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Transgender hormonal therapy: limited prospects for international harmonisation of

practice

Gender dysphoria and the State

The management of gender dysphoria varies hugely across the globe, in respect of models

of service delivery, individual eligibility and funding for transition, access to relevant

specialists and cultural, religious and legal factors, in addition to the actual cross-sex

hormone treatment (CSHT) regimens used. Different countries and cultures also vary in

their socio-cultural tolerance of gender fluidity during the process of transition. In this review,

we highlight contrasting practices in five countries where gender reassignment is well-

established: comprising both economically developed and developing nations, and where

state healthcare involvement ranges from minimal to highly-centralised; concentrating on the

UK, USA and Iran, but also referring to Thailand* and the Netherlands.

In relation to CSHT, the level of formal state- or healthcare system- involvement in the

process of transition – which varies internationally from negligible to near-absolute –

impacts on physician and patient choices in respect of medication, depending on the costs

that patients are required to bear. The UK, Netherlands and Iran are exemplars of state-

supported transition, with highly-subsidised drug costs and fully-funded genital-gonadal

surgery, but with otherwise divergent models of service delivery.

The UK National Health Service

Access to and progress through transition in the UK is supervised by the regional

multidisciplinary teams, although the actual prescribing and monitoring of CSHT is largely

outsourced to primary care. The process is individualised, but given the long waiting list for

formal assessment (at present 12-18 months is not atypical), the majority of people will have

already made a social gender role transition before cross-hormone therapy is prescribed. In

line with WPATH standards of care [1] and the UK good practice guidelines [2] a person


More gender surgical procedures are performed in each of these countries than anywhere else in the world.
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must be in their preferred social gender role for at least one year before surgery in the UK.

The aim of CSHT is to use medical interventions that are progressively less reversible to

help make the person’s physical expression of their gender more congruent with their

internal gender identity, not to mention the expected positive psychological effects and

mental health benefits. Barriers to entry are relatively high and long waiting times can be

frustrating for service users, but the remarkably few subsequent requests for de-transition

indicate that the process is fundamentally robust.

The Islamic Republic of Iran

Although generally considered to be a developing country, Iran generally scores highly in

international comparisons of healthcare systems and education. In Iran, the process of

determining eligibility for (and executing the management of) transition is even more

centralised than in the UK, with the Department of Forensic Psychiatry in Tehran being the

sole competent authority [3]. As per a 1987 fatwa issued by the late Ayatollah Khomeini,

transgenderism has a theological and legal basis in Iran, with the date of surgical

reconfiguration heralding eligibility for re-issue of state identity card and the entitlement to

state-subsidised CSHT. However, although the state is supportive of citizens wishing to

transition, it does not accept same-sex relationships, public transvestitism, or gender fluidity,

for which the potential, if rarely-imposed, sanctions include sentences of imprisonment or

even death. The tempo of transition is thus faster, with mandatory surgery taking place

much earlier in the process, and there is potential for individuals who are gender-fluid, or

engaged in same-sex relationships becoming enmeshed in the machinery of transition

should their lifestyles come to the attention of the authorities [4]. On the positive side,

access to low-cost and high-quality cosmetic hair removal in Iran is reportedly excellent for

both cis- and trans-gendered women. In both countries, eligibility criteria for state-funded

breast-augmentation surgery apply equally to cis- and transgendered women and only those

with the most hypoplastic breasts will typically qualify.

The free-market: USA and Thailand

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By contrast with the UK and Iran, the USA and Thailand represent the more “free market or

non-statist” end of the spectrum”. High-quality medical, psychological and surgical expertise

is available and not subject to state “gate-keeping”, albeit with a shortage of highly-qualified

surgeons to perform certain operations such as vaginoplasty and phalloplasty – particularly

outside major urban centres. Thus, the principle obstacles facing bona fide service-users

are largely financial. This of itself necessarily leads to health inequality, with only those able

to afford transgender healthcare, or eligible for USA Medicaid (subject to varying

entitlements to transgender healthcare accorded by the different States), Medicaid, or

Veterans Administration (VA) programmes. For instance, the VA covers CSHT, but not

surgery. For those with private healthcare insurance, or insured via their employer,

entitlements and exclusions relating to transgender care also vary hugely between different

schemes and insurers. In Thailand, the poorest patients may have no option beyond

unsupervised self-medication as and when they can afford it, although fortunately both

testosterone and estrogen are typically inexpensive [5]. Even with the support and advice of

their supervising physician, trans-gendered individuals in both these countries face

significant choices regarding the most effective way of spending money to achieve their life

goals, such as balancing the relative cost-effectiveness of medical androgen-suppression

versus cosmetic hair removal.

Estrogens

For reasons of historical physician product-familiarity, conjugated equine oestrogen (CEE)

was formerly the estrogen-of-choice for both cis-and trans-gendered females in the USA, but

practice there is now increasingly aligning with the UK and continental Europe [6], where

17,beta estradiol (E2) is preferred to CEE, primarily due to the reported adverse

cardiovascular or thrombotic effects of both CEE and ethinylestradiol (EE) [7,8], but also

because serum concentrations of CEE and EE cannot be monitored.

In relation to route of E2 delivery, observational data from postmenopausal cis-women

suggest that transdermal delivery of E2 is less thrombogenic than oral [9]. However,
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compared with an equivalent Dutch cohort predominantly using transdermal E2, the

observed incidence of venous thromboembolism in UK transgender women using oral E2

was 4-times lower [8]. This may relate to lifestyle measures rigorously embedded in UK

practice, whereby transgender women must give up smoking and avoid excessive obesity in

order to receive high-dose E2 (in contrast to the more libertarian Netherlands). This may act

to reduce the overall VTE risk for this group, so that unlike the Netherlands, oral E2 is thus

acceptable in the UK for all but the highest risk patients. Finally, although hard data are

elusive, physicians report reduced skin-adherence of E2 patch products in hot and humid

tropical countries, such as Thailand.

Progesterone-analogues

Although promoted on some “Trans-Websites” and still prescribed in some centres in the

USA, Thailand and elsewhere, the value of progesterone-analogue therapy to augment

breast development in transgender women has not been substantiated [10,11]. It is

moreover associated in cis-gendered postmenopausal females with significantly higher

cardiovascular and breast cancer risks [12,13]. Nevertheless, in parts of the Middle East,

the availability of oestrogens is poor and both transgender- and hypogonadal cis-women

may thus only be able to access combined oral contraceptive products containing

EE+progesterone-analogue.

Anti-androgen therapy

Adjuvant testosterone (T) suppression-therapy is usually also necessary for the vast majority

of transgender women who fail to suppress gonadotrophin-driven T synthesis with E2

monotherapy pending definitive orchidectomy. In this area there are major divergences in

prescribing practice between Iran, where androgen-suppression is rarely necessary due to

the practice of mandatory gonadectomy, the UK, where long-acting GnRH-analogues

(GnRHa) are now first-line therapy (although most patients will ultimately proceed to

gonadectomy), and most other countries, where antiandrogens - either Cyproterone acetate

(CPA) or Spironolactone - are routinely used, and gonadectomy is neither universal, nor
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necessarily routine. The UK’s divergence from rest-of-world practice relates entirely to

medication cost and reimbursement. GnRHa are indisputably safe, highly-effective and with

minimal side effects, and combination therapy with sex steroids with GnRHa mitigates

hypogonadal symptoms and preserves bone health [14,15], but a single three-monthly depot

injection costs upto US$ 3,000. However, UK patients either receive their approved

medication free-of-charge, or pay a fixed NHS prescription charge that is decoupled from the

actual drug cost.

CPA, a progesterone-derivative with some glucocorticoid-like activity, is also a highly-

effective antiandrogen, albeit potentially associated with hepatic dysfunction, depression,

meningioma development and weight gain. It is unavailable in the USA, having never been

licensed there for any indication. Elsewhere in the world, the unit cost can be ten-fold higher

than the equivalent dose of Spironolactone, which is thus the antiandrogen of choice in most

countries. Although most familiar as a potassium-sparing diuretic due to mineralocorticoid

receptor antagonist action (hence its potential adverse effects of renal dysfunction and

hyperkalaemia), Spironolactone is also a partial antagonist at the androgen receptor and

partial agonist at the estrogen receptor. Compared with CPA, it seems to be associated with

a greater need for users to subsequently undergo surgical breast-augmentation and is hence

rarely prescribed for this indication in the UK.

Testosterone

Testosterone replacement in transgendered men is generally uncontentious, typically

suppressing gonadotropin-stimulated ovarian activity at doses equivalent to those used for

cis-gendered male hormone replacement. For the minority of patients in whom menstruation

does not cease, options include adding GnRHa (typically used in UK), or a progesterone-

analogue (typically norethisterone or medroxyprogesterone), or simply increasing the

testosterone dose and accepting the potential risks of erythrocytosis, acne, or mood change

- as sometimes observed in cis-gendered men using such higher doses for hormonal

contraception.
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Summary

Good quality studies comparing the various available hormonal regimes used in transgender

medicine across the world regimes are lacking, and international variation in hormonal

regimes is multifactorial, principally arising from national licensing agreements, costs,

product availability and medication reimbursement practices, rather than great quality data.

Establishing an international collaboration between major transgender centres to examine

the superiority, or inferiority, of any given hormonal regime would normally be a standard

recommendation, in the interests of safety, efficacy and harmonisation. However, in this

particular therapeutic area, issues of drug cost and availability are likely to predominate in

practice over all but the most informative new evidence.

Yaasir Mamoojee, Leighton J Seal, Richard Quinton

Department of Endocrinology, Newcastle-upon-Tyne Hospitals NHS Trust, Newcastle-upon-Tyne, UK

(YM & RQ); Department of Endocrinology, St George’s Hospital Medical School, London, UK (LJS);
Department of Endocrinology, St George’s Healthcare NHS Trust, London, UK (LJS); Gender Identity
Clinic, West London Mental Health NHS Trust, London, UK (LJS); and Endocrine Research Group,
Institute of Genetic Medicine, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, NE1 3BZ,
UK (RQ)

Richard.Quinton@ncl.ac.uk

We declare no competing interests.

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References

1. Coleman E, Bockting W, Botzer M, et al. Standards of care for the health of transsexual,

transgender, and gender-nonconforming people, version 7. Int J Transgender 2011, 13, 165-232.

2. Wylie K, Barrett J, Besser GM, et al. Good practice guidelines for the assessment and treatment

of adults with gender dysphoria. Sex Relation Ther 2014; 2: 154-214.

3. Saberi SM and Mirsepassi GR. Forensic Psychiatry in Iran. Iran J Psychiatry Behav Sci. 2013; 7:

1–3.

4. HM Home Office. Country Information and Guidance Iran: Sexual orientation and gender identity,

version 2.0. 2016.

(https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/565824/CIG-Iran-

SOGI-v2-September-2016.pdf).

5. Meyer WJ, Webb A, Stuart CA, et al. Physical and hormonal evaluation of transsexual patients: a

longitudinal study. Arch Sex Behav 1986; 15: 121–138.

6. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. Endocrine treatment of

transsexual persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab

2009; 94: 3132-54.

7. Van Kesteren PJ, Asscheman H, Megens JA, et al. Mortality and morbidity in transsexual subjects

treated with cross-sex hormones. Clin Endocrinol (Oxf) 1997; 47: 337–342.

8. Seal LJ, Franklin S, Richards C, et al. Predictive markers for mammoplasty and a comparison of

side effect profiles in transwomen taking various hormonal regimens. J Clin Endocrinol Metab

2012; 97: 4422–28.

9. Bergendal A, Kieler H, Sundström A, Hirschberg AL, Kocoska-Maras L. Risk of venous

thromboembolism associated with local and systemic use of hormone therapy in peri- and

postmenopausal women and in relation to type and route of administration. Menopause. 2016; 23:

593–599.

10. Wierckx K, Gooren L and T’sjoen G. Clinical review: breast development in trans women

receiving cross-sex hormones. J Sex Med 2014; 11: 1240–1247.

 Page 8 of 8

11. Gooren, L. Hormone treatment of the adult transsexual patient. Horm Res 2005; 64(suppl 2): 31-

36.

12. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in

healthy postmenopausal women: principal results From the Women’s Health Initiative randomized

controlled trial. JAMA 2002; 288: 321–333.

13. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary

prevention of coronary heart disease in postmenopausal women. Heart and estrogen/progestin

replacement study (HERS) research group. JAMA 1998; 280: 605–613.

14. Seal LJ. A review of the physical and metabolic effects of cross-sex hormonal therapy in the

treatment of gender dysphoria. Ann Clin Biochem. 2016; 53: 10-20.

15. Dittrich R, Binder H, Cupisti S, et al. Endocrine treatment of male-to-female transsexuals using

gonadotropin-releasing hormone agonist. Exp Clin Endocrinol Diabetes 2005; 113: 586–592.