The sex hormones: testosterone, oestrogen and progesterone are important in the body’s function as well as physical appearance. This article provides an overview of the role of hormones in the body, why they are important and their effect on physiological health in trans and non-binary individuals embarking on gender affirming treatment.
Sex Hormones
There are three main sex hormones that are naturally produced by the body: Oestrogen, Progesterone and Testosterone. However, a range of factors including: the site where the sex hormones are made, the concentration of sex hormone in the blood and interactions with organs in the body, varies between the sexes. This results in the physical differences which can be seen including: different distributions of fat and muscle, fluid retention, density of bones, creation of liver enzymes and fat/sugar/cholesterol metabolism.
In people with testicles, testosterone is the sex hormone in highest concentration in the blood, it is released in a similar amount each day but with slight variations in production throughout the day. Small amounts of oestrogen and progesterone are also released from the testicles, adrenal gland and other tissues such as fat and liver cells. In people with ovaries, oestrogen and progesterone are the sex hormones in highest concentration in the blood. The amount of oestrogen and progesterone produced changes over the month, and small amounts of testosterone are produced by the ovaries and adrenal gland.
Physiological importance of sex hormones
Bone density
Sex hormones play an important role in the formation of bones and bone weight maintenance. Oestrogen is known to be important as, after menopause, cisgender women are more at risk of their bones becoming more fragile which can lead to breakages.
Oestrogen and Testosterone help build bone density through the teenage years and then maintain bone mineral density thereafter. Studies have shown that transgender women may be at higher risk of osteoporosis after starting gender affirming hormones, so it is essential to get the hormone levels right. In transgender men there seems to be no difference in risk after taking gender affirming hormones.
Cardiovascular disease
There is a difference in incidence of heart attacks and strokes (cardiovascular disease) between cis men and cis women. Pre-menopausal cis women have a lower rate of cardiovascular disease than cis men. The risk of cardiovascular disease in cis women increases after the menopause. It is thought that oestrogen helps play a protective role in cardiovascular disease, therefore taking oestrogen as a gender affirming hormone can reduce the individual’s baseline risk of heart disease. There has been shown to be no difference between transgender males and cisgender males of cardiovascular disease risk. There is limited long term data on morbidity risk of cardiovascular disease in transgender men and women but more research is likely to evolve with the increased treatment of transgender youth with gender confirming hormones and their relative risk profile in relation to cis gendered individuals as they will have had limited exposure to their biological hormone profile.
Psychology
Sex hormones have been shown to protect brain cells and create links between brain cells. As sex hormones decline with age their protective effect on the brain lessens and the risk of memory loss and diseases such as dementia increase. Studies have shown differences between the male and female brain in terms of emotional processing, memory storage and language areas. (16-20)
Immunity
Sex hormones also play an important role in immunity. Females have stronger immune responses following immunisation and infections but are also more at risk of autoimmune diseases (where the body attacks itself.) In cisgender females, fluctuations in immune system efficiency have also been seen during different stages of the menstrual cycle.
The effects of taking sex hormones
People who are transitioning may decide to start taking hormones which will suppress their current dominant hormone profile and facilitate their desired hormone profile. This allows them to develop physical and sexual characteristics which are aligned with their gender identity. The effects of the hormones taken will vary between individuals and cannot be guaranteed. The effects of these hormones do not cause immediate physical changes and take a number of years to complete their full effect on the body. Just like any puberty, changes vary from person to person.
Masculinisation
This involves taking testosterone, which can be given as a gel, cream, patch, an injection and in some countries as a subdermal (under the skin) implant.
Effects of testosterone:
- Stopping of periods
- Thickening and increased facial and body hair
- Skin changes, more oily skin, increase in acne
- Increased muscle mass
- Fat redistribution from hips and bottom to stomach
- Increased sex drive
- Deepened voice
- Thinning of vaginal canal
- Increased clitoral size
- Male pattern balding
Some physical changes which may not be altered if testosterone is taken after puberty include: shorter height, broader hips, some remaining feminine subcutaneous fat distribution.
Progesterone can also be given as an injection or implant to stop cyclical bleeding.
Feminisation
This involves taking oestrogen, which can be given orally, as a patch or an intramuscular injection. (25) Additionally, antiandrogens may be taken to reduce the effects of testosterone in the body. These can be given orally, as an intramuscular injection, nasal spray or as an implant. Examples of antiandrogens include: Spironolactone, GnRH agonists, Finasteride.
Some physical changes which may not be altered if oestrogen is taken after puberty include: taller height, broader skeleton, deeper voice and hair pattern.
Effects of oestrogen:
- Breast development
- Increased body fat, redistribution of body fat to hips and bottom
- Thinning and slowed growth of body and facial hair
- Decreased testicle size
- Decreased erectile function
- Reduced muscle mass
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Hormone prescribing comparisons
As outlined above, sex hormones are vital to the optimal functioning of key organs in the body. As such there are serious implications associated with underprescribing. While there is a lack of long-term evidence on the effect on physiological health in transgender individuals with gender affirming treatment, the current gold standard is outlined in international recommendations by the University California San Francisco and The Endocrine Society.
As more trans individuals are facilitated in their gender affirming treatment we expect to see more research emerge which will allow for the further optimisation of hormone prescribing to reduce any long term side effects and to reduce any adverse effects associated with underprescribing.
Below we have compared various clinical guidance on hormone prescribing.
Comparison of treatment doses and target blood test levels with Gender-affirming hormones.
| University California San Francisco | Notes | ||||
| Oestrogen (oral/sublingual ) | 2mg-8mg/d | Doses >2mg divided into two separate doses/day | |||
| Transdermal (patch) Estradiol
(0.025mg release/patch/ 1day) |
100mcg-400mcg (2 patch changes/week) | 1 patch = 100mcg | |||
| Estradiol valerate (Intramuscular injection) | 20-40mg IM every 2weeks | Doses can be halved and given weekly to avoid cyclical symptoms | |||
| Estradiol cyprionate (Intramuscular injection) | 2mg -5mg IM every 2 weeks | Doses can be halved and given weekly to avoid cyclical symptoms | |||
| The Endocrine Society | |||||
| Estradiol Oestrogen (Oral) | 2.0-6.0mg/day | ||||
| Transdermal Oestrogen (patch) | 0.025-2mg/day (new patch every 3-5days) | ||||
| Parenteral Estradiol valerate or cypionate (intramuscular/subcutaneous) | 5-30mg IM every 2 weeks
Or 2-10mg IM every week |
||||
| Devon NHS Partnership | |||||
| First line: Transdermal estradiol (patch/gel) | Evorel patch 1.6mg-9.6mg estradiol/patch, twice weekly patch
Or Oestrogel 0.06% 0.5mg-4mg gel/day |
||||
| Second line: Oral estadiol | 2mg-12mg/day | ||||
| All Wales medicine strategy group | |||||
| Estradiol valerate Oral
Or Estradiol hemihydrate Oral |
2-8mg/day | ||||
| Estradiol gel (Topical) | 1mg-4mg /day | ||||
| Estradiol patch | 50 mcg/24h twice-weekly patch – 200mcg/24h twice weekly patch | ||||
| Leeds and York Partnership | |||||
| Transdermal estradiol | 25–50mcg twice weekly patch
Or 0.5- 1.5mg daily gel |
||||
| Oral oestrogen | 1-2mg/day | ||||
| Tavistock and Portman NHS Foundation | |||||
| Oestradiol tablets | 2mg – 8mg /day | ||||
| Oestradiol patches | 50mcg- 200mcg twice weekly patch | ||||
| Oestradiol gel | 0.5mg- 4mg/day | ||||
| Sheffield health and social care NHS trust | |||||
| Oral Estradiol | 1-6mg/day | ||||
| Estradiol gel 0.06% | 2-4 measures/day = 1.5mg-3mg/day | ||||
| Transdermal estradiol patches | 50-200mcg/24h twice weekly patches | ||||
| Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust | |||||
| 1-6mg/day | |||||
| Sandrena 0.1% gel | 1-3mg/day | ||||
| Oestrogel 0.06% gel | 1.5mg-3mg/day | ||||
| Estradiol Transdermal patches | 50-250mcg/24h twice weekly patches | ||||
| University California San Francisco Notes | ||
| Testosterone
Cypionate (intramuscular/subcutaneous injection) |
50mg-100mg/week | Dose can be doubled for 2 weekly injections |
| Testosterone Enthanate
(intramuscular/subcutaneous injection) |
50mg-100mg/week | Dose can be doubled for 2 weekly injections |
| Testosterone topical gel 1‰ | 50mg-100mg/every morning | / |
| Testosterone topical gel 1.62‰ | 40.5mg -103mg /every morning | / |
| Testosterone patch | 4mg-8mg/every afternoon | Patches come in 2mg or 4mg and can be cut to alter dose |
| Testosterone cream | 50mg-100mg | / |
| Testosterone axillary gel 2% | 60mg-120mg | / |
| The Endocrine Society | ||
| Testosterone enanthate/cypionate (intramuscular/ subcutaneous injection) | 100-200mg/every 2 weeks
Or 50-100mg/every week |
|
| Testosterone undecanoatec
(intramuscular injection) |
1000mg every 12weeks | |
| Testosterone gel 1.6% | 50-100mg/day | |
| Testosterone transdermal (patch) | 2.5-7.5mg/day | |
| Devon NHS Partnership | ||
| Testosterone undecanoate 1000mg intramuscular injection | First injection, second injection 6weeks after and then every 12weeks | |
| Testosterone 2% gel (Tostran®20) 10mg per metered dose from pump | 1-8 pumps per day = 10mg-80mg/day | |
| All Wales medicine strategy group | ||
| Testosterone gel
(Testogel® 16.2 mg/g3, Testavan® 20mg/g4, Tostran® 2%) |
40-80mg/day | |
| Testosteron intramuscular injection (Sustanon or Delateatryl) | 150mg –250 mg every 2-4 weeks | |
| Testosterone Nebido (1000mg/4ml) | 1000mg every 11-13 weeks | |
| Leeds and York Partnership | ||
| Sustanon (or testosterone enantate) Intramuscular injection | 250mg every 4 weeks | |
| Nebido intramuscular injection | 1000mg every 12weeks | |
| Testogel gel pump | 40.5mg/day | |
| Testogel gel sachets | 50mg/day | |
| Tostran gel pump | 40mg/day | |
| Tavistock and Portman NHS foundation | ||
| Sustanon/enantat intramuscular injection | 250mg every 28days
(adjust dose/interval according to trough and peak levels with 4th injection. dose adjusted by 50mg) |
|
| Testogel/Tostran pump | 2 squirts of the pump (40.5mg) adjust dose by 1 squirt up or down according to levels | |
| Nebido intramuscular injection | 1000mg as per loading phase and then every 12 weeks | |
| Sheffield health and social care NHS Foundation trust | ||
| Testosterone undecanoate IM injection 1g/4mls | 250-1000mg every 10-20 weeks; usual dose is 1g IM every 12weeks | |
| Testosterone isocaproate 60mg/1ml and Testosterone decanoate 100mg/1ml IM | IM injection 1ml every 2-6 weeks | |
| Testosterone Enantate 250mg IM Injection 1ml every 2-6 weeks | 250mg every 4 weeks | |
| Testogel 1% sachets | 50-100mg/day | |
| Tostoran gel 2% metered dose pump | 30-80mg/day | |
| Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust | ||
| Nebido 1g/4ml Testosterone undecanoate intramuscular injection | 1g every 12-20 weeks | |
| Sustanon testosterone 250mg/ 1ml intramuscular injection | 250mg every 2-6 weeks | |
| Testosterone enantate 250mg/1ml intramuscular injection | 250mg every 2-6 weeks | |
| Tostran 20 mg/1g topical gel | 40-80mg/day | |
| Testogel 50mg/5g topical gel | 50-100mg/day | |
| Testavan 23 mg/1.15 g topical gel | 23-69mg/day | |
| Testim 50 mg/5 g topical cream | 50-100mg/day | |
Blood concentration hormone ranges comparison
| Organisation | Oestrogen target range (blood concentration) | Testosterone target range (blood concentration) |
| University California San Francisco | Maintain at mid-cycle range 100–200 pg/mL= 367pmol/L-734pmol/L | 350-1100ng/dl = 14.4nmol/L -38.1 nmol/l |
| The Endocrine society | Maintain at mid-cycle range 100–200 pg/mL 367pmol/L-734pmol/L | For testosterone enanthate/cypionate injections: 400–700 ng/dL = 13.9nmol/L- 24.3 nmol/L midway between injections For testosterone undecanoate injections: >400 ng/dL = > 13.9nmol/Lat trough level
Transdermal (measured at least 2 h after application) |
| Devon NHS partnership | 200-600pmol/L | 14-28nmol/L |
| All Wales medicine strategy group | 350-750 pmol/L | 15-20 nmol/L |
| Leeds and York Partnership | 350-750 pmol/l if aged < 40; 300-600 pmol/l if aged 40-50; 200-400 pmol/l if aged > 50 or younger and significant CV risk | Not specified in prescribing guidelines |
| Tavistock and Portman NHS Foundation | Not specified in prescribing guidelines | Not specified in prescribing guidelines |
| Sheffield health and social care NHS Foundation trust | 300-600 pmol/L | < 8 – 12 nmol\L trough level for injections
25 – 30nmol/L peak level for injections 15 – 20nmol/L for gel preparation (4 – 6 hours after application) |
| Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust | 300–750 pmol/l | IM injections: Trough serum testosterone levels in the lower third of the male reference range
Topical treatments: Trough serum testosterone levels in the middle third of the male reference range (18 to 49 years: 8.6 – 29 nmol/L 50 years and over: 6.7 – 25.7 nmol/L) |
(All three tables created from: The Endocrine society’s clinical guidelines
As outlined in the above tables, five out of seven gender clinics in the UK have their recommendations for prescribing available online. The recommendations provided are in keeping with those laid out in the Endocrine society and University California San Francisco guidelines. UK treatment protocols are regional which creates differences in prescribing and monitoring, hence the variation between GICs.
To conclude, sex hormones are important in the body’s function as well as physical appearance. There is good emerging evidence of long-term beneficial effects on physiological health in transgender persons with gender-affirming treatment. While ongoing research into the long-term effects of hormonal interventions in this group is underway, our focus must be on providing ethically sound, patient-centered, gender-affirming care based on the ample evidence that is currently available. It seems imperative that we aim for hormone levels that match those of people who naturally produce the hormones from their testicles or ovaries.