If fetal tissues were to receive erroneous signals at an early stage, or fail to receive appropriate ones, reproductive development could halt, or attempt to proceed down the opposite sex pathway.
Humans, like all other mammals, reproduce sexually. For sexual reproduction to take place, a large gamete called an egg or ovum incorporates a small gamete called a sperm resulting in fertilization. DNA is shared and swopped to make the next unique individual (or individuals in the case of monozygotic ‘identical’ twins). Thenceforth, our bodies develop down one of the two reproductive pathways – a female pathway, characterised typically by 46 XX karyotype, which influences sexual differentiation to support production of eggs, and a male pathway, characterised typically by 46 XY karyotype, which influences sexual differentiation to support production of sperm.
This is such a basic, well-established binary in nature that there are no sexual ambiguities in 99.98% of babies; female genitalia indicate presence of the uterus, ovaries and 46XX karyotype and male genitalia indicate presence of testes and 46 XY karyotype (Maeda et al., 1991; Hamerton et al., 2008). The observation that can be made by parents or birth attendants, let alone trained midwives or doctors, has test characteristics that surpass many other diagnostic tests in medicine.
Because we all develop from a single cell following fertilisation, many structures in our bodies start from one of three common precursor tissues (germ layers), which are then acted upon by different genes and enzymes to signal in which direction development, including sex development, will take place. Although there are standard patterns for organs and systems (face, heart, blood, genitalia etc), the process of evolution by random chance, ‘mistakes’, ‘misreading’, and new combinations of the building blocks of genes drives diversity. Many changes cause recognised congenital anomalies (e.g. cleft lip and palate, atrial and ventricular septal defects, thalassemia, hypospadias). None of these challenge the basic anatomical and physiological functions of human bodies. Instead, congenital variations are variously well-understood differences from the norm (ranging from minor to major), some of which may be associated with illness or disease. Congenital anomalies can also affect the development of the organs of the reproductive system.
Correspondingly, if fetal tissues were to receive erroneous signals at an early stage, or fail to receive appropriate ones, reproductive development could halt, or attempt to proceed down the opposite sex pathway. However, because our genetic template is still either male or female, these anomalies or Disorders/Differences of Sex Development (DSDs) can only impair that template. They cannot switch a male into a female or vice versa. Therefore, DSDs are said to be sex-specific (belonging to one or other sex). Instead, DSDs should be used more specifically to denote those individuals for whom their sex may be difficult for a doctor to immediately observe, which only happens in approximately 0.02% of the population (Sax, 2002). Some congenital differences to genitalia such as cryptorchidism (undescended testicle) and hypospadias (where the opening of the urethra is not at the tip of the penis) may be labelled DSDs. Yet, the example of these two conditions only affect male genitalia, meaning there is no ambiguity over the boy’s sex. Thus, labelling many genital abnormalities as DSDs risks loss of clarity over what the medical concept of DSDs communicates (Lee et al., 2016).
In females, the Müllerian duct develops into Fallopian tubes, uterus, cervix and upper third of the vagina. Male sexual differentiation relies on the presence of Anti-Müllerian Hormone (AMH), produced by the testes. In males, AMH instructs the Müllerian duct to regress so that male-specific reproductive anatomy can develop. In a male-specific DSD termed Persistent Müllerian duct syndrome (Genetic and Rare Diseases Information Center, 2020), the Müllerian duct doesn’t regress, due to the absence of AMH or its receptor. The key to understanding this DSD is to understand that these patients are male but a single faulty gene means that Müllerian ducts do not regress as usual. Consequently, male patients with this condition are often infertile and they retain some reproductive structures that would otherwise be found in females, such as uterus or ovaries, which are non-functional and carry various health risks.
Other 46 XY male DSDs include Partial Androgen Insensitivity Syndrome (or PAIS) and Complete Androgen Insensitivity Syndrome (or CAIS). In these situations, the body is partially or completely resistant to testosterone, due to gene mutations on the X chromosome (NHS, 2021). This results in a typically female appearance and female genitalia (as ‘default’), or underdeveloped male genitalia. However, due to presence of other genes on the Y chromosome, the body doesn’t fully develop reproductively into a female. Patients with this condition don’t have a uterus or ovaries; they are infertile and biologically male. Because testosterone is only required for male sexual differentiation, biological females (46 XX) who carry this mutation display no symptoms or signs.
One of the most common chromosomal abnormalities is found in XXY Klinefelter syndrome (NHS, 2019). Whilst technically not a DSD, this condition illustrates the female-male interface further. Males who are born with an extra copy of the X chromosome develop small testes, shortage of testosterone, low muscle mass and enlargement of breast tissue (gynaecomastia). While typically infertile, some men with Klinefelter are fertile; they produce sperm and father children. When a male body fails to fully masculinise, it does not develop reproductively into a fully female body instead, because the male and female pathways are not interchangeable.
In cases of 46 XX testicular disorder (Genetic and Rare Diseases Information Center, 2015), which affects only females, certain genes which are normally found on the Y chromosome are found on the X chromosome instead. This abnormal exchange of genetic material occurs during the development of the father’s sperm cells. When the egg is fertilised by a sperm that has 23X karyotype but contains a gene normally found on the Y chromosome (called the SRY gene), the female embryo receives the instruction to start developing down the male pathway. This usually results in a male appearance, male or ambiguous genitalia, and infertility. However, due to the absence of all other genes normally found on the Y chromosome, this is not a fully male body, and these patients are still biologically female.
The rarest DSD is called ovotestes. This condition results in both ovarian and testicular tissues, often within the same gonad, and has an approximate incidence of 1 in 20 000 (NORD, 2016). Patients with ovotestes most often have 46XX chromosomes, but this DSD may be caused by a number of different genetic variations, and requires individual assessment. The reproductive organs are typically affected and genitalia may appear ambiguous. The rare subset of such patients who are fertile are so either as males or females, but not as both sexes.
DSDs are a vast topic and this is by no means an exhaustive list of these conditions. Patients with DSDs have changed medical ethics thinking significantly over recent decades, especially about genital surgery (Dreger 1999; Behrens, 2020). The care of patients with DSDs and their families is highly specialist and should not be confused with gender dysphoria. However, this overview hopefully explains a pattern: when sex differentiation processes sometimes do not proceed down the typical male or female pathway, it is the existing template of genetic female (no Y chromosome) versus genetic male (with Y chromosome) that determines the outcome.
Behrens, K.G. (2020) ‘A principled ethical approach to intersex paediatric surgeries’, BMC Med Ethics, 21(108). doi: 10.1186/s12910-020-00550-x.
Dreger, A (1999). Intersex in the Age of Ethics. Hagerstown MD: University Publishing Group.
Genetic and Rare Diseases Information Center (2015) 46,XX testicular disorder of sex development, NIH National Center for Advancing Translational Sciences. Available at: https://rarediseases.info.nih.gov/diseases/399/46xx-testicular-disorder-of-sex-development.
Genetic and Rare Diseases Information Center (2020) Persistent Müllerian duct syndrome, NIH National Center for Advancing Translational Sciences. Available at: https://rarediseases.info.nih.gov/diseases/8435/persistent-mullerian-duct-syndrome.
Hamerton, J. L. et al. (2008) ‘A cytogenetic survey of 14,069 newborn infants’, Clinical Genetics, 8(4), pp. 223–243. doi: 10.1111/j.1399-0004.1975.tb01498.x.
Lee, P. A. et al. (2016) ‘Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care’, Hormone Research in Paediatrics, 85(3), pp. 158–180. doi: 10.1159/000442975.
Maeda, T. et al. (1991) ‘A cytogenetic survey of 14,835 consecutive liveborns’, Japanese journal of human genetics, 36(1), pp. 117–129. doi: 10.1007/BF01876812.
NHS (2019) Klinefelter Syndrome, NHS.UK.
NHS (2021) Androgen insensitivity syndrome, NHS.UK. Available at: https://www.nhs.uk/conditions/androgen-insensitivity-syndrome/.
NORD (2016) Ovotesticular Disorder of Sex Development, National Organization for Rare Disorders. Available at: https://rarediseases.org/rare-diseases/ovotesticular-disorder-of-sex-development/.
Sax, L. (2002) ‘How common is lntersex? A response to Anne Fausto‐Sterling’, The Journal of Sex Research, 39(3), pp. 174–178. doi: 10.1080/00224490209552139.