"Low T Syndrome" and the Fountain of Youth

Psychiatrists are seeing increasing numbers of male patients who are being treated for low testosterone.  The symptoms of "Low T" are being promoted as a reason to get assessed and treated with testosterone.  Not surprisingly, "Low T" is a highly successful pharmaceutical company promotion.  So successful that testosterone seems to have disappeared from the vernacular, replaced by "T".  I have had the opportunity to follow this controversy for the last 30 years.  Back in the days when there were a subgroup of psychiatrists who considered themselves to be "microendocrinologists" testosterone, LH, FSH, and GnRH were studied along with the components of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes,  particularly in depressives.  Despite a lengthy but low intensity research effort on gonadal steroids in both men and women the data on baseline neuroendocrine correlates and results of supplemental treatments are equivocal.  That said, most psychiatrists have encountered women who have often had a significant response to treatment with gonadal steroids.  Seeing a consistent treatment effect is difficult.

As a clinical psychiatrist, I have found that the clearest information on drugs is available in the FDA approved package insert.  In the case of the product being marketed by the "Low T" ads is a form of testosterone gel that is available in two different strengths.  The only indication for the the product according to that package insert is primary hypogonadism (congenital or acquired) or hypogonadotropic hypogonadism (congential or acquired).  Any use for treating depression or augmenting antidepressants is off label use.  If testosterone was effective as an augmenting agent it would join the ranks of most antidepressant augmenting agents as being an off label prescription.  There are three related issues.

The first is the diagnosis of primary or hypogonadotropic hypogonadism.  In most cases, my speculation would be that a middle aged man sees or hears about the "Low T" ad and goes in to see their primary care physician and a testosterone level is ordered.  Most authoritative sources like UpToDate state that testosterone replacement should only occur in men who are hypogonadal.  Making that determination generally requires two low testosterone levels or in the indeterminant cases some expertise in the hypothalamic-pituitary-gonadal axis (HPG), as well as access to a laboratory with some specialized endocrine capabilities.  This is the level where most assessments seem to break down.  The range I am used to seeing is total testosterone levels ranging from about 300-1,000 ng/ml.  Scattergrams of testosterone versus behavioral parameters of interest like libido, aggression, and energy usually show low levels of correlation.  Many men are getting treated for (like the commercial suggests) low testosterone, or a level in the low normal range but not in the deficient range.  That takes treatment into the realm of off label indications because they do not have a diagnosis of hypogonadism.  A definitive algorithm (1) from endocrinologists is available including when to refer to an endocrinologist.

The second issue is whether there is any evidence testosterone either treats depression or is an effective agent to augment the effects of antidepressants.  That would conceivably move testosterone to the level of the augmenting agents used in the STAR*D study of depression.  The best guidance in the literature comes from Pope, et al (2) article on testosterone replacement in men 65 years of age or younger taking serotonergic antidepressants, a total testosterone level of less than or equal to 350 ng/ml, a PSA less than 4.0 ng/ml and an incomplete response to the antidepressant.  The author's conclude that there were no significant differences in response to testosterone or placebo gel.  Their conclusion is that the current practice of testosterone supplementation of antidepressants is not supported, but that there may be identifiable subgroups in larger studies.

Pope's observations are also critical in that he is an expert in anabolic androgenic steroid (AAS) abuse and has observed a euphorigenic hypomanic response to both AAS and prescription testosterone.  In his article he cites this response occurring in about 4.8% of 105 volunteers taking the equivalent of 500 mg/week of testosterone or an equivalent.  These observations are critical because they factor in addictive behaviors associated with substance use and Pope's group has proposed criteria for anabolic-androgenic steroid dependence.  The criteria highlight that fact that there are a number of associated mood symptoms including depression during the withdrawal phase.  Screening for an AAS use disorder and associated comorbidity like muscle dysmorphia

The third issue is the risk benefit analysis and that makes testosterone as an augmenting agent more unique than the other STAR*D agents.  Testosterone has unique medical risks beyond any risk of an additive effect with an antidepressant.  The main risk with other augmenting agents is usually rare cases of serotonin syndrome or side effects specific to the agent.  They are essentially being prescribed for the same indication.  With testosterone, there is no professional body advocating for supplementation in men with a eugonadal state and the risks may be significant starting with the contraindications (breast cancer, known or suspected prostate cancer) and warnings (benign prostatic hypertrophy, exposure to women and children, edema, sleep apnea, and the need to monitor a number of biochemical parameters).  There have also been recent articles showing a possible correlation with a number concerns about increased myocardial infarction, ischemic stroke, and other mortality (3,4,5).

So for all of you psychiatrists out there who are being referred men who are being treated for "Low T" or being sent to you with a question about testosterone there are a couple of necessary steps at this point.  Make sure that a diagnosis of hypogonadism has been established.  Let your patient know that testosterone supplementation of antidepressants in eugonadal men at this time is experimental and carries risks.  I would also inquire about a past history of anabolic androgenic steroid use, their conscious experience of that use ranging from mood changes to body image concerns and any prior psychiatric history including a history of addictions or using performance enhancing drugs.  For men considering an evaluation and treatment for "Low T" it is much more complex than filling out an online questionnaire on pharmaceutical company website.  Have realistic expectations about what you can expect, especially if someone is suggesting that testosterone supplementation is a treatment for depression.  Take a good look at the risk and consider that there will probably never be a major study that takes a good look at this issue with a large population of men.  The prospective studies will probably be similar to Pope, et al of about 100 men followed for a short period of time and the retrospective studies will have some innovative designs but they will also be limited by selection factors and significant stratification factors.  That generally means that additional information about risk may only be available in the form of FDA warnings from post marketing surveillance or their own analysis of data that may not be publicly available.

George Dawson, MD, DFAPA

References:

1.  Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010 May;64(6):682-96. doi: 10.1111/j.1742-1241.2010.02355.x. Review. PubMed PMID: 20518947; PubMed Central PMCID: PMC2948422

2.  Pope HG Jr, Amiaz R, Brennan BP, Orr G, Weiser M, Kelly JF, Kanayama G, Siegel A, Hudson JI, Seidman SN. Parallel-group placebo-controlled trial of testosterone gel in men with major depressive disorder displaying an incomplete response to standard antidepressant treatment. J Clin Psychopharmacol. 2010 Apr;30(2):126-34. doi: 10.1097/JCP.0b013e3181d207ca. PubMed PMID: 20520285

3.  Vigen R, O’Donnell CI, Barón AE, et al. (2013) Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310:1829-1836.

4.  Basaria S, Coviello AD, Travison TG, et al.  Adverse events associated with testosterone administration. N Engl J Med. 2010 Jul 8;363(2):109-22. doi: 10.1056/NEJMoa1000485. Epub 2010 Jun 30. PubMed PMID: 20592293; PubMed Central PMCID: PMC3440621.

5. Cappola AR. Testosterone therapy and risk of cardiovascular disease in men.  JAMA. 2013 Nov 6;310(17):1805-6. doi: 10.1001/jama.2013.280387. PubMed PMID: 24193077.

Tip:  Follow the lead authors of these references on Medline and you will have a comprehensive look at the literature in this area.