Treatment of the TS/TG Patient
By definition, the TS/TG (transsexual/transgendered) patient is one who for whatever reason has a desire to become the opposite sex. This is not a trip to be taken lightly, as there are severe psychological as well as physical and social changes that occur in the process.
While there are many physicians that will prescribe for a patient without any psychological background, there is ample evidence to support the notion that patients should be referred to psychological counseling as quickly as possible.
The Harry Benjamin Standards of Care, which have been designed by the American Psychological Association, are the most commonly followed soc. They call for psychological counseling for a minimum of three months before the patient is prescribed a course of hormones, as well as follow-up counseling by two different therapists over the course of at least a year. In addition, they also call for the patient to live in the gender in which they would like to change to for a minimum of six months. Under the reduction of harm clause, a physician may prescribe hormones for a patient who has been on a self-prescribed regimen of hormones without the three-month waiting period providing the patient provides satisfactory proof of having been on hormones previously. Satisfactory proof includes the patient providing the doctor with samples of the hormones taken, or bills of sale made out to the patient or evidence by physical examination that hormones have been taken; i.e. breast development, beard growth etc. There are those who feel the HBSOC is too restrictive, and perhaps in some cases it might be, but absent any other guidance it is better than nothing.
Of necessity, treatment of the transgendered person will be extended and often leads to a very trusting relationship. Treatment is empirical and is different for every patient. Manufacturers literature never has information regarding dosages that will cause feminization or masculization, as little literature is available. This leads to a cause and effect relationship in which the doctor prescribes a particular dosage, then waits for feedback from the patient in order to determine if the dosage is effective or needs changing. Especially in the beginning, the physician will be seeing the patient quite often to ascertain correct dosages.
It is important for the doctor to remember that the patient is also undergoing psychological changes at the same time as physical changes. The therapist that the patient will see will be encouraging the patient to live and act in the role in which he/she wishes to live. Accordingly, it is important to the psychological health of the patient that the doctor addresses the patient by the patient’s future name and/or gender when possible.
Treatment should not be started without a complete physical exam. This should include baseline blood work especially in the area of liver function. In both the male to female and female to male transition, it is the liver which is most stressed during the process. For male to females, it is helpful to have a baseline mammogram done as well.
Contraindications:
Any previous liver problems need to be carefully evaluated. If the doctor decides that the transition is possible patients with a history of previous liver problems will need to be carefully monitored.
Another area of concern involves the cardiac function. Estrogen in particular has the peculiar effect of often lowering blood pressure for a period of time and then raising it. It is a good idea to advise the patient on taking a daily blood pressure reading at home and recording it. Both the patient and the doctor will then be aware of any cardiac problems that might be occurring before serious damage can occur.
The physician should also be aware that the use of estrogen may mask an elevated PSA test, therefore manual examination of the prostate is often recommended as well. In addition, some physicians recommend that the patient go off of estrogen for 2 days before a PSA check, though many patients will be non compliant.
In taking the health history, it is also important to try to ascertain (if possible) any previous exposure to DES. This may help in alerting the doctor to possible genito-urinary complications that would not ordinarily come to light such as Mullerian duct remnants or previously undecended testicles. Urinary dyssynergia is also an indicator of DES exposure and is often misdiagnosed as BPH. (J. Urology (Apr 2001) 165 (3): 1305-1309). It also may make the doctor aware of possible estrogen hypersensitivity in some individuals.
Lastly, the physician should make it known to the patient that use of estrogen will eventually result in permanent sterility. Accordingly, patients of child bearing age would be well advised to bank their sperm for possible future use.
Treatment
Treatment of the female to male will show remarkable results in a very short amount of time. Treatment usually involves testosterone, either by injection and/or by mouth. Usually major results will be seen within 3 months as evidenced by deepening of the voice and growing musculature. It should be stressed to the patient that once the voice has changed there is no path back to the former voice. Most female to male TG patients will want to have a mastectomy. It is a good idea for the treating doctor to have available a list of surgeons who will perform this procedure on an elective basis. Final SRS (sex reassignment surgery) is a highly specialized procedure that is not entirely effective for the female to male. It is also quite expensive. Many female to male TG patients will be satisfied with a mastectomy and will not opt for the complete SRS usually do to the cost of the procedure.
Treatment of the male to female takes much longer than the female to male, but the results are likely to be much more satisfactory. Treatment usually involves use of an estrogen along with a testosterone blocker. At some point during the treatment, many of the patients will opt for an orchiectomy. It is advisable if the doctor has a list of urologist who will perform this procedure on an elective basis. Statistically speaking, it is estimated that of the TG patients that opt for surgery of some sort, 90% will be satisfied after the orchiectomy and will not pursue total SRS. Psychologically speaking, the male tends to associate the testicles with maleness, and removal of them seems to satisfy the majority of patients. For the
patient that desires full SRS, the operation is easily performed, and is available in the United States for a cost of $10,000 to 20,000 dollars. A great many patients that wish to have SRS are going to Thailand where the cost averages about $5500 dollars. Thailand is quickly becoming the elective surgery capital of the world, with the doctors frequently performing as many as 4 SRS per doctor in one week. Facilities are modern and up to U.S. standards.
Pharmacology
While there are few choices of medications for the female to male, there are many for the male to female. It is important for the treating physician to keep in mind that the objective is not to achieve a typical female hormone level, as that is generally no where near high enough to provide proper feminization, but rather to provide an elevated level of Estrogen in the body commensurate with safety as well as growth.
Estrogens
Perhaps the safest of the estrogens are the injectables. This is because they avoid the first pass through the liver, which occurs with oral meds. It can be argued that all meds eventually pass through the liver, which is true, however it is the first pass, which has the greatest potential to create thrombosis. The thinking in general is that the liver reacts to hormones as would the liver of a pregnant female, and creates clotting factors in preparation for birth. Small amounts of estrogen as found in a normal healthy female will not trigger this reaction, however in the treatment of the male to female patient levels commensurate with the 1st or 2nd trimester of pregnancy are not unusual. The following is a short quote from a medical journal.
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Am J Obstet Gynecol 1987 May;156(5):1326-31 |
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Efficacy
of transdermal estradiol.
Judd H.
Several side effects and risks associated with estrogen replacement therapy are
known to stem from the hormone's impact on the liver. With oral administration,
the enhanced action at hepatic, as compared with nonhepatic, sites is
presumably related to the so-called first-pass effect. Attempts have been made
to avoid this action by administering estrogen nonorally, but heightened
hepatic effects (comparable with those of other preparations) have nonetheless
been seen with both ethinyl estradiol and conjugated equine estrogens given
vaginally. We conducted a series of investigations aimed at evaluating the
effects of estradiol delivered via a transdermal patch. In a 50-patient study
of transcutaneous estradiol (25, 50, 100, or 200 micrograms/day) versus
placebo, a dose-dependent beneficial effect on objectively measured hot flashes
was demonstrated. A second study was designed to compare the effects of these
doses with those of 0.625 and 1.25 mg conjugated equine estrogen administered
orally. Effects on nonhepatic markers were similar for the 50 micrograms patch
and 0.625 mg tablet, as well as for the 100 micrograms patch and 1.25 mg
tablet. None of the doses of transdermal estradiol exerted any measurable
action on hepatic markers of estrogen action, whereas both doses of conjugated
equine estrogen demonstrated actions on both hepatic protein and lipid
synthesis. Our data clearly show that the transdermal administration of
estradiol circumvents the enhanced hepatic actions of the hormone. Possible
explanations for these results are presented.
Publication Types:
· Clinical Trial
· Controlled Clinical Trial
PMID: 3034062 [PubMed - indexed for MEDLINE]
The most commonly used injectable is Estradiol Valerate. Dosage varies from 20 to 50 mg I.M. every 7 to 14 days. Often by the 8th day, the estrogen level is dropping which causes mood swings not unlike PMS. It is advisable to make available transdermal patches, which the patient can use while waiting for the next injection. Estradiol Valerate is the least expensive form of estrogen available. If the patient can be taught to self inject and can be trusted to come in regularly for monitoring it is the medication of choice. Estradiol undecylate can also be used with a longer effective life, but can be very hard to obtain.
Transdermal patches are often used with patients that have had a history of liver problems. They are considered as safe as the injectables and have the advantage that if there is any adverse reaction removal of the patch will result in lowering of the estrogen levels within a few hours. Patches are the most expensive method of treatment, but are invaluable for smoothing out hormone levels and for treating the otherwise untreatable patient. Patches are usually dispensed as .1 mg and are often worn 2 at a time. The older reservoir type patches should be avoided as they often fall off. The Climara brand patches seem to work well, and last the entire week.
Tablets are commonly available and relatively inexpensive. They have the advantage that they are self administered, but also leave themselves open to being abused by the TG that wants faster results and may take more than a recommended dosage. The doctor should counsel with the patient that results will not happen any faster with a higher dosage. Several good articles have been written in medical journals on downregulation and tachyphylaxis, which is the situation which can occur when the estrogen receptors become over saturated with estrogen. For the scientifically inclined patient it might be of benefit to share this information with them. The most common form of estrogen used is Estradiol. Tablets which come in 1 and 2 mg doses. The most common script used is 2 mg. twice a day. For some patients this may need to be increased to 3 times a day.
For the patient that isn’t sure that they are TG, often a prescription of 2 mg. per day for a maximum of 3 months is given. If the patient responds well and feels that estrogen is proper for them, the doctor can then increase the dose. For the patient that finds the estrogen is not for them, effects will wear off relatively quickly and with no permanent loss of libido or ability to procreate.
It is also important to remember that once a patient has been on hormones for more than 6 months the effects are generally irreversible. This should not be interpreted to mean that the patient absolutely cannot impregnate a female, but that the chances of it happening are tremendously reduced in most males. Of course, there is always the one in a million that has been on hormones for years and still gets his wife pregnant.
Perhaps the most dangerous of the
estrogens and the one which should be steered away from at all costs is Ethynil
Estradiol. This product has a
lifetime in the body of about 28 hours. Therefore, as the patient takes this
product they are slowly building up to a very high dose by overlapping doses.
This drug also seems to have an extremely high amount of problems regarding
thrombosis. It has been suggested that this form of estrogen can cause as much
as a 60 percent increase in the chances of thrombosis.
Other tablets used are
Diane 35 and Premarin 1.25, with Premarin being prescribed the most often. It
has been estimated that Premarin causes a 3 fold increase in clotting factors
found in the blood. In addition, since it is a more expensive form of estrogen
and since some patients may have moral problems with its source, it might be a
good idea to steer patients away from it.
A commonly held theory is that the body has a finite amount of estrogen
receptors, which can become overloaded with any one type of estrogen resulting
in no further development. Often it is of value to alter the regime by changing
estrogens to prevent receptor overload.
The following quote it
from the National Institute of Health and discusses sublingual administration
of 17
beta-estradiol.
Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17 beta-estradiol. "OBJECTIVE: To investigate the pharmacokinetic profiles of different doses of micronized 17 beta-estradiol administered by oral or sublingual routes. METHODS: Single doses of micronized 17 beta-estradiol were administered orally (1 mg, 0.5 mg) or sublingually (1 mg, 0.5 mg, 0.25 mg) to six postmenopausal women in a randomized clinical trial. We calculated pharmacokinetic parameters for estradiol (E2) and estrone (E1) of maximum serum concentration, time to maximum serum concentration, terminalhalf-life, area under the concentration curve, and oral clearance. Serum levels of E1 sulfate also were compared at 4, 12, and 24 hours after dosing. RESULTS:Sublingual administration resulted in rapid absorption with significantly higher E2 levels than did comparable oral dosing. Estrone levels did not vary with route of administration but correlated with the dosage administered. Estrone sulfate levels correlated with the dosage administered and also tended to be higher with sublingual administration. Sublingual administration resulted in a significantly lower E1 to E2 ratio during the 24 hours than did oral administration. CONCLUSION: Sublingual administration of micronized 17 beta-estradiol results in a rapid, burst-like absorption into the systemic circulation, yielding high E2 levels that fall rapidly over the first 6 hours."
Many TG patients are also
prescribed an anti androgen. The most commonly prescribed drug is
Spironolactone – usually starting with 50 mg. per day, increasing to 100 over 2
weeks and then to 200 by the end of a month. Spironolactone has the advantage
of also offering some cardiac protection via its diuretic effect. Patients need
to be warned about its potassium sparing ability and told not to use salt
substitutes as well as avoiding bananas. In addition, the doctor needs to be
aware of other drugs the patient may be taking and possible interactions such
as with Lotensin which is also potassium sparing.
Another anti androgen,
which is considered the most powerful one made, is Androcur. This drug
interferes with LH causing the testes to shut down production of testosterone.
Normal testosterone production usually returns about 3 months after stopping
this drug. Some patients report sleeplessness or a sluggish feeling while using
this drug. This is not an FDA approved drug and must be purchased outside the
U.S. It is considered safe and is used in every other country in the world.
Lastly, Casodex has been prescribed for some patients in that
it totally blocks testosterone receptors while still allowing the testes to
produce testosterone.
Some patients react well
to the addition of prometrium or ultrogestan (micronized progesterone). Some
patients take it regularly, others skip estrogen during the last week of the
month and substitute progesterone, though there is no medical reason to mimic
the cycling of the natal female.
Progesterone seems to help with breast development and results in a more
rounded rather than pointed breast shape.
Many TG patients will report fragile nails that delaminate or split.
Progesterone seems to help with this as well. It is all but impossible to reach
a Tanner stage 4 or stage 5 without the use of progesterone.
Some doctors have
prescribed provera or depo-provera for their patients in an effort to save them
money. It is important to be very aware that these products have a history of
causing depression in some patients, which has been known to result in suicidal
tendencies. No such reactions have ever been reported with true progesterones.
Use of provera should be carefully monitored for signs of depression.
Perhaps one of the most
authoritative sites on the internet for treatment of the transgendered patient
is Dr. Ann Lawrence M.D. http://annelawrence.com/. Her site has a
tremendous amount of information on it, and she is a fully transitioned female
as well.
Assuming that the reader
does not have access to the internet, the following is but a small section of
her site regarding prescribing information.
For the record, I believe that taking hormones under medical supervision is by far the best and safest course. But I also believe that transsexual women who decide for whatever reason to take hormones without medical supervision ought to have as much information as possible to guide them. Here are my thoughts:
Some typically used initial estrogen dosages for pre-operative transsexual women who have not had an orchiectomy (castration) are as follows:
Oral estrogens:
Estradiol (Estrace®), 6 mg daily; OR
conjugated equine estrogen (Premarin®), 5 mg daily; OR
ethinyl estradiol (Estinyl®), 100 mcg (0.1 mg) daily; OR
Transdermal estrogen:
Estradiol (e.g., Climara® or equivalent), two 0.1 mg patches, applied simultaneously; OR
Injectable (intramuscular) estrogen:
Estradiol valerate (Delestrogen®), 20 mg IM every two weeks.
Occasionally half the suggested dosage may be sufficient; sometimes the dosage will need to be increased, rarely even doubled. Beyond a certain point, larger dosages will not increase tissue response, but will only cause more side effects.
Oral estrogens are most commonly used, and are typically very satisfactory. Among the oral preparations, I prefer estradiol. It is very inexpensive, and has low hepatic toxicity. Most clinical laboratories can perform estradiol blood levels; it is more difficult to obtain meaningful measurements of blood levels with conjugated equine estrogen or with ethinyl estradiol. Estradiol is also produced synthetically, without cruelty to animals; this is not the case with conjugated equine estrogen (Premarin®), which is prepared from the urine of pregnant mares.
Estradiol tablets can be taken sublingually (placed under the tongue to dissolve) instead of being swallowed. This may reduce possible liver toxicity, since with sublingual administration, much of the medication is absorbed directly into the blood stream, rather than being metabolized by the liver after first passing through the digestive tract. Less metabolism is also likely to result in higher levels of estradiol itself, and lower levels of its less-active metabolites, estrone and estriol. Micronized estradiol tablets are specifically designed for either oral or sublingual use, and dissolve quickly under the tongue without an unpleasant taste.
Premarin® is by far the most expensive oral preparation. One of its few advantages is its relative potency, which is notably higher than estradiol on a milligram-per-milligram basis. This is because some of the equine estrogens in Premarin, especially equilin, have higher biologic potency than the estrogens normally found in humans. Ethinyl estradiol is a chemically modified form of natural estradiol; the ethinyl substitution results in a longer duration of action, and greatly increased potency.
Transdermal estrogen causes less clotting tendency than oral estrogen, possibly important to some patients; but transdermal preparations are more expensive, and skin reactions to the adhesives employed are not uncommon. Injectable estrogen also causes less clotting tendency, and is less expensive. Its major drawbacks are the need to employ syringes and perform injections, and the somewhat greater tendency of injectable estrogen to increase serum prolactin levels. If the former is not a problem, and if the latter can be checked regularly, injectable estrogen can be a very good way to go.
If you have access to laboratory testing, a serum estradiol level of about 150 - 200 pg/ml -- about one-third to one-half the normal female mid-cycle peak -- is often considered ideal, at least for the first two years or so of feminizing therapy. I think that taking 81 mg of aspirin daily is a good precaution for persons taking oral estrogens, assuming no contraindication to aspirin exists. It is not necessary or desirable to "cycle" estrogen, or any other medication, in an attempt to mimic the normal female menstrual cycle.
In persons who have not had an orchiectomy, testosterone levels are also a concern. Although the desired reduction in testosterone can theoretically be accomplished with estrogens alone, the dosage required is usually in excess of what is needed for feminization. Adding an anti-androgen allows lower dosages of estrogen to be used; this is usually highly desirable. Typical dosages of anti-androgens are as follows:
Oral anti-androgens:
spironolactone (Aldactone®), 100 - 300 mg daily in divided doses; OR
cyproterone acetate (Androcur®), 100 - 150 mg daily.
Sometimes 100 mg of spironolactone may be sufficient, but 200 mg is a more typical dose. The Vancouver group uses up to 600 mg daily, apparently without problems. Spironolactone is fairly inexpensive, is readily available, and is usually quite well tolerated. Cyproterone is not available in the US, but is popular elsewhere. If you have access to laboratory testing, a serum testosterone level of about 5 - 85 ng/dl -- the normal female range -- is usually considered ideal. Within this range, lower numbers are not necessarily better.
Progestogens are usually given in an attempt to improve breast development. Based on limited anecdotal evidence, I think that improved breast development sometimes does occur, but it is usually not very significant. Progestogens can also inhibit testosterone, and are sometimes used for this purpose. Medroxyprogesterone, the most commonly used product, has the disadvantage of counteracting some of the beneficial effects of estrogen on blood lipids; some people also find that it causes mental irritability. Micronized ("natural") progesterone is an alternative, but it is more expensive, and sometimes hard to find without prescription. I consider progestogens to be optional, and usually unnecessary. If you decide to take them, here are some typical dosages:
Oral progestogens:
medroxyprogesterone (Provera®), 5 -10 mg daily; OR
Micronized progesterone (Prometrium®), 100 mg twice daily; OR
Injectable (intramuscular) progestogen:
Medroxyprogesterone (Depo-Provera®), 50 mg every two weeks; OR
Progesterone in oil, 50 mg every two weeks.
Following orchiectomy or SRS, anti-androgens can be discontinued, and the estrogen dosage can usually be decreased to one-half or one-quarter of the pre-op dosage, i.e.:
Oral estrogens:
Estradiol (Estrace®), 1 - 2 mg daily; OR
conjugated equine estrogen (Premarin®), 1.25 - 2.5 mg daily; OR
ethinyl estradiol (Estinyl®), 20 - 50 mcg (0.02 - 0.05 mg) daily.
As the reader can see, Dr. Lawrence does not have a prohibition on the administration of ethinyl estradiol. Other areas of disagreement are in dosages, with her recommendations for Estradiol being on the higher side and her dosages for Estradiol Valerate being on the lower side. In addition, recent discussion has led to the thinking that the post orchiectomy or post SRS patient should continue on the higher dose of estrogen for at least five to seven years. The thinking behind this is the genetic female has had a lifetime of estrogen whereas the TG still needs the higher levels to maintain growth. It has even been suggested that some genetic women would benefit from elevated levels of estrogen except for the obvious danger of uterine cancer which the TG does not worry about. Additionally, her suggestion about taking a daily aspirin, while of possible value in the older person for preventing angina, would have no value on reducing the clotting potential of the various forms of estrogen, as an entirely different clotting mechanism is at work which does not respond to the use of aspirin. In severe clotting situations, treatment with low molecular weight heparin has been of great value.
Another local resource is Dr. Becky Allison, who is a cardiologist and section head of cardiology for Cigna in Phoenix. Dr Allison is also a fully transitioned female and is an outstanding resource.
The following is taken from the site of Henk Asscheman, MD and Louis J.G. Gooren, MD . Henk Asscheman and Louis J.G. Gooren are both affiliated with the Division of Andrology/Endocrinology Free University Hospital, Amsterdam.
The following are selected excerpts.
HORMONE TREATMENT IN TRANSSEXUAL PEOPLE
Except for the sex chromosomes and gonads all bodily differences between men and women must be attributed to the actions of sex hormones. While the inherent tendency of the prenatal human organism is to develop along female lines, prenatal differentiation as a male depends on testicular hormones (Mullerian-inhibiting hormone and testosterone and its derivates). The wider bony pelvis in girls in comparison with boys is probably dependent on local effects of prenatal ovarian estrogen production. There is no known fundamental difference in sensitivity to the biological action of sex steroids on the basis of the genetic patterns of 46,XY and 46,XX.
The prepubertal period is hormonally relatively quiescent (Conte, Grumbach, Kaplan & Reiter, 1980). The hormones of puberty accentuate sex differences. Testosterone and its potent derivate 5alpha-dihydrotestosterone (DHT) induce penile growth and secondary sex characteristics as sexual hair, deepening of the voice, a muscular build and the greater average height in males in comparison to the females. In girls, estrogens in conjunction with progestagens induce breast formation and a fat distribution predominantly around the hips; subcutaneous fat padding produces a softness of the body configuration and of the skin. The skin in women is further generally less oily than in men; the latter on the basis of activation of the sebaceous glands by androgens.
Fundamental to sex reassignment treatment is the acquisition to the fullest extent possible of the sex characteristics of the other sex. With the exception of the internal and external genitalia, these characteristics are contingent of the biological effects of the respective sex steroids. Therefore (semi)synthetic sex steroids are indispensable tools in sex reassignment treatment. The use of cross-gender hormone treatment is associated with a better outcome (Hamburger, 1969; Leavitt et al., 1980).
The "two year real-life test" (Money & Ambinder, 1978) is pivotal in diagnostic-therapeutic approach of gender dysphoria. It allows both the gender-dysphoric subject and the psychologist/physician to examine whether sex reassignment relieves the burden of gender dysphorla. The emerging physical changes associated with cross-gender sex hormone treatment will facilitate the assumption of the role as a member of the other sex both in private life and in society.
The attempt to induce cross-gender sex characteristics in transsexuals-generally biologically normally differentiated males and females in their adult years-can be subdivided into two aspects:
1. Annihilation of sex characteristics of the original sex.
2. Induction of sex characteristics of the sex one reckons oneself to belong to.
1. Unfortunately, the annihilation of sex characteristics of the original sex is incomplete. In male-to-female transsexuals, there is no mode of treatment to revert earlier effects of androgens on the skeleton. The greater height, the shape of the jaws, the size and shape of the hands and feet, and the narrow width of the pelvis can not be redressed once they have reached their final size at the end of puberty. Conversely, the relative lower height in female-to-male transsexuals (in the Netherlands an average of 12 cms) and the broader hip configuration will not change under the influence of hormonal treatment.
2. While in the majority of female-to-male transsexuals, a complete and inconspicuously masculine development can be induced with androgenic hormones, the effects of feminizing hormone treatment in male-to-female transsexuals can be objectively unsatisfactory with regard to reduction of male-type of facial/beard hair and induction of breast development.
Transsexuals often expect and sometimes demand rapid and complete changes immediately after the start of the hormonal therapy. The induced effects of cross-sex hormones are, however, limited and appear only gradually. Before starting hormone treatment a clear discussion of the possible changes and the limits in an individual patient, is indispensable in order to prevent unrealistic expectations. In the next and following sections we describe the effects of cross-gender hormones separately for male-to-female and female-to-male transsexual subjects.
Which Hormones and Which Dose?
For each of the above-mentioned aspects of hormone treatment exists a large array of (semi) synthetic sex steroids. There are no solid literature data to prove certain hormonal drugs superior in efficacy to others. Only two published studies give an indication of the value of different hormone schedules in the treatment of transsexuals, but the results are far from conclusive (Meyer et al., 1981 & 1986). The choice of hormonal drugs in the treatment of transsexualism depends on availability (national regulations, pharmaceutical marketing), local traditions, side effects, route of administration, cost and folk belief (in particular from the side of the transsexual subject and his/her peer group, but also from the physician). Optimal dosages of these drugs have not yet been established.
The first effects of the cross-gender sex hormones appear already after 6 to 8 weeks (Futterweit, 1980). Voice changes in female-to-male transsexuals and the development of painful breast noduli in male-to-female transsexuals are the first manifestations. Thereafter the changes take over 6 to 24 months and even longer before they are complete (beard growth may take 4 to 5 years in androgen-treated female-to-male transsexuals).
Cross-Sex Hormone Treatment in Male-to-Female Transsexuals
Annihilation of Male Characteristics
In male-to-female transsexuals suppression of the original sex characteristics can be obtained by compounds that exert directly or indirectly an antiandrogenic effect. Androgens are for their production dependent on stimulation by the pituitary hormone luteinizing hormone (LH), which, in turn, is stimulated by the hypothalamic hormone luteinizing hormone-releasing hormone (LHRH). The biological action of androgens is contingent on their interaction with hormone receptors in the body's tissue cells. Interference with any of these mechanisms will lead to a decline of the biological action of androgenic hormone….
Following orchiectomy we try to reduce or terminate antiandrogen therapy. Sexual hair growth is clearly dependent on androgens for its initiation and it would be logical to believe that antiandrogens are redundant following orchiectomy. Though not verified by research data, patients claim that also after orchiectomy their sexual hair growth is still reduced by antiandrogens. Due to the much shorter life cycle of sexual hair on the trunk, arms and legs as compared to the face and the greater density of hair follicles in the beard area, beard growth is not reduced to a cosmetically acceptable degree by antiandrogens. Other measures like depilation by electrolysis are needed. Those subjects who are young enough to have no significant beard development or whose racial background provides them with little or no beard development, are not in need of antiandrogens for this purpose.
Induction of Female Characteristics
The principal feminizing hormones are estrogens. Estrogens alone can induce most typical female characteristics as has been shown in cases of Turner syndrome in which the ovaries fall to produce hormones. A second sex steroid produced by the ovaries is progesterone. It prime function is to prepare the uterine mucosa for nidation. Its feminizing effect is probably limited, but effects of breast tissue have been described. Meyer et al. (1986) found no difference in breast hemi circumference between male-to-female transsexuals who had used estrogens only and those who had used both estrogens and progestagens, but this study was not a randomized double-blind clinical investigation.
It has been suggested that "unopposed action of estrogens" (by progestagens) would constitute a risk factor for carcinomas of the breast and there are epidemiological data in support of this. On the other hand studies in users of oral contraceptives have suggested that progestagens play a role in breast cancer development, though oral contraceptives overall are associated with a reduced risk of breast cancer. Three cases of breast carcinomas in male-to-female transsexuals have been published but it is difficult to arrive at statistically reliable conclusions on risks since the total number of users is unknown and no data are available on what estrogens and how long these three subjects have been taking this medication. Of note is the fact that breast carcinomas have not been observed in men with prostatic carcinoma taking high doses of estrogens but the follow-up may have been too short in view of their lethal disease. Male-to-female transsexuals should be informed about this risk factor. As with the general female population, they should receive information on self-examination of their breasts. At medical checkups their breasts should be physically examined and if palpation is suspect, mammography and eventually biopsy should follow. The fact that transsexuals have often breast implants may impede physical (self) examination of the breast. In our population of more than 500 hormonally treated male-to-female transsexuals (follow-up 0-20 years with an estimated median of 6.5 years) we have not come across a case of breast carcinoma.
In terms of estrogenic effects there is no superior estrogen. The choice depends mainly on availability, costs and the preference of the subject. Careful clinical studies on side effects in the form of randomized double-blind placebo-controlled studies with different estrogens are non-existent. The chemical formula and the route of administration lead to substantial differences in characteristics of estrogenic drugs. All oral estrogens first pass the liver after intestinal absorption and exert an effect on liver metabolism, evidenced by their effects on lipids, clotting factors and renin The liver metabolism of estrogen is also related to the chemical formula of the estrogen. Ethinyl estradiol is slowly metabolized whereas l7beta-estradiol is broken down rather rapidly, explaining the 10-20 fold difference in daily dosage. Concomitant drug use (anti-epileptics) may induce a more rapid metabolism of estrogens.
1. Ethinyl estradiol (LynoralR), 50 µg orally twice (or more) daily, is the most potent estrogenic drug. It is a chemical modification of 17ß-estradiol, the main estrogen of the body, and it is slowly metabolized by the liver, but has a large effect on other metabolic pathways in the liver. It is very cheap, easily available worldwide and often used by male-to-female transsexuals because it can be obtained from women friends or without prescription in many countries as the oral contraceptive pill (always combined with progestagens). In the current estradiol assays its presence is not measured but the resulting suppression of gonadotropins suggests its use. A specific assay for ethinyl estradiol is commercially available.
2. "Natural" estrogens, which are not natural but metabolized estrogens from other species (pregnant mare urine) are more appropriately called conjugated estrogens (PremarinR and other brands). Active dose in postmenopausal women is 0.625-1.25 mg, but for cross-gender hormone therapy the active dose is 5-10 mg (Meyer et al., 1986). They are largely metabolized at first liver passage. It is said that they have less side effects than other estrogens. However, the supporting scientific evidence is very weak and in trials of secondary prevention of myocardial infarction in men, conjugated estrogens in a dose of 2.5 and 5 mg orally per day are clearly associated with an increased risk of thrombosis. Paradoxically, low doses appear to reduce the risk of cardiovascular disease in postmenopausal women.
3. 17ß-Estradiol (or in short estradiol) is the most potent of the three forms of native estrogens in the human body. It is produced synthetically and can be administered orally (progynovaK, EstrofemR, ZumenonR 2-4 mg per day) metabolized in great part at first liver passage, intramuscularly (progynon-DepotR 20-200 mg per month) or transdermally (Estraderm TI'SR 100 µg, patches are replaced twice weekly). In particular, this latter form is very promising because of its low number of estrogen-induced side effects.
However, its efficacy in cross-gender hormone treatment has not been fully determined (a study is in progress at our clinic). A considerable number of patients (±10%) have skin problems at the application site and its sticking qualities can be a problem in patients that perspire easily or in a hot climate. Another obstacle is the price (US$ 1.00 per day), it is the most expensive estrogen therapy.
4. Estriol (Synapause E3R, OvestinR 2-6 mg orally per day) is a less potent native estrogen that is used in postmenopausal women for atrophic vaginitis and for urinary problems. In cross-gender hormone treatment high doses are necessary and estriol has no advantages over estradiol for this indication.
In our clinic ethinyl estradiol 100 µg orally per day has been the standard treatment for all male-to-female transsexuals until recently. With the introduction of transdermal estrogen we have changed our policy because of the frequent occurrence of thromboembolism in patients over 40 years of age (12%, Asscheman, Gooren & Eklund, 1989). All new male-to-female transsexuals older than 40 years are treated with Estraderm TTSR 100 µg two patches per week from the start. Younger patients are offered the same possibility but they are informed that their risk of thromboembolism is much lower (2.1%) and ethinyl estradiol 100 µg is proposed as an alternative. Intramuscular estrogen depots are not routinely given for two reasons. First, in case of side effects, not infrequent with estrogen therapy, it can take weeks before the serum levels of estradiol have normalized and second, male4o-female transsexuals tend to abuse estrogens under the wrong assumption "the more the better." We have seen subjects who used 800 mg progynon~DepotR, intramuscularly, per week with sometimes serious side effects (Gooren, Assies, Asscheman, de Slegte & van Kessel, 1988). With oral administration abuse is also not uncommon, but the doses are not so extreme.
Cross-Sex Hormone Treatment in Female-to-Male Transsexuals
Annihilation of Female Characteristics
The effects of estrogens on physical characteristics cannot be annihilated by antihormones. Antiestrogens administered to eugonadal women stimulate gonadotropin and subsequently ovarian hormone secretion. Theoretically, LHRH antagonists could be used. The objections have been mentioned earlier.
Transsexuals very much appreciate that their menstrual periods are terminated. This can be accomplished by progestagens with their antigonadotropic properties: medroxyprogesterone acetate (ProveraR, FarlutaiR) 5 mg 1 ~ 2 tablets/day or 150 mg intramuscularly/3 months, lynesterol (OrgametrjiR) 5 mg or norethisterone (Primolut NR) 5 mg both 1 or 2 tablets/day. Androgens to be discussed in the next section have in high dosages also antigonadotropic action. There is no clear advantage in the combination of the two hormones unless androgens alone suppress menstrual bleeding in-sufficiently.
Induction of Male Characteristics
Androgens exert a powerful effect on the virilization process but completion may take as long as 24 years and sometimes even longer. The individual outcome depends on genetic factors both familial and racial. The degree of hairiness of siblings is a fair predictor of the virilization process.
To be used are testosterone esters 200-250 mg/2 weeks intramuscularly. Their brand names vary from place to place (SustanonR, TestovironR). As oral androgens testosterone undecanoate can be mentioned (AndriolR) 160-240 mg/day, not available in the USA. With the latter preparation, menstrual bleeding is insufficiently suppressed in 50% of the patients and addition of a progestagen is required. The use of oral androgens with an alkyl group in the 17a position of the molecule is obsolete due to its hepatotoxicity. Oral androgens as mesterolone and fluoxymesterone are too weak for the induction of virilization.
In approximately 50-60% of the female-to-male transsexuals acne will occur. In 10-15% it is rather serious requiring dermatological treatment. It is now certain that androgen treatment has an unfavorable effect on the lipid profile. It places female-to-male transsexuals in the risk category of men. Therefore they must be advised not to smoke, to exercise moderately and to prevent over-weight and high blood pressure.
Effects of Cross-Gender Hormones in Male to-Female Transsexuals
Annihilation of the male pattern is possible for a number of secondary sex characteristics but only to a limited extent. Reduction of androgen-dependent hair growth with cyproterone acetate and ethinyl estradiol is fairly effective on the trunk and the limbs, but has a very limited success m the face. The body hair does not disappear but following suppression of androgen-dependent growth, the hair becomes less coarse and less visible, resembling the vellus hair on the female body in certain body regions. If hairlessness of the body is desired, only electrolysis is effective. Waxing and shaving can result in temporary hairlessness, which can be prolonged by the decrease in hair growth associated with estrogen and antiandrogen treatment. The beard hairs also become thinner and softer after several years of hormone use. Unfortunately, once the beard growth has fully developed and regular shaving is necessary, the result of antiandrogens alone is cosmetically unacceptable. Only electrolysis is effective in eliminating beard growth. In a few patients who had started treatment before developing visible hair growth, electrolysis could be avoided. After starting hormone treatment, male type scalp hair loss (masculine alopecia) ceases. Re-growth of scalp hair on bald areas is incomplete and of the vellus type. Hairstyle, hair implants or artificial hair techniques ("weaving," partial wigs) can successfully mask the masculine alopecia while hormones can at best make a minor contribution.
Penis length is not reduced by hormones, but due to its almost continuous flaccid state and an increase in lower abdominal fat, may appear reduced. Spontaneous erections are suppressed within 3 months but during erotic arousal erections still occur in the majority of our patients, evidencing the relative androgen-independence of this type of erection. Testicular volume is reduced by 25% within the first year of hormone use. This reduction is appreciated as a sign of progress and also makes hiding of the male genitals easier.
Induction of female characteristics is quite variable. In the initial phase of estrogen therapy, subareolar nodules which can be painful (Futterweit, 1980), are common. The breast size can be quantified by measuring the maximum hemi circumference over the nipple with a flexible ruler (either in the supine position or sitting which is our method). The increase in breast size evolves gradually with often periods of growth and periods of apparent standstill. The mean hemi circumference after 1 year is 10 cm in the supine position and 14 cm in the sitting position (the latter varies from 4 to 22 cm in our patients) and reaches its maximum after 18 to 24 months. In our patients the mean value is 18 cm, but it can vary from 4 to 28 cm. For comparison: in biological females it varies from 12 to 36 cm with a mean of 22 cm (own unpublished observations in a small number of these women). The values in male-to-female transsexuals are several centimeters less than in biological women. Moreover, the width of the male thorax is in general larger than that of the female thorax. Consequently, the proportional effect is judged as unsatisfactory by almost 50% of the male-to-female transsexual subjects. The majority of those unsatisfied requests surgical breast implants. In more than 50% of the male-to-female transsexuals, the estrogen-induced breast size is judged as satisfactory by the transsexual subject herself, obviating breast surgery. In a small number of subjects unilateral or bilateral subcutaneous mastectomy has been performed because of pubertal gynecomastia. The hormonal effect on operated breasts is nil. In the latter cases early breast implants are indicated, but we prefer to wait at least one year before recommending any surgery including breast surgery.
In male-to-female transsexuals, estrogens do not affect the pitch of the voice, and a low voice can be a great handicap. Speech therapy is necessary to achieve a more feminine vocal range. Vocalcord surgery does not obviate the need for speech therapy in almost all cases, but the resulting higher pitched voice facilitates a female public presentation.
The subcutaneous and intra-abdominal fat distribution is sex steroid-dependent. Males preferentially accumulate fat in the upper abdomen ("apples") and females around the hips ("pears"). Estrogen treatment results generally in more fat around the hips but this is not the rule and can vary largely. Skeletal structures like jaws, size of hands and form of the pelvis do not change with the estrogen and/or antiandrogen treatment.
Not infrequently male-to-female transsexuals complain of a dry skin and fragile nails. This is a consequence of the reduction in sebaceous gland activity following antiandrogen treatment. Avoidance of detergents and application of ointment is mostly helpful.
Effects of antiandrogens alone or in combination with estrogens on the mood and the emotional functioning are often reported by our patients and their partners. Definitive scientific proof in transsexuals that they are hormone-related is not available, but it is likely. In view of the consistency of these subjective reports and some studies in hypogonadal patients after substitution with appropriate hormones, an effect of hormones on the brain and consequently on brain functions like mood, is highly plausible.
Effects of Cross-Gender Hormones in Female-to-Male Transsexuals
Generally the virilization process proceeds subjectively and objectively in a satisfactory way and female-to-male transsexuals are pleased with it. It has no effect on their breast size. An oily skin and acne may become a problem. In comparison to other men they are rather short, but a short man is less conspicuous than a tall woman. The clitoris enlarges in all subjects though in a different degree. It sometimes suffices to have vaginal intercourse with a female partner, but that is not the rule. Most subjects indicate an increase of their libido following androgen treatment. Like male-to-female transsexuals female-to-male transsexuals must continue androgen treatment after ovariectomy to prevent hot flashes, loss of male characteristics and above all osteoporosis.
SIDE EFFECTS OF CROSS-GENDER HORMONE
Few systematic studies on side effects of cross-gender hormone treatment in transsexuals have been published. Meyer et al. (1986) found in 90 transsexuals only liver enzyme abnormalities and mild elevations of serum cholesterol and triglycerides. Case reports have described pulmonary embolism, cerebral thrombosis, myocardial infarction, prostatic metaplasia, and breast cancer in estrogen-treated male-to-female transsexuals and recurrent myocardial infarction in a female-to-male transsexual treated with androgens.
In 1989 we published a retrospective study on mortality and morbidity in 303 male-to-female and 122 female-to-male transsexuals who have been treated and followed at our clinic for 6 months to more than 13 years (Asscheman, Gooren & Eklund, 1989). Mortality in male-to-female transsexuals was 6-fold increased compared with the general population. This was in particular due to suicide and death by unknown cause. No deaths occurred in the female-to-male group but the median age was much lower. Side effects were common in the male-to-female transsexual patients. Significant increases were observed for venous thrombosis pulmonary embolism, depressive mood changes, hyperprolactinemia and elevated liver enzymes in the male-to-female transsexual patients. In the female-to-male group acne (12.3%) and weight increases > 10% (17.2%) were the main side effects. Many side effects were reversible with appropriate therapy or temporary discontinuation of hormones.
The occurrence of serious side effects (e.g., the prevalence of thromboembolic disease of 2.1% in patients below 40 years of age and 12% in patients above 40 years) was, however, not rare. In view of the needs of transsexuals these side effects present a difficult dilemma in hormonal gender reassignment. At present no firm guidelines can be given. The cornerstone of the decision to prescribe cross-gender hormones remains with the explanation of the possible side effects to the patients and careful clinical judgment.
Efforts to reduce the risk of thromboembolic events by transdermal administration of estrogen are very promising but not conclusive at this moment. Further follow-up of this relatively young population to disclose long-term side effects is required.
CONCLUSION
Hormones are indispensable tools for the induction and maintenance of the characteristics of the sex the transsexual reckons him/herself to belong to. Following sex reassignment surgery they are hypogonadal and they must receive in principle lifelong hormone replacement in the same fashion as other hypogonadal patients. The main goal is to prevent future osteoporosis manifesting itself in the fifth and higher decades of their lives.
REFERENCES
There are literally hundreds of resources available on the internet for any possible needs of the transgendered patient.
My personal regimen before orchiectomy
I was using Estradiol Valerate I.M. 40 mg (1 CC) every 10 days.
As the level drops beginning on the 7th day I supplement with Climara patches to keep the level reasonably steady and remove the patches 2 days after injection as the EV does not take immediate effect. In addition, I also take 200 mg Prometrium at bedtime. Taking it at bedtime avoids the side effect of sleepiness. For an antiandrogen, I take 50 mg Androcur and 100 mg Spironolactone.
This gives me an estradiol level which is comfortable, controllable and safe while producing the desired results. Consultation with doctors who are familiar with TG issues has revealed that the most difficult time of transition occurs during the first 6 to 9 months, with the greatest risk of thrombosis being at that time. As the body becomes used to feminizing, the risk becomes no greater than that of a natal female, with the exception that there is obviously no risk of endometrial problems.
My personal regimen after orchiectomy
I was using Estradiol Valerate I.M. 40 mg (1 CC) every 7 days. I also take 400 mg Prometrium at bedtime. I do not use any antiandrogen except for taking 1 mg finesteride as a blocker of DHT. I plan to continue this exact same regimen after my SRS.