There are a variety of common psychological or psychopathological conditions, including depression, which have been directly correlated with low testosterone levels (also referred to as hypogonadism).  Many clinical studies throughout the world have either cited as a cause, or closely associated low testosterone levels with depression in both men and women.  This topic is best explored by clearly identifying low testosterone and depression separately, and then cohesively examining the clinically substantiated data that correlates them.

Low Testosterone

Hypogonadism, which mostly affects middle-aged to elderly males, but is also found in males of all ages as well as in menopausal and post-menopausal women, is typically considered to have originated from one of three possible sources.  Specifically, primary hypogonadism which originates from a problem within the testicles or ovaries, secondary hypogonadism which originates from a problem within the pituitary gland or hypothalamus (the two brain areas responsible signaling the testicles and ovaries to produce testosterone), and a source which originates from another internal condition or an external stimulus.

Hypogonadic causes are generally classified as ‘primary’ and ‘central’.  Testicular or ovarian malfunctions are referred to as primary causes.  Some of these include certain autoimmune diseases such as celiac disease, Addison’s disease, Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Alzheimer’s, hypoparathyroidism, and several others.  Common autoimmune disease symptoms include weakness, fatigue, and numbness.  Also considered primary causes are a number of genetic and developmental disorders such as Turner Syndrome, Klinefelter syndrome, Myotonic dystrophy, Prader-Willi syndrome, Kallmann’s syndrome and several other related genetic disorders for which the most common hypogonadic symptoms are:  low testosterone levels; reduced facial hair; reduced body hair; testicular atrophy; gynecomastia (enlarged breasts male breasts); and impotence (the inability to produce sperm).  Other primary causes include viral and bacterial infections, liver and kidney diseases, surgery, and radiation exposure.

Central hypogonadism involves a malfunction in the Hypothalamic-Pituitary-Testicular Axis (HPTA), i.e., the relationship between the hypothalamus and pituitary gland and their production of testosterone.  The main causes of central hypogonadism generally include:  medicines such as opiates and steroids; nutritional deficiencies; hemochromatosis a condition in which the blood contains too much iron significant and or rapid weight loss; significant bodily trauma; internal bleeding; infections like HIV and AIDS; and tumors, such as prolactinoma – a noncancerous pituitary tumor which causes the body to produce too much of the hormone prolactin.  A.D.A.M.Hypogonadic symptoms typically vary in type and severity based on age and gender.  For example girls’ symptoms may include:  irregular or cessation of menstruation; hot flashes; diminished libido (sex drive); loss of body hair; and pre-pubertal symptoms such as delayed breast development, stunted height growth, and delayed menstruation.  Boys’ symptoms may include gynecomastia, decreased facial and body hair growth, muscle loss, and sexual problems like erectile dysfunction, a reduction in libido, impotence, etc.  Hypogonadic adult symptoms are likely to include:

• Loss of body hair
• Loss of menstrual period
• Difficulty sleeping
• Breast discharge
• Impotence
• Loss of body, facial and pubic hair
• Weakness
• Increased body fat
• Reduction in muscle and/or bone mass
• Changes in the size of, or lumps in the breasts, testes, scrotum and penis
• Depression
• Anxiety
• Irritability
• Excessive sweating and night sweats
• Loss of peripheral vision often indicates the presence of a pituitary tumor
• Gynecomastia
• Hot flashes
• Poor concentration and/or memory
• Insulin resistance
• Recent bone fractures; loss of bone mass (osteoporosis)

The prognosis for hypogonadism is good, as patients generally respond well to treatments, which vary depending on the cause, and may include (especially in elderly populations) Testosterone Replacement Therapy (TRT).  This hormone-based therapy employs medication regimens of synthetic testosterone in the form of a transdermal skin patch or skin gel, or by intramuscular injection.  In rare cases, women with hypogonadism who also exhibit diminished libido may be prescribed a low-dose regimen of testosterone.

Depression

Research has conclusively demonstrated that depression can be influenced by both biological (hormone deficiencies, illnesses, genetic conditions, etc.) and environmental factors that promote stress such as financial difficulties, sickness or loss of a loved one, job problems, legal hassles, etc.   On the topic of depression, every book, website, and dime store counselor has a different definition, many of which are catch-all conditions that are inexact and largely illegitimate.  Such haphazard definitions often include a few of several symptoms which are in effect inherent to depression, but do not meet the full span of diagnosis mandated criterion.

The Diagnostic and Statistical Manual of Mental Disorders is the official manual published by the American Psychiatric Association, which lists all psychiatric and psychological disorders and their respective diagnostic criteria.  The Association’s Annual Meeting on May 2013 served as the site for the release of its fifth edition, commonly known as the DSM-V, which defines Major Depressive Disorder (the most prominent diagnosis of depression) as the presence of a single Major Depressive Episode.  It further outlines the criteria for Major Depressive Episode as, “Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure”.  The nine symptoms to which it refers are listed below along with their accompanying descriptions:

1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful).  Note: In children and adolescents, can be irritable mood.
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day.  Note: In children, consider failure to make expected weight gains.
4. Insomnia or hypersomnia nearly every day
5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)
6. Fatigue or loss of energy nearly every day
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

Just as there are differing symptoms, the condition of depression itself is generally classified into subcategories, most notably:

• Major Depression – this is the most common form and its symptoms are outlined above.
• Atypical Depression – patients with this form don’t exhibit the typical symptoms and may experience weight gain, sleep too much, or feeling anxious
• Chronic Depression (Dysthymia) – this is a milder, but recurrent form.
• Postpartum Depression – this form is becoming increasingly common, and may be moderate to severe in women from directly following, to up to a year after childbirth.
• Bipolar Depression (Manic Depression) – the form is characterized by pronounced mood swings of bipolar depression from the manic high mood to the major depression low moods.
• Seasonal Depression – this form often referred to as Seasonal Affective Disorder (SAD) occurs at certain times of the year and has to do with the body’s negative response to a reduction in sunlight during the shortened days of fall and winter months.
• Psychotic Depression – this form has to do with psychosis, hallucinations, and other related experiences.

The treatments for depression vary and are contingent upon cause.  However, treatments often include either a combination of both psychotherapy and pharmacotherapy, or may enlist one or the other.  The most popular medications used in the treatment of depression are Zoloft, Wellbutrin, Prozac, Paxil, and a host of generics.

Low Testosterone and Depression

Studies in the field of research have been highly conclusive and generally comprise a two-pronged approach:

1) the actual measurement of correlational significance with regard to low testosterone subjects and depressive symptoms; and

2) the assessment of TRT impact on depression in subjects with low testosterone.  Probably the best way to examine what proven clinical research has correlated (determined to be a clear link between) low testosterone and depression would be to actually view some of the more conclusive studies in this field along with their accompanying results.

In a March 2008 study from the Archives of General Psychiatry was conducted with the intention of determining whether the association between serum testosterone concentration and mood in older men is independent of physical comorbidity (the presence of two or more different diseases or conditions).  This cross-sectional study at the WA Centre for Health and Ageing, University of Western Australia, Perth, Australia, was comprised of a Perth community sample of men between 71 and 89 years age, and used the 15-item Geriatric Depression Scale (GDS-15) to assess depressed mood while defining clinically significant depression as a score of 7 or greater.  Almeida OP, et al (the conducting researchers) found that of the 3987 men included in the study (203 of which had depression), those participants with depression had significantly lower total and free testosterone concentrations than those without depression.  After adjusting for variables such as age, smoking, low educational attainment, obesity, prior antidepressant drug usage, etc., men with depression were 1.55 and 2.71 times more likely to have total and free testosterone concentrations, respectively, in the lowest quintile.

A study February 2010 study from the Journal of Clinical Endocrinology and Metabolism (JCEM) began with the premise that both low testosterone levels and depression increase with age.  The study aim was designated as an analysis of the cross-sectional association of testosterone levels with depressive symptoms.  Conducted at the EMGO⁺ Institute for Health and Care Research at VU University Medical Center, Amsterdam, the Netherlands, this longitudinal population-based study included 608 men aged 65 years old and above, with a median age 75.6 years.  Using linear and logistic regression as the statistical analysis models, significance was measured between total and free testosterone levels and depressive symptoms gauged on the Center of Epidemiologic Studies Depression (CES-D) scale.  While allowing for a variety of possibly confounding medical and lifestyle factors, Joshi D., et al concluded that free testosterone levels below 170 pmol/l (picomole per liter) are significantly associated with depressive symptoms.  Furthermore, they determined that free testosterone levels below 220 pmol/l (lowest quintile in population) actually predicted the onset of depressive symptoms.

A July of 2010 study entitled, ‘Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome’, investigated the effects of testosterone administration on 184 men averaging 52.1 years of age and suffering from both the metabolic syndrome (MetS) and hypogonadism.  This randomized, double-blind, placebo-controlled, phase III trial (ClinicalTrials.gov identifier: NCT00696748) measured depression using a scale called the Beck Depression Inventory (BDI-IA), and treated subjects for a duration of 30 weeks with either:

1. 1,000 mg intramuscular injections of parenteral testosterone undecanoate (TU), also known as Nebido, or

1. Placebo injections

Subsequently, Giltay EJ, et al found that TU administration significantly improved depressive symptoms as measured by the post-test BDI-IA (mean difference vs. placebo) after 30 weeks as depression scores dropped a full 2.5 points.

A cohort study from the Journal of Endocrinology in December of 2012 out of the Department of Family Medicine, Gulhane School of Medicine, Ankara, Turkey, undertook research with the expressed the specific aim of assessing associations between low testosterone levels and psychological symptoms (cited as depression, anxiety disorders, and antidepressant use).  The test subjects included thirty-nine young males with congenital hypogonadotropic hypogonadism (CHH), while the control group was comprised of 40 age matched healthy males.  More specifically, depression angle of this study assessed the impact of testosterone replacement (TRT) on the depression levels for which the Beck Depression Inventory (BDI) was employed for both pre/baseline and post/ending measurements.  Aydogan U, et al found the post-treatment experimental group (those receiving TRT) had significantly improved (p=0.011) BDI scores as compared to the placebo group after 6 months of treatment, which suggests that low testosterone levels are directly related to an increased incidence of psychological symptoms.

There are still dissenting studies which either did not find a direct link between low testosterone and depression, or are inconclusive, and it is unclear what the majority of research proves.  However, the studies provided here and scores more like them clearly and conclusively cite a profound correlation between low testosterone and depression.

REFERENCE LIST

• Definition for Substance Abuse
• Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V)
• American Psychiatric Association
• Increased frequency of anxiety, depression, quality of life and sexual life in young hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on these conditions.
• Aydogan U, Aydogdu A, Akbulut H, Sonmez A, Yuksel S, Basaran Y, Uzun O, Bolu E, Saglam K.
• Endocr J. 2012 Dec 28;59(12):1099-105. Epub 2012 Aug 31.
• Salivary testosterone: associations with depression, anxiety disorders, and antidepressant use in a large cohort study.
• Giltay EJ, Enter D, Zitman FG, Penninx BW, van Pelt J, Spinhoven P, Roelofs K.
• J Psychosom Res. 2012 Mar;72(3):205-13. doi: 10.1016/j.jpsychores.2011.11.014. Epub 2012 Jan 11.
• Partial androgen deficiency, depression, and testosterone supplementation in aging men.
• Amore M, Innamorati M, Costi S, Sher L, Girardi P, Pompili M.
• Int J Endocrinol. 2012;2012:280724. doi: 10.1155/2012/280724. Epub 2012 Jun 7.
• Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome.
• Giltay EJ, Tishova YA, Mskhalaya GJ, Gooren LJ, Saad F, Kalinchenko SY.
• J Sex Med. 2010 Jul;7(7):2572-82. doi: 10.1111/j.1743-6109.2010.01859.x. Epub 2010 May 26.
• Low free testosterone levels are associated with prevalence and incidence of depressive symptoms in older men.
• Joshi D, van Schoor NM, de Ronde W, Schaap LA, Comijs HC, Beekman AT, Lips P.
• Clin Endocrinol (Oxf). 2010 Feb;72(2):232-40. doi: 10.1111/j.1365-2265.2009.03641.x. Epub 2009 May 25.
• Low free testosterone concentration as a potentially treatable cause of depressive symptoms in older men.
• Almeida OP, Yeap BB, Hankey GJ, Jamrozik K, Flicker L.
• Arch Gen Psychiatry. 2008 Mar;65(3):283-9. doi: 10.1001/archgenpsychiatry.2007.33.