Keywords

Depression, depressive disorder, men, systematic review, testosterone

 

Authors

  1. See, Chee Keong

ABSTRACT

Objective: The objective of this review is to examine the association between serum testosterone concentration and the presence and severity of depression in men.

 

Introduction: Cross-sectional and longitudinal cohort studies examining the relationship between serum testosterone concentration and depression in men have produced mixed results. There has not, however, been any prior attempt to systematically interrogate the data. Clarification of the relationship has clinical importance because depression may be under-diagnosed in men.

 

Inclusion criteria: This review will consider studies involving community-dwelling men who are not receiving testosterone replacement therapy. The exposure of interest reviewed will include endogenous testosterone concentration measured through validated assays. Studies measuring total and testosterone fraction concentration will be included. This review will include studies with depression or incident depression outcomes as defined by either clinical diagnosis of depression or validated self-administered questionnaire assessing depression symptomatology.

 

Methods: This review will follow the JBI approach for systematic reviews of etiology and risk. The following sources will be searched: PubMed, PsycINFO, Embase, the Cochrane Central Register of Controlled Trials, Australian New Zealand Clinical Trials Registry and the ISRCTN Registry. Analytical observational studies including prospective and retrospective cohort studies, case control studies and analytical cross-sectional studies published in English or other languages with English translation will be considered. Retrieval of full-text studies, assessment of methodological quality and data extraction will be performed independently by two reviewers. Data will be pooled in statistical meta-analysis, where possible.

 

Systematic review registration number: PROSPERO CRD42018108273

 

Article Content

Introduction

Depression affects approximately 4.4% of the world's population and is ranked as the single largest cause of global disability by the World Health Organization.1 As defined by the 2013 Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), a diagnosis of major depressive disorder (MDD) requires at least two weeks of either depressed mood or loss of interest, and four additional symptoms, which may include difficulty with sleep, appetite disturbance, fatigue or low energy, low self-esteem or inappropriate guilt, psychomotor retardation or agitation, cognitive impairment or suicidal ideation. Significant distress or impairment in functioning must also be reported.2 The core criteria to diagnose MDD have remained in use since 1994 with few changes.3

 

Depression is considered to occur more commonly in women than in men.4 Although men more often complete suicide, men and women attempt suicide with equal frequency.5 It seems likely, therefore, that the apparent discrepancy in the prevalence of depression between men and women reflects a detection or presentation bias,6,7 and the under-diagnoses of depression in men mostly likely reflects sex-related differences in the experience of and response to the disorder, with a dominance of somatic symptoms.8-11

 

The prevalence of depression is similar in prepubescent girls and boys.12 The incidence of depression in females increases after puberty when fluctuations in sex steroid levels, predominantly 17[beta]-estradiol (E2) and progesterone, occur prior to menstruation, following pregnancy and during the peri-menopausal period.13-16 Studies in female monkeys have shown that estrogen is protective against depression, and the decrease in estrogen levels increases the risk of depression.17-19

 

In males, testosterone produced by the Leydig cells of the testis is the predominant circulating sex steroid.20,21 The majority of the circulating E2 derives from aromatase-induced biotransformation of testosterone that occurs in a tissue-specific manner.22 Deprivation of testosterone has been shown to induce a depressive state in rodents with associated reduction in expression of serotonin and 5-hydroxytryptamine 1A receptors in brain dorsal raphe.23 A study with surgically castrated male rodents demonstrated that low testosterone was associated with development of depressive-like behavior, attenuated weight gain, reduced hippocampal neurogenesis and neuroplasticity when exposed to unpredictable chronic mild stress.24 The changes seen in the hippocampus of rodents reflect those seen in animal models of depression.25,26 Rates of depressive symptomatology and depressive disorder diagnosis increase following androgen deprivation therapy as a treatment for prostate cancer.27,28

 

Multiple epidemiological, cross-sectional and longitudinal cohort studies have studied the relationship between testosterone and depression. While smaller epidemiological studies suggest a correlation between low testosterone levels and depression, larger cross-sectional studies have not confirmed this relationship. Results from prospective cohort studies are also mixed.29-31 There are a few possible explanations for the discrepancies in the literature regarding the relationships between testosterone and incident depression. First, the fraction of testosterone measured and the testosterone assay used may differ. While most studies measured total testosterone, some measured or calculated free testosterone or bioavailable testosterone.29-31 Second, there are multiple interacting factors modulating the hypothalamic-pituitary-gonadal axis that affect endogenous testosterone concentration at any age.32 Although longitudinal cohort studies report a small annual decline of testosterone, this decline is not an inevitable part of aging. Smoking behavior and intercurrent changes in health status, particularly obesity and depression, are associated with the decline of testosterone levels.33-36 Acute medical illnesses, diabetes mellitus, nutritional deficiency, excessive exercise and concurrent opioid or anabolic steroid use result in lower testosterone concentration. Obesity, diabetes, hypothyroidism, steroid use and nephrotic syndrome are associated with lower sex hormone-binding globulin (SHBG), thus reducing total testosterone concentration.37 Third, the diagnosis of a depressive disorder requires a detailed clinical interview, whereas assessment of depression in most epidemiological and clinical studies is conducted through patient self-administered questionnaires.

 

Numerous questionnaires have been developed to facilitate screening and assessment of depression in different healthcare settings.38 Commonly used questionnaires include the Beck Depression Inventory,39-41 Patient Health Questionnaire-9,42 Hospital Anxiety and Depression scale,43 Geriatric Depression Scale44 and Center for Epidemiologic Studies Depression Scale-Revised.45 Despite their ease of use, these questionnaires have limitations. For example, retrospective recall of symptoms over the previous one to two weeks is vulnerable to measurement errors and affected by daily mood variations and concurrent stressful life events.46 Although most questionnaires correlate well with the DSM diagnostic criteria for MDD, discordance is often observed in depression detected through patient self-administered and clinician-administered questionnaires. This reflects a difference in how clinicians and patients view depressive symptoms.47,48 These questionnaires are also not designed to capture characteristics of atypical depression subtypes, as well as other depressive disorders such as dysthymia, depression due to a medical condition and bipolar disorder. This would result in under-detection of atypical depression and depression subtypes.48 As depression is a polythetic disorder, many combinations of symptoms can constitute MDD, yet self-report questionnaires substantially differ in the types of symptoms measured.49

 

A review of the Cochrane Library, PROSPERO and the JBI Database of Systematic Reviews and Implementation Reports did not show any recent systematic reviews examining the association between endogenous testosterone and depression that had been performed or were underway. Establishing the association of serum testosterone and depression would have clinical importance.

 

Review questions

i) What is the association between serum testosterone concentration and incident depression in men? ii) What is the association between serum testosterone concentration and depression severity in men?

 

Inclusion criteria

Participants

This review will consider studies involving men at any age conducted in a non-acute or non-critical care setting. The participants will not be on testosterone replacement therapy or multiple hormonal replacement therapy (i.e., thyroxine, hydrocortisone, desmopressin). Studies with participants experiencing hypopituitarism from pituitary surgery or with traumatic brain injury will be excluded.

 

Exposure of interest

The exposure of interest is the endogenous testosterone concentration. Both serum and salivary sample for testosterone measurement will be included in the review. Blood sampling for studies measuring total testosterone must be obtained in the morning. All studies measuring total and testosterone fraction concentration will be included in the review.

 

Total testosterone should be measured with the liquid chromatography mass spectrometry or radioimmunoassay method. Free testosterone fraction should be measured directly with equilibrium dialysis or ultrafiltration method, or calculated using an algorithm based on various models of testosterone binding to SHBG or empirical equations. Bioavailable testosterone fraction should be measured through ammonium sulfate precipitation of SHBG-bound testosterone or concanavalin-A method, or calculated using empirical equations or based on law-of-mass action theory. Alternative methods or assays applied for measurement will be evaluated for validity and reliability during critical appraisal and data analysis. Assessment of free testosterone and bioavailable testosterone will require a valid SHBG measurement.50-55

 

Outcomes

This review will consider studies that include depression or incident depression outcomes. Depression or incident depression can be defined as follows:

 

i. A diagnosis of depression according to recognized and standardized clinical criteria, such as a structured clinical interview based on DSM-III-TR, IV or 5 criteria or International Classification of Diseases criteria M,2,3 or a diagnosis made by a qualified professional in medical records (e.g., psychiatrist, general physician). Depression will be considered as any MDD or dysthymia or other depression disorder.

 

ii. A validated self-administered depression questionnaire such as the Becks Depression Inventory-IA or II, Patient Health Questionnaire-9, Hospital Anxiety and Depression scale, Geriatric Depression Scale, Center for Epidemiologic Studies Depression Scale.38-45

 

iii. Composite of i and ii.

 

 

The definition of depression in each study included will be assessed and evaluated during critical appraisal and data analysis.

 

Types of studies

This review will consider analytical observational studies including prospective and retrospective cohort studies, case-control studies and analytical cross-sectional studies. This review will also consider descriptive cross-sectional studies for inclusion. Studies published in English or other languages with English translation will be included.

 

Methods

The proposed systematic review will be conducted in accordance with the JBI methodology for systematic reviews of etiology and risk.56 The study was registered with the International Prospective Register of Systematic Reviews (PROSPERO; reference number CRD42018108273).

 

Search strategy

The search strategy will aim to find both published and unpublished studies. An initial limited search of PubMed and Embase has been undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe articles. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all included reports and articles will be searched for additional studies.

 

Information sources

The databases to be searched will include PubMed, PsycINFO and Embase. The trial registers to be searched will include Cochrane Central Register of Controlled Trials, Australian New Zealand Clinical Trials Registry and the ISRCTN Registry. Search terms will include combinations of the following terms: testosterone, total testosterone, free testosterone, bioavailable testosterone, depression, depressive, major depression, men and male. The proposed search strategy from PubMed is presented in Appendix I.

 

Study selection

Following the search, all identified citations will be collated and uploaded into EndNote X8 (Clarivate Analytics, PA, USA) and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. Studies that may meet the inclusion criteria will be retrieved in full and their details imported into JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; Joanna Briggs Institute, Adelaide, Australia). The full text of selected studies will be retrieved and assessed in detail against the inclusion criteria. Full-text studies that do not meet the inclusion criteria will be excluded, and reasons for exclusion will be provided in an appendix in the final systematic review report. Included studies will undergo a process of critical appraisal. The results of the search will be reported in the final report and presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.57

 

Assessment of methodological quality

Selected studies will be critically appraised by two independent reviewers at the study level for methodological quality using standardized critical appraisal instruments from JBI for cohort studies, case-control studies and analytical cross-sectional studies.56 Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. The results of the critical appraisal will be reported in narrative or tabular formats. All studies, regardless of their methodological quality, will undergo data extraction and synthesis (where possible).

 

Data extraction

Data will be extracted from papers included in the review by two independent reviewers using the standardized data extraction tools in JBI SUMARI. The data extracted will include specific details about the exposure of interest including different exposure categories if applicable, populations, study methods and outcomes or dependent variables of significance to the review question and specific objectives. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. Authors of papers will be contacted to request missing or additional data where required.

 

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI SUMARI. All results will be subject to double-checking to ensure fidelity. Effect sizes expressed as odds ratio or hazard ratios (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard chi-square and I2 tests and explored using subgroup analyses based on any systematic differences between studies. Sensitivity analysis will be performed where possible. Potential subgroups will be based on study quality, differences in maternal demographics attrition rates, depression outcome (disorder diagnosis versus questionnaire), age at baseline (< 50 or >= 50 years), or alternatively as mean or median age in meta-regression. Due to the nature of observational studies, random effects models are most likely to be appropriate for meta-analysis. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation, where appropriate. Publication bias will be investigated using funnel plots and statistical analysis where there is a sufficient number of studies to do so (> 10).

 

Appendix I: Search strategy for PubMed

 

1. ((("testosterone" [MeSH Terms] OR "testosterone" [All Fields]) OR (("sex" [MeSH Terms] OR "sex" [All Fields]) AND ("steroids" [MeSH Terms] OR "steroids" [All Fields]))) OR ("gonadal steroid hormones" [MeSH Terms] OR ("gonadal" [All Fields] AND "steroid" [All Fields] AND "hormones" [All Fields]) OR "gonadal steroid hormones" [All Fields] OR ("sex" [All Fields] AND "hormone" [All Fields]) OR "sex hormone" [All Fields])) OR ("androgens" [Pharmacological Action] OR "androgens" [MeSH Terms] OR "androgens" [All Fields] OR "androgen" [All Fields])

 

2. ((("depressive disorder" [MeSH Terms] OR ("depressive" [All Fields] AND "disorder" [All Fields]) OR "depressive disorder" [All Fields] OR "depression" [All Fields] OR "depression" [MeSH Terms]) OR ("depressive disorder" [MeSH Terms] OR ("depressive" [All Fields] AND "disorder" [All Fields]) OR "depressive disorder" [All Fields])) OR ("depressive disorder, major" [MeSH Terms] OR ("depressive" [All Fields] AND "disorder" [All Fields] AND "major" [All Fields]) OR "major depressive disorder" [All Fields] OR ("major" [All Fields] AND "depressive" [All Fields] AND "disorder" [All Fields]) OR "major depressive disorder" [All Fields] OR "depressive disorder" [MeSH Terms] OR ("depressive" [All Fields] AND "disorder" [All Fields]) OR "depressive disorder" [All Fields] OR ("major" [All Fields] AND "depressive" [All Fields] AND "disorder" [All Fields]))) OR depressive[All Fields]

 

3. (("men" [MeSH Terms] OR "men" [All Fields]) OR ("male" [MeSH Terms] OR "male" [All Fields] OR "males" [All Fields])) OR ("male" [MeSH Terms] OR "male" [All Fields]

 

4. 1 AND 2 AND 3

 

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