Dexamethasone

As a follow-up to a previous post in March concerning CAH - congenital adrenal hyperplasia.

From TIME :

Langford and her husband learned they were silent carriers of the genetic variation that causes CAH when their son was diagnosed with the condition after birth. Their son — like the 1 in 16,000 babies born with CAH each year in the U.S. — faces a lifetime of taking powerful steroid medications to compensate for his faulty adrenal glands. When Langford contacted New about her second pregnancy, New, who was not Langford's regular doctor, called a local pediatric endocrinologist. That doctor prescribed Langford a commonly used medication for CAH. "Dr. New told me I had to start taking dexamethasone immediately," says Langford, 30, who lives in Tampa. "We felt very confident in someone of her stature and that what she was telling us was the right thing to do."
...
The early prenatal use of dexamethasone, or dex, has been shown to prevent some of the symptoms of CAH in girls, namely ambiguous genitalia. Because the condition causes overproduction of male hormones in the womb, girls who are affected tend to have genitals that look more male than female, though internal sex organs are normal.
...
Langford says also that neither New nor her prescribing physician mentioned that prenatal dexamethasone treatment is an off-label use of the drug (an application for which it was not specifically approved by the government) or that the medical community is sharply divided over whether dexamethasone should be used during pregnancy at all.

And now a series of articles from Bioethics. First, Preventing Homosexuality (and Uppity Women) in the Womb?:

The majority of researchers and clinicians interested in the use of prenatal “dex” focus on preventing development of ambiguous genitalia in girls with CAH. CAH results in an excess of androgens prenatally, and this can lead to a “masculinizing” of a female fetus’s genitals. One group of researchers, however, seems to be suggesting that prenatal dex also might prevent affected girls from turning out to be homosexual or bisexual.

Pediatric endocrinologist Maria New, of Mount Sinai School of Medicine and Florida International University, and her long-time collaborator, psychologist Heino F. L. Meyer-Bahlburg, of Columbia University, have been tracing evidence for the influence of prenatal androgens in sexual orientation. In a paper entitled “Sexual Orientation in Women with Classical or Non-Classical Congenital Adrenal Hyperplasia as a Function of Degree of Prenatal Androgen Excess” published in 2008 in Archives of Sexual Behavior, Meyer-Bahlburg and New (with two others) gather evidence of “a dose-response relationship of androgens with sexual orientation” through a study of women with various forms of CAH.

They specifically point to reasons to believe that it is prenatal androgens that have an impact on the development of sexual orientation. The authors write,

"Most women were heterosexual, but the rates of bisexual and homosexual orientation were increased above controls . . . and correlated with the degree of prenatal androgenization.”

They go on to suggest that the work might offer some insight into the influence of prenatal hormones on the development of sexual orientation in general. “That this may apply also to sexual orientation in at least a subgroup of women is suggested by the fact that earlier research has repeatedly shown that about one-third of homosexual women have (modestly) increased levels of androgens.” They “conclude that the findings support a sexual-differentiation perspective involving prenatal androgens on the development of sexual orientation.”

And it isn’t just that many women with CAH have a lower interest, compared to other women, in having sex with men. In another paper entitled “What Causes Low Rates of Child-Bearing in Congenital Adrenal Hyperplasia?” Meyer-Bahlburg writes that “CAH women as a group have a lower interest than controls in getting married and performing the traditional child-care/housewife role. As children, they show an unusually low interest in engaging in maternal play with baby dolls, and their interest in caring for infants, the frequency of daydreams or fantasies of pregnancy and motherhood, or the expressed wish of experiencing pregnancy and having children of their own appear to be relatively low in all age groups.”

In the same article, Meyer-Bahlburg suggests that treatments with prenatal dexamethasone might cause these girls’ behavior to be closer to the expectation of heterosexual norms: “Long term follow-up studies of the behavioral outcome will show whether dexamethasone treatment also prevents the effects of prenatal androgens on brain and behavior.”

In a paper published just this year in the Annals of the New York Academy of Sciences, New and her colleague, pediatric endocrinologist Saroj Nimkarn of Weill Cornell Medical College, go further, constructing low interest in babies and men – and even interest in what they consider to be men’s occupations and games – as “abnormal,” and potentially preventable with prenatal dex:

“Gender-related behaviors, namely childhood play, peer association, career and leisure time preferences in adolescence and adulthood, maternalism, aggression, and sexual orientation become masculinized in 46,XX girls and women with 21OHD deficiency [CAH]. These abnormalities have been attributed to the effects of excessive prenatal androgen levels on the sexual differentiation of the brain and later on behavior.” Nimkarn and New continue: “We anticipate that prenatal dexamethasone therapy will reduce the well-documented behavioral masculinization . . .”

Now, from Prenatal Dex: Update and Omnibus Reply :

It appears that in the vast majority of cases, New did not enroll these women in an IRB-approved treatment trial of prenatal dex. Indeed, in spite of many admonitions from colleagues to undertake this risky, experimental treatment only under IRB oversight (if at all), New seems for many years to have promoted the off-label use of this Class C drug to pregnant women as safe and effective, and to have simultaneously sought and obtained NIH funding to study these women and children after birth to see if the drug was, in fact, safe and effective. (The follow-up studies have had IRB approval, but those overseeing the follow-up studies should have been asking where all these exposed subjects were coming from.) The American Academy of Pediatrics, the European Society for Pediatric Endocrinology, and the Lawson Wilkins Pediatrics Endocrine Society have been among those specifically arguing that this powerful steroid should not be employed for this use outside IRB-approved prospective studies.

In February, 32 researchers in bioethics and allied disciplines signed letters of concern to New’s institutions, to the FDA Office of Pediatric Therapeutics, and to the HHS Office for Human Research Protections.
...
Studies of prenatal dexamethasone give us substantial reason for concern for these mothers' and children's physical and mental well-being, particularly given that this usage is aimed at preventing a cosmetic issue (one not shown to increase psychosocial risk) and that 87.5% of the mothers started on prenatal dexamethasone will not even be carrying a fetus that is 46,XX 21-hydroxylase deficient. Studies have already shown some adverse effects on exposed children.[5,24,25] In addition, some researchers have raised concerns about possible epigenetic effects that might even impact these children's children's well-being.[25]

We do not find evidence that animal studies have shown that prenatal dexamethasone is likely to be safe in humans; on the contrary, studies showing harm to animals exposed prenatally to dexamethasone have been used by the teams associated with New to try to figure out what defects they might find in the exposed children.[9] This certainly looks to us like an improper move to human experimentation on pregnant women of a Class C steroid without satisfactory establishment of safety in animal studies. That this human experimentation may even be done without IRB oversight astonishes us.

References:
[5]Trautman PD, Meyer-Bahlburg HF, Postelnek J, New MI. Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 1995;20:439-49.
[9]Meyer-Bahlburg HF, Dolezal C, Baker SW, Carlson AD, Obeid JS, New MI. Cognitive and motor development of children with and without congenital adrenal hyperplasia after early-prenatal dexamethasone. J Clin Endocrinol Metab 2004;89:610-4.
[24]Hirvikoski T, Nordenstrom A, Lindholm T, et al. Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. J Clin Endocrinol Metab 2007;92:542-8.
[25]Lajic S NA, Hirvikoski T. Long-term outcome of prenatal treatment of Congenital Adrenal Hyperplasia. In: WL FCaM, ed. Disorders of the Human Adrenal Cortex. Endocrine Development ed. Basel: Karger; 2008:82-98.

From the letter to Lawson Wilson Pediatric Endocrine Society mentioned above:

By 1999, through the Cornell-affiliated group lead by Dr. New, it appears there were at least 403 instances of diagnosis and treatment by 2001, at least 532 by 2003, at least 600.

Treatment to prevent physical Intersex symptoms which can cause serious problems such as vaginal fistulae is, absent any side-effects, a worthy goal. From BigThink :

An enlarged clitoris is one common feature of masculinization. However, the effects can be far more serious and affect not merely the girl's appearance, or even her gender presentation, but the health and functionality of her entire genitourinary tract.

In severe cases, the vagina and the urethra may open into a common sinus, instead of being separate tubes. Surgery may be required to create separate vaginal and urethral openings. Otherwise, urine can flow into the vagina, which creates an indirect kind of incontinence when it dribbles out again. Urine in the vagina can also cause chronic irritation and increase the risk of vaginal infections.

Sometimes the vaginal canal isn't wide enough to carry menstrual blood out of the body, in which case, surgery is required. Unfortunately, reconstructed vaginas tend to narrow over time. So, the patient may have to undergo still more surgery and/or months of painful training with dilators to stretch her vagina enough to have intercourse.

Treatment to "normalise" functional genitalia is more controversial, but I think most would approve of it, again absent any side effects. Some Intersexed people may differ on that, just the way many hearing-impaired people might not see congenital deafness as an undesirable defect, but a mere variation, a difference. I think though that this is a distinctly minority view, and that informed parental choice should have a role here, rather than a directive from those not personally involved. There is an argument against such therapy, and even if I personally think it's weak, I see no great harm in not having treatment should Society be moderately sane about it.

Treatment to prevent Transsexuality, again if it had no side effects, is something I would consider even more strongly justified though. Even if Society was sane. Because there could be a substantial mismatch between body-image and somatic form, which can cause immense suffering.

Treatment to make girls bidable, demure, maternal, and above all straight on the other hand... now we're getting into ethically dubious territory. We have to look at the rights of the parent. Are they unfettered? Do we have a right to prevent a parent from having a gay child? Or educating them to be racist, bigoted, even sadistic and sociopathic?

I don't think the rights of a parent should be unfettered. But I also see a distinction between the two cases above. In the second, there is harm not (just) to the child, but to those who they will interact with in their lives. In the first, as medical technology improves and society hopefully gets saner, they will have the same reproductive abilities regardless of whether gay or straight. Choosing sexual orientation for a child is no worse - and no better - than choosing eye colour, or handedness.

Of course the GLB advocacy groups who have remained silent when only Intersexed and Trans kids were experimented on this way, are now having a large economy-sized cow over the subject. Human Nature of course, but still Ironic.

The ethical issues are moot though. Because all of the above is predicated on there being no adverse consequences. And that is something that we are not only not sure of, we have reason to believe is not true.

From a comment by Faith over at Joe.My.God:

The risks are common risks of corticosteroid therapy, and, in some cases the benefits outweigh the risks, such as in the case of underdeveloped lungs -- however, if the risk is that the child will be less likely to play with dolls or want to make babies the risk/benefit ratio does not pan out. No IRB in their right mind would approve this study and she is not doing it under the purview of an IRB. Incredible.

Otero L, Conlon C, Reynolds P, Duval-Arnould B, Golden SM. Neonatal leukocytosis associated with prenatal administration of dexamethasone. Pediatrics 1981;68:77880.

Avery ME. The argument for prenatal administration of dexamethasone to prevent respiratory distress syndrome. J Pediatr 1984;104:240.

Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86:2424.

And from Kirstin:

So I found and read the list of side effects. And, while reading them I kept in mind that this drug was being or going to be delivered to developing fetuses... These side effects have been reported and are happening to already born humans. Can you imagine submitting a developing fetus to something that can and has caused anything off the list below?

Dexamethasone Side Effects - for the Professional:
The following adverse reactions have been reported with Dexamethasone or other corticosteroids:

Cardiovascular
Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction, edema, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic
Acne, allergic dermatitis, dry scaly skin, ecchymoses and petechiae, erythema, impaired wound healing, increased sweating, rash, striae, suppression of reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine
Decreased carbohydrate and glucose tolerance, development of cushingoid state, hyperglycemia, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Fluid and Electrolyte Disturbances
Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention.

Gastrointestinal
Abdominal distention, elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis.

Metabolic
Negative nitrogen balance due to protein catabolism.

Musculoskeletal
Aseptic necrosis of femoral and humeral heads, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture, vertebral compression fractures.

Neurological/Psychiatric
Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo.

There's rather more, at Psychology Today, at ScienceBlogs and elsewhere. Including this comment:

Aaaargh.

Some things about me fit into stereotypical gender roles. (I'm a cisgendered, heterosexual woman.) Some don't.

I'm happily married to a man and do eventually want kids. I have good verbal and emotional skills, I prefer collaboration to argument, I like to cook and bake, I like to knit, I like kittens, and sometimes I enjoy putting on femme costume (dresses, heels, makeup, jewelry).

But: I proposed to my now-husband. I majored in physics (where I was the only woman), I have an M.S. and am working on a Ph.D in biomedical engineering (so I also have good logical/mathematical skills), and deferred kids to prioritize that education. In fact, I wasn't sure I wanted kids at all until recently. I'm very good at coding, I dislike and avoid cleaning, I like using power tools of all kinds, I like building things, I like comic books, I like lifting weights, and I usually dress in non-ornamental t-shirts and jeans without makeup -- I'd be miserable having to dress and groom super-femme all the time, though I have fun with doing it occasionally. I particularly enjoy doing coded-masculine things while dressed/groomed in a more-femme way, just to mess with people.

In short, I'm a human being, with varied skills, interests, likes and dislikes. Gender essentialism is a load of BS.

Well, sort of. One possible effect of this therapy is to make women like her extinct. Whether deliberately, a bug or a feature, I think it likely that it would.

I don't think that would be a good thing. Some do.

The worst thing from a scientific viewpoint - after doing the Mengele act, telling pregnant women - and not just a few, but hundreds - that the drug was proven safe (when we have good reason to believe that is not the case) - the follow-up on the effects has been slipshod too. So much so that it's possible the findings were not to their liking, and they concealed them to avoid lawsuits.

It's been six years since Dr New last prescribed this drug. The first patients - though it's possible that the word "victims" might be accurate, and "experimental subjects" more accurate still - will be 11 years old now. Old enough for us to see many of the effects on psychology, and virtually all on non-neurological anatomy. I hope we're lucky, and my fears groundless.

Because she's playing with fire in an explosives factory. As Alice Dreger said in her article in Psychology Today:

This drug is unequivocally experimental and risky. That's why, back in February, I organized interested members of the Bioethics community to fight to make sure every woman offered dex for CAH knows the truth about its experimental and risky nature. (You can read about our efforts in Time magazine. And you can about the medical establishment's resultant mad scampering to make sure everyone knows this is experimental here.) Make no mistake: In spite of Dr. Maria New's outrageous FDA-regulation-flaunting claims that this off-label drug use "has been found safe for mother and child," it ain't been. New is a rogue pediatrician whom medical societies have been nudging (and sometimes yelling at) for years. Because she apparently wouldn't stop experimenting on these women and children without ethics oversight, in January I got called in to help by a few freaked-out clinicians. And I called in my colleagues to call out the feds. New just looks and sounds safe for mothers and children. Which is why she's really dangerous.

It's the height of Irony that Ms Dreger is one of the greatest supporters of Michael Bailey. Someone infamous for ignoring neuro-anatomy as a factor in transsexuality, and who insists that all trans women are actually deceptive gay or sexually perverse men. And someone who thinks it just fine and dandy that "teh gay" be prevented by pre-natal intervention.