Congenital adrenal hyperplasia (CAH) is a group of rare autosomal recessive disorders affecting the endocrine system. The disease affects production pathways for glucocorticoids (GCs) and mineralocorticoids (MCs) such as cortisol and aldosterone. In affected individuals, cortisol levels do not normalize, resulting in a runaway steroidogenesis process and an overabundance of androgens (male sex hormones). Individuals with CAH develop adrenal hyperactivity and abnormally large adrenal glands (hyperplasia). Symptoms may be mild or severe and presentations may vary from ambiguous female genitalia, underdeveloped male genitalia, precocious pseudopuberty, skeletal malformations, to a very serious salt-wasting crisis. Some females may present with symptoms that resemble polycystic ovarian syndrome (PCOS), displaying unusual excessive hair growth, irregular or absent menstrual cycles, and anovulation (lack of an ovum release during menstruation).
CAH is one of the most commonly inherited metabolic disorders and it is characterized by a deficiency of 1 of the 4 enzymes needed to synthesize cortisol, or the electron donor enzyme cytochrome P450 oxidoreductase. The P450 oxidoreductase enzyme is essential for the synthesis and metabolism of various chemicals and molecules, including steroids. However, the overwhelming majority of CAH cases are associated with a 21-hydroxylase deficiency (90%-95%). The 21-hydroxylase enzyme is encoded by the CYP21A2 gene (cytochrome P450, family 21, subfamily A, polypeptide 2 gene) located on chromosome 6. There are estimates of more than 100 mutations that may cause 21-hydroxylase deficiency, with an overall incidence rate of roughly 1 in 10,000 to 15,000 live births. This deficiency is broken into 2 groups: classical and nonclassical.
Nonclassical CAH (late-onset)
Nonclassical CAH is generally not life-threatening and symptoms are comparatively mild. At birth, there are no recognizable symptoms and the afflicted become symptomatic in early childhood and adolescence. Because of increased cortisol and androgen levels, these children tend to have rapid growth spurts and undergo puberty at an early age. Literature also suggests that females may become masculinized and experience irregular menstruations.
Classical CAH is divided into 2 forms: simple virilization and severe salt-wasting. About 75% of individuals have the salt-wasting form and must be put on a lifelong regimen of salt-retaining hormones as well as cortisol replacement therapy. For these individuals, therapies must be customized because patients have either a severely compromised ability or a complete inability to produce cortisol and aldosterone. Symptoms of severe salt-wasting may include hyponatremia, hypokalemia, and low-serum and urinary aldosterone with high plasma renin activity. They may also have similar symptoms to that of simple virilization CAH, such as varying degrees of external genitalia virilization or pseudohermaphroditism.
Simple virilization CAH gets its name from its most identifiable symptom, which is ambiguous female genitalia. The degree of virilization varies. In the most severe cases, girls may be born with a fused or partially fused labia and an unusually large clitoris resembling male genitalia. In some cases, girls are born with a urogenital sinus (a joined urethra and vagina). Surgery had been the standard of care for these girls, although that began to change after 1984. At that time, a prenatal intervention was discussed in The Journal of Pediatrics. French researchers Michel David and Maguelone Forest proposed the use of dexamethasone (DEX) throughout a pregnancy to treat pseudohermaphroditism that may accompany CAH. This treatment had no effect on the more severe symptoms such as salt-wasting but did show promise in normalizing female genitalia. Since then, DEX has been given, off-label, to countlessmothers. In some circles, it is still considered the standard of care. However, there are a number of ethical issues surrounding this experimental intervention.
Steroids, DEX, and fetal development
Today, there is no doubt that GCs are a major influence on the development of the fetal brain. They affect synaptic plasticity, play a role in neuronal migration, and influence neurotransmitter activity. Decades of research suggest that excess GCs can reprogram the fetal brain and may have other epigenetic effects. Corticotropin-releasing hormone (CRH) plays a pivotal role in fetal development and maturation. Unlike in adults, fetal CRH and cortisol levels are regulated by a positive feedback loop. In this loop, fetal development is intrinsically tied to maternal CRH and placental signaling. Maternal cortisol levels may increase 2- to 4-fold during pregnancy in response to fetal needs. Even elevated maternal stress levels correlate with problems in infant and child stress regulation.
DEX is powerful synthetic glucocorticoid that is 25 times stronger than cortisol and passes freely through the placenta. The use of DEX in utero may have far-reaching consequences. It has been suggested that excess GCs have a negative influence on lung maturation and surfactant synthesis. It has also been suggested that excessive gestational exposure to GCs may have adverse effects on female reproductive functioning. Excessive exposure may alter cardiovascular function and wreak havoc on the amygdala and hypothalamic-pituitary-adrenal axis (HPA axis). Animal studies examining DEX fetal exposure suggest it may have neurotoxic effects on the developing brain. Those studies correlate fetal exposure to a multitude of developmental and physiological issues, including low birth weight, developmental difficulties, lower brain volume, decreased pyramidal neurons, behavior abnormalities, sexualdifferentiations, CNS reprograming, hippocampal/HPA axis deficiencies, hyperinsulinemia, and hypertension.
DEX: Making good little girls and wives
Over the past few years, opposition to prenatal DEX intervention has grown. Some within the medical community believe it to be a safe and less-invasive alternative to surgery despite insufficient data. Because DEX has already been approved for other uses, it has fallen through one of the great regulatory loopholes. New drugs must undergo rigorous trials testing their efficacy and, more importantly, their safety for their intended use. Often, safety concerns will be exposed early in animal trails. If a drug is shown to be unsafe for a specific use (eg, to treat in utero), it may never come to market, and if it does, it will be contraindicated for that use. However, older drugs aren’t subject to the same rigors of new drug applications (NDAs) and may be used off-label. An existing drug can be used off-label without a signed informed consent, unless insight into its efficacy is being explored. However, with that said, often it is much easier to conduct an experiment with an existing drug than a new drug. This is especially true in cases where a drug is alreadyconsidered safe and is more or less an accepted treatment. Such is the case with prenatal DEX for CAH.
DEX was approved sometime before 1984 (the FDA cannot verify dates of drugs approved before 1984). An Internet search for DEX reveals a few mentions and patent results that date back to the late 1950s and early 1960s. There are no contraindications for specific groups (eg, pregnancy) but there is a list for conditions such as diabetes, hypertension, psychosis, osteoporosis, GI ulceration, infections, and renal insufficiency. It cannot be stressed enough that prenatal DEX has no effect on the more serious symptoms of CAH and may only normalize female genitalia about 80% of the time. Since CAH is a recessive disorder, there’s a 1 in 4 chance of inheriting it when both parents are carriers. Considering there is a 50-50 chance of conceiving a female child, the odds of having offspring that could possibly benefit from prenatal DEX falls to 1 in 8. However, this intervention must be started as soon as a pregnancy is confirmed, often well before the child’s sex is known. Some claim that it is a low-dose treatment. However, research suggests that fetal exposure ranges from 60 to 100 times normal levels. That translates to roughly 90% of fetuses that will be exposed to dangerously high levels of DEX during the first trimester.
Notwithstanding the fact that the majority of fetuses would be exposed unnecessarily to DEX, there is also a homophobic undercurrent associated with this treatment. Researchers have described CAH females as having increased rates of “behavioral masculinization” and increased rates of “bisexual and homosexual orientation.” At the center of this controversy sits Dr. Maria New, a pediatric endocrinologist, and her colleague, psychologist Heino F.L. Meyer-Bahlburg. Dr. New has publically taken credit for treating over 600 pregnant women with DEX. Dr. Meyer-Bahlburg has devoted a bulk of his research into studying sexual orientation and gender identity. Together, they have written several papers on CAH. In one study, they concluded “that the findings support a sexual-differentiation perspective involving prenatal androgens on the development of sexual orientation,” suggesting CAH women have a decreased interestin having sex with men, compared to controls.
In another paper, Meyer-Bahlburg writes,
“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.”
Meyer-Bahlburg suggests that DEX treatment may normalize these abnormalities. In a separate paper in theAnnals of the New York Academy of Sciences, Dr. New suggests that CAH women are somehow “abnormal,” displaying low interests in babies and men andchoosing to pursue traditionally male occupations and games. Reports of a damaging video from 2001 have also surfaced. In the video, Dr. New overtly states that the goal of DEX therapy is to make good wives and mothers. The recording took place at a CARES Foundation meeting and was directed to a group of parents. In the presentation, Dr. New put up a slide of a CAH girl with ambiguous genitalia and went on to say,
“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. And she has all the machinery for motherhood, and therefore nothing should stop that, if we can repair her surgically and help her psychologically to continue to grow and develop as a girl.”
In a 1996 NIH grant application, Dr. New specifically promised to determine “the success of DEX in suppressing behavioral masculinization.” In 2012, in the journal Bioethical Inquiry, Alice Dreger, Ellen K. Feder, and Anne Tamar-Mattis published an article about prenatal DEX for CAH. Outside of glaring ethical issues about initiating prenatal DEX with sexual orientation in mind, they described the poor quality of studies to date. In 2010, a systematic review and meta-analysis of this intervention was issued by the Clinical Endocrinology task force. A literature search into DEX intervention resulted in 1083 studies identified. Of those 1083 studies, only 4 were considered of a “high enough scientific quality to be considered for a meta-analysis.” However, they too lacked specific methodologies, had insufficient protocols, and were observational in nature. In effect, they were of low quality as well, but far superior to 99.63% of all other available research.
Dreger and her colleagues contacted the FDA due to concerns about Dr. New’s continued FDA approval and NIH funding despite adequate controls, poor experimental designs, questionable informed consent, and little to no follow-up. The FDA rebuffed the complaints and said that they could do nothing. To add insult to injury, an examination of Dr. New’s grant applications explicitly suggests that DEX treatments are safe for both mother and child, yet she has done little follow-up to confirm this. There is a growing body of research indicating that high-dose glucocorticoid therapy negatively affects both prenatal and postnatal brain development. Interestingly, Dr. New coauthored a paper reporting increased white matter abnormalities and temporal lobe atrophy in prenatally treated CAH patients, yet the cause was undetermined. Another interesting aspect of a recent study conducted by Dr. New is a strange exclusionary rule. Anyone who could not understand the follow-up questionnaire (eg, DEX-exposed children who have mental deficiencies) was excluded fromthe long-term study. Basically, this rule makes it impossible to determine if prenatal DEX may cause developmental disorders because those very same individuals are excluded.
In 2012, Sweden halted a long-term prospective study of 43 children exposed to prenatal DEX due to severe adverse events. They indicated that they found impaired verbal working memory in children exposed to short-term DEX (ie, children who began treatment until it was determined they were negative for CAH). Other adverse events included scholastic difficulties, higher social anxiety, and neutral gender behavior, as well as instances of feminization in DEX-exposed boys. In the experimental group, they also reported 3 instances of failure to thrive, 1 instance of mental retardation, 1 instance of hydrocephalus, and 1 instance of severe mood fluctuations. However, in the control group, only 1 child was reported with any disorder, and it was Down syndrome.
Treating CAH with prenatal DEX is highly controversial, and it should be noted that it is explicitly an experimental treatment. The Endocrine Society provides a strong recommendation regarding this treatment: it should only be done under specific protocols and with IRB approval. However, it has yet to be determined by any American scientific body, including The Endocrine Society, if the intervention’s risks vs benefits are acceptable despite roughly 30 years of experimentation. There is no doubt that the scientific community is split. However, as one pours over the literature, it becomes evident that initiating this therapy is based more on social sexual dogmas and less on serious health concerns. Science, and particularly medicine, is traditionally a conservative endeavor but this type of de facto experimentation seems anything but conservative and eerily similar to the diethylstilbestrol tragedy. It is supposed to make the lives of girls with CAH better; however, one is hard pressed to find someone with CAH in favor of it. There are CAH women who are against this intervention and there is also at least one mother who received DEX treatment who is attempting litigation. She was never informed of any potential side effects, and never given a consent form. She received the treatment outside of a clinical trial and therefore informed consent was not needed. Now her 3 year old has mysterious health issues unrelated to CAH but potentially as a direct result of the therapy.
With this therapy, there’s really only one question that needs to be asked: is it better than surgery? Surgery doesn’t expose children to dangerous steroids unnecessarily. Surgery doesn’t reprogram the fetal brain. Surgery has far fewer unforeseen consequences and we know that it works. With surgery, one can determine if corrective measures are even warranted. Not every child will have ambiguous genitalia and there is no evidence that an enlarged clitoris may cause sexual dysfunction. A surgical option also gives parents valuable time to learn about their child’s condition and make an informed decision. Of course, there are issues with reconstructive surgery. However, the only reason DEX may be a preferable option is if you believe girls and women have traditional roles. In Germany, soon they will have a third option on birth certificates, “undetermined sex.” This law is designed for those special cases where the child’s sex is in doubt. It affords children the opportunity to choose what gender they identify themselves as later in life. On this issue, perhaps we should look toward Germany.
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