Monday 6 January 2014

Time to get my genes re-tested.

Identification of de novo copy number variants associated with human disorders of sexual development. Tannour-Louet et al PLoS One. 2010 Oct 26;5(10):e15392.

Disorders of sexual development (DSD), ranging in severity from genital abnormalities to complete sex reversal, are among the most common human birth defects with incidence rates reaching almost 3%. Although causative alterations in key genes controlling gonad development have been identified, the majority of DSD cases remain unexplained. To improve the diagnosis, we screened 116 children born with idiopathic DSD using a clinically validated array-based comparative genomic hybridization platform. 8951 controls without urogenital defects were used to compare with our cohort of affected patients. Clinically relevant imbalances were found in 21.5% of the analyzed patients. Most anomalies (74.2%) evaded detection by the routinely ordered karyotype and were scattered across the genome in gene-enriched subtelomeric loci. Among these defects, confirmed de novo duplication and deletion events were noted on 1p36.33, 9p24.3 and 19q12-q13.11 for ambiguous genitalia, 10p14 and Xq28 for cryptorchidism and 12p13 and 16p11.2 for hypospadias. These variants were significantly associated with genitourinary defects (P = 6.08×10(-12)). The causality of defects observed in 5p15.3, 9p24.3, 22q12.1 and Xq28 was supported by the presence of overlapping chromosomal rearrangements in several unrelated patients. In addition to known gonad determining genes including SRY and DMRT1, novel candidate genes such as FGFR2, KANK1, ADCY2 and ZEB2 were encompassed. The identification of risk germline rearrangements for urogenital birth defects may impact diagnosis and genetic counseling and contribute to the elucidation of the molecular mechanisms underlying the pathogenesis of human sexual development.
  • incidence rates reaching almost 3%
  • the majority of DSD cases remain unexplained.
  • Most anomalies (74.2%) evaded detection by the routinely ordered karyotype

1 comment:

Hugh said...

Aside from genetic defects, another thing that might be causing abnormalities of male development, is the medical use of testosterone-blocking drugs during pregnancy.

In "problem" pregnancies where the mother is at risk of miscarrying or giving birth prematurely, it's common practice to give treatment involving quite high doses of progestins and corticosteroids. One example is "Proluton Depot" (Makena in the US), an injectible form of the progestin hydroxyprogesterone caproate. This very same drug can be used to provide a progestin component in transgender HRT, except in doses several times smaller than are used for preventing premature births.

In adult men, progestins are highly effective "antigonadotrophins", which basically means that they shut down production of the hormones that instruct the testicles to produce testosterone (the two drugs most commonly used to chemically castrate sex offenders, medroxyprogesterone acetate and cyproterone acetate, are both progestins). If progestins have the same effect on a male fetus (and why wouldn't they?), then clearly they also have the potential to cause abnormalities of sexual development in a male fetus.

The prescribing guidelines for hydroxyprogesterone caproate state that treatment should be started between 16 and 21 weeks after conception and continued until the 37th week of the pregnancy, too late for it to have much effect on genital development, but during the time the brain development responsible for gender identity later in life seems to take place.

A second example I've found is where a mother who's thought to be in imminent danger of going into premature labour, is given an injection of a long acting corticosteroid (dexamethasone or betamethasone being the usual choices), so as to promote lung maturation in her unborn baby. This greatly increases his chance of surviving if born prematurely. The effect is only shortlived though, so the treatment can end up being repeated several times in the course of a difficult pregnancy. The usual time this treatment is given is from about week 25 to week 34 I think.

A known effect of high doses of corticosteroids is to suppress testosterone production by about 60 percent through a direct action on the testicles (rather than by suppressing gonadotrophins), meaning that it's very likely that a male fetus exposed to this treatment is having his testosterone suppressed. Again this treatment is being given too late to have much affect on physical sex, but during the time the brain development responsible for gender identity is taking place.

What do you think? Am I right to be concerned that these treatments could be having the unintended consequence of creating people who are likely to be gender dysphoric and become MTF transsexuals later in life?