Transgender

What is an androgen?

What is an anti-androgen?

Anti-androgens are drugs that counteract or block the biological effects of the male hormone testosterone or its active metabolite DHT on a wide range of tissues where they normally have biological activity.  They are usually steroidal and fat soluble and pass through the cell membrane to interact with the androgen steroid receptors inside the cell and compete with testosterone or DHT for these receptors.  This blocks expression of genes involved in the development and maintenance of male characteristics. 

Products for blocking the action of androgens

• Dutasteride and Finasteride are 5α-reductase inhibitors and work by inhibiting the action of the enzyme type II 5α-reductase, which converts the male hormone testosterone to DHT
• Flutamide is a non-steroidal anti-androgen that blocks the action of androgens by binding to same receptor but has no steroid effects
• Bicalutamide is a non-steroidal anti-androgen
• Cyproterone is a steroidal anti-androgen
• Spironolactone is a synthetic steroid which is primarily a diuretic but has anti-androgenic activity as a side effect and works by by decreasing androgen production 

About estrogen

Estrogens are produced by the ovaries along with progesterone at certain stages of the menstrual cycle and their production is under control of follicle stimulating hormone (FSH) and luteunising hormone (LH) produced by the pituitary gland, which are in turn under the control of gonadotrophin releasing hormones produced by the hypothalamus in the brain.  

Different forms of estrogen

Estrogen exists in several forms and with different potencies:

• Estradiol, specifically 17-beta-estradiol or E2, is the major and most active form of natural estrogen in the body produced by the ovaries and is responsible for the main actions of estrogen
• Ethinyloestradiol is a synthetic form of 17-beta-estradiol that is more resistant to metabolism in the liver than natural estradiol but has the same biological activity. 
• oestradiol valerate is a prodrug (or precursor) of natural human oestradiol and is converted to 17-beta-estradiol by esterase enzymes in the blood and liver.  It is an effective form of estrogen used for intramuscular administration (injection) as it is absorbed slowly and lasts longer that estradiol itself. 
• Estrone or E1 becomes the most prominent form of natural estrogen during menopause, as estradiol drops, and is produced primarily in the adrenal glands.  Estrone is readily converted into a long lasting form estrone sulphate which concentrates in breast tissue of post-menopausal women and is thought to be involved the development of breast cancer, by being converted to estradiol.  
• Estriol or E3 is the weakest of the three natural forms of oestrogen.  It is the prominent form of estogen during pregnancy and is produced by the placenta, but plays no significant role in non-pregnant women as it is mild, short acting and normally present in small amounts.
• Conjugated oestrogens are a mixture of several different forms of estrogen (at least 10) isolated from horse urine.  They contain mainly forms of estrogen that are in the sulphate form and can be easily absorbed and converted to the active form estradiol.

Delivery methods for estrogens

Estrogen hormone replacement therapy is available in several different preparations and routes of administration.  These include:

• Oral preparations which are subjected to metabolism by the liver and is associated with side effects, such as painful swollen breasts, nausea, headache.
• Skin patches allow oestrogen to diffuse through the skin and into the blood and allows for lower doses to be used, as estrogen bypasses liver and is therefore, not subject to first pass metabolism by the liver.  It also provides more constant blood levels as it diffuses into the blood at a steady rate
• Topical transdermal creams and gels which are rubbed into the skin so that the estrogen diffused through the skin directly into the blood circulation, allowing the estrogen to be released slowly through the skin. 

Products available for estrogen hormonal therapy

The most commonly used estrogens as part of a feminising regime for transgender hormone therapy are the more potent forms of estrogen including estradiol (17-beta-estradiol), oestradiol valerate and conjugated oestrogens.  Estriol can also be used but is less effective.

• estradiol for oral administration, skin patch or injection
• oestriol for oral administration
• conjugated oestrogens for oral administration
• oestradiol valerate for injection

Hormonal control of hair development

Androgen hormones are responsible for secondary sexual characteristics in men, including facial hair growth.  Androgens regulate the hair follicles and at puberty transform them from vellus follicles that produce the tiny almost invisible hairs that cover both male the and female body into the larger terminal follicles, producing pigmented hairs typical of the male facial hair, as well as chest hair and other body hair.  Androgens, particularly the active metabolite of testosterone dihydrotestosterone (DHT) also inhibit hair in other parts of the body, such as on the scalp by causing the terminal follicles to regress to vellus follicles, causing male pattern baldness or androgenic alopecia.

The hair growth cycle and its regulation

Hair goes through a 3-stage growth cycle.  The anagen phase, which is the active growth phase, catagen, where the hair stops growing and shrinks, before being shed during the telogen phase, to be replaced by a new hair.

Blocking hair growth

What are progestins and progestogens?

Progesterone is the female hormone that in women prepares the endometrium (lining of the uterus) for a potential pregnancy.  Progestogens have the same biological activity as naturally occurring progesterone but the chemical structure has been slightly altered to improve stability and absorption. Progestins are synthetic progestogens that have a different chemical structure to progesterone but similar biological effects. 

Use of progestins and progestogens for transgender hormone therapy

Although the clinical opinion is mixed on their effectiveness of use, progestins and progestogens can be used as part of the feminization regime for male to female transgender hormone therapy¹.  The rational for this is that adding progesterone in some form more closely simulates the female hormone cycle.  However, there are also some side effects including, weight gain, oedema, and mood swings.  There is also an increased risk of developing breast cancer².

Progestin products

Progestins, which are synthetic progestogens, available are:

• Medroxyprogesterone
• Hydroxyprogesterone
• Dydrogesterone

Progestogen products

Micronized progesterone, in which natural progesterone is reduced to tiny particles for better absorption, is available as a gel and as capsules.

References

1. Wierckx K, Gooren L, T'Sjoen G. Clinical review: Breast development in trans women receiving cross-sex hormones. J Sex Med 2014 May;11(5):1240-7
2. Axlund SD, Sartorius CA. Progesterone regulation of stem and progenitor cells in normal and malignant breast. Mol Cell Endocrinol 2012 Jun 24;357(1-2):71-9. 

Anti-oestrogens

Anti-oestrogen medicines, such as tamoxifen and anastrozole, are used to treat breast cancer in women.  They can also be used to support the gender reassignment process for female to male transgender patients.  Anastrozole blocks the synthesis of oestrogen in peripheral tissues such as adrenal glands and fat tissue, where testosterone can be converted to oestrogen.  Tamoxifen blocks activation of the oestrogen receptor, preventing stimulation of female secondary sexual characteristics like breast tissue.  Both medications help reduce the amount of oestrogen, which supports the suppression of female characteristics and the increase in masculine characteristics.

Combination products

Combining medications that promote female characteristics while suppressing male characteristics, can help with the male to female gender reassignment process.

Medications combining oestrogen with an antiandrogen like cyproterone, are used to treat conditions in women caused by overproduction of androgens.  These conditions include hirsutism (unwanted hair) and acne.  Cyproterone alone is used to control extreme sexual desire in men that can cause aggressive behaviour.  A combination of oestrogen with an antiandrogen can also be used to promote feminization while suppressing male characteristics, which helps support the gender reassignment process for male to female transgender patients.  Oestrogens promote female characteristics, such as stimulating breast development and help make changes to the male body, such as reducing muscle mass and redistributing body fat.  Antiandrogens are drugs that block the production and the effects of the male hormone testosterone and its more potent form, dihydrotestosterone (DHT).  Development of secondary male characteristics are stimulated by DHT.  These include growth of the prostate gland, the testes, and body and facial hair. 

Several forms of oestrogen can be used to promote the feminization process.  These include conjugated oestrogens, which is a mixture of natural oestrogen in different forms.  This preparation of oestrogen is used for hormone replacement therapy in women, to relieve symptoms of menopause.  Conjugated oestrogens can also be used for hormone therapy as part of the gender reassignment process in male to female patients.  Oestrogen combined with a progestogen like medroxyprogesterone, a synthetic form of the female sex hormone progesterone, may enhance the feminization process.  Progesterone is involved in breast development.  It also has antiandrogenic activity and works by blocking testosterone production.

Topical anaesthetic cream

A cream containing a combination of two topical anaesthetics is used for pain relief during minor superficial surgical procedures.  These types of surgery may be needed during the gender reassignment process, for example, surgery involving genital skin.