Partial Androgen Insensitivity Syndrome

Back Partial Androgen Insensitivity Syndrome

Published 16/03/2023 - Edited 16/07/2024

The Androgen Insensitivity Syndrome (AIS) is the most common form of Variation in Sex Characteristics (VSC)/Difference of Sex Development (DSD) in individuals with XY chromosomes. A genetic mutation of the androgen receptor (AR) reduces the masculinizing action of testosterone (reduced virilization) at various stages of a person's life. The degree of de-virilization depends on how low the androgen receptor activity has become. When the receptor activity is partially conserved, the partial androgen insensitivity syndrome (PAIS) develops, reducing virilization more than expected. PAIS may appear at birth as atypical external genitalia, i.e. not resembling the genitalia typically considered masculine or feminine. The appearance of the external genitalia of infants with PAIS can vary from typically female with enlarged clitoris (clitoromegaly) to typically male with hypospadias. The testicles that have not completely descended into the scrotum may be located in the inguinal canal, in the labioscrotal folds (a bifid scrotal sac that resembles the labia majora, hence the name) or, more rarely, in the abdomen. Typically, there is a less than expected display of male secondary sex characteristics during puberty, and development of breasts (gynecomastia) is common. The final height the person reaches in adulthood is generally intermediate between typically female and typically male.

Genetic traits
The gene for the androgen receptor (AR) is located on the X chromosome; therefore PAIS is a hereditary “X-linked” condition, even though in about a third of cases it is the result of a de novo mutation, i.e. without the mother carrying the genetic anomaly. In any case, the AR gene can have hundreds of different mutations, and individuals with PAIS do not often present a specific gene variant. Thus, the genetic framing of PAIS remains a very complex issue.

Identification
The condition is usually recognized clinically at birth by the presence of atypical male external genitalia and palpable testicles. In the newborn, the features of the external genitalia are the same as in other VSCs/DSDs of reduced virilization (such as 5 alpha reductase deficiency or 17 beta-hydroxysteroid dehydrogenase type 3 deficiency).
The endocrinological evaluation usually reveals mildly elevated luteotropin (LH) and testosterone levels, and normal follicle-stimulating hormone (FSH) levels. PAIS diagnosis requires that the variant of the genus AR be identified; this, however, only happens in 40% of cases.
Medical options Infants with PAIS do not have hormonal deficits posing immediate health risks. Nevertheless, the assignment of gender at birth (which is often based on the characteristics of the external genitalia) can be difficult in some cases. Most studies report a 50% female and a 50% male gender assignment, with a tendency towards agreement between gender assigned at birth and gender identity/expression. In spite of this, some cases of gender incongruence in individuals with PAIS have been recorded. Therefore, the literature recommends a case-by-case assessment to establish the gender to be assigned at birth. Obviously, only the individual will later be able to express their gender identity, which may or may not be congruent with the gender assigned at birth. Accordingly, the most recent international recommendations support the need to postpone partially reversible or irreversible, non-urgent medical-surgical interventions for the physical health of the minor to a moment in which the person can express their informed consent. All this considered, if at puberty the person identifies as female and desires to affirm the female gender, orchiectomy (removal of testicles, unless already removed in infancy) can be contemplated to prevent virilization and the onset of testicular tumours. And to simulate female pubertal development, hormonal therapy with estrogens will also be undertaken, followed by replacement therapy in adulthood. Some people may want surgery aimed at feminizing the genitals, and to ensure adequate sexual and urinary function. Individuals with PAIS and male gender identity who have not had orchiectomy may require medical or surgical treatment of gynecomastia at puberty. In some cases, a short treatment (six months) with high-dose testosterone or with dihydrotestosterone (DHT) gel is undertaken to optimize virilization, especially regarding penile development. Long-term testosterone replacement therapy is generally not necessary. Testosterone is also an essential hormone for spermatogenesis (the production of sperm), and therefore for fertility because all forms of PAIS are usually associated with infertility. On the other hand, anecdotal cases of persons with PAIS treated with high doses of testosterone showed improved spermatogenesis, and were able to induce pregnancy by medically assisted procreation (MAP) methods. In PAIS individuals whose testicles have not descended into the scrotum, the risk of developing testicular cancer after puberty rises to 50%; they must therefore resort to preventive strategies. The person can opt for a surgical approach: orchiectomy (removal of the testicles) or orchidopexy (procedure that moves an undescended testicle into the scrotum), preferably when the person has reached an age where they can give their informed consent to the procedure, and this is in line with their gender affirmation requests. On the other hand, it is possible to set up annual monitoring via ultrasound or magnetic resonance, depending on the case, to promptly identify any new potentially malignant testicular lesions. If the testicles are located in the scrotum, orchiectomy is not recommended, although the risk of developing testicular cancer in these cases is unknown.

Bibliography
Batista RL et al. Androgen insensitivity syndrome: a review. Archives of Endocrinology and Metabolism. 2018 Mar-Apr;62(2):27-235
Coleman E et al. Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health. 2022 Sep 6;23(Suppl 1):S1-S259
Domenice S et al. 46,XY Differences of Sexual Development. Last Update: August 21, 2022. In: Endotext [Internet]
Loch Batista R et al. Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development. The Journal of clinical endocrinology and metabolism. 2019 Apr 1;104(4):1160-1170