Hormonal treatments

Hormone therapy is one of the possible clinical pathways for individuals with Variations of Sex Characteristics (VSCs)/Differences of Sex Development (DSDs). Careful counselling of the intersex person and their family is mandatory, before starting any hormone treatment, which must be carried out according to each person's uniqueness, age and reported gender identity. Furthermore, this is when individuals and their families must also be adequately informed about the possible impact of hormone therapy on future fertility.

Hormone therapy can have different indications, so it will be described in more detail in the sections on individual VSC/DSD. In some cases, hormone therapy is life-saving because it replaces hormones necessary for survival, as in the case of salt-wasting 21-hydroxylase deficiency. However, in most cases where hormone therapy is considered, there is a more or less marked reduction in the activity of the gonads (testes and ovaries) and thus in the production of sex hormones (testosterone, oestrogen, progesterone). This condition is called hypogonadism. In detail, hypogonadism may be due to:

• decreased functional activity of the gonads which produce insufficient sex hormones (e.g., gonadal dysgenesis or testosterone synthesis defects)
• surgical removal of the gonads due to a potentially increased risk of developing postpubertal cancer
• moreover, a lack of tissue response to the action of sex hormones may be present (as in the case of the androgen receptor insensitivity syndrome)

Clinical manifestations of hypogonadism vary according to the age in which the condition emerges. In the case of individuals with ovaries, it can manifest through failed mammary development, irregular menstrual cycle, short stature in the paediatric population. In adulthood, other symptoms can prevail, such as vaginal dryness or hot flashes. Individuals with testicles can manifest hypogonadism during pre-puberty, through specific characteristics of the external genitals (bifid scrotum, hypospadias), small testicles, scarce body hair, a rather feminine body shape or higher voice timbre. In adulthood, manifestations are less specific and usually characterized by sexual disorders, such as little sexual desire and low muscular strength. Both individuals with ovaries and with testicles, hypogonadism can also develop low bone mineral density and infertility.

In all these cases, hormone therapy with estrogen or testosterone is necessary in childhood to induce puberty, and subsequently to maintain secondary sexual characteristics. It is important to underline that, if the gonads are removed, the importance of lifelong hormonal therapy (possibly in accordance with gender identification) must be shared with the person and/or parents or legal guardians (in the case of the minors) to protect physical health. In adulthood it is equally important to maintain adequate levels of sex hormones to prevent metabolic, cardiovascular and bone problems, as well as to support psychological well-being.

Estrogen therapy is used to achieve/maintain female sexual characteristics, including menstrual bleeding in individuals with a uterus, for whom estrogen therapy (oral or transdermal) is combined with progestogens. When the therapy is used to induce puberty, sex hormones should be administered in gradually increasing doses, to ensure a correct height development of the adolescent until they are ready for adult dosing. Therapy with transdermal oestrogens is generally recommended to induce puberty, since they are more manageable at reduced doses as compared to the oral formulation and, having a lower impact on the liver function, it also reduces the risk of thromboembolic events potentially linked to oestrogen therapy.

Testosterone therapy is used to induce/maintain male secondary sexual characteristics. Again, if therapy is undertaken with a view to inducing puberty, the doses of sex hormones must be gradually increased until reaching an adult dose, to ensure a correct height development of the adolescent. Short-acting, injectable, transdermal, or even oral testosterone forms can be used.

Dihydrotestosterone-based gels can be useful for increasing the penile length, avoiding the undesirable effect of gynaecomastia, i.e. enlargement of breasts due to growth of glandular tissue. In adults, standard doses of testosterone in the form of long-acting injections or gels are generally used.

Bibliography
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Cools M et al. Caring for individuals with a difference of sex development (DSD): a Consensus Statement. Nature Reviews. Endocrinology. 2018 Jul;14(7):415-429
Domenice S et al. 46,XY Differences of Sexual Development. Last Update: 2022 Aug 21. In: Endotext [Internet]
Warne G L et al. Hormonal therapies for individuals with intersex conditions: protocol for use. [Abstract]. Treatments in endocrinology. 2005;4(1):19-29