The Mother of All FDA Fails

The FDA has never required drug safety assessment for fetal germline impact, even though FDA staff understand that gestational exposures can adversely affect developing germ cells. We must end this catastrophic omission, while also granting all Americans access to their own prenatal medical records.

Worse than thalidomide? The consequences of mass prenatal progestin exposure, 1950s-70s


by Jill Escher (Follow me on Twitter @autism_exposed)

When we think of prenatal drug disasters, we usually think of the sedative thalidomide, which caused horrific birth defects, and synthetic estrogen DES, which caused cancer and infertility in offspring, among other horrors.

Ignored, however, have been the downstream effects of the extensive use of progestin drugs in obstetric and fertility practice from the late 1950s through today. Progestins, not estrogens, were the most widely used anti-miscarriage drugs during several decades of practice that placed near-unquestioning faith in modern pharmaceuticals combined with near-nonexistent concern about impacts on the fetus.

These potent pseudo-hormones were given to countless millions of women who were deemed to be “at-risk” for miscarriage or who were termed “habitual aborters,” defined very liberally at the time as women who had suffered two or three prior miscarriages. The most common synthetic progestins administered in these protocols appear to have been Colprosterone, Delalutin, Deluteval, Norlutin Acetate, Provera, and Provest. (Reinisch and Karow, Prenatal Exposure to Synthetic Progestins and Estrogens: Effects on Human Development, Arch. Sex. Behav. 6:4 1977).

A 1969 medical text, “The Use of Progestins in Obstetrics and Gynecology,” by RW Kistner explained to physicians the then-standard of care for treatment of the “habitual aborters.” Please note the acute nature of the timing and dosage; the old practices resulted in massive fetal exposure to high doses of potent endocrine disrupting chemicals.
Provera: ... 10 mg daily, orally, during the first trimester of pregnancy; then 20 mg daily, orally, during the second trimester and 30 mg, daily, orally, during the third trimester.

Delalutin: (hydroxyprogesterone caproate) 375-500 mg (3-4 cc., intramuscularly) every week, starting as soon as pregnancy is confirmed and continuing to fetal viability.

Deluteval (hydroxyprogesterone caproate plus estradiol valerate): 500 mg. Delalutin plus 10 mg Delestrogen, intramuscularly, every week from the time of confirmation of pregnancy until fetal viability.”

If progesterone is administered, it is best started before conception and continued during pregnancy.... Progesterone, hydroxyprogesterone caproate and oral medroxyprogesterone acetate may be used in the prophylatic management of the habitual aborter.
Kistner, pp 112-13.

Nine years earlier, Dr. Edward Tyler, founder of the Tyler Medical Clinic in Los Angeles, had published his influential 1960 book, “Sterility: Office Management of the Infertile Couple,” (available online free at http://catalog.hathitrust.org/Record/001566807) which touted the use of the new synthetic hormones for a variety of fertility and other obstetric problems.

Dr. Tyler also endorsed large doses of synthetic progestins for miscarriage prevention:
A new injectable progestogen, 17a-hydroxyprogesterone caproate (17-AHPC) [note: this is Delalutin, which had been approved by the FDA for miscarriage prevention in 1956], differs from progestone in two major respects: large doses, for example, 250 mg per injection, can be given with relative freedom from local reactions; and, the therapeutic effect of each injection is prolonged so that a single injection produces progestational activity for 8 to 10 days. These qualities of prolonged action and relative freedom from local reactions make 17-AHPC a generally more desirable therapeutic agent than progesterone for intramuscular use, but dosage must be controlled carefully.
Sterility, pp. 253-56. Tyler's colleague, Dr. M Edward Davis, contributed a chapter concerning endocrine therapy for threatened miscarriage, explaining the theoretical basis for such intervention.
Progesterone is the pregnancy hormone and the logical substance to use in threatened abortion. If it can be demonstrated that the pregnancy is still viable, this hormone can be administered in moderately large doses. This key steroid may compensate for inadequate production of hormones by the corpus luteum or early chorion. Temporary supplementation of this vital steroid may bridge the gap during the transition from corpus luteum to chorionic hormonal support of the pregnancy. 
It has been argued by some authors that no therapy is indicated in patients who threaten to abort, for in more than one-half of these women threatening symptoms will subside and the pregnancies will culminate successfully. Furthermore, the high incidence of ovular defects decreases tremendously the number of pregnancies that are worth salvaging. However, such an attitude of defeat and resignation does not conform with modern dynamic medicine. If only 5 or 10 per cent of patients in whom the threatened abortion would have become inevitable can be helped to carry their pregnancies by intelligent therapy it is worthwhile.
Sterility, pp. 326-27 (emphasis mine). Dr. Davis continues his enthusiastic endorsement of the "over-abundant" clinical use of synthetic progesterones in “modern dynamic medicine” as follows:
Until the last two years, 100 mg of progesterone in oil was administered intramuscularly to the patient four or five times each week. This was continued until she felt life at about 16 to 18 weeks if on previous occasions she belonged to the group who aborted early in pregnancy. If the pattern for previous abortions indicated that the terminations occurred most often at midpregnancy, however, the medication was continued until the baby reached a safe period of viability, about 6 weeks from term. No other steroids were administered.
The frequency of the intramuscular administration and the occasional discomfort they induced interfered to some extent in the above regimen. Unfortunately, progesterone is metabolized rapidly, for the administration of 50 mg per day to the patient who is not pregnant produces no holdover effects for longer than 48 hours. The introduction of 17a-hydroxyprogesterone caproate (Delalutin) provided a long-acting progestational agent. Although its metabolism differs from crystalline progesterone, its biologic action is similar. The length of its action is dependent on an adequate supply of estrogens. It is possible that additional estrogens may be indicated in some cases. The habitual aborter can now receive 250 mg of 17a-hydroxyprogesterone caproate intramuscularly twice a week, or even 500 mg once a week. There have been no undesirable sequelae following the administration of this new progestational agent. The administration of crystalline progesterone and 17a-hydroxyprogesterone caproate during pregnancy has not resulted in virilism in the newborns in our experience.
[...]
[A]n overabundance of [progesterone] may improve the uterine environment of the conceptus and result in a more adequate circulation, a more substantial implantation, and a quiescent abode for the embryo.
Sterility, pp. 332-333.

It is very important to note that in a subset of infertility patients, the use of corticosteroids such as prednisolone was also advised. These cases included women with adrenogenital syndrome, women with amenorrhea, or infrequent menses, and with no signs of masculinization, patients with fallopian tube obstruction, patients with long- standing infertility, and a group of husbands showing oligospermia. Sterility pp. 381-82. Tyler described the clinical use of prednisolone for fertility as follows:
Patients were given 5 mg four times daily for 2 days, then 5 mg three times daily for 2 days, and then were placed on a maintenance dosage of 5 mg twice daily for 12 weeks, or slightly longer. When therapy was to be discontinued the dosage was tapered off gradually, so that during one week 5 mg was administered daily, and the dose decreased to 5 mg every other day the following 2 weeks, then 5 mg twice a week for 2 weeks, at which time the medication was then stopped.
Sterility, p. 382.

In sum, the literature reflects a once widespread medical practice of prophylactically drugging pregnant women who had suffered more than one previous miscarriage with heavy doses of synthetic hormones, particularly progestins, and to a lesser extent estrogens and corticosteroids, sometimes in combination with each other. This practice was particularly prevalent among somewhat upper income women who could afford the expensive therapies.

I am a perfect example of a child exposed in utero to these synthetic chemicals in the 1960s.  As fate would have it, I was the subject of the study, "Prenatal Exposure to Synthetic Progestins and Estrogens: Effects on Human Development," by Dr. June Reinish.  Thanks to meticulous record-keeping by Dr. Reinisch and the Kinsey Institute, where she had served as director,  I just recently obtained the records of my own exposures.  They were:





Deladroxate (dihydroxyprogesterone acetophenide enanthate, maybe combined with 10-mg estradiol) by injection for 7 weeks, 100 mg once a week (first trimester);

Deluteval (hydroxyprogesterone caproate (also known as Delalutin) plus estradiol valerate) by injection 250 mg every week, for 19 weeks (second and third trimesters); and

Prednisolone, oral, preconception through first trimester, approx. 35 mg for 10 weeks.

A birth control pill has about .2 mg of synthetic hormones. I was exposed to about 6,000 mg [note: at first I thought it was about half that] of these chemicals in utero, most during the first half of pregnancy, the very period during which my eggs developed. As far as I can tell, although millions of us were exposed to these insane and genotoxic anti-miscarriage protocols, I'm the only one who has recovered her prenatal records.

The heavy use of synthetic hormones for anti-miscarriage began to fade in the 1970s, first with the revelations about DES toxicity in 1971, and then with the publication of various studies beginning to question the fetal impacts of these exposures, including, notably, the aforementioned 1977 study of developmental effects by June Reinisch, in which she found distinct personality differences in the exposed children, as compared to their unexposed siblings. The differences can be summed up this way: we were a bit “Aspie,” that is more independent and less groupish, and somewhat gender-bended. Reinisch and others later found prenatal corticosteroid exposure to have teratogenic effects on the fetus, including fetal growth retardation.

OH DEAR, you are thinking, WHY DOES ANY OF THIS MATTER?  I TURNED OUT OKAY, RIGHT?

Yes, I turned out okay, but my children are not.  They are autistic.  Their brains do not work.  They cannot talk.  They cannot learn.  They spend their days engaged in constant stims, like shredding paper or chewing on toys.  They will never have jobs.  They will require tens of millions of dollars in 24/7 support over their lifetimes.  And now, seemingly out of the blue, there are hundreds of thousands of others just like them.

You see, the drugs screwed up my eggs.  The process of fetal germline (egg or sperm) development depends on the appropriate delivery of precise chemical messages, including hormonal molecules. Impostor hormones such as progestins, estrogens or corticosteroids, singularly and in combination, can hijack a fragile and unfathomably complex system that evolved over billions of years, upsetting the normal molecularly-controlled developmental processes necessary for normal sperm and egg development. This process has been demonstrated in a great many studies over the past decade. [FN1]  In addition, as mentioned above, the use of these novel synthetic medications was particularly intense in the first half of pregnancy, which is precisely the timeframe of epigenetic programming of the vulnerable fetal germline.

Did progestins, with or without combined estrogens and corticosteroids scramble the intracellular signals needed for normal epigenetic synthesis, resulting in developmental abnormalities in our egg and sperm, and therefore in our progeny, our children? In light of the vast exposure history, what we know about germline disruption caused by impostor hormones, and the strongly epigenetic nature of neurodevelopment, it is more than plausible, it is indeed highly likely. Already I have found many autism families with prenatal exposure histories just like mine.

It is time for the “hidden history” of mass use of progestins and other endocrine-disrupting synthetic steroid hormone drugs in pregnancy to come out of the closet. Researchers are almost totally ignorant about what occurred in countless doctor's offices over several decades, resulting in one of the greatest toxic events in the history of humanity. No doubt, it will explain a portion of the glut of quasi-genetic disorders in the generation born 1980s to today, a generation rife with autism, ADHD, mental disorders, learning disabilities, and other “idiopathic” public health mysteries of our era. If there is a connection, and of course there is, the implications are vast and of profound importance.


FN1 Endocrine disrupting compounds have repeatedly been shown to induce epimutations and impact gene expression profiles of germ cells, at both low and high doses. See, eg, Manikkam et al, Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations, PLOS One 8(1): e55387. doi:10.1371/journal.pone. 0055387 (2013); Crews, Epigenetic transgenerational inheritance of altered stress responses, PNAS USA. 2012 doi: 10.1073/pnas.1118514109; Susiarjo et al 2013, Bisphenol A Exposure Disrupts Genomic Imprinting in the Mouse, PLoS Genet 9(4): e1003401. doi:10.1371/journal.pgen.1003401; Walker and Gore, Transgenerational neuroendocrine disruption of reproduction, Nature Reviews Endocrinology 7, 197-207 2011. Doyle et al. (2013), Transgenerational Effects of Phthalate on Male Germ Cells, BOR Papers in Press Published on March 27, 2013 as DOI:10.1095/biolreprod.112.106104; Manikkam et al, Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations, PLoS ONE 7(9): e46249. doi:10.1371/journal.pone.0046249 (2012); Del Mazo et al, The effects of different endocrine disruptors defining compound specific alterations of gene expression profiles in the developing testis, Reproductive Toxicology 33:1, 106–115 (2012).

14 comments:

  1. Interesting - especially the fact that you and the others in your hormone-exposed group actually feel somewhat gender-bended. This is something I've been trying to make people aware of, that there are significant differences between the brains of men and women that have profound effects on a person's psychology and behaviour later in life. Sexual development is hormone-driven, and exposure to these artificial sex hormones during the second and/or third trimester of pregnancy (which is when most sexually dimorphic brain development takes place), can create a person with an intersexed or partially opposite-sexed brain.
    I think that the increasing use of these drugs during pregnacy is the real reason why we're suddenly seeing so many gender variant people all over the place (and going on what I've seen among the DES sons, probably has a lot to do with soaring rates of infertility and endocrine disorders as well).
    http://desinfo411.wordpress.com/2013/03/07/a-des-son-speaks-out/

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    1. My name is Alan. I was born on 08-15-50. I have struggled all my life due to the fact that my mother took thalidomide during the 2nd or 3rd trimester of pregnancy for nausea. I have been searching for some time now for information on why I want to be with men, yet am so very sickened to have sex with them. Most of my friends are women because I don't feel like much of a man. My mother did not tell me about the thalidomide until I was 51 yrs. old. She has been so harsh and belittling and led me to believe I was just a mutant. I really wish there were a way to wrap my head around all this so I could feel better about myself, defects and all. martad15.wm@gmail.com

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  2. Thanks, Hugh, for your comment. I totally agree with you. There's no question my exposure to multiple synthetic hormones in utero had a variety of impacts on my body, brain, and germ cells (eggs). In terms of sexual identity, I'm very heterosexual but have always fought against a tomboy edge, wishing I could somehow pull off pink and frilly (I can't). Physically, I'm all girl but with some slightly strange proportions and asymmetries (thanks, prednisolone).

    To learn more about effects of synthetic hormone exposure (and more), please watch this recent presentation by June Reinisch, PhD, director emerita of the Kinsey Institute and an authority on developmental effects of these exposures:

    http://media.mindinstitute.org/video/epigenetics/reinisch_epigenetics_2013_web.mov

    jill e

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  3. That presentation was quite interesting. I do recall reading somewhere that epigenetic programming of DNA differs between eggs and sperm, so it seems plausible that progestins and other artificial sex hormones could interfere with epigenetic programming as part of messing up the normal process of sexually dimorphic development.

    The early progestins are actually derivatives of the testosterone molecule, and have the ability to push female development into the male pathway. See:
    http://en.wikipedia.org/wiki/Progestin-induced_virilisation
    If you're right about the number of women given progestins in the course of miscarriage treatment during the 1950s and 60s, the true number of baby girls born intersexed due to progestin exposure must be far larger than the 160 or so cases mentioned in the article. As with intersex conditions in baby boys due to DES, that disaster has been completely hidden from the public (but at least it has a Wikipedia article!).

    Ovulation is quite a complex process involving a kind of hormonal feedback loop between the hypothalamus and pituitary in the brain, and the maturing egg in the ovaries that is being prepared for release that month. There's a critical window during brain development where exposure to masculinising hormones will masculinise the hypothalamus and pituitary so they are no longer capable of generating the appropriate signals for ovulation (the "LH surge") later in life. At least that's what happens in sheep, and presumably the same is true in humans too.

    "The results of the present study clearly document that exposure of the female sheep fetus to androgens during a critical period for sexual differentiation of the brain progressively disrupts reproductive cycles in the adult ewe. Similar effects of androgenization on reproductive function have been described in other species. Specifically, the effects of prenatal androgen exposure have been shown to alter the timing of puberty in female rats (20), guinea pigs (21), and primates (22). In addition, pre- or neonatal testosterone treatment leads to the production of abnormal reproductive cycles in rodents (23) and primates (24), supporting the conjecture that a relatively short exposure to male gonadal hormones early in development can program the reproductive axis of the female to malfunction in later life, leading to sub- or infertility."
    (taken from the discussion section of "Prenatal programming of reproductive neuroendocrine function", http://www.ncbi.nlm.nih.gov/pubmed/12639926)

    The sheep in that experiment were no longer able to generate the LH surge that normally triggers egg release, but while they were young, their system was able to compensate enough so that most were still able to produce eggs and become pregnant. None of them became pregnant during the second breeding cycle though. Basically they suffered from reduced fertility and premature reproductive failure.

    I'm wondering whether the human equivalent of those sheep are women with polycystic ovary syndrome, i.e. that PCOS is actually an iatrogenic condition caused by being prenatally exposed to progestins. Women with PCOS aren't able to generate a normal LH surge and one effect of that is that they have eggs that failed to release properly turning into ovarian cysts. Other effects are that probably the eggs that do get released often aren't in the correct stage of development, which might be contributing to autism and other 3rd generation effects. Does that theory sound plausible?

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  4. Jill, I think that feeling's mutual - in a platonic way of course!

    It seems like we've stumbled on two different aspects of the same, larger problem: developmental abnormalities caused by medical hormone use in pregnancy. I've been focusing on the potential these drugs have to cause intersexed or opposite-sexed brain development and produce a person whose brain doesn't properly match their physical sex. You've been looking at them as a cause of disrupted epigenetic programming in germ cells, leading to autism in the F2 generation.

    I think these are just two aspects of a bigger problem though, which is that steroid hormones seem to be heavily involved in controlling many aspects of the growth and development taking place in an unborn child. When you add artificial medical hormones to the mix they completely scramble this chemical messaging system. The result is that whatever part of the body or brain that happens to be developing at the time ends up being built incorrectly, and this leads to all sorts of often subtle developmental abnormalities that don't necessarily manifest themselves until much later in life.

    Steroid hormones and steroid hormone mimics are probably the single most widely used class of drugs there are, and yet they appear to have this terrible dark side to them which nobody wants to acknowledge or admit to because so many people are potentially affected. It's like the situation you sometimes get in business, where a disastrously ill-conceived project keeps lumbering on and on for years because so much money has already been sunk on it that nobody is prepared to be the one to admit the mistake and pull the plug. Well, that's how I see it anyway! What do you think?

    P.S. feel free to contact me by email if you wish.

    Hugh

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  6. Hi Hugh,
    You are seriously brilliant and absolutely correct on all counts. People have no clue how totally important this issue is, how catastrophic the consequences have been. Where is Rachel Carson when we need her? How can we be so blind to this folly?
    I would love to email you, could you send me your address to autismhormoneproject@gmail.com? Important things are about to HAPPEN. SERIOUSLY.
    Still in love with you (in whatever way! :) )
    jill e

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  7. Dear Jill,
    Thank you for your most informative blog. I really appreciate your efforts to articulate this phenomenon. I too was exposed to a form of progesterone in utero. This was given to my mother in an attempt to avoid repeated miscarriage. I know this because I questioned the doctor who prescribed her medication. Unlike yourself, I have experienced multiple effects of the type now recognised as connected to endocrine disrupting chemicals, affecting the reproductive, neurological and immune systems. Prominent among these are: unilateral failure of breast development; depression; multiple allergies, food drug and chemical intolerances; a condition resembling hemiplegic migraine and various chronic inflammatory problems. I had already worked out the connection with chemical exposure, both in utero and environmentally, but it is illuminating to read about your experience with autism. I also appreciate your experience trying to gain recognition for this issue. I too think endocrine disruption is the coming issue with enormous health implications but it is profoundly challenging to our current culture and to the medical, drug and chemical industries, hence the denial. I am now a physician and health scientist and having recently retired, I am planning to establish a website on the subject to help bring people together here in the UK. I would appreciate any relevant information or advice you may have available.
    Best wishes, Cath M

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  8. Great to hear from you, Cath, and I'm sorry to hear your story. But I am thrilled you are planning to establish a website on the subject of the enduring deleterious consequences of old prenatal exposures.

    Most resources I know of are linked via this blog, especially the recent post on the Escher Fund for Autism, and also as videos and research links on autismepigenetics.org.

    The mass ignorance of the history of mass prenatal pharmaceutical use is shocking, but so is the mass ignorance about the ongoing, multigenerational effects thereof.

    If you can email me your email address, I can forward you two PDFs of presentations I'm making this month here in California, one at the Environmental Mutagenesis and Genomics Society (a really big deal!), and one at a local autism conference. They are packed with info you are free to use. Please email autismhormoneproject@gmail.com.

    Thank you for finding my blog and your interest in this horrible hidden history.

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  9. It is really good to finally make contact with someone else who has experienced this type of chemical damage. My sympathies go out to you too for the awful hurt it has caused you and your family. I agree, it is amazing how such a major issue can be swept under the carpet and remain out of sight. I suppose, not only is it a very difficult subject to study (in humans), or even talk about, but few people care to admit to making big mistakes, particularly on such a grand scale. I see it as a distinct part of the wider problem of exposure to chemicals via drugs, foods, lifestyles and the environment which add up to a kind of toxic 'brave new world'. I would be very interested to see your presentations and I'll e-mail you shortly. Cath M

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