Disorders (or Differences) of sexual development (DSD) refers to a range of developmental glitches (or differences) that result in a body being grown in the womb that isn’t standard issue male or female. They used to be called (and sometimes still are) intersex conditions.
These differences are more common than you might think – it is estimated that congenital adrenal hyperplasia (CAH) is the cause of DSD in one in every 15,000 live births globally, with smaller abnormalities more frequent.
There are only a set number of ways the body can grow differently in the womb, and diagnosis has come along in leaps and bounds. Early gender assignment remains controversial, however, despite the progress in surgical genital reconstruction and other management techniques. It is now understood that gender identity starts in the womb.
Each person will be considered one of the following variations (updated names from the old term hermaphrodite):
- 46, XX DSD – a genetic female with ambiguous genitalia and organs – caused by ovarian development disorders (ovotesticular DSD, testicular DSD, gonadal dysgenesis (Swyer syndrome)), androgen excess in the womb (congenital adrenal hyperplasia (CAH)), vaginal atresia, cloacal exstrophy
- 46, XY DSD – a genetic male with female or ambiguous genitalia and reproductive organs – caused by disorders of testicular development, impaired androgen synthesis (CAIS, PAIS, MAIS), androgen biosynthesis defect, disorders of anti-Müllerian hormone (AMH)/receptor, hypospadias/epispadias, cloacal exstrophy
- Ovotesticular DSD – both ovaries and testicles, and possibly other organs
- 46, XX testicular DSD – a genetic female with testicles
- 46, XY complete gonadal dysgenesis (Swyer syndrome) – a genetic male without gonads (testicles or ovaries)
Other genetic mixes include:
- 45, X – caused by Turner syndrome
- 47, XXY – caused by Klinefelter syndrome (an extra X chromosome causing otherwise phenotypical males to develop breasts, have feminine fat distribution, reduced body hair, infertility, and others)
- 45, X / 46, XY – mixed with ovaries, testicles
- 46, XX / 46, XY – chimeric (a mix of what appears to be two people, possibly male/female)
How it works in the embryo
Sex determination begins in the embryo and what follows is a logical progression of foetal growth. The chromosomes determine gonadal sex, which then determines what’s known as phenotypic sex. Phenotypic means the physical characteristics, like body shape. The gender one identifies as is not only determined by how we look (phenotypic sex), but by the development scenario of the brain pre- and postnatal.
Month two of foetal life sees an undifferentiated gonad turn – if directed by testis-determining factor (TDF) in conjunction with the SRY region of the Y chromosome – into a testicle. If the instructions are faulty or don’t exist, the default is to turn into an ovary.
46, XX testicular DSD people are not explained by this, since they don’t have the Y chromosome, and the SRY region doesn’t exist in 46, XX (genetic females). Luckily, there are other genes involved in the development of the testicles to blame (DAX1, SF1, WT1, AMH).
The ducting systems
If testicular tissue is absent, ducts and phenotypic features form as if the foetus was a genetic female. Testicular tissue produces two substances that cause male ducting and phenotypical characteristics – testosterone and Müllerian-inhibiting substance (MIS) or AMH.
Male ducting includes the primordial Wolffian structures which eventually develop into the epididymis, vas deferens, and the seminal vesicle. The areas closest to the source of testosterone see the strongest changes and impacts, which means people with ovotesticular DSD often have some Wolffian development near the testicular tissues, even if they are joined to an ovary (ovotestis). The mother’s androgen levels do not dictate male internal differentiation in females or females with CAH.
MIS is critical for the development of normal male ducting – it represses the default development of the Müllerian ducts (fallopian tubes, uterus, upper vagina), and stimulates Wolffian ducts. Oestrogen and testosterone both act as modulators for MIS, but they are not directly in charge of it. Testosterone can inhibit some Müllerian duct development, and oestrogen can interfere with MIS action – this could result in some Müllerian ducting being present.
At seven weeks in the womb, both sexes are identical, and in the absence of androgens (testosterone and dihydrotestosterone (DHT)), everyone turns into a phenotypical girl regardless of chromosomes. The next eight weeks see males differentiate over the coming two months, moderated by testosterone (converted into DHT by 5-alpha reductase).
DHT leads to the translation and transcription of genetic material, which then leads to normal male external genitalia – the scrotum appears from genital swellings, to form the shaft of the penis from its folds, and the glans from the tubercle. The prostate appears from the urogenital sinus.
If the DHT doesn’t work as it’s supposed to, incomplete masculinsation occurs. Hormones provided by the mother continue the process of building up the male tissues after the testosterone surge ends at about 14-weeks gestation.
Causes of 46, XX DSD
- Congenital adrenal hyperplasia (CAH)
- Maternal androgens – This can be drug induced if androgens or progestational agents are used during the first trimester, causing phallic enlargement without labioscrotal fusion. These drugs were previously used to avoid spontaneous miscarriage in women with frequent miscarriages.
Causes of 46, XY DSD
- Isolated deficiency of MIS – a rare syndrome whereby a phenotypic male presents with a uterus and fallopian tube in an inguinal hernia, and a vas deferens.
- Deficient testosterone biosynthesis – there are five steps to this, and each can be interrupted.
- Complete androgen insensitivity syndrome (CAIS) – the end organ doesn’t develop properly resulting in a genetically male foetus with feminised genitalia.
- Partial androgen insensitivity syndrome (PAIS) – individuals can have a spectrum of external genitalia ranging from very feminine (Lubs syndrome) to more masculine (Gilbert-Dreyfus syndrome), to quite masculine (Reifenstein syndrome). (These syndrome names have gone out of use.)
- 5-alpha-reductase deficiency – A 46, XY foetus with normal testes is lacking in enzyme 5-alpha reductase in the external genital cells, with the urogenital sinus unable to produce DHT as a result.The foetus develops with minimally virilised genitalia, with some phallic enlargement.
- Swyer syndrome – genetic male but presents completely female, without functional ovaries