Gynecomastia and Pseudoprecocious Puberty Following Diethylstilbestrol Exposure

A.M.A. journal of diseases of children, 1958

“For a time the mother packaged the pellets by machine at home, and diethylstilbestrol dust was present in the air on a number of occasions. The estrogenic effects here were presumably due to inhalation of the diethylstilbestrol dust and contact with the mother’s contaminated clothing.”


The purpose of this paper is to report the occurrence of gynecomastia in a 3-year-old boy and pseudoprecocious puberty in his 23-month-old sister following exposure to diethylstilbestrol (stilbestrol).

Report of Cases A 38/12-year-old white boy was seen in the Yale Private Diagnostic Clinic on Oct. 22, 1956, because of bilateral breast enlargement present since January, 1956. There were no other complaints. Growth and development had otherwise been normal. The child was in the 50th percentile for height and 90th percentile for weight. As illustrated in Figure 1, the breasts were enlarged to a moderate degree. Freely moveable, circumscribed masses of glandular tissue about 2 cm. in diameter were palpable under the areolae. The nipples, areolae, and linea alba were deeply pigmented. A scanty amount of downy pubic hair was present. Axillary hair was absent. Neurologic and funduscopic examinations were negative. The testes were of normal size. No palpable testicular masses.



From malformations to molecular mechanisms in the male

Three decades of research on endocrine disrupters, 2001


For three decades, we have known that estrogens alter the development of the mammalian reproductive system in predictable ways.

In mice exposed prenatally to diethylstilbestrol (DES) or other estrogens, the male offspring exhibit structural malformations including cryptorchidism, epididymal cysts and retained Mullerian ducts. The estrogen-associated alterations in the genital tract phenotype can be usefully considered as a model called Developmental Estrogenization Syndrome. While estrogen treatment during critical periods of morphogenesis of the male reproductive system has been associated with these changes, the mechanisms at the molecular level are still being discovered. Parallel findings on the hormones involved in Mullerian duct regression and testicular descent have helped guide research on the mechanisms of developmental estrogenization of the male. Cellular localization of molecular signals associated with key steps in genital tract development, use of mice with gene disruption, and knowledge of the mechanisms underlying persistent changes in gene expression are beginning to provide a blue print for both the physiological role and pathological effects of estrogens in reproductive tract development.

Since many of the same biological principles underlie genital tract morphogenesis in mammals, one may expect some of the same changes in males of other species exposed to estrogen during the appropriate developmental periods.


  • From malformations to molecular mechanisms in the male: three decades of research on endocrine disrupters, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, NCBI PubMed, PMID: 11469497, 2001.
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Endocrine-disrupting chemicals and male reproductive health: a review

EDCs among other health problems generate reproductive disorders in males, such as decreases in sperm count and quality, increases in testicular germ cell numbers, prostate and breast cancers, cryptorchidism and hypospadias, impaired fertility, and infertility.

2017 Abstracts

“The group of known EDCs is extremely heterogeneous and includes different groups of chemicals such as steroids (ethinyl estradiol, 17β-estradiol, estrone, mestranol and diethylstilbenstrol),…”

Testicular dysgenesis syndrome

“Cryptorchidism, hypospadias, poor semen quality, and testicular germ-cell cancers are defined as the testicular dysgenesis syndrome (TDS). They propose that the aetiology of TDS lies in the diminished androgen action in fetal developmental periods and has a negative impact on the proper functioning of Sertoli cells (the cells supporting germ cells) and Lydig cells (where androgen synthesis occurs). This hypothesis proposes a strong association between environmental exposures (e.g., to phthalates, polychlorinated biphenyls (PCBs), dioxins and non-resistant pesticides) and development of TDS. Identifying environmental causes of TDS in humans is difficult because developing fetal tissues are inaccessible for examination. Thus, the majority of mechanistic evidence linking EDCs to TDS comes from animal experiments.”

Cryptorchidism and hypospadias

Several studies have shown that sons of mothers treated with diethylstilbestrol (DES) during pregnancy are at increased risk of cryptorchidism and hypospadias“.

Decreasing sperm counts and quality

” Several studies have shown that sons of mothers treated with DES during pregnancy are at increased risk of decreased sperm count.”

Testicular cancer

“During recent decades, there has been a significant increase in the incidence of testicular cancer, albeit with clear racial and geographical differences (the highest incidence is among white men in northern Europe) suggesting that both genetic and environmental factors are important in the development of testicular cancer. The main risk factor for testicular cancer is cryptorchidism, followed by hypospadias. Testicular cancer is most common among young men between the ages of 15–34 years. The origins of testicular cancer are elusive; however, many investigators are exploring the possibility that fetal and early-life EDCs exposures can disrupt the critical hormonal balance during development, and in turn contribute to the formation of testicular cancer later in life. It was found that men who have some form of gonadal dysgenesis are more likely to develop testicular cancer in conjunction with other male reproductive abnormalities such as hypospadias and cryptorchidism. The mechanisms behind the development of testicular cancer are still unknown, but both environmental and lifestyle factors have been associated with its development.”



Endocrine disrupting chemicals and carcinogenicity

Diethylstilbestrol is carcinogenic to humans

1999 Review Abstract

Endocrine disrupting chemicals (EDC) seem to be different from classic environmental toxicants in several points:

  1. EDC operates during critical period (s) in the early stage of life characterized by rapid cell differentiation and organogenesis, leaving irreversible disruption thereof.
  2. EDC may not demonstrate any clear threshold in exerting its “toxicological” effects
  3. and EDCs may act synergistically or additively.

Except for few cases such as diethylstilbestrol causing cancer in female offspring, a clear cause effect relationship between cancers in humans and EDC is still hard to demonstrate. Thanks to continual epidemiological endeavors, a few reports suggests such relationship between prostate cancer and herbicides.

Because of its frequent association in incidence with inborn abnormalities of male reproductive organs such as undescended testis, hypospadias and degenerated quality of sperm, testicular cancer is suspected to have common or related pathogenesis with them. A hypothesis advanced by Carlsen et al was introduced.


  • Endocrine disrupting chemicals and carcinogenicity, Gan to kagaku ryoho. Cancer & chemotherapy, NCBI PubMed, PMID: 10065088, 1999.
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Etiologic factors in testicular germ cell tumors

Several case reports have noted the occurrence of testicular cancer in DES sons

2009 Paper Abstract

Globally, testicular cancer incidence is highest among men of northern European ancestry and lowest among men of Asian and African descent. Incidence rates have been increasing around the world for at least 50 years, but mortality rates, at least in developed countries, have been declining. While reasons for the decreases in mortality are related to improvements in therapeutic regimes introduced in the late 1970s, reasons for the increase in incidence are less well understood. An accumulating body of evidence suggests, however, that testicular cancer arises in fetal life. Perinatal factors, including exposure to endocrine disrupting chemicals, have been suggested to be related to risk.

“The effect of exogenous, as well as endogenous, hormone exposure has also been examined. Diethylstilbestrol (DES), a nonsteroidal estrogen first synthesized in 1938, is several times more potent than the endogenous estrogen, 17β-estradiol. Prescribed to prevent miscarriage between the late 1940s and mid 1970s, DES was removed from the market after being associated with clear cell adenocarcinoma of the vagina and cervix among daughters of exposed women. Several case reports have noted the occurrence of testicular cancer in sons of DES-exposed mothers, and a multi-center study reported a non-significant three-fold risk of TGCT based on seven cases in the exposed group and two cases in the non-exposed group. Other researchers have reported conflicting results and reviews of the literature have concluded, in general, that the supporting data are equivocal.”



Increased risk of testicular cancer in sons

Diethylstilbestrol (DES) Update: Recommendations for the Identification and Management of DES-Exposed Individuals, 2003


An increased risk of testicular cancer in sons exposed to DES has not been ruled out or confirmed.

Depue et al. conducted a case control study of 108 cases of testicular cancer in men under 30 years old and found a relative risk of 8.0 for testicular cancer in DES sons compared with men who were not exposed to DES in utero.

An unpublished study by Sant et al. in 1985 found 3 of 11 DES-exposed sons with rete testis cancer, noteworthy because this type of cancer is exceedingly rare in the general population, typically occurring in men over age 50. (The rete testis is a discrete cell structure within the testicle.)

The most definitive clinical evidence of the association between in utero exposure to DES and testicular cancer was found in a prospective study of 3,613 men including four different DES cohorts. These investigators found elevated levels of testicular cancer among men exposed to DES in utero compared with men enrolled in the study who were not exposed to DES in utero (RR 3.05; 95% CI 0.65-22.0), a finding that was slightly more than in population-based rates.(RR 2.04; 95% CI 0.82-4.20). However, the increases were not statistically significant. The investigators concluded

“it is highly unlikely that DES exposure plays a major role in the increases in testicular cancer rates that have been observed in developed countries over the past 60 years.”

Nonetheless, they conclude that the findings of the study did

“lend support to the hypothesis that the prenatal hormonal environment may influence the development of testicular cancer in adults.”

Because some studies show that DES-exposed men have an increased prevalence of undescended and hypoplastic testicles, it is important for health care providers to remember that these conditions of themselves are secondary risks for testicular cancer.


  • Diethylstilbestrol (DES) Update: Recommendations for the Identification and Management of DES-Exposed Individuals, Journal of Midwifery & Women’s Health, medscape, 2003.
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Men exposed in utero and cancer of the testes

Diethylstilbestrol – IARC Monographs, 2018


Prenatal exposure to diethylstilbestrol may be associated with testicular cancer but findings have been inconsistent.
Diethylstilbestrol is carcinogenic to humans.
A positive association has been observed between in-utero exposure to DES and cancer of the testis.



Prenatal Diethylstilbestrol Exposure and Risk of Depression in Women and Men

Prenatal exposure to diethylstilbestrol (DES), an endocrine disrupting chemical, may be associated with depression in adulthood, but previous findings are inconsistent

2019 Study Abstract

Women (3,888 DES exposed, 1,729 unexposed) and men (1,021 DES exposed, 1,042 unexposed) participating in the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study were queried in 2011 for any history of depression diagnosis or treatment. Hazard ratios (HR; 95% confidence intervals (CI)) estimated the associations between prenatal DES exposure and depression risk.

Depression was reported by 993 (26%) exposed and 405 (23%) unexposed women, and 177 (17%) exposed and 181 (17%) unexposed men. Compared with the unexposed, HRs for DES and depression were 1.1 (95% CI: 0.9, 1.2) in women and 1.0 (95% CI: 0.8, 1.2) in men. For medication-treated depression, the HRs (CIs) were 1.1 (0.9, 1.2) in women and 0.9 (0.7, 1.2) in men. In women, the HR (CI) for exposure to a low cumulative DES dose was 1.2 (1.0, 1.4), and for DES exposure before 8 weeks’ gestation was 1.2 (1.0-1.4). In men, the HR for low dose was 1.2 (95% CI 0.9,1.6) and there was no association with timing. In women, associations were uninfluenced by the presence of DES-related vaginal epithelial changes or a prior diagnosis of DES-related adverse outcomes.

Prenatal DES exposure was not associated overall with risk of depression in women or men. In women, exposure in early gestation or to a low cumulative dose may be weakly associated with an increased depression risk.



The “testicular dysgenesis syndrome” (TDS) hypothesis

Endocrine disruption: fact or urban legend? 2013


“A current hypothesis has suggested that, in modern industrial societies, human male fertility is declining, whereas the incidence of diseases or birth defects of the male reproductive system is increasing. The hypothesis that human sperm count is declining whereas the incidence of testicular cancer, cryptorchidism (undescended testis) and hypospadias (abnormally placed urethral opening at the underside of the penis) is increasing and that these changes are associated with human exposure to hormonally active chemicals.

…, this hypothetical syndrome has been named the “Testicular dysgenesis syndrome” (TDS). It postulates that, in Western industrialised countries

  • human male fertility, in particular sperm count, has declined and continues to decline,
  • the incidence of human testicular cancer is increasing,
  • the incidence of cryptorchidism
  • and hypospadias in newborn male infants has increased.

An additional hypothesis is that the increased incidence in the TDS may be due to chemical EDC in the human environment.”