Increased estrogen level can be associated with depression in males
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.
Section snippets
Study cohort
Data included to this study were obtained from the LIFE-Adult-Study, a population-based cohort study with more than 10,000 randomly selected deeply phenotyped adults aged 40–79 years. The LIFE-Adult-Study aimed to investigate the prevalences, early onset markers, genetic predispositions and role of lifestyle factors of major civilization diseases, particularly focused on obesity. This study was conducted by the Leipzig Research Centre for Civilization Diseases (LIFE) over 3 years (2011–2014).
Association between BMI and sex hormones
After exclusions, 2244 men <60 years old (47.6 ± 8.0 years) were included into analyses. In the study group, 34.5% were normal weight (mean BMI 23.1 ± 1.5 kg/m2), 44.8% were overweight (mean BMI 27.1 ± 1.3 kg/m2) and 20.6% were obese (mean BMI 33.5 ± 3.6 kg/m2). The sex hormone-binding globulin was significantly decreased in overweight (35.4 ± 14.1 nmol/L, p < 0.001) and obese men (31.8 ± 14.3 nmol/L, p < 0.001) compared to normal weight men (43.5 ± 16.0 nmol/L). A significant decrease in total testosterone level in
Discussion
We have shown that overweight and obese men have significant differences in serum sex hormone levels compared to normal weight individuals, and that BMI is the strongest predictor for these variations. We have also observed several hormonal differences between younger (<60 years old) and older (>60 years old) men, particularly in levels of free testosterone, bioavailable testosterone and estradiol with increasing BMI. Depressive symptomatology in younger men was significantly associated with
Conclusions
This is one of the first studies to show an association between higher estradiol levels and depression in younger men. Nevertheless, we did not confirm that this is directly associated with increased BMI in men, a condition also associated with altered sex hormone levels. As the prevalence of depression and obesity is increasing, there is an urgent need to elucidate the role of estrogens and BMI in the mechanism of depression in males. To this aim, studies of severely obese younger men would be
Funding
This work was supported by LIFE − Leipzig Research Center for Civilization Diseases, University of Leipzig. LIFE is funded by means of the European Union, by means of the European Social Fund (ESF), by the European Regional Development Fund (ERDF), and by means of the Free State of Saxony within the framework of the excellence initiative. The Integrated Research and Treatment Center Adiposity Diseases is funded by the German Federal Ministry of Education and Research (Grant 01EO1501). J.S. is
Contribution statement
All authors contributed to the study design and reviewed the manuscript critically and approved the final version. Daniela Stanikova made the conception and design of the study, analysed the data and wrote the manuscript; Yoon Ju Bae, Joachim Thiery, Uta Ceglarek, Christoph Engel, Kerstin Wirkner acquisited the data, Tobias Luck, Cornelia Enzenbach, Juraj Stanik, Juergen Kratzsch and Steffi Riedel-Heller contributed to interpretation of the data and critically revised the manuscript.
Acknowledgements:
We thank all people who participated in the studies. We very gratefully appreciate the help of physicians who performed the clinical examinations and data collection.
References (57)
Reproductive aging in men
Endocrinol. Metab. Clin. North Am.
(2013)- et al.
Object recognition memory deficit and depressive-like behavior caused by chronic ovariectomy can be transitorialy recovered by the acute activation of hippocampal estrogen receptors
Psychoneuroendocrinology
(2015) - et al.
Attenuating effects of testosterone on depressive-like behavior in the forced swim test in healthy male rats
Brain Res. Bull.
(2009) - et al.
The anxiolytic and antidepressant-like effects of testosterone and estrogen in gonadectomized male rats
Biol. Psychiatry
(2015) - et al.
Salivary testosterone: associations with depression, anxiety disorders, and antidepressant use in a large cohort study
J. Psychosom. Res.
(2012) - et al.
Soy protein isolate increases urinary estrogens and the ratio of 2:16alpha-hydroxyestrone in men at high risk of prostate cancer
J. Nutr.
(2007) - et al.
Effects of estrogen and testosterone treatment on serotonin transporter binding in the brain of surgically postmenopausal women? A PET study
Neuroimage
(2015) - et al.
Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: the Third National Health and Nutrition Examination Survey
J. Diabetes Complications
(2017) - et al.
Depressive symptoms in overweight and obese older adults: a test of the jolly fat hypothesis
J. Psychosom. Res.
(1996) - et al.
Establishing regional specificity of neuroestrogen action
Gen. Comp. Endocrinol.
(2014)
Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels
Metabolism
Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men
Biol. Psychiatry
Sex differences in psychopathology: of gonads, adrenals and mental illness
Physiol. Behav.
Reduced testosterone and adrenal C19 steroid levels in obese men
Metabolism
Testosterone, androstenedione and dihydrotestosterone concentrations are elevated in female patients with major depression
Psychoneuroendocrinology
The effect of aromatase on the reproductive function of obese males
Horm. Metab. Res.
Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone
Metabolism
New horizons in testosterone and the ageing male
Age Ageing
Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17beta-estradiol: a preliminary study
J. Clin. Psychiatry
The association between premature coronary artery disease and level of testosterone in young adult males
Arch. Iran. Med.
The neuroprotective actions of oestradiol and oestrogen receptors
Nat. Rev. Neurosci.
Comparing depression diagnostic symptoms across younger and older adults
Aging Ment. Health
Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo study
J. Clin. Endocrinol. Metab.
The benefits and risks of testosterone replacement therapy: a review
Ther. Clin. Risk Manag.
Testosterone levels and psychological health status in men from a general population: the Tromso study
Aging Male
Endogenous sex hormones in relation to age, sex, lifestyle factors, and chronic diseases in a general population: the Tromso study
J. Clin. Endocrinol. Metab.
The role of selective estrogen receptor modulators in the treatment of schizophrenia
Psychiatr. Danub.
Estrogen-related mood disorders: reproductive life cycle factors
ANS. Adv. Nurs. Sci.
Cited by (23)
Systematic review of sex differences in the relationship between hormones and depression in HIV
2022, PsychoneuroendocrinologyCitation Excerpt :One study of estradiol in men found men under 60 years old with depression had higher estradiol levels. Stanikova et al. (2018) Estradiol has been shown to regulate the expression of monoamine oxidases, the serotonin transporter, and the serotonin-1A receptor in women. Hernández-Hernández et al. (2019) Given the known role of serotonin and monoamine oxidases in depression, estradiol likely has profound impacts on depression in women.
Dynamics between psychological distress and body mass index throughout adult life; evidence from 3 large cohort studies
2021, Journal of Psychiatric ResearchCitation Excerpt :To explore the interplay between different facets of psychological distress, we used data from three large cohorts from different historical time points and two countries, accounting for changes in the shape of the distribution of BMI over the last 30 years. Owing to established sex and ethnic differences in the trajectories of BMI (Sacker and Wiggins, 2002) and the prevalence of mental disorders (Stanikova et al., 2018), RI-CLPM models were considered in males and females separately, and in blacks and whites separately in the United States cohort. We used data from one American cohort and two British birth cohorts, described in Fig. 1.
Testosterone, estradiol, DHEA and cortisol in relation to anxiety and depression scores in adolescents
2021, Journal of Affective DisordersCitation Excerpt :The hypothalamus-pituitary-gonadal (HPG) axis is also associated with internalizing behaviors, varying by gender and age. For females, there is a negative association between serum 17-β estradiol (estradiol) concentrations and severity of depressive syndromes (Baischer et al., 1995; Schmidt et al., 2000), while in adult men younger than 60 years old, higher estradiol level was associated with increased depressive symptomology, whereas in older men there were no differences (Stanikova et al., 2018). Testosterone has also been found to modulate depression and anxiety symptoms.
CYP19A1 rs2470152 polymorphism increases susceptibility to depression in Chinese Han population
2019, Neuroscience LettersCitation Excerpt :Nevertheless, an impact of the rs2470152 polymorphism on serum estrogen levels in males has also been reported [16]. Increased estradiol levels have been related to depressive symptoms in the young male population (<60 years), independently of body mass index [28]. It is thus likely that gender-related differences in the frequency of functional CYP19A1 polymorphisms can influence depression susceptibility and risk prediction.
Changes in gonadal function at different stages of chronic restraint stress-induced depression animals
2019, Physiology and BehaviorCitation Excerpt :In our study, serum E2 steadily increased during CRS, and the serum E2/T ratios were elevated. It is worth noting that sustained lower estrogen levels are associated with female depression [48], while depression in males is accompanied by increased levels of estrogen [41]. The differential effect of E2 on male and female emotions may, therefore, have a gender basis.