DES link to AIS?

[Pearlstone]

Does anyone know of any research or articles out there which have made a connection between pregnant mothers in the 1950's who were given DES as hormone treatment, and the incidence of their child being AIS?

stonec@<hidden>

[Glenn]

It seems like there's some related connection, but I haven't found anything specific to AIS.

In http://gendertree.com/When%20Does%20It%20Happen.htm they note:

"The effect of DES (diethylstilbestrol), a synthetic therapeutic agent, like many of the compounds mentioned above, are estrogenic. Daughters born to mothers who took DES now suffer increased rates of vaginal clear cell adenocarcinoma, various genital tract abnormalities, abnormal pregnancies, and some changes in immune responses. Both sons and daughters exposed in utero experience congenital abnormalities of their reproductive system and reduced fertility."

Many of the other links from a search on "diethylstilbestrol androgen insensitivity syndrome" led to similar vague statements, and comments about DES causing male infertility.

Is DES related to progestin? Have you looked for research into Progestin-Induced Androgenization?

Glenn

[Dana Gold]

The DES statement caught my eye and since I have a lot of reason to believe that my mother took this with me (she had previous miscarriage) in Germany under careUS Army Hosp.personnel in year 1949) However I cannot gain conclusive evidence from anybody in my family, most of whom are deceased. DES is an estrogenic endocrine disruptor, causing anatomical hyperplasias and cancers consistent with hyperestrogenism linked with estrogen-dependant tumors (metabolite of estrone specifically) in genetic females. The effect in genetic males is similar as an anti-androgen resulting in undermasculinization and feminiztion in varying degrees. In both male and female, profundity of altered anatomy and physiology is dependant upon start of DES administration (i.e 1st trimester, 2nd etc), dosage amount and frequencey, and duration of administration. Long-term effects upon 2nd and 3rd generation offspring are unclear, but some research and patient profiles have shown reduced, yet stil someDES-related symptomologies., I got this from NIH website specifically investigating DES, I believe the ISNA is involved in some research about DES also, as well as other environmental endocrine disruptors (PCBs etc, )which have been shown to cause intersex conditions in aquatic animals where the chemical waste has been dumped into their habitat. Recent concern has also been raised about such getting endocrine disrupting chemicals into the water tables from ground leeching, or drugs ( outdated estrogen as well as other medications into toilet or sink ).... A current major concern of environmenal health and safety institutions. Read on please: the below iis a snipping from NIH research site devoted to DES .
Footnote: The stuff was passed out like candy (worldwide) for children to women primarily for miscarriage and as stabilizer of pregnancy, which studies show it was ineffective. Note: below results not just for mouse models but actual observations in humans.
Terrible, terrible.

As in young women, the induction of vaginal adenocarcinoma in the absence of DES exposure normally is rare in mice. Other effects observed in mice that parallel those in humans include infertility and subfertility; oviductal, cervical, and uterine malformations; paraovarian cysts of mesonephric origin; salpingitis isthnica nodosa of the oviduct (an epithelial change in the oviduct); immune dysfunction; and vaginal adenosis. Observations in DES-exposed male offspring (both humans and mice) include subfertility and infertility, decreased sperm counts, hypoplastic cryptorchid testes, epididymal cysts, testicular tumors, anatomical feminization, microphallus, hypospadias, retained Müllerian remnants, and prostatic inflammation. Thus, the prenatally DES-exposed mouse model appears to be valid and to parallel the human condition. To that end, the model has been used to replicate and predict many of the lesions observed in similarly exposed humans. Exposure to DES early in gestation results in structural, functional, and long-term changes, including neoplasia, in both humans and mice.

[Dana Gold]

PS:

http://searchosp1.nci.nih.gov/whealth/DES/index.html

[claraJane]

Dear Dana,

Just some thoughts...

The effects of estrogenic chemicals and/or androgen inhibitors on fetal development, although profound, are fundamentally different than AIS, which is a mutation-caused malfunction of the androgen receptors.

Note that progestin induced virilization may result in gross virilization of the external genitalia but it doesn't affect receptor function. Indeed, it proves adaquate androgen receptor function.

If one were to take Finasteride/Propecia during pregnancy, one could have the equivalent of a 5-alpha reductase deficiency baby. (i.e. female external genitalia with internal, functional testes, and a fairly normal masculine puberty.)

In order to show that DES causes AIS, one would first have to demonstrate that DES causes genetic mutations. I can't think of a reason why DES, as an estrogenic chemical, would target the androgen receptor genes for mutation. And DES wasn't known for causing mutations, at least not in the way that some other infamous drugs did (e.g. thalidimide).

In my opinion, the effects of DES are much more likely to be related to the estrogenic activity during fetal development. Androgens, rather than being inhibited at the receptor level, are inhibited at their source, due to dysgenetic testicular development.

For what it's worth, that's my take on it.

cjs

[Dana Gold]

Yes, Clara Jane, you are absolutely right and I retract my use of the word anti-androgen. AIS is an androgen receptor condition wherein the body does not respond to effect of testosterone, so in the genetic male 46XY, high to normal levels of androgens exist but no masculinization, or varying degrees of. By anti-androgen I meant the balance/ratio of hormones with DES in utero shift to predominance of estrogen to testosterone, preventing the "testosterone wash" to varying degrees, a prosaic analogy of anti-androgen, but, as you pointed out, scientifically incorrect, and so I thank you . DES does promote its profound effects because as all synthetic estrogens (especially ones with molecular structure very much different than body-natural estrogen) it stays in the system much longer (than the molecular similar) because the liver does not or cannot metabolize it, or does so very slowly. Hence these continue to promote their biological effects and with dose after dose the blood levels increase. A good example is"the pill" with ethinyl estradiol given in very low doses ( 0.05 mg) with "same" biological effects as 1 mg "natural"oral dose. However, some researchers (especially NIH , refer to URL in previous post) are investigating whether DES has effects in children born to those exposed in utero ( i.e teratogen) DES has been shown to induce cancers in females. The mechanics of cancer may induce genetic alterations on a subtle level.. (just think of the medical history when doctors ask if any relatives have/have had cancer, heart disease.etc...ie the concept of "carrier genes") . AS someone in another area of BLO stated: "Nature comes up with some very heretofore unknown syndromes" BUT when humankind does something it beats Mother Nature hands down! Your assessment of DES would be valid if talking about natural estrogens BUT DES is a xeno-estrogen, an endocrine disruptorwith entirely different molecular structure and a "foreigner" to the human body and possible teratogen. Other environmental "toxins" linked to such xeno-estrogenic activity have produced carcinomas, reproductive system anomalies, sex-reversals and mutagenic (malformations) effects in animals AND I know that animal models don't equate to human, But I'll "bet your bippy" (quote from 70's show "Laugh-In) that these toxins (DES included) produce mutagenic and teratogenic effects....genetic changes. Time will tell. OH! Thank you for your reply, a science nerd, I like talking about such stuff with others. Take care, have a nice whatever.

Dana

[claraJane]

Dear Dana,

I have no problem accepting the mutagenic properties of pollutants as well as of drugs. As I said, thalidimide is a prime example. My hesitation was in accepting a theory that maintained that an estrogenic chemicals would specifically cause mutations leading to AIS.

Estrogenic chemicals may act directly on the estrogen receptors. They may act as anti-androgens by suppressing FSH and/or LH. They may cause secondary problems such as raising Prolactin levels. And, yes, they may cause cancers.

Note that most of the cancers are in estrogen-sensitive tissues, that is, tissues with an abundance of estrogen receptors. Note the increased risk of breast cancer among long-time high-dose estrogen HRT patients.

You make a good point about synthetic estrogens. I would encourage anyone on synthetic estrogens to consider switching to human estrogen (not phytoestrogens!). Both estradiol and progesterone are available and in forms readily usable by the body. And, if you use an estradiol patch, you minimize risk.

Once again, that's my take. I'm not a doctor.

cj

[Dana Gold]

Dear Clara Jane;

Oh, but you're right, I don't think DES causes AIS either. But the teratogen may affect the reproductive systems of future offspring of exposed parents (male or female in both cases) and produce/cause various "anomalies" and reproductive failures and or deficiencies. AIS is something completely different, an x chromosome -linked (dominant or recessive?) genetic condition, I think. Different mechanism altogether.

Dana

[Dana Gold]

PS:

YESSS!! , Clara Jane,

I would advice anybody to avoid Premarin (horse-p*ss), and medroxyprogesterone acetate ( it is a progestin...NOT progesterone )...17-B estradiol tabs sublingually and patches go directly into blood stream and avoid liver consequences, as well as being rapidly metabolized to estrone) Progestins are bad, recent studies show that they cause more harm than good. Clara Jane, you aren't a doctor but I can tell you have done your research, Bye again.

Dana

[Dana Gold]

to avoid misunderstanding...oral estrogens (stomach absorbed) are first-passed by liver and rapidly converted to estrone....that's not what happens in the body....ovarian estrogen goes directly into bloodstraem..not to the stomach. a metabolite of estrone has been linked to carcinogenic properties in post-menopausal women....ooops again, gotta go...have a meeting here at EH&S (I'm at work...no PC at home)...bye.

Dana