Birth defects of diethylstilbestrol

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Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen which was previously used clinically to support pregnancy, has been linked to a variety of long-term adverse effects in women who were treated with it during pregnancy and in their offspring. [1]

Contents

First generation

An estimated 3 million pregnant women in the USA were prescribed DES from 1941 through 1971. [2] [3] DES was also widely prescribed to women in Canada, the UK, Europe, Australia, and New Zealand during a similar period. Women who were prescribed DES during pregnancy have been shown to have a modestly increased risk of breast cancer and breast cancer mortality. [4]

Second generation

DES daughters

DES gained notoriety when it was shown to cause a rare vaginal tumor in girls and young women who had been exposed to this drug in utero. In 1971, the New England Journal of Medicine published a report showing that seven of eight girls and young women (ages 14 to 22) who had been diagnosed with vaginal clear cell adenocarcinoma had been exposed prenatally to DES. [5] Subsequent studies have shown an approximate 40-fold increased risk of vaginal/cervical clear cell adenocarcinoma in women exposed in utero to DES. As a consequence of this evidence, DES is considered an established human carcinogen. DES was one of the first transplacental carcinogens discovered in humans, meaning a toxin could cross the placenta and harm the fetus. It had originally been believed that the placenta protected the developing fetus but it is now known that is not true. Daughters exposed to DES in utero may also have an increased risk of moderate to severe cervical squamous cell dysplasia and an increased risk of breast cancer. [6]

In addition to its carcinogenic properties, DES is a known teratogen, an agent capable of causing malformations in daughters and sons who were exposed in utero. DES-exposed daughters are at an increased risk of abnormalities of the reproductive tract, including vaginal epithelial changes such as vaginal adenosis (which means a type of cell normally found in the uterus, columnar cells, are also present in the vagina), an increased cervical transformation zone, and uterine abnormalities, such as T-shaped uterus. These anomalies contribute to an increased risk of infertility and adverse pregnancy outcomes in prenatally DES-exposed daughters. The most recent published research on DES daughters' adverse health outcomes documented by the U.S. National Cancer Institute (NCI) appears in the October 6, 2011 issue of the New England Journal of Medicine under the authorship of RN Hoover et al., and lists these adverse effects and risk factors: Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5%; spontaneous abortion, 50.3% vs. 38.6%; preterm delivery, 53.3% vs. 17.8%; loss of second-trimester pregnancy, 16.4% vs. 1.7%; ectopic pregnancy, 14.6% vs. 2.9%; preeclampsia, 26.4% vs. 13.7%; stillbirth, 8.9% vs. 2.6%; early menopause, 5.1% vs. 1.7%; grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4%; and breast cancer at 40 years of age or older, 3.9% vs. 2.2%. [7] Daughters with prenatal exposure to DES may also have an increased risk of uterine fibroids, and incompetent cervix in adulthood. [8]

In an animal model designed to study environmental estrogens, DES turned out to be an obesogen capable of causing adult weight gain in female mice which had been exposed to DES during neonatal development. The excess weight gain was not apparent at birth or in infancy, but occurred in adulthood. [9] [10]

DES sons

Initially, fewer studies documented risks of prenatal exposure to DES on males (referred to as "DES sons"). In the 1970s and early 1980s, studies published on prenatally DES-exposed males investigated increased risk of testicular cancer, infertility and urogenital abnormalities in development, such as cryptorchidism and hypospadias. [11] [12] Research published in the U.S. by Palmer et al. in 2009 further confirmed evidence of these findings. [13] Additional research published in Finland in 2012 has further confirmed an increased risk of cryptorchidism among males exposed prenatally to DES. [14]

The U.S. Centers for Disease Control (CDC) has acknowledged the link between DES exposure and noncancerous epididymal cysts. [15]

The American Association of Clinical Endocrinologists (AACE) has documented that prenatal DES exposure in males is positively linked to a condition known as hypogonadism (low testosterone levels) that may require treatment with testosterone replacement therapy. [16]

Sexual differentiation

Research investigating the possible behavioral and psychosexual effects of prenatal DES exposure in human males occurred as early as 1973. [17] This research has centered on a long-standing question of whether prenatal exposure to DES in offspring of mothers who were prescribed DES may have included sexual orientation and gender-related behavioral effects and physical intersex conditions. [18] Kaplan published the first-known medical study (1959) of intersex condition in a male prenatally-exposed to DES. [19]

There is some evidence linking prenatal hormonal influences on sexual orientation, gender identity and transgender development, but this is an area of behavioral research that remains controversial. [20] [21] [22] [23] Several published studies in the medical literature have examined the hypothesis that prenatal exposure to estrogens (including DES) may cause significant developmental impact on sexual differentiation of the brain, and on subsequent behavioral and gender identity development in exposed males and females.[ citation needed ] One of the leading investigators of this area of research is June Reinisch, former director of the Kinsey Institute for Research in Sex, Gender, and Reproduction. [17] [24] Reinisch cited several cases of "male feminization" among prenatally DES-exposed males.[ citation needed ]

An Internet survey reported a high rate of transgender and intersex identity in people assigned male at birth participating in an online support forum for DES sons. [25] [26] [27] Of 500 respondents, about 32% identified as transgender, transsexual, gender dysphoric, or intersex (90, 48, 17, and 3, respectively). [25] [27] [26] The first real study on transgender identity in people assigned male at birth who were prenatally exposed to DES was published in 2020 and found a very low incidence of transgenderism (2 in about 930 or around 0.2%). [28] It wasn't possible to determine whether the incidence was higher than in controls due to the small number of cases, but the findings did indicate in any case that the influence of prenatal DES exposure on likelihood of being transgender would be only small at most. [28] A French 2024 study on 253 DES males, however, found almost eightfold occurrence, 1.58%, of male to female transsexuals among DES males. [29]

DES Daughters and Sons study

A study conducted by the US National Cancer Institute, which assessed about 5,600 women and 2,600 men who had documented prenatal exposure to DES, called "DES Daughters" and "DES Sons", respectively, found that "DES Daughters were just as likely as unexposed women to be left-handed. DES Sons were slightly more likely to be left-handed than unexposed men (14% vs. 11%, respectively). [30] The researchers found no association between DES exposure and reported mental illness in DES Daughters, although the authors cautioned that this aspect may be under-represented due to the nature of self-reported data. In addition, no association was found between DES exposure and anorexia or bulimia." [31]

Psychological anomalies

Most of the initial research documenting the psychological effects of prenatal DES exposure was poorly conducted, often by mail card. Despite that, some more carefully conducted studies show a clear link to depression, [32] [33] and a more recent French study asserts that there was an 83% increase in psychological disorders for offspring that were prenatally exposed to DES. [34]

Third generation

Current research also looks at DES in the third generation. These are the grandchildren of women who were given DES during pregnancy and whose mother or father was therefore exposed to DES in utero. Studies of the third generation are important because DES might be associated with epigenetic changes, which involve changes to the way genes behave (not involving the DNA itself) that may be heritable from one generation to another. If epigenetic changes occur and are heritable, studies of the DES-exposed third generation have implications for the influence of environmental endocrine disruptors on human health and evolution.

Recent studies from the US National Cancer Institute (NCI) show that the daughters of women who were exposed in utero to DES may be less likely than the unexposed to have regular menstrual periods. [35] A possible increased risk of infertility in the older, third generation daughters was also noted. The NCI study provides limited evidence of an increased risk of birth defects in the sons or daughters of women who were exposed prenatally to DES. An increased risk of ovarian cancer in the daughters of women exposed in utero was observed, but it was based on three cases of almost 800, so the finding is considered preliminary and requires further study.

Some evidence suggests the sons of prenatally DES-exposed women might have an increased risk of hypospadias, [36] [37] but other studies suggest the increase in risk might not be as great as once thought. [38]

Related Research Articles

<span class="mw-page-title-main">Diethylstilbestrol</span> Chemical compound

Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency, treatment of prostate cancer and breast cancer, and other uses. By 2007, it was only used in the treatment of prostate cancer and breast cancer. In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer. While most commonly taken by mouth, DES was available for use by other routes as well, for instance, vaginal, topical, and by injection.

<span class="mw-page-title-main">Birth defect</span> Condition present at birth regardless of cause

A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth defects are divided into two main types: structural disorders in which problems are seen with the shape of a body part and functional disorders in which problems exist with how a body part works. Functional disorders include metabolic and degenerative disorders. Some birth defects include both structural and functional disorders.

<span class="mw-page-title-main">Endocrine disruptor</span> Chemicals that can interfere with endocrine or hormonal systems

Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine systems. These disruptions can cause numerous adverse human health outcomes including, alterations in sperm quality and fertility, abnormalities in sex organs, endometriosis, early puberty, altered nervous system function, immune function, certain cancers, respiratory problems, metabolic issues, diabetes, obesity, cardiovascular problems, growth, neurological and learning disabilities, and more. Found in many household and industrial products, endocrine disruptors "interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of homeostasis ."

<span class="mw-page-title-main">Anogenital distance</span> Distance from midpoint of the anus to the genitalia

Anogenital distance (AGD) is the distance from the midpoint of the anus to the genitalia, the underside of the vagina, the clitoris or the scrotum. It is considered medically significant for a number of reasons, in both humans and other animals, including sex determination and as a marker of endocrine disruptor exposure. It is regulated by dihydrotestosterone, which can be disrupted by phthalates common in plastics.

Xenoestrogens are a type of xenohormone that imitates estrogen. They can be either synthetic or natural chemical compounds. Synthetic xenoestrogens include some widely used industrial compounds, such as PCBs, BPA, and phthalates, which have estrogenic effects on a living organism even though they differ chemically from the estrogenic substances produced internally by the endocrine system of any organism. Natural xenoestrogens include phytoestrogens which are plant-derived xenoestrogens. Because the primary route of exposure to these compounds is by consumption of phytoestrogenic plants, they are sometimes called "dietary estrogens". Mycoestrogens, estrogenic substances from fungi, are another type of xenoestrogen that are also considered mycotoxins.

Clear-cell adenocarcinoma of the vagina is a rare adenocarcinoma often linked to prenatal exposure to diethylstilbestrol (DES), a drug which was prescribed in high-risk pregnancy.

Masculinizing hormone therapy, also known as transmasculine hormone therapy or female-to-male hormone therapy, is a form of hormone therapy and gender affirming therapy which is used to change the secondary sexual characteristics of transgender people from feminine or androgynous to masculine. It is a common type of transgender hormone therapy, and is predominantly used to treat transgender men and other transmasculine individuals who were assigned female at birth. Some intersex people also receive this form of therapy, either starting in childhood to confirm the assigned sex or later if the assignment proves to be incorrect.

Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.

Prenatal stress is exposure of an expectant mother to psychosocial or physical stress, which can be caused by daily life events or by environmental hardships. This psychosocial or physical stress that the expectant mother is experiencing has an effect on the fetus. According to the Developmental Origins of Health and Disease (DOHaD), a wide range of environmental factors a woman may experience during the perinatal period can contribute to biological impacts and changes in the fetus that then causes health risks later in the child's life.

<span class="mw-page-title-main">Reproductive toxicity</span> A hazard associated with chemical substances

Reproductive toxicity refers to the potential risk from a given chemical, physical or biologic agent to adversely affect both male and female fertility as well as offspring development. Reproductive toxicants may adversely affect sexual function, ovarian failure, fertility as well as causing developmental toxicity in the offspring. Lowered effective fertility related to reproductive toxicity relates to both male and female effects alike and is reflected in decreased sperm counts, semen quality and ovarian failure. Infertility is medically defined as a failure of a couple to conceive over the course of one year of unprotected intercourse. As many as 20% of couples experience infertility. Among men, oligospermia is defined as a paucity of viable spermatozoa in the semen, whereas azoospermia refers to the complete absence of viable spermatozoa in the semen.

<span class="mw-page-title-main">Health effects of pesticides</span> How pesticides affect human health

Health effects of pesticides may be acute or delayed in those who are exposed. Acute effects can include pesticide poisoning, which may be a medical emergency. Strong evidence exists for other, long-term negative health outcomes from pesticide exposure including birth defects, fetal death, neurodevelopmental disorder, cancer, and neurologic illness including Parkinson's disease. Toxicity of pesticides depend on the type of chemical, route of exposure, dosage, and timing of exposure.

<span class="mw-page-title-main">Prenatal hormones and sexual orientation</span> Hormonal theory of sexuality

The hormonal theory of sexuality holds that, just as exposure to certain hormones plays a role in fetal sex differentiation, such exposure also influences the sexual orientation that emerges later in the individual. Prenatal hormones may be seen as the primary determinant of adult sexual orientation, or a co-factor with genes, biological factors and/or environmental and social conditions.

<span class="mw-page-title-main">Developmental toxicity</span>

Developmental toxicity is any developmental malformation that is caused by the toxicity of a chemical or pathogen. It is the structural or functional alteration, reversible or irreversible, which interferes with homeostasis, normal growth, differentiation, development or behavior. Developmental toxicity is caused by environmental insult, which includes drugs, alcohol, diet, toxic chemicals, and physical factors.

Vaginal adenosis is a benign abnormality in the vagina, commonly thought to be caused by intrauterine and neonatal exposure of diethylstilbestrol and other progestogens and nonsteroidal estrogens, however it has also been observed in otherwise healthy women and has been considered at times idiopathic or congenital. Postpubertal lesions have also been observed to grow de novo. It has a rather common incidence, of about 10% of adult women.

<span class="mw-page-title-main">T-shaped uterus</span> Medical condition

A t-shaped uterus is a type of uterine malformation wherein the uterus is shaped resembling the letter T. This is typically observed in DES-exposed women. It is recognised in the ESHRE/ESGE classification, and is associated with failed implantation, increased risk of ectopic pregnancy, miscarriage and preterm delivery. There is a surgical procedure to correct the malformation.

The fetal origins hypothesis proposes that the period of gestation has significant impacts on the developmental health and wellbeing outcomes for an individual ranging from infancy to adulthood. The effects of fetal origin are marked by three characteristics: latency, wherein effects may not be apparent until much later in life; persistency, whereby conditions resulting from a fetal effect continue to exist for a given individual; and genetic programming, which describes the 'switching on' of a specific gene due to prenatal environment. Research in the areas of economics, epidemiology, and epigenetics offer support for the hypothesis.

<span class="mw-page-title-main">Dimestrol</span> Chemical compound

Dimestrol, also known as dianisylhexene, 4,4'-dimethoxy-α,α'-diethylstilbene, diethylstilbestrol dimethyl ether, and dimethoxydiethylstilbestrol, is a synthetic nonsteroidal estrogen of the stilbestrol group which is related to diethylstilbestrol. It has been used clinically as a hormonal therapy in cases of delayed female puberty, hypogonadism, menopausal, and postmenopausal symptoms. It is known to induce the development of female secondary sexual characteristics in the case of female delayed puberty or hypogonadism. The drug has also been used as a growth promoter in livestock.

Antiandrogens in the environment have become a topic of concern. Many industrial chemicals, including phthalates and pesticides, exhibit antiandrogen activity in animal experiments. Certain plant species have also been found to produce antiandrogens. In animal studies, environmental antiandrogens can harm reproductive organ development in fetuses exposed in utero as well as their offspring.

<span class="mw-page-title-main">High-dose estrogen therapy</span> Type of hormone therapy

High-dose estrogen therapy (HDE) is a type of hormone therapy in which high doses of estrogens are given. When given in combination with a high dose of progestogen, it has been referred to as pseudopregnancy. It is called this because the estrogen and progestogen levels achieved are in the range of the very high levels of these hormones that occur during pregnancy. HDE and pseudopregnancy have been used in medicine for a number of hormone-dependent indications, such as breast cancer, prostate cancer, and endometriosis, among others. Both natural or bioidentical estrogens and synthetic estrogens have been used and both oral and parenteral routes may be used.

Fetal programming, also known as prenatal programming, is the theory that environmental cues experienced during fetal development play a seminal role in determining health trajectories across the lifespan.

References

  1. ↑ Bamigboye AA, Morris J (2003). "Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes". Cochrane Database Syst Rev. 2010 (3): CD004353. doi:10.1002/14651858.CD004353. PMC   9039959 . PMID   12918007.
  2. ↑ "Problems in Research: Regulations—The Diethylstilbestrol Tragedy". The Medical Bag. 12 April 2013. Retrieved 29 April 2014.
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  4. ↑ Titus-Ernstoff L, Hatch EE, Hoover RN, Palmer J, Greenberg ER, Ricker W, Kaufman R, Noller K, Herbst A, Colton T, Hartge P (January 2001). "Longterm cancer risk in women given diethystilbestrol (DES) in pregnancy". British Journal of Cancer. 84 (1): 126–133. doi:10.1054/bjoc.2000.1521. PMC   2363605 . PMID   11139327.
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  8. ↑ Office of Research on Women’s Health, NIH, DHHS (March 2006). "Status of Research on Uterine Fibroids (leiomyomata uteri) at the National Institutes of Health" (PDF). United States National Institutes of Health. Archived from the original (PDF) on 2010-05-27. Retrieved 2018-07-21.{{cite web}}: CS1 maint: multiple names: authors list (link)
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  18. ↑ Hines M (April 2011). "Prenatal endocrine influences on sexual orientation and on sexually differentiated childhood behavior". Frontiers in Neuroendocrinology. 32 (2): 170–82. doi:10.1016/j.yfrne.2011.02.006. PMC   3296090 . PMID   21333673.
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  20. ↑ Michel A, Mormont C, Legros JJ (October 2001). "A psycho-endocrinological overview of transsexualism". European Journal of Endocrinology. 145 (4): 365–76. doi: 10.1530/eje.0.1450365 . PMID   11580991.
  21. ↑ Selvaggi G, Ceulemans P, De Cuypere G, VanLanduyt K, Blondeel P, Hamdi M, Bowman C, Monstrey S (November 2005). "Gender identity disorder: general overview and surgical treatment for vaginoplasty in male-to-female transsexuals" (PDF). Plastic and Reconstructive Surgery. 116 (6): 135e–145e. doi:10.1097/01.prs.0000185999.71439.06. PMID   16267416. S2CID   24406081. Archived from the original (PDF) on 2013-10-14. Retrieved 2018-07-21.
  22. ↑ Dingfelder S (2004). "Gender Bender: New Research Suggests Genes and Prenatal Hormones Could Have More Sway in Gender Identity than Previously Thought". APA Monitor on Psychology. 35 (4): 48.
  23. ↑ Hood E (October 2005). "Are EDCs blurring issues of gender?". Environmental Health Perspectives. 113 (10): A670–7. doi:10.1289/ehp.113-a670. PMC   1281309 . PMID   16203228.
  24. ↑ Reinisch JM, Ziemba-Davis M, Sanders SA (1991). "Hormonal contributions to sexually dimorphic behavioral development in humans". Psychoneuroendocrinology. 16 (1–3): 213–78. doi:10.1016/0306-4530(91)90080-D. PMID   1961841. S2CID   44814972.
  25. 1 2 Ettner, Randi (2015). "Etiopathogenetic Hypotheses of Transsexualism". In Carlo Trombetta; Giovanni Liguori; Michele Bertolotto (eds.). Management of Gender Dysphoria. pp. 47–53. doi:10.1007/978-88-470-5696-1_6. ISBN   978-88-470-5695-4. Diethylstilbestrol (DES), the most studied endocrine disruptor, has been implicated in numerous health problems in female offspring of exposed women [46]. Curiously, few studies have examined the impact on male offspring, the DES sons. An online forum, DES Sons International, conducted a survey of members. Of 500 respondents, 90 members indicated they were transsexual; 48 described themselves as transgender; 17 identified themselves as "gender dysphoric"; and 3 identified themselves as "intersex." By 2004, more than 130 individuals had joined a forum called "DES Trans" [44]. Clearly, the prevalence of gender dysphoria in persons exposed to DES warrants further study.
  26. 1 2 Ettner, Randi (2020). "Etiology of Gender Dysphoria". In Loren S. Schechter (ed.). Gender Confirmation Surgery: Principles and Techniques for an Emerging Field. pp. 21–28. doi:10.1007/978-3-030-29093-1_2. ISBN   978-3-030-29092-4. S2CID   213843302. Diethylstilbestrol (DES), the most widely studied endocrine disruptor, has been implicated in numerous health problems in female offspring of exposed women [34]. Few studies, however, have examined its impact on male offspring. DES Sons International, an online forum, surveyed 500 member respondents, 90 of whom identified as "transsexual," 48 described themselves as "transgender," 17 identified as "gender dysphoric," and 3 as "intersex" [35].
  27. 1 2 Randi Ettner; Antonio Guillamon (20 May 2016). "Theories of the Etiology of Transgender Identity". In Randi Ettner; Stan Monstrey; Eli Coleman (eds.). Principles of Transgender Medicine and Surgery. Routledge. pp. 3–15. ISBN   978-1-317-51460-2. Diethystilbestrol (DES), the most widely studied endocrine disruptor, has been implicated in numerous health problems in female offspring of exposed women (Langston, 2010). Few studies, however, have examined its impact on male offspring. DES Sons International, an online forum, reported that in a survey of 500 member respondents, 90 identified as "transsexual"; 48 described themselves as "transgender"; 17 identified as "gender-dysphoric"; and three as "intersex" (Kerlin, 2004).
  28. 1 2 Troisi R, Palmer JR, Hatch EE, Strohsnitter WC, Huo D, Hyer M, Fredriksen-Goldsen KI, Hoover R, Titus L (February 2020). "Gender Identity and Sexual Orientation Identity in Women and Men Prenatally Exposed to Diethylstilbestrol". Arch Sex Behav. 49 (2): 447–454. doi:10.1007/s10508-020-01637-7. PMC   7031187 . PMID   31975033.
  29. ↑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10801508/
  30. ↑ Titus-Ernstoff, Linda (March 2003). "Psychosexual characteristics of men and women exposed prenatally to diethylstilbestrol". Epidemiology. 14 (2): 155–160. doi: 10.1097/01.EDE.0000039059.38824.B2 . PMID   12606880. S2CID   31181675.
  31. ↑ "Recent DES Research: Psychosexual Characteristics of Men and Women Exposed Prenatally to Diethylstilbestrol". CDC. Retrieved 16 May 2017.
  32. ↑ Pillard RC, Rosen LR, Meyer-Bahlburg H, Weinrich JD, Feldman JF, Gruen R, Ehrhardt AA (1993). "Psychopathology and social functioning in men prenatally exposed to diethylstilbestrol (DES)". Psychosomatic Medicine. 55 (6): 485–91. doi:10.1097/00006842-199311000-00003. PMID   8310108. S2CID   25925008.
  33. ↑ O'Reilly EJ, Mirzaei F, Forman MR, Ascherio A (April 2010). "Diethylstilbestrol exposure in utero and depression in women". American Journal of Epidemiology. 171 (8): 876–82. doi:10.1093/aje/kwq023. PMC   2877444 . PMID   20332145.
  34. ↑ Soyer-Gobillard MO, Paris F, Gaspari L, Courtet P, Sultan C (2016). "Association between fetal DES-exposure and psychiatric disorders in adolescence/adulthood: evidence from a French cohort of 1002 prenatally exposed children" (PDF). Gynecological Endocrinology. 32 (1): 25–9. doi:10.3109/09513590.2015.1063604. PMID   26172930. S2CID   207490080.
  35. ↑ Titus-Ernstoff L, Troisi R, Hatch EE, Wise LA, Palmer J, Hyer M, Kaufman R, Adam E, Strohsnitter W, Noller K, Herbst AL, Gibson-Chambers J, Hartge P, Hoover RN (August 2006). "Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES)". International Journal of Epidemiology. 35 (4): 862–8. doi: 10.1093/ije/dyl106 . PMID   16723367.
  36. ↑ Klip H, Verloop J, van Gool JD, Koster ME, Burger CW, van Leeuwen FE (March 2002). "Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study". Lancet. 359 (9312): 1102–7. doi:10.1016/S0140-6736(02)08152-7. PMID   11943257. S2CID   45769124.
  37. ↑ Kalfa N, Paris F, Soyer-Gobillard MO, Daures JP, Sultan C (June 2011). "Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study". Fertility and Sterility. 95 (8): 2574–7. doi: 10.1016/j.fertnstert.2011.02.047 . PMID   21458804.
  38. ↑ Brouwers MM, Feitz WF, Roelofs LA, Kiemeney LA, de Gier RP, Roeleveld N (March 2006). "Hypospadias: a transgenerational effect of diethylstilbestrol?". Human Reproduction. 21 (3): 666–9. doi: 10.1093/humrep/dei398 . PMID   16293648.
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