Toxicology Series I: SSRIs and Testosterone
Dana Houser, MD, MHSA, CISSN
first published online November 6, 2007

Introduction

It was only about two decades ago that cytochrome P450 bench techniques were in their infancy, and US FDA requirements were much less stringent. Unfortunately that left mere trial and error as how we would discover the side effects associated with some of the early agents used in the battle against various mood disorders.

Long since, some of those earlier agents like Tricyclic Antidepressants (TCA's) are infrequently used today secondary to the significant cardiac manifestations that could result from their use. This article will concentrate on the newer and most frequently prescribed class of agents used to aid our plight toward "happiness." Both endogenous (naturally produced) and exogenous (outside introduction - e.g. - PH/PS/DeS/AAS, HRT, etc...) androgenic effects will be explored in turn.

Endogenous Test

There have been multiple case reports of lowering of serum testosterone while on these agents on the order of ~200ng/dl. In fact, free serum testosterone levels in both men and women study subjects were found to be below the normal ranges in 75 percent (on average) of subjects across multiple trials that dosed correctly in the therapeutic range (dependent upon volume of distribution data). Unfortunately, diurnal variations have NOT been adequately accounted for and that may be the answer as the research continues.
In the mean time, whether or not you reach a clinical cut-off for hypogonadism will still, however, likely dictate whether or not you are treated with some form of hormone replacement therapy (HRT). This could certainly be an unfortunate fault that precludes a male's sexual health over time and even contribute to a deeper state of mood disorder affecting a male's confidence and sexual prowess.

Now, we have understood that certain SSRIs (most notably Paxil) have had association with sexual dysfunction properties in males and in some cases, it delays the time to orgasm (which could be seen as a positive or negative). It was, in fact, seen as a positive when it was first being studied - perhaps an off-label use that would eventually earn acceptance as widespread therapeutics for men with ailing sexual existences. As more data is uncovered, however - it seems to be evident that this is merely the beginning of what may be still to come.

The cytochrome P-450 system is the subgroup of chemical detoxifying liver enzymes involved in the metabolism of testosterone which we will explore how this has been postulated to affect exogenous testosterone introduction later on. [color=red][b]Author's Note: Please see "Short Topic Series II: Introduction to Enzymatic Targets & Phase Metabolism" for more] Many antidepressants are substrates of these isoenzymes. Nevertheless, enzyme-induction is unlikely to account for lowered free testosterone levels when not orignating in an exogenous manner (i.e. - PH/PS/DeS/AAS). Changes in sex hormone binding globulin levels can influence the quantity of circulating free testosterone. Estrogen-modulating supplements (i.e. - those aromatizable, or mixed agonist/antagonist) will increase the levels of SHBG and thereby reduce levels of free testosterone.

While the jury is obviously still out as to whether or not we completely understand the mechanism, there is one common bond readily being accepted these days. SSRIs will, in effect, be responsible for some level of natural free testosterone decline. We can only hope that this effect doesn't make matters of the initial mood disorder being treated worse.

Exogenous Test

Not all SSRI's are created equal when we are considering exogenous therapeutics (i.e. - when you are employing various PH/PS/DeS/AAS while on SSRI therapy).

Testosterone is metabolized extensively through the cytochrome enzyme 3A4. As mentioned above, this is the very system that is influenced by SSRI metabolism. This limits use or minimally offers rationale for dose adustments of four agents in particular that we have a wealth of toxicology data with:

[1] Fluoxetine (Prozac)
[2] Fluvoxamine (Luvox)
[3] Paroxetine (Paxil)
[4] Sertraline (Zoloft)

All 4 agents inhibit the cytochrome P450 3A4 enzyme. What this means is that the primary enzyme responsible for steroid metabolism is inhibited, causing higher levels of the androgens. While this may sound like a great method to get higher plasma levels, it certainly has its limitations.

Those limitations include (but are NOT LIMITED TO):
- higher level of hepatotoxicity with minimal dosing (especially C17-alkylated agents),
- higher lipid panel (cholesterol) derrangements,
- progestin-induced hypertension (high blood pressure),
- progestin-induced arrythmias (faulty heart contraction states),
- amongst others

Pharmacologic science has saw to the evolution of this class of agents, however. This has left some viable alternatives that have NO INHIBITORY EFFECT on the 3A4 enzyme as agents discussed above:

[1] Citalopram (Celexa)

-and-

[2] S-citalopram (Lexapro)

Now, understand that both of these agents do see extensive metabolism at the 3A4 site (as well as 2C19 and 2D6) which can see some effect by another drug if introduced to the system. If this "other" drug induces these enzymes, it would decrease the amount of SSRI in your system; if it inhibits, you would see an increased amount of SSRI in your system - both of which have varying clinical effect. Still, because of the diversity and relative lack of P450 inhibition, there are few drug interactions with these two agents and they remain preferred for the testosterone user.

Conclusion

The science of toxicology is very important to understand when embarking on any type of therapeutic regime. That said, there is not a class of drugs that tax the ink of a doctor's pen like the SSRIs. Our continued understanding of these interactions that could occur are imperative to our successful employment of such agents and perhaps, even prevention of making the mood disorder in question responsible for SSRI installment worse.

If you take away nothing else from this article, understand that there are likely the least amount of clinical interactions with the particular SSRIs: citalopram and its more pharmacologically active enatiomer, S-citalopram. Knowing this one fact may allow your increased mood to be coexistant with your sexual satisfaction.