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Grumpy No More: Testosterone Deficiency & Depression

Does DHEA Raise The Levels Of Bioavailable Testosterone In Men?

August 2002

Is replacement therapy the answer?

Image with Caption
…age alone did not reliably predict
depression as assessed by the
standard depression inventory; low
levels of free testosterone were the
best predictor of depression,
regardless of age.

Clinical observation and anecdotal accounts confirm that testosterone replacement has a strong antidepressant effect. Dr. Eugene Shippen, an authority on testosterone replacement, points to the existence of a substantial body of scientific literature that consistently links the decline in testosterone to almost all aging-related diseases, including depression, cognitive dysfunction and neurodegenerative brain disorders. Dr. Regelson quoted a clinician who prescribes testosterone: "I have a number of patients whom I've been treating with testosterone for the past five years, and most of them would not come off it even if you offered them a small piece of the Federal Reserve." Cheerful, energetic, self-confident mood may be a much more important reason for this than enhanced libido.

Free testosterone has also been found to be the most important biomarker of aging in men. It is insufficient to have your total testosterone tested; men should insist on a blood test for free testosterone. Because of diurnal variations, some suggest early afternoon as the best time for a blood test.

But before we can draw firm conclusions, controlled experimental studies are needed. Predictably, Barrett-Connor concludes by calling for more research on the effects of testosterone replacement. "I would like to stress that since the number of women using testosterone has expanded exponentially in the last few years, we badly need more studies on the effects of testosterone replacement in women as well as in men. Clinicians have observed that women patients respond to correct testosterone replacement with reports of greater zest, energy, assertiveness, and overall improved sense of well-being. The hormone of strength, the hormone of desire apparently has a significant impact on mood and brain function in general in both sexes. Is testosterone the primary hormone of good cheer? Only more research can provide a definite answer."

The whole approach

Image with Caption
"Laypeople and a portion of the
medical profession have woken
up to the fact that hormones
contain the juice of youth and,
without their presence in optimal
quantities, vital, vigorous life is
nearly impossible."

At the 1995 A4M conference in Las Vegas, Dr. Whitaker raised a rhetorical question: "Are we going to give hormones only to women, while men are supposed to just wither away?" Rather than making jokes about grumpy old men, we should keep searching for ways to restore optimal neurochemistry for both sexes. Safe hormone replacement appears to be the key, but may not be the whole answer. Nutrients such as phosphatidyl-serine and acetyl-L-carnitine are also very helpful in preserving a more youthful brain function, and SAMe can work wonders as an antidepressant. But depressed midlife and older men would do well to have their free testosterone tested. While weight training and a diet that provides sufficient healthy fat while restricting insulin-raising refined carbohydrates help preserve youthful levels of free testosterone, there eventually comes a time when testosterone replacement needs to be considered.

Dr. Whitaker continued, "Whatever comes first, the eventual effect of the male menopause is an erosion of the underpinnings of our personal strengths. Loss of athletic ability, loss of dynamic executive capabilities, loss of self-confidence, eagerness, aggressive energy-a sense of loss magnified and multiplied by the total unexpectedness of what we are undergoing. This is a change, indeed. The sharp edges of youth are replaced by the well-traveled roads of habit and lethargy.

"Lay people and a portion of the medical profession have woken up to the fact that hormones contain the juice of youth and, without their presence in optimal quantities, vital, vigorous life is nearly impossible."

While at this point men are far behind women in hormone replacement-some clinicians say men are 15 to 20 years behind-there is an emerging consensus that male hormone replacement is going to become as common as postmenopausal hormone replacement for women. It is routinely offered at anti-aging clinics, and even the more innovative HMO doctors are beginning to prescribe it.

Testosterone replacement does not need to be expensive or inconvenient. You do not have to wear a patch or get shots. Compounding pharmacies, such as Women's International Pharmacy or College Pharmacy, can prepare testosterone gels and creams that are well-absorbed (prescription required) for under $20 a month. Friendly compounding pharmacists can provide more information to you and your doctor.

Sublingual testosterone is also available from compounding pharmacies, as well as oral testosterone in oil capsules. The transdermal route (cream or gel), however, is widely regarded as the best, producing steady levels and the least stress on the liver. Methyl-testosterone is to be avoided, since it is harmful to the liver; in fact, it has been banned in Europe. The patch (Testoderm or Androderm) uses only natural testosterone.

Studies have shown that neither testosterone shots nor the patch cause a rise in PSA. Some clinicians even suggest that beginning testosterone replacement early prevents prostate cancer by maintaining a youthful androgen/estrogen ratio. Still, every man's greatest fear when it comes to testosterone replacement is the risk of prostate cancer. Life Extension Foundation has written extensively about new findings indicating that it is excess estrogen together with DHT that combine to overstimulate the prostate. Life Extension Foundation's Natural Prostate Formula is a top-of-the-line product. It is unique in that it provides protection not only against excess DHT, but also against excess estrogen. Some innovative physicians would in fact argue that it is testosterone-deficient men who are more in need of various measures to protect the prostate, due to their typically unfavorable androgen/estrogen ratio, which may cause changes in prostate cancer cells that make them more susceptible to mutations that result in prostate cancer.


Zinc (which appears to act as an aromatase inhibitor in the prostate, lowering men's estradiol levels), soy phytoestrogens, green tea, polyphenols in strawberries and other berries, lycopene and conjugated linoleic acid (CLA) have also shown to protect against prostate cancer, and in some cases even reverse it. Finally, keeping the percentage of body fat as low as possible is itself a very effective preserver of a youthful hormonal profile and correct androgen/estrogen ratio.

In some cases DHEA replacement seems sufficient to produce the benefits suggesting increased levels of free testosterone, even though total serum testosterone is unaffected (in women, total serum testosterone does rise after DHEA replacement). Fortunately, a well-controlled study published in the prestigious Journal of Clinical and Experimental Endocrinology and Metabolism did in fact find a significant rise in free testosterone in men aged 60 to 84 years, after three months on 100 mg of DHEA. There was no rise in total testosterone or in PSA. Even at lower doses of DHEA, one would expect a rise in tissue levels of testosterone, undetectable in the serum but nevertheless of considerable physiological importance.

There is of course every reason for men to take DHEA along with testosterone replacement for enhanced benefits, such as improved immune function. The next five years ought to bring us more much needed information on hormone replacement for men.

Cautionary notes: When men use testosterone drugs (even those that provide natural testosterone), there is a propensity for the body to aromatize this testosterone into estrogen. Some men on testosterone drug replacement therapy develop dangerously high estrogen levels. Estrogen can be suppressed by taking an aromatase-inhibiting drug like Arimidex (0.5 mg twice a week) or using a supplement like Super Mira Forte (six capsules daily). Regular blood tests are important to make sure enough aromatase inhibiting drug-nutrient is being taken to keep estradiol levels under 30 (pg/mL).

Life Extension recommends that any man taking testosterone drugs have a blood test every 45 to 60 days during the first six months of use to guard against estrogen-overload or detect an elevated PSA that could rise if there were an occult prostate tumor present. Prostate cancer should be ruled out before testosterone is prescribed by both a blood PSA test and a digital rectal examination. A small percentage of men who have occult prostate cancer will have a normal PSA and show no other signs of the disease until they begin taking testosterone drugs. Annual blood testing to measure free testosterone, estradiol, liver function and PSA is mandatory for those taking testosterone drugs. Refer to Life Extension's "Male Hormone Modulation Protocol" at for complete information about safe testosterone replacement therapy.

Resources mentioned in this article:

  • Women's International Pharmacy: 800-279-5708
  • College Pharmacy: 800-888-9358


Barrett-Connor E, von Muhlen D, Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. J Clin Endocrinol Metab 1999; 84:573-77.

Flynn MA. DHEA replacement in aging humans. J Clin Exper Endocrinol Metabolism 1999; 84:1527-33.

Regelson W, Colman C. The Superhormone Promise. Simon and Schuster, 1996; pages 132-135).

Shippen ER. Testosterone, a critical link between health and age-related decline, disease, and disability. Lecture delivered at the 1998 A4M Conference, Las Vegas.

Shippen ER and Fryer W. The Testosterone Syndrome: The Critical Factor For Energy, Health and Sexuality - Reversing the Male Menopause. M. Evans and Co, 1998; p.8.

Zava, DT. New theories on the origins of breast and prostate cancers: hormonal and nutritional strategies for prevention. Lecture delivered at the 1998 A4M Conference, Las Vegas.