Related post – More evidence against DEXA for prenatal treatment of CAH (10/21/11)

Fetal Sex Development

All fetuses are initially intersex (sexually bipotential) and have both male and female parts. 6-7 weeks after conception, fetuses begin to produce the sex hormones that bring about the process of sexual differentiation. There are many steps involved in this process and often only one misstep is needed to deviate development from the norm. An excellent animated and interactive atlas of child anatomy and physiology that visually depicts the process of typical and atypical sex development is available from the Hospital for Sick Children in Toronto, Ontario, Canada.

Intersex / disorder of sex development (DSD)

The medical nomenclature of atypical sex development has undergone several shifts due in part to increased understanding of its cause. For many years it was referred to as “hermaphroditism”, named after the androgenous Hermaphroditus of Greek mythology. Later “intersex” became the vogue given its literal definition of “between sexes”. As of 2005 the accepted medical term is “disorder of sex development” (DSD) however that is not to say that everyone is happy about the change. Many adults with this condition prefer the term “intersex” and feel degraded by the new terminology. “Hermaphrodite” is even more offensive. Younger people may prefer the new term. In my attempt to be medically accurate and considerate I will refer to these conditions as “intersex/DSD”.

Congenital adrenal hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) is a genetic disorder of cortisol deficiency that can result in an intersex/DSD condition in affected females. Prevalence is 1 in 14,500 live births. Cortisol is one of our major stress hormones and it is requires 5 different enzymes to be synthesized in our bodies. If one of these enzymes is defective then cortisol deficiency develops. When cortisol levels are too low, the body ramps up production of precursor chemicals to try to make up the difference. Unfortunately having excess substrate does not produce the desired effect of increasing cortisol production. Instead the excess chemicals spill over into other pathways that results in overproduction of testosterone and other androgens. When this happens in female fetuses it causes masculinization of both genitalia and the mind. Physical features of CAH in girls include enlargement of the clitoris, fusion of the labia and elongation of the urethra. In severe cases incorrect sex assignment may occur and difficult reconstructive surgery may be attempted. Boys are not so affected and are not abnormally masculinized.

Androgens like testosterone cause sexually dimorphic structural changes in the fetal brain. For example, these hormones permanently inhibit the growth of certain areas of the left hemisphere and facilitates the growth of the same areas in the right hemisphere in the developing fetus. The human bed nucleus of the stria terminalis (BSTc) is smaller and has fewer neurons in men compared to women. CAH affected females demonstrate more male-typical performance in spatial orientation, visualization, targeting, personality and cognitive abilities. There are behavioral shifts as well including preference for male playmates and toys; decreased interest in infants, marriage, motherhood and “feminine” appearance; and male-typical interests, peer associations, career and leisure time preferences. CAH affected women are more likely to report use of physical aggression in conflict situations, 1/3 self-identify as lesbian, bisexual or queer and 3-5% indicate a desire to live as males.

Prenatal treatment

While the results of masculinization described are not medical problems per se, they can be disturbing for family members and affect the quality of life of affected females. In 1965 Dr Jeffcoate was the first to diagnose CAH prenatally by way of amniocentesis. Attempts to treat affected fetuses with cortisol derivatives (cortisone, hydrocortisone) were initially unsuccessful because a placental enzyme that protects the fetus is highly effective at metabolizing them. However Dr Maguelone of Forest, France discovered that dexamethasone (DEX), another cortisol analog, was effective in the prenatal treatment of CAH-affected female fetuses and wrote about it in 1978. In 1986 Dr Maria New, a professor at Mount Sinai School of Medicine in New York, introduced his technique to the US and as of 2010 has subsequently treated over 600 pregnant women at risk for the birth of a CAH-affected child.

Controversy

In 2010 Dr Alice Dreger, a professor at Feinberg School of Medicine in Illinois, orchestrated a “Letter of Concern from Bioethicists” to report suspected violations of the ethics of human subjects research in the off-label use of prenatal DEX by Dr New. The letter was submitted to the FDA Office of Pediatric Therapeutics, the DHHS Office for Human Research Protections and 3 universities where Dr New has appointments. These accusations were also published in Time magazine and online at fetaldex.org. Her accusations are as follows:

1. Experimentation on pregnant women and their unborn children without informed consent. Dr New and colleagues routinely state that treatment is safe and fail to inform patients that treatment is highly controversial within the medical community.
2. Endangerment of women & their children
• Known adverse effects in women include
• Increased appetite
• Rapid and excessive weight gain
• Increased stretch marks
• Increased edema
• Insomnia
• Mood fluctuations
• High blood pressure
• Known adverse effects in children include
• Decreased birth weight
• More shyness, social anxiety and emotionality
• Less sociability
• Poorer working memory (ie reading comprehension) and self-perceived scholastic competence
• Less masculine males with more neutral gendered behaviors
• Because treatment must begin before prenatal diagnosis can be made, 7 out of 8 fetuses are unnecessarily exposed to the risks of DEX
• To date there has been poor follow-up of DEX-exposed children thus increasing the chances that adverse effects will continue to go unnoticed
3. Questionable experimental objectives. While masculinization of female genitalia may increase infection risk and/or preclude coitus (heterosexual vaginal intercourse) in some cases,
• Not all girls with CAH have masculinized genitalia and only a fraction of those that do will need surgery
• Surgical reconstruction of ambiguous genitalia is for the most part “cosmetic” & not “medically necessary”
• Ambiguous genitalia do not cause physiological problems nor do they increase psychosocial risk
• Surgery has its own risks including decreased sexual sensation and function, suboptimal cosmetic results and psychological trauma to little girls who may need repeat procedures and/or physical therapy
• Evidence exists that people with ambiguous genitalia do just as well as those who are surgically “corrected”
• Strong evidence of heterosexist bias and agenda exists. Homosexuality and gender nonconformity are not medical problems, not easily measured and not a subject of published studies. However statements made to the contrary include:
• Dr Maria New: “The overall objective is to fill the gap of knowledge about the long-term consequences of early-prenatal DEX treatment on childhood development on the one hand, and the success of DEX in suppressing behavioral masculinization in the sub-sample of girls with definitive congenital adrenal hyperplasia on the other.”
• Dr Maria New: “The spectrum of behavioral effects ranges from mild or marked tomboyish behavior of childhood to increased adolescent/adult bisexuality and lesbianism; through full male identification with request for sex reassignment surgery and legal gender change in adolescence or adulthood… Preventive prenatal [DEX] exposure is expected to improve this situation.”
• Dr Maria New: “The challenge here is […] to see what could be done to restore this baby to the normal female appearance which would be compatible with her parents presenting her as a girl, with her eventually becoming somebody’s wife, and having normal sexual development, and becoming a mother.”
• Ms Amber Vos: “This therapy helps affected girls to avoid the psychological stress of ambiguous genitalia and the risks of reconstructive surgery, increases the likelihood of heterosexual behavior, and likely helps to preserve fertility.”

The rebuttal

• Dr Maria New: “All of my studies have been conducted under IRB approval. I have also received permission from the FDA to administer [DEX] prenatally.”
• Dr Laurence McCullough: “At this low dose, DEX does not have teratogenic potential, and furthermore, because the therapy does not begin until just before the ninth week of gestation, organogenesis of the major organs has been completed.”
• Dr Laurence McCullough: “The short-term outcome of preventing genital ambiguity in the affected female is 100% effective, provided that the pregnant woman is compliant and the [DEX] is administered properly.”
• Dr Laurence McCullough: “To date more than 800 fetuses have been diagnosed by genetic analysis of fetal tissue worldwide, so that in many countries, including the United States, prenatal diagnosis and treatment has become the standard of care.”
• Dr Maria New: “The surgical treatment of genital ambiguity has not been studied as well as prenatal treatment with DEX for CAH.”
• Dr Maria New: “I have no interest in preventing lesbianism or homosexuality nor have I ever proposed it.”

Standard of care

In 2010 The Endocrine Society Clinical Guidelines Subcommittee Task Force published the following opinions & recommendations concerning the prenatal treatment of CAH:

• Treatment is directed toward reducing need for surgery rather than toward preserving life or intellectual capacity
• Treatment remains controversial
• Treatment should continue to be regarded as experimental
• “Therefore, in validating earlier expert opinion, this Task Force placed a higher value on preventing unnecessary prenatal exposure of mother and fetus to [DEX] and avoiding potential harms associated with this exposure and a relatively lower value on minimizing the emotional toll of ambiguous genitalia on parents and patients.”

Summary

In closing, I would like to echo the words of Dr Elizabeth Reis, PhD:

“Physicians should not sell themselves short in imagining that they cannot — with their words as much as with their knives and drugs — influence parents to accept their children’s bodies and the possibility that their children could lead rewarding lives with those bodies.”

References