Important note: Information in this article was accurate in 2006. The state of the art may have changed since the publication date.
Translated by Act-Up-Paris from the French version of May 10th, 2006
Dr. Nicolas Hacher, Endocrinology and Diabetes Department of Metabolic Diseases and Sterility
Interactions between antiretroviral drugs (ARV) and estrogen-progestogen combinations, which are substrates of cytochrome P450 CYP3A4, are presently well-known and are possibly associated with a risk of over or under dosage of hormonal levels, depending on the occurrence of enzyme inhibition or induction. On the other hand, there are few data on these kinds of interactions with the variety of hormonal treatments prescribed to transsexuals who are HIV positive, whether they take estrogens, anti-androgens or androgens. And yet the issue deserves to be raised insofar as this population often presents with multiple pathologies associated with multidirectional drug interferences. In addition to the risks associated with alterations in hormone levels, one must add the glucide and lipid metabolic disturbances that combine with those induced by ARV drugs, the risk of thromboembolism, as well as hepatic toxicity. All these risks are further increased by the frequent practice of self-medication, which involves unsuited products and doses.
Transsexualism is an idiopathic disorder of gender identity, characterised by the full and irreversible feeling of belonging to the opposite sex associated with suffering and the desire for medical attention, a situation that can lead to surgical gender reassignment. There is no absolute consensus for health care monitoring, only guidelines such as those provided by the Harry Benjamin International Gender Dysphoria Association and its "Standards of care for gender identity disorders, sixth version, February 2001" (www.hbigda.org/soc.htm).
1. Hormonal treatments
Before surgical gender reassignment, the aim of hormone treatment is to begin transforming the body in order to conform with the psychological sex. In addition to its importance for pursuing this transformation, hormone treatment also preserves bone integrity and prevents cardiovascular complications following surgery.
1.1 Male to female transgender women
1.1.1 Anti-androgens
There are four different types: non-steroidal, steroidal, 5-alpha reductase inhibitors and GnRH agonists (chemical castration).
Before surgery, only cyproterone and spironolactone are used in France for male to female transgender reassignment.
1.1.2 Estrogens
As a reminder, ethinyl-estradiol (EE) is especially used in many foreign countries at doses ranging from 50 to 100 micrograms per day per os (oral administration).
The current trend is to prescribe 17 beta estradiol, whether per os at 1 to 2 mg per day, as a daily or weekly transdermal patch or as a gel delivering 0.5 to 0.75 mg per application (1 to 3 per day).
1.1.3 After surgical reassignment
Estrogens are maintained and cyproterone can be replaced by natural progesterone, thus providing the equivalent of a treatment for hormonal substitution.
1.2 Female to male transgender men
The compounds used are:
In certain pre-operative cases, a synthetic progestogen can be added for amenorrhoea. Only testosterone is kept post-surgery.
2. Interactions
2.1 Induction - inhibition of cytochrome P450 by ARV drugs (protease inhibitors and non-nucleoside reverse transcriptase inhibitors)
The type of effects described for the alteration of ethinyl-estradiol levels with contraceptive pills cannot necessarily be carried over for the compounds used by transsexuals, since there are few data regarding the interaction between hormones (natural estrogens, cyproterone, testosterone) and ARV drugs. In any case, such combined treatments can lead to the same hormonal fluctuations as observed with ethinyl-estradiol. ARV treatment should be initiated with caution - all the more so with ARV drugs known to inhibit cytochrome P450 - and should involve low doses of natural estrogens and CPA (cyproterone acetate) for male to female transsexuals, and testosterone for female to male transsexuals. In practice, it is essential to monitor the levels of plasmatic estradiol, with the aim of reaching a level equal or superior to 60 picograms per mL (the minimal level to prevent bone loss and ensure cardiovascular protection), while allowing a suitable feminization. CPA at a dose of 50 milligrams per day does not give rise to any problems, no more so than testosterone at usual doses whatever the mode of administration.
The complexity of these kinds of interactions is proportional to the number of compounds involved, in particular those that have effects on the induction or inhibition of cytochrome P450 : IPP, Rifampicine and Rifabutine, Ketoconazole, anti-comitial compounds [for epilepsy], Methadone, Griseofuline, Glitazone, Hypericum Perforatum, statins. For the latter, special caution should be taken (in particular with Lovastatin and Simvastatin), which should not be given concomitantly with protease inhibitors (especially with ritonavir). Otherwise, there will be increases of up to 3000% in their circulating levels and of 343% in Atorvastatin, with a risk of rhabdomyolysis.
We should note, however, that the interaction effects are not always detrimental. This is observed in the case of Ritonavir, whose enzymatic inhibitory effect is associated with the strengthening of the action of protease inhibitors taken concomitantly during antiretroviral therapy (boosting effect).
2.2 Cumulative metabolic effects
It is important to take metabolic effects into account in the short and long terms: acute pancreatitis, thromboembolic complications and coronary diseases.
2.2.1 Glucide abnormalities
More than 50% of patients treated with protease inhibitors present with a spectrum of glucide disorders, ranging from hyperinsulinism-insulin resistance to insulin-dependent diabetes with or without metabolic syndrome. It is known that protease inhibitor, especially Indinavir, have a direct inhibitory effect on the glucose transporters GLUT4, associated with an effect on adipose tissues. Gooren et al. (1994) studied the effects of ethinyl-estradiol in men and testosterone in women, by using the assay of a hyperinsulinemic-euglycemic clamp before and 4 months post hormonotherapy. The study involved 13 female-to-men transsexuals receiving esters of testosterone (250 mg every two weeks) and 18 male-to-female transsexuals receiving either ethinyl estradiol alone (0.1 mg per day, orally) or associated with CPA (100 mg per day, orally). It showed that insulin-resistance was induced by these treatments. This effect will be added to those produced by protease inhibitors. In this study, the biological men receiving ethinyl estradiol exhibited a decreased insulin-sensitivity in spite of a reduction in testosterone levels. Insofar as testosterone injections induce an insulin-resistance in women, an increase in insulin-sensitivity was expected when testosterone levels were clearly diminished. Two hypotheses may explain this apparent paradox: first of all it can be argued that the effects of reduced testosterone levels on insulin-sensitivity were less potent than the effects of increased estrogen levels; the second hypothesis involves a difference in response to testosterone as a function of sex, testosterone inducing insulin-resistance only in women. All of this points to the difficulty in predicting what will happen in the transsexual population from the pharmacological knowledge derived from iso-sexual hormonal treatments. There is indeed something peculiar to cross-treatments. Contrary to the effect of ethinyl estradiol, however, estradiol 17 beta has opposite effects at physiological doses : lowering of glycaemia on an empty stomach, reduction of HbA1c, of diabetes occurrence, whatever the mode of administration, orally or percutaneously. On the other hand, CPA, a derivative of 17-hydroxy-progesterone, is a factor for insulin-resistance, but it can be compensated for the natural estrogens that are associated with it.
Such glucide metabolic disorders must be taken care of according to the present recommendations in diabetes research, with the aim of lowering HbA1c below 6.5%, and by treating the factors responsible for other cardiovascular risks. This implies a therapeutic escalation that must always involve counselling on a hygienic diet, associated if needed with oral anti-diabetes treatment and insulin-therapy. Among oral anti-diabetes compounds and their potential associations, a particular emphasis can be put on the additional benefit of glitazones (rosiglitazone and pioglitazone) for lipoatrophies linked to HIV, through an increase in subcutaneous lipogenesis to the detriment of visceral fat.
2.2.2 Lipid disorders
Hypertriglyceridemia (in 35% of cases) and hypercholesterolemia (in 25% of cases) predominate. It is essentially ritonavir that causes the most pronounced effects (increase in hepatic production of VLDL and decrease in their clearance by LPL) on triglycerides. Once again, there are potential cumulative effects associated with the cross-hormonal treatments taken by transsexuals. With the mixed hyperlipidemia associated with ARV treatments, among which hypertriglyceridemia predominates, comes the possible effects of cross-hormonotherapies specific to transsexuals, the effects of which are all the more profound given that they involve oral ethinyl estradiol at a dose of 50 to 100 microgram per day, as shown by the study of Gooren et al. in 2003. This study involved 20 male to female and 17 female to men transsexuals receiving, respectively, CPA at 100 mg plus ethinyl estradiol 100 micrograms and testosterone at 250 mg every two weeks intramuscularly. Whereas the association between CPA 100 mg and estradiol 100 micrograms enabled an increase in HDL and a decrease in LDL, something beneficial, it nevertheless increased the triglyceride levels, arterial pressure, visceral and subcutaneous fat and decreased the size of LDL particles, as well as insulin-sensitivity, all of this being detrimental at the cardiovascular level. As for testosterone, it decreased HDL levels and the size of LDL particles but increased triglyceride levels and the activity of the hepatic lipase. There was also an android distribution of fat to the benefit of visceral adipose tissues. Arterial tension, total cholesterol and LDL levels, the activity of the hepatic lipase and insulin-sensitivity were practically unaltered. These results should lead us to use, as often as possible, natural estrogens, percutaneously and at the same doses used in the treatment for hormonal substitution after menopause, especially in patients using protease inhibitors. As indicated above, the dosage of plasmatic estradiol is necessary to reach a level ranging from 60 to 70 picograms per millilitre. Natural estrogens induce a decrease in cholesterol, LDL and lipase activity, as well as an increase in HDL. On the other hand, this increase in HDL is more important when compounds are taken orally as compared to the percutaneous administration. Finally, there is a slight increase in triglyceride levels orally, but not percutaneously.
2.2.3 Venous thrombosis and thromboembolic complications
Thromboembolic complications are potentially life-threatening and preventing them is of great importance. Their incidence in male-to-female transsexuals receiving ethinyl estradiol orally is significantly higher than with percutaneous 17 beta estradiol, whether it is associated with cyproterone acetate or not. The 2003 study by Gooren et al. showed that this difference was due to the specific effect of ethinyl estradiol on haemostasis factors. Cyproterone acetate alone, the association between percutaneous estradiol and cyproterone acetate, or oral estradiol plus cyproterone acetate had few effects on haemostasis factors, whereas ethinyl estradiol induced an important increase in resistance to activated protein C (p < 0.001), a slight increase in protein C levels (p < 0.012) and a significant decrease of 30% in total and free protein S. The difference between the effects of oral ethinyl estradiol and oral 17 beta estradiol proves that it is a difference at the molecular level rather than the consequence of first-pass effects in the liver. This explains why male-to-female transsexuals receiving oral ethinyl estradiol have a higher risk of developing thromboembolic accidents than those receiving percutaneous estradiol. On the contrary, testosterone prescribed to female-to-male transsexuals induces an anti-thrombotic effect.
3. Conclusion
Taking care of the diverse metabolic disorders linked to ARV treatments and the HIV infection have been thoroughly addressed in former publications and will not be further detailed in this report, which aims at studying the specificities for transsexuals and their medication.
The unique aspects of monitoring the health of transsexuals treated with ARV drugs lie in the cross-hormonotherapy that characterises them and can lead to multidirectional interactions and secondary effects. Caution should be exercised with protease inhibitors inhibiting cytochrome P450 (efavirenz, indinavir) and with the associated risk of increasing the hormone levels. It is clear that preference should be given to the use 17 beta estradiol percutaneously and that ethinyl estradiol should no longer be used by populations at cardiovascular risk. For those suffering from diabetes, glitazones should be studied in terms of potential benefit for lipoatrophies. Hypertriglyceridemias insufficiently controlled by fibrates may benefit from the addition of nicotinic acid (Niaspan), active to reduce both VLDL and LDL and increase HDL. Also, numerous protocols analysing the effects of replacing protease inhibitors by non nucleoside or nucleoside reverse-transcriptase inhibitors seem promising. The objective for these patients, besides feminization or masculinization, is to maintain antiretroviral efficiency, to prevent short-term thromboembolic complications and long-term cardiovascular accidents.
References
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