity regulation as well as central and peripheral energy balance. Developmental exposure to DES in mice induced adipogenesis and caused mice to become obese or overweight.

Other chemicals classified as environmental estrogens, particularly BPA, produced similar effects. Perinatal exposure to low doses of BPA caused increased body weight; adiposity; alterations in blood levels of insulin, leptin, and adiponectin; as well as a decrease in glucose tolerance and insulin sensitivity in an age-dependent manner.



Environmental Estrogens, Obesity, and Metabolism

Perinatal exposure to DES and latent development of high body weight and obesity

Abstract from “Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement”, 2009

White adipose tissue metabolism is under the control of the sympathetic nervous system and is modulated by hormones including sex steroids. The impact of environmental estrogens on adipose tissue may be through direct modulation of lipogenesis, lipolysis, and adipogenesis, or indirect by affecting food consumption and leptin secretion targeting the central nervous system or lipid homeostasis in liver.

The estrogenic pharmaceutical chemical DES illuminates the relationship between perinatal exposures and latent development of high body weight and obesity. Moreover, there is a complex relationship between the concentration of estrogen to which pregnant animals are exposed and the weight of the offspring in adulthood. Specifically, according to a recent experiment by Newbold et al., mice neonatally exposed to DES experience increased body weight in adulthood associated with excess abdominal body fat. Interestingly, the dose of DES determines the chronic manifestation of the observed alterations, with high doses leading to initially decreased body weight and a peripubertal “catch-up” and low doses causing an increase in weight detectable only in adulthood. Moreover, the timing is important because gestational administration in rodents results in the offspring’s low birth weight, an unchanged metabolic characteristic throughout life. Along with an increase in body fat stores, the adipokines leptin and adiponectin, IL-6 (an inflammatory marker), and triglycerides were all elevated in DES-exposed mice.

An in vitro study using a culture system of 3T3-L1 preadipocytes showed that 4-nonylphenol and BPA stimulated lipid accumulation, accelerating their differentiation to mature adipocytes in a time- and concentration-dependent way. The underlying mechanism appeared to involve up-regulation of gene expression involved in lipid metabolism and adipocyte differentiation. In the second part of the experiment, fat accumulation was observed in human hepatocellular carcinoma cell lines exposed to those endocrine disruptors. These findings are consistent with previous in vitro studies using mouse fibroblast cell lines in which a link between environmental chemicals including nonylphenol, BPA, and genistein in the development of body weight imbalance was suggested.


  • Full study (free access) : Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement, Endocrine Society endocrine reviews, PMC2726844, 2009 Jun.

Pharmacologic sex hormones in pregnancy in relation to offspring obesity

2014 Study objective : to assess the association between in utero exposure to either diethylstilbestrol (DES) or an oral contraceptive in pregnancy and offspring obesity

What is already known about this subject

  • In animal models, in utero exposure to exogenous estrogenic agents is associated with offspring adiposity.
  • In in vitro and animal models, diethylstilbestrol exposure has led to an increase in stem cell differentiation into preadipocytes and adipocytes.

What this study adds

  • An evaluation of the association between in utero exposure to pharmacologic estrogens and subsequent obesity in humans.
  • A novel approach to studying the potential for developmental origins of obesity as conferred through in utero exposure to estrogenic agents.


Using data from the Collaborative Perinatal Project (1959-1974), a multicenter prospective study of pregnant women and their offspring, we examined overweight or obesity among 34,419 children with height and weight data at age 7 years. Generalized linear models to estimate the adjusted odds ratio (aOR) for overweight or obesity (≥85th percentile) or obesity (≥95th percentile) in the offspring according to exposure during different months of pregnancy were used.

Oral contraceptive use during pregnancy was positively associated with offspring overweight or obesity and obesity. The magnitude of association was strongest in the first 2 months of pregnancy for obesity (aOR 2.0, 95% CI: 1.1, 3.7). DES use was also associated with offspring overweight or obesity and obesity, with the association being strongest for exposure beginning between months 3 and 5 (e.g., for exposure beginning in months 3-4, the aOR for obesity was 2.8, 95% CI: 1.3, 6.3).

Pharmacologic sex hormone use in pregnancy may be associated with childhood obesity. Whether contemporary, lower dose oral contraceptive formulations are similarly associated with increased risk of childhood obesity is unclear.


  • Full study (free access) : Pharmacologic sex hormones in pregnancy in relation to offspring obesity, Obesity (Silver Spring), PMID: 20688618, 2014 Nov.
  • Featured image i yunmai.

Impact of environmental endocrine disrupting chemicals on the development of obesity

Developmental effects of diethylstilbestrol DES on obesity

2010 Review Abstracts

Environmental chemicals with hormone-like activity can disrupt programming of endocrine signaling pathways during development and result in adverse effects, some of which may not be apparent until much later in life. Recent reports link exposure to environmental endocrine disrupting chemicals during development with adverse health consequences, including obesity and diabetes. These particular diseases are quickly becoming significant public health problems and are fast reaching epidemic proportions worldwide. This review summarizes data from experimental animals and humans which support an association of endocrine disrupting chemicals, such as diethylstilbestrol, bisphenol A, phytoestrogens, phthalates, and organotins, with the development of obesity. Potential mechanisms are summarized and future research needs are discussed.

Also, the developing fetus and neonate have increased metabolic rates as compared to adults which in some cases may make them more vulnerable to chemical toxicity. It is now well established in the fields of nutrition and endocrine disruption that exposure to environmental chemicals during development can interfere with complex differentiating endocrine signaling pathways and cause adverse consequences later in life; the well known reproductive tract toxicity of diethylstilbestrol (DES) is one of the best examples of adverse consequences of endocrine disrupting chemicals. The concept of the “developmental origins of adult disease”, as the term implies, suggests that there is a time lag between exposure and manifestation of disease. In other words, the effects of exposure during development may not be readily apparent until much later in life.

DES, a potent synthetic estrogen, was widely prescribed to pregnant women from the 1940s through the 1970s in the mistaken belief that it could prevent threatened miscarriages. It was estimated that a range of 2 to 8 million pregnancies worldwide were exposed to DES. Today, it is well known that prenatal DES exposure resulted in a low but significant increase in neoplastic lesions and a high incidence of benign lesions in both the male and female offspring. The DES paradigm was a clear example that prenatal exposure could lead to adult-onset disease. To study the mechanisms involved in DES toxicity, we developed experimental mouse models of perinatal (prenatal or neonatal) DES exposure in which outbred mice were treated with DES on days 9-16 of gestation (the period of major organogenesis in the mouse) or days 1-5 of neonatal life (a period of cellular differentiation of the reproductive tract and a critical period of immune, behavioral, and adipocyte differentiation). These perinatal DES animal models have successfully duplicated, and in some cases predicted, many of the alterations (structural, functional, cellular, and molecular) observed in similarly DES-exposed humans. Further, these models have also shown multigenerational transmission of disease patterns implicating epigenetic mechanisms in the transmission of these effects.

Although our initial focus was on reproductive tract abnormalities and subfertility/infertility, we subsequently examined the relationship of perinatal DES treatment with the development of obesity later in life. We wanted to determine if DES was an “obesogen” as well as a reproductive toxicant and, if so, what were its molecular targets and the mechanisms through which it might act. For our obesity experiments, mice were treated with DES on days 1-5 of neonatal life using a low dose of 0.001 mg/day (1 µg/kg/day); this dose did not affect body weight during treatment but was associated with a significant increase in body weight in the adult animal by 4 to 6 months of age; male mice treated as neonates did not have an increase in body weight.

Unlike the low dose of DES (0.001 mg/day = 1 µg/kg/day), a higher dose (1000 µg/kg/day =1 mg/kg/day) caused a significant decrease in body weight during treatment but it was followed by a “catch-up” period around puberty and then finally resulted in an increase in body weight of the DES-treated mice compared to controls after ~2 months of age. This “catch-up” in weight between treated and control animals is reminiscent of the thrifty phenotype which is a well known phenomenon in the field of nutrition and was described in human infants who received poor nutrition during fetal life but later had “catch-up” growth that finally resulted in overweight and obesity later in life. Further studies indicated that the increase in body weight in DES-exposed mice was associated with an increase in the percent of body fat as determined by mouse densitometry.

Increased body weight in both low and high DES-treated mice compared to controls was observed throughout adulthood; however, by 18 months of age, statistical differences in body weight between DES-treated mice and controls were difficult to show because individual animal variability within groups increased as they aged due to the altered health status of the DES animals. We concluded that since various doses of DES resulted in obesity whether or not pups were underweight during treatment, multiple pathways might be involved in the programming for obesity related to environmental estrogens.
Since densitometry images of DES-treated mice suggested excessive abdominal fat, specific fat pads were weighed to see if particular fat pads were affected by DES treatment or whether there was a generalized change throughout the mouse, since it is well known that increased abdominal fat is associated with cardiovascular disease and diabetes in humans. Weights of inguinal, parametrial, gonadal, and retroperitoneal fat pads were all increased in DES treated mice as compared to controls at 6-8 months of age, suggesting a potential impact on cardiovascular disease following developmental exposure to DES. Brown fat weights were not significantly different in these animals.

Examination of DES-treated mice (1000 µg/kg/day =1 mg/kg/day) and controls at 2 months of age, prior to the treated mice becoming overweight and obese, showed elevated serum levels of leptin, adiponectin, IL-6, and triglycerides, suggesting that these endpoints may be important early markers of subsequent adult disease. Elevated levels of leptin are not surprising considering the increase number and size of the adipocytes in the DES-treated mice, but the increase in adiponectin was not expected since low levels usually correlate with obesity and diabetes in humans. This may indicate insensitivity to these hormones and/or a loss of the negative feedback mechanisms that regulate adipogenesis. Nevertheless, additional studies are needed to determine the mechanisms involved. At 6 months of age, insulin and all of the serum markers except triglycerides were found to be significantly elevated as compared to controls.

Glucose levels were also measured in DES (1000 µg/kg/day =1 mg/kg/day) and control mice at 2 months of age prior to the development of obesity and excessive weight gain. Interestingly, 25% of the DES-treated mice had significantly higher glucose levels than controls; these mice also showed a slower clearance rate of glucose from the blood since higher levels were seen throughout the experiment. Additional glucose measurements in older mice may help determine if a higher percentage of mice are affected with age and if higher and sustained levels of glucose can be demonstrated. To date, our data suggest that overweight and obesity observed in perinatal DES-treated mice will be associated with the development of diabetes, similar to the association of obesity with diabetes in humans. Further studies from our laboratory support a role for altered glucose metabolism as we have shown a high prevalence of islet cell hyperplasia in mice exposed to DES or other environmental estrogens including BPA and genistein.

Since the imbalance of activity levels and food intake are known contributors to obesity, ambulatory activity was measured in DES (1000 µg/kg/day =1 mg/kg/day) and control mice at 2 months of age before a difference in body weight could be detected. Overall, no statistical difference could be shown in activity between groups, although the DES group showed slightly less movement as compared to controls. This slight difference was not sufficient to explain the enhanced weight gain in DES mice as they aged.

Food consumption was also assessed; DES-treated mice consumed more than controls over the course of the experiment (~3 grams more), but the amounts were not statistically different between the groups. Taking into account both the marginal decrease in activity and the increase in food intake in DES-treated mice as compared to controls, it is unlikely that these two parameters can solely explain the development of obesity in DES-treated mice.

A recent study indicated a role for developmental genes in the origins of obesity and body fat distribution in mice and humans. We examined whether exposure to environmental chemicals which exerted hormonal activity would alter expression of genes involved in programming adipocytes during development. Several genes were found to be implicated in altered adipocyte differentiation and function (Hoxa5, Gpc4, and Tbx15) as well as fat cell distribution (Thbd, Nr2f1, and Sfrp2). We investigated changes in gene expression by microarray analysis in uterine samples from DES-treated mice (1000 µg/kg/day =1 mg/kg/day) compared to controls at 19 days of age. Genes involved in adipocyte differentiation were not different in the uterus following neonatal DES exposure. However, genes involved in fat distribution were altered; Thbd and Nr2f1 were significantly down-regulated and Sfrp2 was significantly up-regulated in DES-treated uteri compared to controls. These findings support the idea that environmental estrogens may play a role in regulating the expression of obesity-related genes in development. The identification of genes and molecular mechanisms that may be associated with EDCs and obesity is an exciting area of new research.

Although only neonatal exposure to DES has been discussed thus far in this review, exposure during prenatal life has also been shown to be associated with obesity later in life. Interestingly, high prenatal DES doses caused lower birth weight compared to controls, followed by a “catch-up period”, finally resulting in obesity; low prenatal DES doses had no effect on birth weight but it still resulted in obesity later in life. Thus, it appears that the effects of DES on adipocytes may depend on the time of exposure and the dose and that multiple mechanisms may be altered and result in the same obesity phenotype. Other investigators have also reported analogous findings with DES and other estrogenic chemicals.


  • Full study (free access) : Impact of environmental endocrine disrupting chemicals on the development of obesity, Hormones, PMID: 20688618, 2010 Jul-Sep.
  • Featured image PMC1931509/figure/F6.

Perinatal exposure to DES linked to obesity increase in a sex-dependent manner

The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice

2012 Study Abstract

Epidemiology studies indicate that exposure to endocrine disruptors during developmental “window” contributes to adipogenesis and the development of obesity.

Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated.

Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action.

DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) γ as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARγ activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo.

In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated.

These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders.


  • The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice, Toxicology and applied pharmacology, PMID: 22710028, 2012.
  • Featured image trbimg.

Developmental exposure to estrogenic compounds and obesity

DES fetal life influence on body weight

2005 Study Abstract

For >20 years, research in our laboratory has focused on the effects of estrogenic compounds on development and differentiation. Our working premise has been that the developing organism is extremely sensitive to perturbation by chemicals with estrogenic or endocrine disrupting activity and that exposure to these chemicals during critical stages of differentiation may have permanent long-lasting consequences, some of which may not be expressed or detected until later in life. Diethylstilbestrol (DES) is a well-known example of such a chemical; thus, we have used DES as a model chemical to study environmental estrogens.

DES, a synthetic estrogen, was widely prescribed from the 1940s through the 1970s for the prevention of threatened miscarriage. A range of 2–8 million treated pregnancies worldwide has been estimated. Today it is well recognized that prenatal DES treatment results in a low incidence of neoplasia in the female offspring and a high incidence of benign abnormalities in both the male and female offspring.

To study the mechanisms involved in the toxicity of DES, we developed an animal model using outbred CD-1 mice treated with DES by subcutaneous injections on GD 9–16 (the period of major organogenesis in the mouse) or days 1–5 of neonatal life (a period of cellular differentiation of the reproductive tract and a critical period of immune and behavioral differentiation). The prenatal DES animal model has successfully duplicated and, in some cases, predicted many of the alterations (structural, function, cellular, and molecular) observed in similarly DES-exposed humans.

Although our major focus has been on reproductive tract abnormalities, we also examined the effects of DES on body weight over a wide dose range of exposure.

  • High prenatal DES doses (10–100 μg/kg of maternal body weight) caused a decrease in the offspring’s adult body weight;
  • likewise, high neonatal DES doses (1000 μg/kg/day on days 1–5 [1 mg/kg/day]) caused a decrease in body weight later in life.
  • However, low doses of DES (either prenatal or neonatal) caused an increase in body weight; Figure 1 illustrates control and neonatal DES 0.001 mg/kg/day treatment (DES-0.001).
  • Note that body weight was not different between DES-exposed and unexposed controls during the time of treatment and shortly thereafter, but it gradually reached significance by 6 weeks of age.
  • Further, data from our laboratory indicate that this increase in body weight in DES-exposed mice is associated with an increase in the percentage of body fat. Using Lunar PIXImus mouse densitometry (Lunar PIXImus, GE Healthcare, Waukesha, WI), we measured the percentage of fat in untreated controls and neonatal DES-treated mice at 16 weeks of age. As seen in the image, mice treated neonatally with DES are markedly larger than controls. Measurements obtained from densitometry show a significant increase in the estimated body weight, estimated fat weight, and percent fat compared to controls.
  • Neonatal exposure to other estrogens such as 2OH estradiol (20 mg/kg/day) and 4OH estradiol (0.1 mg/kg/day), which are approximately equal estrogenic doses to DES-0.001, also caused an increase in body weight at 4 months of age, suggesting that DES is not a unique estrogenic chemical in causing this increased obesity.
  • Further, neonatal exposure to the naturally occurring phytoestrogen genistein at 50 mg/kg/day, an approximately equal estrogenic dose to DES, caused a significant increase in body weight at 3 and 4 months of age compared to untreated controls.

We are currently comparing the weight of fat depots from mice exposed neonatally to various environmental estrogens to determine possible alterations in adipose tissue, including size of specific fat pads and hormone levels (e.g., leptin, adiponectin). By 18 months age, differences in body weight between genistein-treated and untreated controls are difficult to determine due to large individual animal variability within groups.

Taken together, our data support the idea that brief exposure to low levels of environmental estrogens early in life increases body weight as the mice age. Whether our results can be extrapolated to humans, as in the reproductive abnormalities from the DES mouse model, remains to be determined, but this is a fruitful area for further research. In addition, the use of this mouse model to study mechanisms involved in altered weight homeostasis (direct and/or endocrine feedback loops, e.g., ghrelin, leptin) by environmental endocrine disrupting chemicals is an important basic research area that may shed light on the future prevention and treatment of obesity.



Ability to produce offspring significantly diminished by DES exposure

Avian transgenerational reproductive toxicity test with in ovo exposure

2006 Study Abstract

Ecological risk assessment of environmental pollutants requires effective laboratory assays and extrapolation of the resultant data to wild species. Because avian reproductive disorder and accumulation of persistent compounds in wild birds and their eggs have long been observed in polluted regions, we have developed an assay for investigating whether pollutants accumulated in eggs impair the reproduction of the exposed birds and the survival of the next generation using the Japanese quail.

A typical estrogenic compound, diethylstilbestrol (DES), dissolved in olive oil was injected into the air-chamber of fertilized eggs on day 10 of incubation.

After sexual maturation of hatched chicks, we mated pairs of male and female quails following an observation period of egg production and collected their eggs. The collected eggs were incubated and checked for the fertility and hatchability, and then the hatchlings were raised and observed in growth for 3 weeks.

A dosage of 5 ng/g per egg of DES caused eggshell thinning in eggs laid by exposed females and reduction in eggshell strength. DES also induced shortening of the left oviduct and unexpected development of the right oviduct, while testis weight was reduced symmetrically.

The ability of quail pairs to produce offspring was significantly diminished by exposure of females to DES independently of exposure of males, which mainly arose from production of abnormal and inviable eggs. Fertility of normal-shelled eggs and hatchability of fertilized eggs were unchanged regardless of treatments.

External morphological abnormalities, which were mostly unopened toes of the foot, were frequently observed in hatchlings from exposed males independently of exposure of females.

Additionally, we attempted to extrapolate the experimental results to the northern bobwhite and to predict population trends for quails in a polluted habitat using a population projection model composed of a combination of a Leslie matrix and the logistic equation.

In the event of accumulation of an estrogenic compound equivalent to a dosage of 5 ng/g DES in quail eggs,

  • the average population size was predicted to decrease by 20.2% after 1 year,
  • to approximately half after 4 years,
  • and to a fifth after 14 years.

When observed weakening of individuals and the risk of egg breakage are taken into consideration, the decline in population was further accelerated. The proposed assay appears to be suitable not only for assessing adverse effects of chemicals on avian reproduction but for population projection of affected wild birds.


  • Avian transgenerational reproductive toxicity test with in ovo exposure, Archives of toxicology, NCBI PubMed PMID: 16758213, 2006.
  • Featured image credit jiangxulei1990.

Epigenetics, brain, behavior, and the environment

Some studies looked at whether DNA methylation (a process at the DNA level which affects which genes get turned on and turned off) has a link to increased risk for schizophrenia or schizophrenia-like conditions among the DES-exposed

Both men and women exposed to diethylstilbestrol (DES) in utero (hence having a body burden of the chemical) are more prone to depression compared to their unexposed siblings. Indeed, an issue of national concern is the significant environmental exposure to common-use chemicals in the household, a factor suggested as contributing to the increased incidence of affective disorders in the general population.

2010 Review Abstract

Early experiences can modify regulatory factors affecting gene expression in such a way that, although the DNA sequence itself is not changed, the individual’s physiology and behavior is substantially influenced.

In some instances these epigenetic effects are exerted upon exposure, while in other instances they are transmitted across generations via incorporation into the germline. Examples of both types of epigenetic effects are presented.

First, experience with siblings (littermates) organizes behaviors and their underlying neural substrates in such a way that, as adults, rats and knockout mice behave differently. Second, exposure to the fungicide vinclozolin early in pregnancy imprints the male lineage in such a manner that rats exhibit distinct behavioral profiles as well as unique patterns of gene expression in relevant brain regions.

Taken together, this work demonstrates that present and past environments alike modify both social and affiliative related behaviors and their related metabolic activity in specific brain nuclei as well as influencing the abundance of specific genes altering the epigenome in the target brain areas.



Family History is Underestimated in Children with Isolated Hypospadias

A French Multicenter Report of 88 Families, 2018

In humans massive exposure to strong EDCs (DES) has effects through several generations and may contribute to some familial expression of hypospadias.


While familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed to determine the frequency of hypospadias in families of boys with hypospadias, to establish whether these familial forms exhibit a particular phenotype and to evaluate the prevalence of genetic defects of the main candidate genes.

Materials and methods
A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1.

Family history of hypospadias was more frequent than expected (88 patients, 22.3%). In 17 instances (19.3%) familial hypospadias cases were multiple. Familial hypospadias was related to the paternal side in 59.1% of cases, consisting of the father himself (30.7%) as well as paternal uncles and cousins. Premature birth, assisted reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of genetic analysis combined with previous data on androgen receptor sequencing revealed that familial cases more frequently tend to demonstrate genetic defects than sporadic cases (5.68% vs 1.63%, p = 0.048).

Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated forms justify a full clinical investigation of the family history. Detecting these hereditary forms may help to determine the underlying genetic defects, and may improve followup and counseling of these patients.



Neurodevelopmental disorders in children exposed in utero to synthetic progestins

Analysis from the national cohort of the Hhorages Association, 2018


The medical and scientific communities have not yet fully acknowledged the undesirable effects of the synthetic hormones that have been administered to pregnant women for decades.

The somatic effects of in utero exposure to diethylstilbestrol (DES), such as genital malformations, infertility, and cancer, have long been recognized but this has not been the case concerning psychiatric disorders.

The progestins used in contraception and hormone replacement therapy are known to affect the adult brain, but no data exist on their effects due to in utero exposure of children.

The Hhorages Association, a national patient support group, has assembled a cohort of 1200 women who took synthetic hormones during pregnancy.

These women had a combined 1934 children. We obtained full questionnaire responses from 46 women treated with progestins only – and not an estrogenic cocktail – who gave birth to 115 children.

Three groups were observed:

  1. Group 1 (n = 18): firstborn unexposed children,
  2. Group 2 (n = 62): children exposed in utero to synthetic progestins,
  3. and Group 3 (n = 35): children born after a previous pregnancy treated with progestins.

No psychiatric disorders were reported in Group 1 and the incidence of psychiatric disorders was drastically elevated in Group 2.

Our work shows a striking increase in psychiatric disorders among children exposed in utero to progestins and strongly suggests that prenatal exposure is associated with a high risk of psychiatric disorders in adolescence and adulthood, whether accompanied or not by disorders of sex development.


  • Neurodevelopmental disorders in children exposed in utero to synthetic progestins: analysis from the national cohort of the Hhorages Association, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, DOI: 10.5772/intechopen.80969, November 5th 2018.
  • Image credit Alexander Krivitskiy.