Increased estrogen level can be associated with depression in males

Highlights

• Overweight and obesity was associated with decreased levels of sex hormone-binding globulin, and total testosterone in men.

• Significantly increased estrogen level was only in overweight and obese men >60 years.

• Increased estrogen level was associated with depressive symptomatology regardless of BMI in younger men.

Abstract

Background

Several studies have shown a positive association between depression and obesity; however the underlying mechanisms are not fully understood. It is not known if this association is driven by altered sex hormone levels in men due to increased BMI.

Patients and methods

Data were obtained from the LIFE-Adult-Study, a population-based cohort study. A total of 3925 men (2244 < 60 years and 1681 > 60 years) were included into analyses. Associations between BMI, sex hormones and depressive symptomatology according to CES-D score were evaluated.

Results

Obese men had compared to normal weight controls lower total testosterone (12.6 ± 4.7 vs 19.4 ± 5.5 nmol/L, p < 0.001 in <60 years, and 13.8 ± 6.9 vs 18.3 ± 5.9 nmol/L, p < 0.001 in >60 years group) and free testosterone (249.0 ± 73.9 vs 337.2 ± 82.0 pmol/L, p < 0.001, and 217.8 ± 71.2 vs 263.4 ± 72.2 pmol/L, p < 0.001), and increased estradiol in older group only (97.3 ± 43.0 vs 82.3 ± 34.2 pmol/L, p < 0.001 in obese). Men <60 years old with depressive symptomatology had higher estradiol levels compared to those without depressive symptomatology (96.3 ± 40.7 vs 84.4 ± 36.6 pmol/L, p < 0.001), however no association with BMI was observed.

Conclusions

Selected sex hormone parameters were significantly different in overweight and obese compared to normal weight males and certain differences could be seen between younger and older males. Depressive symptomatology was associated with increased estradiol levels in younger men, regardless of BMI.

Introduction

According to World Health Organization (WHO), by 2020, depression will be the second leading cause of disability worldwide (WHO, 2001). Depression is one of the most common, serious and recurrent disorders. It is associated with diminished role functioning and poorer quality of life as well as with increased medical morbidity and mortality (Kessler and Bromet, 2013). Understanding of the etiology of depression is of key importance to developing and determining more focused and effective treatment strategies.

Although human and animal research has provided some information about etiology, the underlying mechanisms of depression are still subject to debate. Several psychosocial and biological factors have been shown to play a role in the etiopathogenesis of depression. Among psychosocial factors, lower socioeconomic status, financial, occupational and legal stressful life events and prior history of major depression were shown to be associated with depression in men (Kendler and Gardner, 2014). Among often-discussed biological factors are hormonal changes, particularly changes of sex hormones.

The important role of androgens and estrogens in the etiology of mental disorders is supported by several observations. One observation is that females are more than twice as likely as males to be afflicted by mood disorders (Kessler et al., 2005) with a higher incidence in times of hormonal flux such as puberty, perimenstrual and postpartum periods or menopause, mostly driven by changes in estrogen levels (Ahokas et al., 2001, Solomon and Herman, 2009). On the other hand, there is a lower incidence of depression in postmenopausal women connected to pituitary attenuance. Contrary to depression in females, depression prevalence in males increases with age and with a drop in plasma testosterone (Khera, 2013).

Testosterone is a major male sex hormone that plays a key role in the development of male reproductive tissues, sexual secondary characteristics, muscle and bone mass and well-being (Bassil et al., 2009). Testosterone levels decline gradually with age (Basaria, 2013), although several other factors (including obesity) contribute to its diminution also in younger men (Khera, 2013). It has been shown that a low testosterone level in hypogonadal men is associated with numerous non-specific symptoms including depression and anxiety (Alkamel et al., 2014, Khera, 2013). Among them, testosterone-replacement therapy has been shown to greatly improve mood, alleviate anxiety and mitigate symptoms of depression (Kanayama et al., 2007, Zarrouf et al., 2009). Jovanovic et al. also showed that testosterone modulates serotoninergic transmission playing a crucial role in the development of depression (Jovanovic et al., 2015). On the other hand, standard antidepressant treatment leads to the normalization of testosterone (Pope et al., 2003). These findings suggest a strong and also reciprocal relationship between testosterone and depression; not only that lower testosterone can lead to depression but also that depression can lower testosterone.

Estrogen, normally considered as a female hormone, plays a crucial role in a number of physiological functions in men, including bone metabolism, cardiovascular, testicular and sexual functions (Rambhatla et al., 2016). In men, the majority of circulating estradiol is primary derived from the peripheral aromatization of circulating testosterone by adipocytes (Lakshman et al., 2010), but also by certain tissues requiring the hormone for its normal tissue homeostasis, such as bones and the brain (Arevalo et al., 2015). The role of estradiol in the explanation of gender differences in schizophrenia prevalence (estrogen-protection hypothesis) is widely accepted (Bratek et al., 2016).

The association between estrogen and depression in men is not so far described.

Obesity can also be associated with changes in sex hormone levels (Lee et al., 2013). A study of obese men showed that BMI is negatively correlated with total testosterone concentration and positively correlated with estradiol (Vermeulen et al., 1993). These abnormalities are mediated by excessive adipose tissue leading to increased aromatase activity with the increased peripheral conversion of androgens to estrogens (Zumoff et al., 2003). The adipose tissue also affects hypothalamic-pituitary-testicular axis, reducing the release of gonadotropin. Also through other mechanisms adipose tissue and androgens influence each other in a bidirectional and reciprocal way (Lee et al., 2013).

A positive association between obesity and depression has been shown in several large studies and meta-analyses (Simon et al., 2006, Zhao et al., 2009). Luppino et al. showed that obese men have a 31% increased risk of developing depression over time, whereas depressive men do not have a significant risk of becoming obese (Luppino et al., 2010).

We suggest that obesity, sex hormones and depression are strongly interconnected; nevertheless the role of sex hormone alterations associated with increased BMI in men per se on depression is still not understood.

The aim of this study was to investigate the associations between 1. BMI and sex hormone levels, 2. depressive symptomatology and sex hormone levels, and 3. the role of BMI and altered sex hormone levels in depressive symptomatology in men.