Testosterone as treatment for depression
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Testosterone for the treatment of depression: A comprehensive review.
By liftsiron
Abstract:
Testosterone is the primary male sex hormone, 2009 will mark the 104th anniversary of the term “hormone” named by Ernest Starling. Although the biological effects of testosterone were known for many centuries, the name testosterone was only coined in 1935, when Ernest Liqueur isolated testosterone from bull testes. Modern androgen therapy started in 1935 when testosterone was chemically synthesized by Aldolf Butenandt and Leopold Ruzicka. In 1951 it was discovered that testosterone can improve nitrogen retention and increase lean muscle mass. This started a trend for use in sports by athletes to improve performance, and non-athletes to improve strength and for cosmetic change in body appearance.
The major FDA approved medical use for testosterone in the United States is for male hormone replacement, although medical doctors are also prescribing testosterone for low libidos in both male and female patients. Many studies are currently being done at present in the United States and abroad for other medical uses of the drug. One area is the therapeutic use of testosterone for the treatment of depression in males with depressed testosterone levels. Although there are not an overwhelming amount of studies available in literature on the subject, those that are available, suggest that the outlook appears to be very promising.
Review Criteria: All available published literature on the clinical use of testosterone for treatment of depression and associated disorders of a psychological nature, were considered for this review.
Intoduction:
Testosterone is responsible for normal growth and development of male sex organs and maintenance of secondary sex characteristics. It is the primary androgenic hormone, and its production and secretion are the end product of a series of hormonal interactions. Gonadotropin-releasing hormone is secreted by the hypothalamus and controls pulsatile secretion of luteinizing hormone and follicle-stimulating hormone by the anterior pituitary. Luteinizing hormone regulates the production and secretion of testosterone by the Leydig cells of the testes, and follicle-stimulating hormone stimulates spermatogenesis.
Testosterone replacement should in theory approximate the natural, endogenous production of the hormone in a circadian pattern. The average male produces 4-7 mg of testosterone per day. Testosterone therapy helps in stabilizing or increasing bone density, enhancing body composition by increasing lean muscle mass and reducing adipose tissue, improving energy and mood, maintaining or restoring secondary sexual characteristics, libido and erectile function. Reducing cognitive dysfunction by replacing testosterone to eugodnal levels in hypogonadal older men improves scores on cognitive tests. (Grey et al.2005)
Types of Testosterone Replacement Therapy
Testosterone replacement therapy should produce and maintain physiologic serum concentrations of the hormone and its active metabolites without significant side effects.
Several different types of testosterone replacement are currently available through prescription. We will skip oral medications, as they are rarely used because of adverse side effects and toxicity concerns.
Intramuscular injection:
Testosterone cypionate and enanthate are frequently used preparations that provide a safe means of hormone replacement in hypogonadal men. Testosterone is esterified to inhibit degradation and to make it soluble in oil-based injections that retain the drug in muscle tissue and released slowly. In men 25 -60 years of age, an intramuscular injection of 200 to 300 mg testosterone enanthate generally produce serum testosterone levels that are above normal within the first few days following injection and fall into the normal ranges over the next 14 days. Fluctuations in testosterone levels may cause variations in libido, sexual function, energy, and mood. A dose of 300 to 400 mg may allow for maintenance of eugonadal levels of serum testosterone for up to three weeks. Higher doses will not lengthen the eugonadal period.
Transdermal systems:
Currently, three testosterone transdermal systems are marketed: a system applied to the scrotum that has no permeation enhancers. Two systems contain permeation enhancers for application to appendage or torso skin. Scrotal patches produce high levels of circulating dihydrotestosterone (DHT) due to the high 5-alpha-reductase enzyme activity of scrotal skin, DHT is implicated in prostate hypertrophy and perhaps cancer of the prostate. All 3 transdermals may cause skin irritation. Testosterone is a schedule III class drug and must be prescribed by a physician and possession without a valid prescription is a potential felony. The primary use for prescription testosterone in the United States at present is for hormone replacement in eugonadal men.
The normal dose prescribed is 100-200 milligrams either weekly or bi-weekly. The most commonly prescribed esters are cypoinate and enanthate and may be used interchangeably. At present testosterone is being studied as beneficial for treatment in numerous ailments which include but are not limited to cardiovascular disease, arteriosclerosis, thrombosis, hypertension, obesity, andropause, autoimmune disease, cognitive dysfunction and depression. However for the purpose of this paper we will explore the effects of testosterone replacement as treatment for depression.
Indications:
The FDA has approved the medically use of testosterone for male hormone treatment. Currently the FDA is reviewing the requests for use as treatment for female libido problems. Testosterone is often prescribed by medical doctors for male libido problems and erectile dysfunction. It is estimated that approximately 2-3 million men and women in the United States obtain the drug from the black market and self administer, often at a dose five to ten times the medically prescribed dose. For very long periods of time, in some cases, years without a break. (Kanayana et al.2006)
Pharmacokinetics:
Routes of administration include patch, transdermal gel, and injection. Injection certainly seems to be the best method in my estimation, because it insures a regulated timed release of the drugs. Gels are messy and often the dose is inaccurate or unintentionally removed from the skin before fully absorbed. Patches are reported to raise levels of DHT, which is a concern in regard to prostate problems. Both patch and gels can cause local skin irritation.
Concerning mechanism of action, as of this writing it’s seems that testosterone provides the majority of its benefits to individuals especially elderly men by correcting testosterone deficiency. (Okum et al.2002)
Metabolism:
Testosterone circulating in the blood is present in several forms. Testosterone is present as a free hormone (not bound to any protein) or bound weakly to the protein albumin. The majority of testosterone in circulation is bound to sex hormone binding globulin (SHBG). The (SHBG) bound testosterone is not available for biological activity. The free testosterone and the testosterone weakly bound to albumin comprise the bioavailable testosterone fraction which is responsible for peripheral androgenic effects.
Testosterone is converted to other clinically important compounds. Dihydrotestosterone (DHT) is produced by reduction through the action of 5-alpha- reductase, which is present in genital tissue, skin and the prostate. Estradiol (E2) is produced by the aromatase enzyme action on testosterone. The rate of conversion of testosterone to estradiol can be increased in obese men and in men with liver failure. Elevated levels of E2 can down regulate the hypothalamic-pituitary-gonadal axis, resulting in decreased gonadrotropin secretion and decreased circulating testosterone levels. The half life and elimination time depend entirely the ester added to the synthetic testosterone molecule when prepared as an oil soluble injectable .
Toxicology:
The toxic effects are an exaggeration of the normal pharmacological effects.
Discussion:
This paper is intended to explore various psychological effects of testosterone other than aggression. The association between testosterone and human aggression has been the focus of considerable research. ( O’Connor et al.2004)
Testosterone effects on human aggression remain controversial. Previous studies have been criticized because of low androgen dose, lack of placebo control etc. In one study 600mgs of testosterone enanthate a week was used. 43 eugonadal men, 16-40 years of age were randomized into 1-4 groups. Conclusion: suraphysiological doses of testosterone, when administered to normal men in a controlled setting, do not increase angry behavior. (Tricker et al. Journal of Clinical Endocrinology and Metabolism, vol. 81, 3754 3758)
A single dose of testosterone was administered to test weather the drug would increase the functional connectivity in a cortico-cortical depression circuit. Fourteen healthy females received (sublingually) a single dose of 0.5mg testosterone or placebo in a randomly assigned fashion. Three hours after the drug was given the functional coupling between the left prefrontal and right parental cortex was established by EEG. Testosterone administration significantly increased the functional connectivity. (Schutter et al. 2005)
Age associated hypogonadism occurs in 30% of men after the age of 55: it is associated with decreased muscle mass, bone density, libido, anorexia, fatigue, and irritability. Although some of these symptoms overlap with those of depression, the association between the two disorders is unclear. In a study which objective was, to determine if hypogondal men have an increased incidence of depressive illness compared with eugondal men. In a historical cohort study using computerized medical records followed by a normal record review. 278 men aged 45 years and older with constantly normal or low testosterone were assessed. The study concluded that hypogondal men showed an increased incidence of depressive illness and a shorter time to diagnosis of depression. (Shores et al.2004)
Another study investigated the impact of constant testosterone withdrawal on the central nervous system in humans. The design was a double blind assessment of the effects of short term hypo-gonadism and subsequent replacement with testosterone and placebo in a crossover design. Twelve health male volunteers participated. Observations of decreased sexual interest were noted during the hypogonadal state.
(Blough et al.2006)
Many patients with Parkinson’s disease (PD) suffer from nonmoteor symptoms including depression, anxiety, sexual dysfunction, decreased energy as well as an over all decline in perceived quality of life. This study reviewed case studies of five patients with ( PD) who had symptoms of testosterone deficiency, all five patients had low serum testosterone levels. Following testosterone replacement all five patients experienced improvements in their refractory nonmotor symptoms. The findings from this study reveal the unrecognized high prevalence of elderly male patients with (PD) that are hypogonadal similar to that found in the general population. And that they may respond favorably to testosterone replacement treatment. (Okum et al.2002)
Seventy men with symptomatic human immunodeficiency virus illness (HIV) enrolled in a double-blind placebo-controlled 6-week trail study with biweekly testosterone injections. Major outcome measures were Clinical Global Impressions ratings for libido, mood, energy, and erectile function; Hamilton Depression Rating Scale scores, and Chalder Fatigue Scale scores. Results as follows: for perception of a large improvement in libido, randomized for testosterone 74%, placebo 19%. For improved Axis I depressive disorder at baseline 58% of the testosterone treated patients reported improved mood as compared to 14% of the placebo group. Fatigue at baseline 59% of the subjects who received testosterone reported improvement as compared to 25% receiving placebo.
Testosterone supplementation may produce antidepressant effects in men. In a randomized, placebo-controlled trail, a testosterone transdermal gel was administered to men aged 30-65 who had refractory and low or borderline testosterone levels. Each subject continued his present antidepressant regimen during the trail. Ten subjects receiving testosterone and nine receiving placebo completed the 8-week trail. Subjects receiving testosterone had significantly greater improvement in scores on the Hamilton Depression Rating Scale. A significant difference was also found on the Clinical Global Impression severity scale but not on the Beck Depression Inventory. The authors conclude that these preliminary findings suggest that testosterone gel may produce antidepressant effects in the, and probably under recognized population of men with low testosterone levels. These findings may have important consequences for public health. In a given year 8% of American men over age 30 exhibit major depressive disorders. If this subgroup with refractory depression has a 43% prevalence of low testosterone levels as found in the present study, then in theory hundreds of thousands of men may be candidates for testosterone supplementation to treat depression. (Pope et al. 2003)
Serum concentration levels of gonadal hormones have been associated with various measures of well being but it’s unclear whether their association with mood is confounded by concurrent physical morbidity. The objective of the study described was to determine whether the association between serum testosterone concentration levels in older men is independent of physical comorbidity. Of 3987 men included in the study, 203 had depression. The participants with depression had significantly lower total and free testosterone concentration levels than the nondepressed participants. However the depressed men were also more likely to smoke and to have low educational attainment, a body mass index categorized as obese, a Mini-Mental State Examination score less than 24, a history of antidepressant drug treatment, and greater concurrent physical morbidity. After adjusting for these factors and for age, men with depression were 1.55 (95% CI, 0-91-2.63) and 2.71 (95% CI, 1.49-4.93) times more likely to have total and free testosterone levels in the lowest quintile. Conclusions: A free testosterone concentration in the lowest quintile is associated with a higher level of depression and this association cannot be explained by physical comorbidity. (Osvaldo et al. (2008)
A cross sectional population based study examined the association between endogenous sex hormones and depressed mood in older men living in a community setting. The participants were 856 men aged 50-89 years. Total and bioavailable testosterone, total and bioavailable estradiol and dihydrotestosterone levels were measured by radioimmunoassay. Depressed mood was assessed with the Beck Depression inventory (BDI). Levels of bioavailable testosterone and bioavailable estradiol decreased with age, but total testosterone, dihydrotestosterone, and total estradiol did not. BDI scores increased with age. Low bioavailable testosterone and high BDI scores were associated with weight loss and lack of physical activity, but not with cigarette smoking and alcohol intake. By linear regression the BDI scores were significantly and inversely associated with bioavailable testosterone. Bioavailable testosterone levels were 17% lower for 25 men with categorically defined depression than levels observed in all other men in the study. Neither total or bioavailable estradiol was associated with depressed mood. The results give a good indication that testosterone treatment might improve depressed mood in older men with depressed testosterone levels. (Barret-Conner et al. 1999)
Low testosterone levels in men certainly appear to be associated with depression in men, but does depression affect the activation of the hypothalamic-pituitary- adrenal system, which may negatively affect gonadal function at every level of regulaton. In a German study testosterone, pulsatile LH secretion, FSH, and cortisol were assessed using frequent sampling during a 24 hour period in 15 male inpatients with major depression of moderate to high severity and 22 healthy comparison subjects age range 22-85 years. An analysis of covariance showed that after adjustment for age only, daytime testosterone, nighttime testosterone, and 24 hour mean testosterone secretion were significantly lower in the depressed male patients. There was also a notable trend for for a decreased LH pulse frequency in the depressed patients. Conclusions: Gonadal function may be disturbed in men with a depressive episode of moderate to high severity. (Schweiger et al. 1999)
A comprehensive review of literature was performed by Howard C. Margolese, MD., the object was to note the hormonal changes that occur in aging males in order to determine if testosterone declines in relation to depressed mood and if testosterone might prove useful in treatment of depression. Articles reviewed were identified through a Medline search from 1966-1999. Findings include that there is a moderate decline of bioavailable testosterone in aging males. Elderly males who suffer depression appear to have the lowest testosterone levels. In some studies testosterone replacement in hypogondal males show a significant effect in association with depression, whereas some other studies do not. (Margolese, 2000.)
Summery:
In men testosterone secretion affects neurobehavioral functions, such as sexual arousal, aggression, emotions, and cognition. Beginning at the approximate age of 50, (younger in many cases) men secrete progressively lessening amounts of testosterone. Approximately 20% of men over age 60 have lower than normal testosterone levels. The psychiatric implications are poorly understood, yet there is considerable evidence of an association with depressive symptoms. (Seidman et al. 1999)
There continues to be mounting evidence that suggest that testosterone and several other anabolic-androgenic steroids may be effective treatment of depression, especially in aging men or men who experience a hypogondal condition. Despite the mounting evidence that testosterone treatment may be effective for the treatment of depression, cognitive disorders and certain nonmotor dysfunctions in certain diseases, the published literature in these areas are extremely limited in their availability for those pursuing research on the subject. Testosterone treatment for depression remains to be considered an experimental procedure by many in the medical and allied health field. It’s unfortunate that a drug so available, inexpensive and relatively low in adverse side effects is not researched more aggressively and thoroughly by our medical and scientific communities.
It appears by the data established in the reviewed literature used for the purpose of writing this paper, that low testosterone levels in males cause multiple physical and psychological disease and impairments. It also appears that as we age total bioavailable testosterone (the testosterone available for biological functions) levels fall most often without much change in the total testosterone levels. Unless Medical doctors run specific tests for bioavailable or free testosterone, men suffering from hypogondal symptoms may appear to have testosterone levels within the normal limits. Some early studies pre 1950’s suggest that testosterone was as effective as electroconvulsive therapy in trating depression in males, but with the development of tricyclic antideprssants and monamine oxidase inhibitors, testosterone was all but forgotten as a viable treatment for depression. However, over the past decade, interest in the testosterone/depression association has sparked renewed research in this area. There certainly great need for more research into the area of testosterone replacement as a possible treatment for a number of psychological or neurobiological disorders. Synthetic testosterone, is readily available, inexpensive, and relatively low in adverse side effects when use at a therapeutic dose.
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