Hormone Treatment For Male To Female Transsexuals

                                                  

A gender reassignment program for male to female transsexuals normally includes the prescription of feminising hormones, estrogen and progesterone which develop female secondary sexual characteristics. In addition this may be accompanied before surgery by anti-androgen treatment to reduce the effect of the patient's own male sex hormones. There can be risks attached to hormone therapy in both men and women and therefore it is definitely inadvisable to take any form of hormone product unless it is medically prescribed. The manufacturers of estrogen and progesterone products specify them for medical use in females and do not acknowledge their use for transsexuals, so there is little clinical data available regarding this usage. The effect of feminising hormones varies between patients, but many experience changes within two to three months such as change in skin tone, development of breasts, expansion of the nipples, redistribution of body fat causing fuller cheeks, a more pronounced waist and fleshier hips and buttocks. Body and scalp hair may change in texture but hormone treatment will not inhibit beard growth or improve male pattern baldness. Emotions may be heightened with a greater tendency to mood swings, but in general the transsexual will feel more comfortable with the new self that is emerging. For this reason hormone therapy can be a useful diagnostic tool, as a male who is not transsexual is unlikely to feel this heightened ease with themselves and may become anxious at the drop in their male sex drive. The transsexual on hormone treatment should receive regular check-ups from their doctor. There are various forms of hormone products available and the following is a review of those commonly in use.

Estrogens

Estrogens are responsible for the development of female secondary sexual characteristics, so the main component of any hormone regime for a TS patient will be some form of estrogen. Typically this is obtained either from combined oral contraceptives or estrogen tablets intended for HRT in postmenopausal women. The principle natural estrogen produced from the ovaries in a natural-born premenopausal female is 17 beta-oestradiol. Numerous derivatives and metabolites exist and play specific roles in the female body. While some of the metabolites (e.g. estrogen, oestriol) may be used successfully in treating menopause symptoms in post menopausal women, they are not suitable for transsexual patients; it is necessary to supply 17 beta-oestradiol or a synthetic replacement for it. Estrogen therapy must be continued for life in a post-operative subject, otherwise numerous problems can occur. In particular, several very severe case of osteoporosis have been reported in post-ops who have discontinued their estrogen treatment. Menopause-like symptoms also occur if oestrogen is discontinued.

Oestradiol Valerate

This drug is equivalent to natural 17 beta-oestradiol. It is generally well-tolerated, and clinical data from postmenopausal women suggest it is safer than ethinyloestradiol for long-term use, with less risk of breast cancer, thromboembolic events, or liver problems. It is not certain whether this improved safety applies in the high doses necessary for pre-op transsexuals. This is widely regarded as the estrogen of choice for long-term maintenance in post-op TS patients due to its good safety record; typical post-op dose would be 1-2mg daily, ideally divided into two doses. Oestradiol Valerate appears to be less effective at inducing feminisation in pre-op subjects than ethinyloestradiol, probably due to it's short serum half life-particularly, as it appears to fare poorly when "in competition" with endogenous male hormones; adequate results have been obtained with oestradiol valerate combined with an effective anti androgen. Typical pre-op dose would be 4-6mg daily in divided doses (1 or 2mg per dose); if menopause-type symptoms appear (hot flushes, night sweats, etc) this can often be a sign that the dose is not sufficient to overcome the endogenous male hormones and a switch to ethinyloestradiol would probably be advisable.

Ethinyloestradiol

This drug is a synthetically-produced modification of natural 17 beta-oestradiol. The modified molecule is eliminated only slowly by the liver, giving it a far greater potency and much longer half life that other estrogens. It is generally well-tolerated, but appears to be less safe in very long-term use that oestradiol valerate. Ethinyloestradiol is widely regarded as the estrogen of choice in pre-operative subjects. A dose of 100ug daily in two doses) is typical; this can be increased to 150ug if necessary. It's long half life and potency give it excellent feminising effects. In post-op patients, this drug may still be used, especially for patients whose feminisation has not completed by the time they have GRS. For short-term post-op use, the full pre-op dose of 100ug may be used, this is normally reduced to 50ug after 6-12 months. For long-term post-op use, the full pre-op dose, oestradiol valerate is probably preferable. It should be noted here that estrogen over dosage may paradoxically cause vasomotor symptoms similar to those produced by insufficient estrogen dosage.

This is sometimes seen in post-op patients who are still on pre-op dosage, and if this effect is suspected then the estrogen dosage should immediately be reduced to a typical post-op level. This effect is more likely with ethinyloestradiol than with other estrogens due to its high potency, and consideration may be given to an early switch to oestradiol valerate if the problem persists.

Conjugated Natural Estrogens (Premarin)

This drug is a mixture of various estrogenic substances extracted from the urine of pregnant mares. It lacks the potency of ethinyloestradiol, and there is no evidence that it has any advantages over oestradiol valerate. Many patients dislike this drug because of ethical concerns over the manner in which it is produced. It is increasingly regarded as an outmoded treatment for TS patients. It is also more expensive than the synthetically-manufactured drugs. A typical pre-op dose would be 5-7.5mg daily in divided doses, reducing to 1-2.5mg daily post up.

Other
Estrogens

A number of other estrogenic drugs exist, many of which have been tried in the past in TS patients. It has already been mentioned that metabolites such as oestrone and oestriol are not suitable for use in TS patients; other estrogen derivatives exist but have no advantages over the three estrogens listed above. Diethylstilboestrol has been used in the past, and while it certainty produces worthwhile feminising effects, its safety record contraindicates its use in TS subjects : many serious problems, including fatalities, have been reported.

Progestogens

 Progestogens administered alone do not produce feminisation in a phenotypic male. However, progestogens are generally quite anti-androgenic and will often promote a useful degree of testosterone suppression in a pre-op patient, and more importantly when administered in conjunction with estrogen, improve the feminisation attained compared to estrogen-only therapy, particularly in terms of breast weight and texture. One UK endocrinologist has claimed that progestogens have no effect in transsexual patients, however numerous studies both in the UK and elsewhere have demonstrated that this claim is false. Progestogens are now very widely used in conjunction with estrogens in the treatment of male-to-female Transsexualism. Progestogens may also lessen the risk of cancer associated with long-term estrogen treatment, according to some studies in natural-born females. In addition, some patients report that progestogens affect them psychologically, particularly in terms of maintaining the libido. For all these reasons, it may well be desirable to continue with a low dose of Progestogens post operatively, even though there is no absolute need for it. No reliable data exists regarding the incidence of breast cancer in transsexuals. Many are lost to follow-up and conceal their transsexual past after completing their treatment, and any instances of breast cancer in this group are likely to be recorded as occurring in normal women rather than transsexuals. One researcher has claimed to find a significant excess of breast cancers among certain chromosomally-intersexed patients who have been reassigned to female. A few patients experience androgenic effects from some progestogens, possibly including an increase in body hair. If this occurs, a different Progestogen should be tried. Similarly, if fluid retention occurs, a switch to an alternative drug will probably resolve it.

Medroxyprogesterone Acetate

This progestogen (trade name Provera) is normally used for treating irregular menstrual bleeding or endometriosis, and its safety record is good. It is widely regarded as the preferred progestogen, at least when the patient is not using combined contraceptive pills as a low-cost source of estrogen and progestogens. Some patients, however, report slight virilising effects including, occasionally, a return of some degree of male sexual function even in post-orchidectomy subjects, which can be found disturbing; it appears that a proportion of the drug may be metabolised into testosterone in some patients. Medroxyprogesterone acetate is generally less virilising than the testosterone-derived synthetic progestogens (e.g. norethisterone and levonorgestrel), but more virilising than dydrogesterone. If a patient experiences virilising effects with medroxyprogesterone acetate then a switch to dydrogesterone should be considered. A typical pre-op (or early post-op) dose (to maximize feminisation) would be 10mg in two doses; post-op 5mg or even 2.5mg may be sufficient to maintain the patient's libido.

Dydrogesterone

This progestogen (trade name Duphaston) may be used as an alternative to medroxyprogesterone acetate. It is not metabolised into testosterone within the body, and is therefore ftee of the virilising effects which some patients experience ftom other progesterones. Conversely it may be less effective in maintaining libido than medroxyprogesterone acetate. Dydrogesterone is regarded as the progestogen of choice when patients have experienced virilising effects from other progestogens. A typical pre-op (or early post-op) dose would be 20mg in two doses, reducing to a single dose of 10mg daily post-op.

Natural Progesterone 

USP This drug. which is probably unavailable in the UK, has a small but vocal group of transsexual adherents in the USA, who claim that it is superior to other progestogens. The present authors have been unable to find any clinical data to support this claim; while it appears to be free of virilising effects, first-pass effects are liable to make it relatively ineffective relative to dydrogesterone, which is also non-virilising. The main problem with 'Natural Progesterone' is that it is largely destroyed by the digestive tract and liver upon ingestion, so very large doses (hundreds of milligrams) are used. Since the precise percentage of the drug metabolised in this way is variable and unknown, the actual serum levels obtained are unpredictable.

Synthetic Progestogens This heading covers substances such as levonorgestrel and norethisterone, which are usually found in combined contraceptive tablets, usually with ethinyloestradiol. Contraceptive pills provide a useful low-cost source of feminising hormones for patients who have to pay for their own medications, but of course the patient is limited to the combinations of substances available, and cannot 'mix and match' as one can with separate estrogen and progestogen drugs. Care should be taken with some preparations (for example, Brevinor) as they contain too high a ratio of progestogen to estrogen, so that taking enough tablets to obtain a suitable dose of estrogen would result in a dangerously high intake of progestogen.
One combined tablet that has been used widely in the treatment of transsexual patients is Ovran; a typical pre-op dose of two tablets daily gives 100ug of ethinyloestradiol and 500ug of levonorgestrel. Most patients tolerate this well, and it generally produces satisfactory feminisation, but levonorgestrel appears (anecdotally) to give more frequent problems with water retention, hypertension and weight gain than medroxyprogesterone acetate. Safety fears have also been raised in the past about levonorgestrel-based contraceptive implants. Some patients experience virilising effects with norethisterone or levonorgestrel, which may impair the feminising effects of estrogen. If this is suspected then an alternative progestogen should be tried.

ANTIANDROGENS, GnRH AGONISTS AND ORCHIDECTOMY 

Hormone treatment in pre-operative male-to-female subjects is normally supplemented by some form of antiandrogen treatment. While oestrogens and progestogens are to some extent antiandrogenic in themselves, a number of other methods exists to suppress the effects of androgens and make the feminising hormones more effective without having to administer the latter in unreasonably high doses. These treatments also, of course, cause a significant reduction in male sex drive (and indeed sexual function), which is generally considered highly desirable by transsexual subjects. There are three approaches to antiandrogen treatment:
1 . Antiandrogen drugs. 2. GnRN (Gonadotropin-releasing-hormone) agonists. 3. Bilateral orchidectomy (castration).
These treatments are not applicable to patients who are post-operative, as their bodies will, by definition, be incapable of producing gonadal androgens. Adrenal androgens are produced in small amounts by both sexes, and no attempt should be made to suppress them unless a serum androgen test has indicated significant overproduction, as in cases of adrenal hyperplasia. In general it is considered unwise to administer antiandrogens to post-operative subjects (and indeed to severely hypogonadal subjects such as certain intersexed patients), as the small amount of adrenal androgens remaining in such subjects are necessary for normal functioning.

Antiandrogen Drugs These drugs either inhibit gonadal androgen production, interfere with androgen receptor sites, or both. Most are likely to produce some side effects in effective doses; some patients cannot tolerate some or all antiandrogen drugs, in which case bilateral orchidectomy is likely to be a preferable treatment. The effect of these drugs on fertility and male sexual function is reversible to an extent, however (like feminising hormones) irreversible infertility may ensue after some months of treatment. All antiandrogen drugs, like feminising hormones, must be withdrawn prior to major surgery This may lead to a degree of reversion towards masculinity, which may be pronounced and disturbing in some patients.

Cyproterone Acetate 

This drug (brand names Androcur, Cyprostat) is widely regarded as the antiandrogen of choice by practitioners in Europe (it is not approved in the USA). It is an androgen receptor antagonist and weak gonadal androgen production inhibitor;
normal dose is 50mg daily, which may be increased to 100 or in exceptional cases 150mg daily if required. In these doses there are some risks associated with the drug, particularly a heightened risk of thromboembolic disease or liver damage.
Carbohydrate metabolism changes are also reported; patients should receive regular blood tests (LFT and fasting glucose) and BP checks. Possible side effects include severe lassitude, loss of concentration and depression, also weight gain and nausea. Anecdotal reports suggest that the side effects can be lessened by taking the drug after meals; opinions differ as to the best time of day to take a single dose to minimise the tiredness effect: patients are best advised to experiment for themselves, though after lunch or after the evening meal seem to be the usual choices.

Flutamide 

This is a relatively new drug which has been used with success in some transsexual patients, particularly those who have experienced unacceptable side effects with cyproterone. There is relatively little clinical data available for this drug in transsexual patients. It is a strong androgen receptor antagonist. Like cyproterone it can be hepatotoxic, it can also have significant adverse haematological effects (reduced platelet, leukocyte or erythrocyte count) or cause hypertension, and it can also produce less serious side effects such as fluid retention. Regular LFTs and blood checks are advisable when using this drug. This drug also produces psychological side effects which can be severe in some patients. Depression, anxiety or nervousness can be extreme, and patients should be made aware of this possibility Lassitude, insomnia and gastrointestinal disturbances have also been reported. Typical dose is 250mg to 750mg daily (one to three 250mg tablets).

Spironolactone 

This drug was originally developed as an antihypertensive/diuretic; it is also a weak androgen receptor antagonist. It is much less effective as an antiandrogen than cyproterone or flutamide, but can find use in patients who have hypertension or severe fluid retention, either pre-existing or as a result of hormone treatment. Side effects may include lassitude, loss of concentration, and various gastrointestinal problems. There is a risk of potassium retention. Doses range typically from 100 to 400mg daily.

Finasteride 

This drug is not suitable as a general antiandrogen, but is mentioned here as it can be useful in countering male-pattern baldness in transsexuals. Classed as an androgen conversion inhibitor, it blocks the conversion of testosterone to DHT. It is generally ftee ftom significant side effects, but does not appear to affect male sex drive. Typical dosage is 5mg daily.

GnRH Agonists 

These drugs take a different approach to antiandrogens: they act on the pituitary, initially overstimulating it and then rapidly desensitising it to GnRH. The effect of this is that over a period of weeks, gonadal androgen production is greatly reduced. Their principal advantages are that they are generally fullly reversible in their effects, which makes them a useful treatment in adolescent subjects where it is desired to stall the changes of puberty but not desired to induce permanent feminisation until the subject is older; and that they do not carry the risks of thromboembolic disease associated with antiandrogens. This can be particularly useful when hormones/antiandrogens are withdrawn prior to surgery - GnRH agonist treatment can be used to minimise the reversion to male biochemistry that many transsexual subjects find deeply disturbing. GnRH agonists do carry risks of significant side effects and should be used with great caution. There is as yet relatively little clinical data on the use of these substances in transsexual subjects, particularly in long-term use.

Nafarelin 

Acetate Normally administered as a nasal spray (typical dosage 1600l.tg daily). May cause depression, insomnia. skin problems and other side effects. Being administered daily, the drug can easily be withdrawn should side effects occur.

Goserelin Acetate 

Administered as a depot (i.e. time-release) injection (typically 3.6mg monthly). Reported adverse effects include heart failure, obstructive pulmonary disease and severe allergic reactions as well as more minor side effects such as lethargy and nausea. In view of the fact that it is a depot injection, this drug should be treated with caution as it cannot be rapidly withdrawn should problems occur.

Leunrorelin Acetate 

Similar to Goserelin Acetate, with a typical dose of 3.75mg every 4 weeks. This drug has been used to good effect in adolescent subjects. Allergic reactions and other side effects have been reported.

Bilateral Orchidectomy 

Orchidectomy offers several advantages over antiandrogen or GnRH-agonist therapy: After orchidectomy, the patient is endocrinologically equivalent to a post-operative subject. This has clear safety advantages especially in patients thought to be at elevated risk of thromboembolic events. Some patients report transient lethargy as their body adapts to the loss of androgens, but all the side effects associated with antiandrogens or GnRH agonists are eliminated. There are some disadvantages to orchidectomy such as irreversibility and shrinkage of scrotal tissue. Bilateral orchidectomy normally requires a referral from a psychiatrist; some surgeons may require a second opinion from an independent psychiatrist.

This information sheet is based on the paper Transsexualism: A Medical Overview published by The Looking Glass Society in March 1998.