Guest Writers Hélène Hazera of Act-Up Paris, France and Dr. Nicholas Hacher: ARV Therapies and Hormonal Interactions?

This article by Dr. Nicolas Hacher was submitted by Hélène Hazera of Paris, France. It was translated for distribution by a member of Act-Up Paris. As with any medical information, be sure to discuss any issues you may have with your medical professionals before changing your medications.


Translated from the French version of May 10, 2006
Doctor 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).

 The most commonly used compound in France is cyproterone acetate with a
50 milligrams per day dosage. It has three properties: it is an anti-androgen,
an anti-gonadotrophic compound, and a synthetic progestogen. It induces the
inhibition of the binding of 5 alpha DHT to its cytosolic receptor in the target
cells. It is derived from 17 hydroxyprogesterone.
 Spironolactone at 100 to 200 mg per day is an anti-mineralo corticoid
with anti-androgen effects and is an alternative to cyproterone.
 Among non-steroidal drugs : Anandron, Flutamide and Casodex, all used
under specific circumstances in prostate cancer ; Finasteride is prescribed for
the hypertrophy of the prostate.
 Finally, the LHRH or GnRH agonists are prescribed in some early puberty
cases, for prostate cancer, as well as in medically-assisted procreation
protocols.

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:

 Androtardyl : as phials for intramuscular administration at 250 mg
every 2, 3 or 4 weeks.
 Nebido : testosterone undecanoate at 1000 mg per 4 milliliter, one
phial intramuscularly every 3 months.
 Androgel : 50 mg per dose of gel, one percutaneous dose every day.
 Andractim : dihydrotestosterone, one dose percutaneously each day.
 Pantestone : as a capsule of 40 mg of testosterone undecanoate, 2 to 4
times a day.

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

1 - Jolanda M.H. Elbers, Erik J. Giltay, Tom Teerlink, Peter G ;Scheffer, Henk
Asscheman, Jacob C. Seidell and Loui J.G. Gooren. 2003 Effects of sex steroids
on components of the insulin resistance syndrome in transsexual subjects.
Clinical Endocrinology 58 562-571.

2 - Kees H. Polderman, Louis J.G. Gooren, Henk Asscheman, Abraham Bakker, and
Robert J. Heine. 1994 Induction of insulin resistance by androgens and
estrogens. Journal of Clinical Endocrinology and metabolism. Vol 79. N°1.

3 - A.W.F.T. Toorians, M.C.L.G.D. Thomassen, S. Zweegman, E. J. P. Magdeleyns,
G. Tans, L. J. G. Gooren, and J. Rosing 2003 Venous thrombosis and changes of
hemostatic variables during cross-sex hormone treatment in transsexual people.
Journal of Clinical Endocrinology and metabolism. 88 (12): 5723-5729.

4 - Alan Winston and Marta Boffito 2005 The management of HIV-1 protease
inhibitor pharmacokinetic interactions. Jounal of antimicrobial chemotherapy
(2005) 56, 1-5.

5 - Andy Levy, Anna Crown and Russell Reid 2003 Endocrine intervention for
transsexuals. Clinical endocrinology (2003) 59, 409-418.

6 - Eva Moore, Amy Wisniewski, and Adrian Dobs 2003 Endocrine Treatment of
transsexual people: a review of treatment regimens, outcomes, and adverse
effects. Journal of clinical endocrinology and metabolism. 88(8): 3467-3473.

7 - Jaclyn H. Chu, Stephen J. Gange, Kathryn Anastos, Howard Minkoff, Helen
Cejtin, Melanie Bacon, Alexandra Levine, and Ruth M. Greenblatt. 2005 Hormonal
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