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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.