Article

Testosterone, Gonadotropin, and Cortisol Secretion in Male Patients With Major Depression

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Abstract

Previous studies of sex hormone concentrations in depression yielded inconsistent results. However, the activation of the hypothalamic-pituitary-adrenal system seen in depression may negatively affect gonadal function at every level of regulation. The objective of this study was to explore whether major depressive episodes are indeed associated with an alteration of gonadal function. 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 in 22 healthy comparison subjects (age range 22-85 years). An analysis of covariance model showed that after adjustment for age only, daytime testosterone (p < .01), nighttime testosterone (p < .05), and 24-hour mean testosterone secretion (p < .01) were significantly lower in the depressed male inpatients. There was also a trend for a decreased LH pulse frequency in the depressed patients (p < .08). Gonadal function may be disturbed in men with a depressive episode of moderate to high severity.

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... In the "vitality" sub-study where fatigue was a major factor, testosterone therapy had very limited effectiveness [19]. It is noteworthy that exploring for depression is barely mentioned in two leading endocrine clinical practice guidelines regarding male hypogonadism [20,21] and further that only 6.3% of veterans of all ages receiving a prescription for testosterone had classical hypogonadism while the rest were eugonadotropic [17,20]. This is the first epidemiologic report on the associations of hypogonadism limited to men 40 and younger, excluding conditions known to result in hypogonadism. ...
... In the "vitality" sub-study where fatigue was a major factor, testosterone therapy had very limited effectiveness [19]. It is noteworthy that exploring for depression is barely mentioned in two leading endocrine clinical practice guidelines regarding male hypogonadism [20,21] and further that only 6.3% of veterans of all ages receiving a prescription for testosterone had classical hypogonadism while the rest were eugonadotropic [17,20]. This is the first epidemiologic report on the associations of hypogonadism limited to men 40 and younger, excluding conditions known to result in hypogonadism. ...
... What other findings support the concept of depression or stress-induced hypogonadism as a possible explanation for these results? Stress-induced hypogonadism occurs in depressed patients [20]. Reduced reactivity of the hypothalamic-pituitary-gonadal axis in depression [21] and a marked reduction in GnRH impulse strength due to fasting [22] are attributed to activation of the hypothalamic-pituitary-adrenal axis, which inhibits GnRH secretion. ...
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The specific objective of this study was to test the clinically derived hypothesis associating a high prevalence of depression in young men with non-classical hypogonadism. We studied the entire population of men, ages 18-40 who had an outpatient visit to an academic health system in the years 2013-2015. The study group included 186 patients with a diagnosis of eugonadotropic hypogonadism and a testosterone value below 10.4 nmol/L with no apparent cause. We compared their demographic factors, other diagnoses and treatments with a) the entire population, b) a matched population of 930 controls and c) 404 controls with normal testosterone determinations and no hypogonadism diagnosis. Depression, defined as either an ICD-9 diagnosis or treatment with an antidepressant medication was found in 22.6% of cases versus 6.6% of population controls (p<0.001), OR 1.13(1.09-1.17). Obesity was also higher in the cases p<0.001. The matched controls, had a depression rate of 13.4% compared to the cases (p<0.002), OR 1.14(1.08-1.17). Controls with normal testosterone determinations had a depression rate of 16.8% (p=0.121) OR 1.04(0.96-1.12), suggesting that clinicians may have ordered a testosterone determination because of symptoms consistent with both depression and hypogonadism. The high incidence of depression in non-classical hypogonadism in young men, while only associative, supports a depression evaluation and treatment as appropriate as well as investigation of the proximate causes of this form of hypogonadism.
... Circulating testosterone concentrations have not been consistently associated with major depressive disorder in men (128,129, [395][396][397][398]. Rather, testosterone levels appear to be associated with a late-life low grade persistent depressive disorder (dysthymia) (128,129, [395][396][397][398]. Intervention trials have failed to demonstrate statistically significant or clinically meaningful improvements in patients with major depressive disorder (399). ...
... Circulating testosterone concentrations have not been consistently associated with major depressive disorder in men (128,129, [395][396][397][398]. Rather, testosterone levels appear to be associated with a late-life low grade persistent depressive disorder (dysthymia) (128,129, [395][396][397][398]. Intervention trials have failed to demonstrate statistically significant or clinically meaningful improvements in patients with major depressive disorder (399). ...
Chapter
In male mammals, changes at all levels of the hypothalamic-pituitary-testicular axis, including alterations in the GnRH pulse generator, gonadotropin secretion, and testicular steroidogenesis, in addition to alterations of feed-forward and feed-back relationships contribute to the age-related decline in circulating testosterone concentrations. The rate of age-related decline in testosterone levels is affected by the presence of chronic illness, adiposity, medication, sampling time, and the methods of testosterone measurement. Epidemiologic surveys reveal an association of low testosterone levels with changes in sexual function, body composition, physical function and mobility, and increased risk of diabetes, late life persistent depressive disorder (dysthymia), unexplained anemia of aging, osteoporosis and bone fractures. Age-related decline in testosterone should be distinguished from classical hypogonadism due to known diseases of the hypothalamus, pituitary, and the testis. In young hypogonadal men who have a known disease of the hypothalamus, pituitary, and testis, testosterone therapy is generally beneficial and has been associated with a low frequency of adverse events. However, neither the long-term benefits in improved health outcomes nor the long-term risks of testosterone therapy are known in older men with age-related decline in testosterone levels. Well-conducted randomized trials have found that testosterone replacement of older men with unequivocally low testosterone levels improves sexual desire, erectile function, and overall sexual activity; lean body mass, muscle strength and some measures of physical function and mobility; areal and volumetric bone density and bone strength; depressive symptoms; and corrects anemia of aging. Testosterone treatment does not worsen lower urinary tract symptoms but the effects of long-term testosterone treatment on the risk of prostate cancer and major adverse cardiovascular events remain unknown. Although testicular morphology, semen production, and fertility are maintained up to a very old age in men, there is clear evidence of decreased fecundity with advancing age and an increased risk of specific genetic disorders related to paternal age among the offspring of older men. Thus, reproductive aging of men is emerging as an important public health problem whose serious societal consequences go far beyond the quality-of-life issues related to low testosterone levels. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
... Circulating testosterone concentrations have not been consistently associated with major depressive disorder in men (117,118,(307)(308)(309)(310). Rather, circulating testosterone levels appear to be associated with a late-life low grade persistent depressive disorder (dysthymia) (117,118,(307)(308)(309)(310). ...
... Circulating testosterone concentrations have not been consistently associated with major depressive disorder in men (117,118,(307)(308)(309)(310). Rather, circulating testosterone levels appear to be associated with a late-life low grade persistent depressive disorder (dysthymia) (117,118,(307)(308)(309)(310). Intervention trials have failed to demonstrate statistically significant or clinically meaningful improvements in patients with major depressive disorder (311). ...
Chapter
In male mammals, changes at all levels of the hypothalamic-pituitary-testicular axis, including alterations in the GnRH pulse generator, gonadotropin secretion, and testicular steroidogenesis, in addition to alterations of feed-forward and feedback relationships contribute to the age-related decline in circulating testosterone concentrations. The rate of age-related decline in testosterone levels is affected by the presence of chronic illness, adiposity, medication, sampling time, and the methods of testosterone measurement. Epidemiologic surveys reveal an association of low testosterone levels with changes in body composition, physical function and mobility, risk of diabetes, metabolic syndrome, coronary artery disease, and fracture risk. Age-related decline in testosterone should be distinguished from classical hypogonadism due to known diseases of the hypothalamus, pituitary and the testis. In young hypogonadal men who have a known disease of the hypothalamus, pituitary and testis, testosterone therapy is generally beneficial and has been associated with a low frequency of adverse events. However, neither the long-term benefits in improved health outcomes nor the long-term risks of testosterone therapy are known in older men with age-related decline in testosterone levels. Well-conducted studies of up to one-year duration have found improvements in sexual desire, erectile function, and overall sexual activity; mobility; and volumetric bone density, and correction of anemia with testosterone replacement of older men with unequivocally low testosterone levels. Although testicular morphology, semen production, and fertility are maintained up to a very old age in men, there is clear evidence of decreased fecundity with advancing age and an increased risk of specific genetic disorders related to paternal age among the offspring of older men. Thus, reproductive aging of men is emerging as an important public health problem whose serious societal consequences go far beyond the quality of life issues related to low testosterone levels. Freely available at Endotext.org
... 15 However, testosterone-depression studies have similarly been inconsistent, 16 with reliable effects observed only in certain sub-populations, especially older, hypogonadal men. [17][18][19][20] Cortisol and testosterone are both stress-reactive, 21 suggesting prior mixed findings may be due, in part, to a lack of considering environmental stress. Understanding the role of endocrine systems in depression may be informed by examining how hormones are influenced by stress, and in turn, how hormonal activity moderates the stress response. ...
... Overall, the findings support simultaneous examination of basal and endocrine stress-reactivity markers, and baseline depression severity within a diathesis-stress framework when estimating risk for depression. The finding that low testosterone elevated risk for stressevoked depression is consistent with sex differences in depression prevalence, 15 findings linking low testosterone to depression, [17][18][19] and evidence that testosterone ameliorates depression. 35 However, contrary to predictions, testosterone reactivity amplified the depressogenic impact of monthly stressors. ...
Article
Introduction The major challenges of efforts to reveal biological risk factors and biomarkers of depression include the complexity of underlying systems, interactions with other systems, and contextual factors governing their expression. Altered endocrine function is believed to be a central contributor to depressive illness, but across studies, evidence for a link between endocrine markers and depression has been mixed, inconclusive, or conditional in nature. In the present study, we evaluated basal testosterone (T), cortisol (C), and CO2 inhalation-stress-reactivity measures of these hormones (TR, CR) as pre-deployment moderators of the later impact of war-zone stressors on depression symptoms in-theater. Materials and Methods At pre-deployment, U.S. soldiers (N = 120) completed demographic, clinical and hormone measures, and during deployment, they completed monthly, web-based assessments of war-zone stressors and depression symptoms (N = 533 observations). Mixed effects models estimated the effects of the pre-deployment hormone profiles in moderating war-zone stressors’ impact on in-theater depression. Models also tested whether hormonally linked risk for later stress-evoked depression depends on pre-existing depression. Results Controlling for pre-deployment depression, high T was protective; whereas TR had depressogenic effects that were amplified by pre-deployment depression. Further, high C was protective, but heightened CR was depressogenic, but only among those with elevated pre-deployment depression. Conclusions Findings highlight the importance of examining basal and reactivity measures of endocrine function, and use of prospective, longitudinal models to test hypothesized causal pathways associated with depression vulnerability in the war-zone. Results also suggest that pre-existing depression and cortisol may work in tandem to increase vulnerability for later stress-evoked depression in the war-zone.
... This same study did not find any significant differences between oral testosterone, testosterone gel, oral dehydroepiandrosterone or intramuscular testosterone use. The same study showed that in these men, depression was associated with a decrease in total or plasma concentrations of testosterone [76]. In another study, hypogonadal men with MDD who were unresponsive to SSRIs showed improved response after testosterone replacement therapy (TRT) [77,78]. ...
Article
Full-text available
Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically.
... First, low levels of testosterone are associated with depression (Davies et al., 1992;Rubin, 1981;Rubin, Poland & Lesser, 1991;Schweiger et al., 1999;Unden et al., 1988;Vogel, Klaiber & Broverman, 1978;Yesavage et al., 1985). It has frequently been found that patients with major depression report diminished sexual desire or libido, which is indicative of reduced testosterone. ...
... Psychological factors such as stress and worry which were reported in the present clinical trial have been listed as the causes of poor digestion (ajirna) leading to poor nutrition and oligozoospermia. Experimental studies show that there is hypothalamic testicular suppression due to stress which results in deranged spermatogenesis leading to oligozoospermia [19] . ...
Article
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Background: Parenthood is one most desired goal of every couple, and failure to procreate causes great anguish. Infertility is a social stigma at many places in India dominated by illiteracy and lower socioeconomic standards. It affects the psychological harmony, marital life and social functioning of those affected. Infertility is the inability of a sexually active, non-contracepting couple to achieve spontaneous pregnancy in 1 year. Shodhana(bio-purification) is recommended in such cases to enhance the effects of ayurvedic anti infertility therapy (vajikarana). Virechana(therapeutic purgation) is largely indicated for cases having a semen abnormality (shukra dushti). Phala Ghrita (PG) is a poly herbal formulation reported to be useful in improving fertility.. Aim: This study aimed to evaluate efficacy of Phala Ghrita oral administration after performing a course of virechana in cases of oligozoospermia. Materials and Methods: 51 eligible male participants between the age of 21 and 40 years, with sperm count <15 million/ml, received Phala Ghrita for 8 weeks in the dose of 10g, after undergoing virechana. Percentage changes in the semen parameters and associated symptoms of oligozoospermia in comparison to baseline were the primary outcomes measured. Results: Phala Ghrita administered after virechana provided increase of 66.07 % in total sperm count, 45.19% increase in sperm motility, 15.73% increase in normal form of total sperm, 40.62% decrease in abnormal forms, and increase in semen volume by 43.12%.. Conclusion: Administration of Phala Ghrita after performing virechana provided statistically highly significant improvement on various seminal parameters related to male infertility including oligozoospermia..
... Given the apparent gap in multimodal studies of outcome prediction in MDD, we have combined a range of clinical and biomarker predictors that have shown significant associations to MDD in previous works but are yet to be used for ML-based rehospitalization trajectory modelling. Modalities used included clinical 18 , blood biomarker [19][20][21] , structural imaging 16 , electrocardiography 22 , genetic 23 , cognitive 24 , nutritional 25 , sleep 26 , and exercise 27 . Using these modalities, we predicted rehospitalization in a cohort of patients within 2 years of initial hospitalization for an acute episode of MDD. ...
... In the case of MDD, controversial results about testosterone levels and depressive symptoms have been reported (Barrett-Connor, Von Muhlen, & Kritz-Silverstein, 1999) (Davies et al., 1992;Kaneda & Fujii, 2002;McIntyre et al., 2006;Schweiger et al., 1999). As observed by Fiacco, Walther, and Ehlert (2019), the higher the level of testosterone, the less depressive symptoms in men, whereas in women results depend on their menopausal status. ...
Article
Objective: to compare testosterone levels between female depressed patients and female bipolar patients. Methods: Sixty-one female patients with major depressive disorder (MDD) (n = 23) or bipolar disorder (BD) (n = 38) between 18 and 45 years old were included in the study. Participants were evaluated during a depressive or manic episode with the Hamilton depression rating scale (HDRS) or Young mania rating scale (YMRS), respectively. No patients in the MDD group were taken valproate while in the BD group 14 (36.84%) were taken valproate. Total testosterone (TT) and free testosterone (FT) levels were quantified during the early follicular phase of the cycle, with radioimmunoassay or solid phase enzyme-linked immunoassay. Data were collected from May 2016 to February 2017. Results: Mean TT serum levels were significantly higher in BD patients in comparison to MDD patients. Although age and diagnosis were related to TT levels, however when we added valproate use in the analysis, only the relation between TT and valproate use remained significant. Conclusions: In this sample, TT levels were related to valproate use in patients with BD. More studies regarding the role of testosterone in affective symptoms should be conducted to clarify the relation between testosterone, affective disorders, and medication. • Keypoints • We observed that testosterone levels were significant higher in bipolar women compared to women with MDD. • The use of valproate could be associated with the testosterone levels in female patients with BD. • Evaluation of women suffering BD should include a testosterone levels determination, particularly when they are taking valproate.
... Testosterone replacement therapy (TRT) is increasingly promoted and suggested to be a possible curative way for the adverse effect of low testosterone on CVDs in elderly men. Whereas, the effectiveness of TRT in hypogonadal men has been shown to be effective in alleviating the symptoms of fatigue, sexual dysfunction, depression, decreased bone density, decreased muscle mass, among others [138][139][140][141], uncertainties remain with respect to cardiovascular safety for its use. In 2004, a committee on assessing the need for clinical trial of testosterone replacement therapy by Institute of Medicine (IOM) in a review concluded largely based on placebo control trials and show that there is no clear evidence on benefit of the heath outcome examined. ...
... A number of studies reported that low T is associated with behavioral changes, including "decreased libido, fatigue, irritability, dysphoria, sleep disturbances, low dominance, loss of memory and headaches", and T therapy (TTh) appears to improve many of these symptoms [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]. However, it remains unclear if men with psychiatric diagnoses of depressive illness may exhibit lower T levels [31] attributed to loss of feedback mechanism on the hypothalamic-pituitary-adrenal (HPA) axis, resulting in lower luteinizing hormone (LH) and T levels [32]. ...
Background During the past 50 years, motivational studies have evolved from the logical inference of logically required “intervening variables” to explain behavioral change, to electrophysiological and molecular analyses of the mechanisms causing such changes. Aim The purpose of this review article is two-fold: first to describe the logic of sexual motivation in a way that applies to laboratory animals as well as humans, and the second is to address some of the problems of sexual motivation experienced by men. Results When problems of motivational mechanisms are stripped down to their essentials, as performed in the laboratory animal models and are available for reductionistic studies, then the problems can be solved with certainty, as illustrated in the first part of this review. However, with respect to human sexual motivation, the various determinants which include so many behavioral routes and so many brain states come into play, that definite conclusions are harder to come by, as illustrated in the second part of this review. Conclusions This review highlights a number of key questions that merit further investigation. These include (a) What mechanisms do cultural and experiential influences interact with androgenic hormone influences on human sexual motivation? (b) How would epigenetic effects in the human brain related to changes in motivation be investigated? (c) What are the effects of unpredictable traumatic and stressful human experiences on sexual motivation; (d) How such mechanisms are activated upon unpredictable traumatic and stressful insults? (e) What are the outstanding differences between sexual motivational drive and motivations driven by homeostatic systems such as hunger and thirst?
... Testosterone, a product of the hypothalamic-pituitary-gonadal (HPG) axis, has been consistently found to be positively related to delinquency (Banks & Dabbs, 1996), aggression (Grotzinger ete al., 2018), antisocial behavior (Dabbs & Morris, 1990), dominance (Mehta & Josephs, 2010;Prasad et al., 2017), and risk-taking (Mehta, Welker, Zilioli, & Carré, 2015) in both males and females. Individuals with higher than average levels of testosterone are more likely to engage in externalizing behaviors such as aggression, while those with low levels of testosterone demonstrate more internalized emotional dysfunction, including depression (Giltay et al., 2012;Schweiger et al., 1999) and anxiety (Giltay et al., 2012). ...
Article
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The current study provides a test of General Strain Theory by examining the relations between strain, negative emotions, and biological hormones in the prediction of antisocial behavior across gender. Findings from a diverse sample of 512 undergraduate students reveal that strain and the ratio between testosterone to cortisol reactivity are associated with higher levels of antisocial behavior in males, but not females. In contrast, the effect of depressive symptoms on antisocial behavior is stronger at higher levels of strain and ratio of testosterone to cortisol reactivity in females. Drug use and depressive symptoms were found to partly mediate the association between strain and antisocial behavior in females, but not males.
... Given the apparent gap in multimodal studies of outcome prediction in MDD, we have combined a range of clinical and biomarker predictors that have shown significant associations to MDD in previous works but are yet to be used for ML-based rehospitalization trajectory modelling. Modalities used included clinical 18 , blood biomarker [19][20][21] , structural imaging 16 , electrocardiography 22 , genetic 23 , cognitive 24 , nutritional 25 , sleep 26 , and exercise 27 . Using these modalities, we predicted rehospitalization in a cohort of patients within 2 years of initial hospitalization for an acute episode of MDD. ...
Article
Full-text available
Machine learning methods show promise to translate univariate biomarker findings into clinically useful multivariate decision support systems. At current, works in major depressive disorder have predominantly focused on neuroimaging and clinical predictor modalities, with genetic, blood-biomarker, and cardiovascular modalities lacking. In addition, the prediction of rehospitalization after an initial inpatient major depressive episode is yet to be explored, despite its clinical importance. To address this gap in the literature, we have used baseline clinical, structural imaging, blood-biomarker, genetic (polygenic risk scores), bioelectrical impedance and electrocardiography predictors to predict rehospitalization within 2 years of an initial inpatient episode of major depression. Three hundred and eighty patients from the ongoing 12-year Bidirect study were included in the analysis (rehospitalized: yes = 102, no = 278). Inclusion criteria was age ≥35 and <66 years, a current or recent hospitalisation for a major depressive episode and complete structural imaging and genetic data. Optimal performance was achieved with a multimodal panel containing structural imaging, blood-biomarker, clinical, medication type, and sleep quality predictors, attaining a test AUC of 67.74 (p = 9.99−05). This multimodal solution outperformed models based on clinical variables alone, combined biomarkers, and individual data modality prognostication for rehospitalization prediction. This finding points to the potential of predictive models that combine multimodal clinical and biomarker data in the development of clinical decision support systems.
... 42 Furthermore, it is not surprising that a diagnosis of major depression appears to affect gonadal function. Men with depressive episodes of moderate-to-severe severity have been shown to have lower levels of testosterone 43 as well as lower sex hormone-binding globulin and DHEA-S, higher secretion of cortisol and prolactin, and lower semen volume and sperm density. 44 Given the widespread and often long-term use of antidepressant medications, there is a clear need for further data regarding their impact on semen quality and male fertility. ...
Article
Antidepressant medications are commonly used in males of reproductive age for long‐term treatment of depression, as well as other disorders. Although antidepressants are known to be associated with sexual side‐effects, their effects on semen parameters and other markers of male fertility have been less thoroughly described. The majority of available studies have focused on selective serotonin reuptake inhibitors, which have been shown to negatively impact semen quality in in vitro, animal and human studies. Fluoxetine, in particular, has been the subject of multiple studies and has been associated with gonadotoxic effects, including decreased sperm concentration and motility, increased deoxyribonucleic acid fragmentation, and decreased reproductive organ weights. Studies of several other selective serotonin reuptake inhibitors have yielded similar results. Reassuringly, this effect does seem to be reversible. The data regarding serotonin–norepinephrine reuptake inhibitors, norepinephrine–dopamine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors and atypical antidepressants are sparse, varied and conflicting. Given the widespread and often long‐term use of antidepressant medications, there is a clear need for further data regarding their impact on semen quality and male fertility.
... Antidepressant effects of oestrogen were observed in several animal studies 29,30 and have been shown to be dose and receptor-dependent 31 . While alterations in testosterone levels are largely accepted to influence the pathogenesis of depression in men [32][33][34][35] , recent findings suggest that testosterone may play a critical role in depression susceptibility in women as well, although the findings are mixed [36][37][38] . While the concentration of testosterone in women is ten times lower than in men 39 , it has been shown that women are more sensitive to it 40 . ...
Article
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Accumulating evidence supports a link between depression and being overweight in women. Given previously reported sex differences in fat accumulation and depression prevalence, as well as the likely role of sex hormones in both overweight and mood disorders, we hypothesised that the depression-overweight association may be mediated by sex hormones. To this end, we investigated the association of being overweight with depression, and then considered the role of sex hormones in relation to being overweight and depression in a large population-based cohort. We included a total of 3124 women, 970 premenopausal and 2154 postmenopausal from the LIFE-Adult cohort study in our analyses. We evaluated associations between being overweight (BMI >25 kg/m2), sex hormone levels, and depressive symptomatology according to Centre for Epidemiologic Studies Depression (CES-D) scores, and explored mediation of depression in a mediation model. Being overweight was significantly associated with depressive symptoms in premenopausal but not postmenopausal women. Both premenopausal and postmenopausal overweight women had higher free testosterone levels compared with normal weight women. Premenopausal women with depressive symptomatology had higher free testosterone levels compared to women without. We found a significant mediation effect of depressive symptomatology in overweight premenopausal women through free testosterone level. These findings highlight the association between being overweight and depressed, and suggest that high free testosterone levels may play a significant role in depression of overweight premenopausal women. Based on this, pharmacological approaches targeting androgen levels in overweight depressed females, in particular when standard anti-depressive treatments fail, could be of specific clinical relevance.
... Moreover, several studies suggest a negative association between testosterone and depressive symptoms only to be present in subgroups of men, such as hypogonadal or elderly men (2001b, Seidman, Araujo et al., 2001, 2002, and subtypes of depression, including atypical depression (Rodgers et al., 2015). Furthermore, studies investigating basal testosterone levels in explicitly depressed compared with non-depressed men, suggest a link between reduced testosterone levels in men diagnosed with major depressive disorder (MDD) (McIntyre et al., 2006;Schweiger et al., 1999;Shores et al., 2004), however, no association has also been reported (Asselmann et al., 2019;Davies et al., 1992;Rubin, Poland, & Lesser, 1989;Sigurdsson, Palsson, Aevarsson, Olafsdottir, & Johannsson, 2014). Studies focusing on dysthymic disorder demonstrate a more consistent association with reduced testosterone levels and mood impairment (Markianos, Tripodianakis, Sarantidis, & Hatzimanolis, 2007;Seidman et al., 2002). ...
Article
Background: Rodent and human studies indicate that testosterone has an antidepressant effect. The mechanisms via which testosterone exerts its antidepressant effect, however, remain to be elucidated. Some studies assume downstream effects of testosterone on sexual function and vitality followed by improvement of mood. Emerging evidence suggests that testosterone may be acting in the brain within depression-relevant areas, whereby eliciting direct antidepressant effects, potentially via neuroplasticity. Methods: Literature was searched focusing on testosterone treatment and depression and depression-like behavior. Due to the unilateral clinical use of testosterone in men and the different modes of action of sex hormones in the central nervous system in men and women, predominantly studies on male populations were identified. Results: The two proposed mechanisms via which testosterone might act as antidepressant in the central nervous system are the support of neuroplasticity as well as the activation of the serotonin system. Additionally, tes-tosterone downregulates glucocorticoid output and reduces levels of pro-inflammatory markers, thereby acting as important counter regulatory agent reducing levels of neurotoxic factors in the central nervous system. Conclusion: Although it is possible that testosterone acts via the serotonin system or the downregulation of the immune or hyperactive stress physiological systems, recent evidence supports the hypothesis that testosterone also elicits anti-depressant effects via directly promoting neuroplasticity. Potential implementations of testos-terone treatment in mood disorders are discussed.
... In men, a relationship between depression and a reduction in total or plasma concentrations of testosterone has been observed [143,144]. Moreover, hypogonadal men with MDD who are insensitive to SSRI treatment showed improved antidepressant response following testosterone restitution [145,146]. ...
Article
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Major depressive disorder (MDD) is a debilitating chronic illness that is two times more prevalent in women than in men. The mechanisms associated with the increased female susceptibility to depression remain poorly characterized. Aberrant neuronal oscillatory activity within the putative depression network is an emerging mechanism underlying MDD. However, innate sex differences in network activity and its contribution to depression vulnerability have not been well described. In this review, current evidence of sex differences in neuronal oscillatory activity, including the influence of sex hormones and female cycling, will first be described followed by evidence of disrupted neuronal circuit function in MDD and the effects of antidepressant treatment. Lastly, current knowledge of sex differences in MDD-associated aberrant circuit function and oscillatory activity will be highlighted, with an emphasis on the role of sex steroids and female cycling. Collectively, it is clear that there are significant gaps in the literature regarding innate and pathologically associated sex differences in network activity and that the elucidation of these differences is invaluable to our understanding of sex-specific vulnerabilities and therapies for MDD.
... Por ejemplo, la reserpina aumenta los niveles de hormonas tiroideas, en tanto que en humanos lo más común es que la depresión curse con hipotiroidismo (Ruiz et al.). Se conoce muy poco la manera en que la reserpina afecta otras variables relacionadas con depresión en humanos, tales como la espermatogénesis y los niveles de testosterona, que se encuentran en niveles más bajos en individuos deprimidos (Schweiger et al., 1999;Zarrouf et al., 2009). ...
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Reserpine, a drug that depletes central monoamines, has been used as an antipsychotic and arterial hypotensive, and to model depression in animals. The present study analyzed, in adolescent male rats, the effects of chronic reserpine treatment on molecular indexes of testicular function. A week after termination of the treatment (4 doses of 0,0 or 1,0 mg/Kg/every 48 h) the animals were tested for anxiety response and depression patterns in an elevated plus maze. They were then euthanized, their testes dissected, fixed and embedded in paraffin to obtain blocks. Histological sections (6 µm) were obtained and used to measure the diameter of seminiferous tubules and the expression in Leydig cells of Brain-derived neurotrophic factor (BDNF), Proliferating cell nuclear antigen (PCNA), Caspase-3 and androgen receptors, by immunohistochemistry. Behavioral results indicated significant alterations in anxiety responses and a significant motor depression (e.g., greater latency to escape from the white sector). There were no differences between groups in the diameter of seminiferous tubules nor in the androgen receptors positivity. Reserpine-treated animals, however, exhibited more BDNF and PCNA positive cells, and less positive Caspase-3 cells in Leydig cells, than control animals. The results corroborate the efficacy of reserpine to reproduce some of the behavioral components of depression. The drug, however, does not seem to exert in rats the same effects on testicular function that have been found in humans diagnosed with depression. Furthermore the drug seems to enhance some aspects of testicular function related to Leydig cells function in rats
... Se ha sugerido que el riesgo de presentar la EA y la aparición/progresión de sus marcadores biológicos se asocia negativamente con los niveles de andrógenos en el envejecimiento. [156][157][158][159][160][161] los AndRógenos ModulAn lA exPResIón de lA PRoteínA tAu Existe muy poca información respecto al efecto de la DHEA o DHEA-S en la memoria y su relación con la hiperfosforilación de la proteína tau. Weill-Engerer et al. 162 encontraron que los pacientes con EA presentaron niveles disminuidos de DHEA-S en el estriado, cerebelo e hipotálamo cuando se comparan con los sujetos control igualados en edad. ...
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Aging and Alzheimer's disease (AD) are associated with a declination of cognition and memory, whose severity increases in AD. Recent investigations point to a greater participation of neurofibrillary tangles (NFTs) than that of senile plaques, as responsible for cognitive impairment in AD and normal aging. On the other hand, aging is related with reduced levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) as well as testosterone (T). Basic and clinical studies give evidence that hypoandrogenism is associated with memory impairment. Accordingly, some animal studies show that the administration of these hormones improves the performance of cognitive tasks. However, effects of DHEA, DHEA-S, and T in the clinical setting, are not clear in part because of the balance between the benefits and risks of hormone therapy in aging subjects and because the cellular mechanism underlying its effects on memory in old age and related pathologies are unknown. The objective of this review is to analyze the role of DHEA, DHEA-S, and T, on memory in normal aging and in AD, and to determine whether these hormones modulate the hyperphosphorylation of tau protein, a molecular marker in AD pathology. The method used in the review included articles from the PubMed database, using the following search terms: DHEA, DHEA-S, T, memory, androgen deprivation therapy, tau protein, aging, and AD. Finally, we analyze the use of these steroids as an adjunct in the treatment of memory deficits in aging subjects and AD patients.
... Psychological stress may also impair reproductive functions. Stress and depression are believed to decrease testosterone and LH pulses resulting in disruption of gonadal functions, which ultimately results in decline in normal sperm parameters (109,110). Women who obtain support and counselling for increased anxiety and depression levels have increased chances of becoming pregnant (111). Cigarette smoking in men results in decrease in semen volume (112), decline in total sperm count, abnormal morphology, motility and poor fertilizing capacity (113,114,115). ...
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Fertilization is a hallmark event of sexual reproduction marked by the fusion of male and female gamete to form zygote. It is a highly complex, yet a robust process that is intricately regulated by various signalling molecules. A healthy fertilization is determined by the quality of zygote which is contingent on the health of egg and sperm. The relationship between infertility and gametic health can be reciprocal. On one hand gametogenesis has to be dynamic and unremitting to sustain the reproductive health, while on the other hand it has to be error free for proper embryonic development. Complex cellular interactions make gametogenesis highly vulnerable to extrinsic as well as intrinsic intrusions. Molecular disparities during these phases may result in complete fertilization failure. Present review provides an overview of the regulation of gametogenesis, determinants of healthy gamete, players at fertilization window and what may go wrong during the development of zygote to embryo leading to implantation failure. We have outlined different 'windows' of vulnerability during gametogenesis supported by evidences affecting the fertility potential of both the partners.
... Psychological stress may also impair reproductive functions. Stress and depression are believed to decrease testosterone and LH pulses resulting in disruption of gonadal functions, which ultimately results in decline in normal sperm parameters (109,110). Women who obtain support and counselling for increased anxiety and depression levels have increased chances of becoming pregnant (111). Cigarette smoking in men results in decrease in semen volume (112), decline in total sperm count, abnormal morphology, motility and poor fertilizing capacity (113,114,115). ...
Article
Full-text available
Fertilization is a hallmark event of sexual reproduction marked by the fusion of male and female gamete to form zygote. It is a highly complex, yet a robust process that is intricately regulated by various signalling molecules. A healthy fertilization is determined by the quality of zygote which is contingent on the health of egg and sperm. The relationship between infertility and gametic health can be reciprocal. On one hand gametogenesis has to be dynamic and unremitting to sustain the reproductive health, while on the other hand it has to be error free for proper embryonic development. Complex cellular interactions make gametogenesis highly vulnerable to extrinsic as well as intrinsic intrusions. Molecular disparities during these phases may result in complete fertilization failure. Present review provides an overview of the regulation of gametogenesis, determinants of healthy gamete, players at fertilization window and what may go wrong during the development of zygote to embryo leading to implantation failure. We have outlined different 'windows' of vulnerability during gametogenesis supported by evidences affecting the fertility potential of both the partners.
... Sex differences in stress response and the prevalence of psychiatric disorders have also been linked to dysregulation of HPG function. Human studies have found deficits in gonadal function in MDD (Goldstein, et al, 2014;Rubinow & Schmidt, 1996;Harlow et al, 2003;Jacobs et al, 2014), including androgens (Rubinow & Schmidt, 1996;Schweiger et al, 1999;Weiner et al., 2004), estradiol (Young et al., 2000;Holsen et al, 2011;Jacobs et al, 2014;Harlow et al, 2003), and progesterone (Schiller et al., 2014). HPA (e.g., hypercortisolemia) and HPG (hypogonadal) deficits have also characterized people with psychotic disorders, such as schizophrenia and bipolar disorder (Collip et al., 2011;Walker & Diforio, 1997;Walder et al., 2000;Seeman & Lang et al., 1990;Canuso et al., 2000;Kulkami et al., 2001). ...
Article
Background: Maladaptive responses to negative affective stimuli are pervasive, including clinically ill and healthy people, and men and women respond differently at neural and hormonal levels. Inspired by the Research Domain Criteria initiative, we used a transdiagnostic approach to investigate the impact of sex and dysphoric mood on neural-hormonal responses to negative affective stimuli. Methods: Participants included 99 individuals with major depressive disorder, psychosis and healthy controls. Functional magnetic resonance imaging (fMRI) was complemented with real-time acquisition of hypothalamo-pituitary-adrenal (HPA) and -gonadal (HPG) hormones. fMRI data were analyzed in SPM8 and task-related connectivity was assessed using generalized psychophysiological interaction. Results: Across all participants, elevated cortisol response predicted lower brain activity in orbitofrontal cortex and hypothalamus-amygdala connectivity. In those with worse dysphoric mood, elevated cortisol response predicted lower activity in hypothalamus and hippocampus. In women, elevated cortisol response was associated with lower activity in medial prefrontal cortex and low hypothalamo-hippocampal connectivity. In women with high dysphoric mood, elevated cortisol response was associated with low hypothalamo-hippocampal connectivity. There were no interactions with diagnosis or medication. Limitations: There was limited power to correct for multiple comparisons across total number of ROIs and connectivity targets; cortisol responses were relatively low. Conclusions: We conclude that the pathophysiology in neural-hormonal responses to negative affective stimuli is shared across healthy and clinical populations and varies as a function of sex and dysphoric mood. Our findings may contribute to the development of hormonal adjunctive therapeutics that are sex-dependent, underscoring the importance of one's sex to precision medicine.
... In animal models, a possible effect of low testosterone levels on serotonin neurotransmission has been demonstrated [22]. Lower testosterone levels in elderly men have been associated with depression in several studies [23][24][25]. Also, there has been a dramatic improvement after testosterone replacement in hypogonadal men with depression [26][27][28]. ...
Article
Androgen deprivation is a therapeutic option for patients with prostate cancer (PC). However, it has negative effects on sleep quality and psychological condition. Here, we evaluated the appearance of sleep disturbances in patients on androgen deprivation therapy (ADT). We administered Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), Epworth Sleepiness Scale (ESS), and Fatigue Severity Scale (FSS) to consecutive prostate cancer patients who had undergone radical prostatectomy and are presently either under adjuvant ADT or followed in an unmedicated program (non-ADT). The results of the tests in ADT and non-ADT groups in addition to the demographic data and the features of the malignancy were statistically compared. Of the 106 patients enrolled, 48 (45.3%) were receiving adjuvant ADT and 58 (54.7%) were not. Age, disease duration, and education levels showed no difference between the two groups. Compared with the non-ADT group, the patients receiving ADT showed higher levels of depression, worse quality of sleep, and more severe fatigue (p < 0.001, for each). There was no significant difference among the two groups regarding excessive daytime sleepiness (p = 0.856). The mean PSQI scores showed a positive correlation with BDI and FSS scores (r = 0.710, p < 0.001; r = 0.528, p < 0.001, respectively). Additionally, ADT was strongly associated with PSQI and FSS scores at multivariate analysis (p = 0.037, p = 0.043, respectively). We conclude that PC patients receiving ADT are likely to be fatigued, more depressed, and had poorer sleep quality. Our study showed that receiving ADT therapy is strongly associated with poor sleep quality and fatigue.
... Numerous studies have tried to elucidate the link between sex steroids and sex differences in brain structure, but a plethora of contradictory findings have emerged at every level of development [10,12]. For example, patients suffering from schizophrenia and depression have been observed to exhibit both increases and decreases in sex steroids, compared to controls [13][14][15][16][17][18][19][20]. These conflicting findings suggest that other factors modulate CNS effects of sex steroids in humans. ...
Article
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Sex steroids are thought to play a critical developmental role in shaping both cortical and subcortical structures in the human brain. Periods of profound changes in sex steroids invariably coincide with the onset of sex differences in mental health vulnerability, highlighting the importance of sex steroids in determining sexual differentiation of the brain. Yet, most of the evidence for the central effects of sex steroids relies on non-human studies, as several challenges have limited our understanding of these effects in humans: the lack of systematic assessment of the human sex steroid metabolome, the different developmental trajectories of specific sex steroids, the impact of genetic variation and epigenetic changes, and the plethora of interactions between sex steroids, sex chromosomes, neurotransmitters, and other hormonal systems. Here we review how multimodal strategies may be employed to bridge the gap between the basic and clinical understanding of sex steroid-related changes in the human brain.
... In contrast to the notion that reduced T might promote nurturant behavior, low T can potentially contribute to the patho- physiology of depression due to the hormone's neuromodulatory effects and its interactions with other neuroendocrine systems implicated in mood disorders ( Ebinger et al., 2009;Kim and Swain, 2007). For men, evidence supporting this model emerges from a variety of research designs and sample populations, including large cross-sectional studies (Barrett-Connor et al., 1999;Booth et al., 1999), evaluations of depressed subjects in clinical settings ( Schweiger et al., 1999), and approaches that incorporate admin- istration of exogenous T to hypogonadal men and measure improvement in mood and depressive symptomology afterward ( Pope et al., 2014). It should also be noted that a number of studies have failed to support such a low T-depression link (reviewed in Ebinger et al., 2009). ...
Article
Partnered adults tend to have lower risks of depression than do single individuals, while parents are more commonly depressed than non-parents. Low testosterone men, and possibly women, are also at greater risk of depression. A large body of research has shown that partnered parents have lower testosterone than single non-parents in some cultural settings, including the U.S. Here, we drew on a large (n = 2438), U.S.-population representative cohort of reproductive aged adults (age: 38.1 years ± 11.1 SD) to test hypotheses regarding the intersections between partnering and parenting, testosterone, socio-demographic characteristics, and depression outcomes. Men and women's depression prevalence did not vary based on testosterone. Partnered fathers had lower testosterone than single (never married, divorced) non-fathers, but were less commonly depressed than those single non-fathers. Partnered mothers had reduced testosterone compared to never married and partnered non-mothers. Never married mothers had higher depression prevalence and elevated depressive symptomology compared to partnered mothers; these differences were largely accounted for by key health-related covariates (e.g. cigarette smoking, BMI). We found significant three-way-interactions between socioeconomic status (SES), testosterone, and parenting for adults' depression risks. High testosterone, high SES fathers had the lowest prevalence of mild depression, whereas low testosterone, low SES non-fathers had the highest. Compared to other mothers, low SES, low testosterone mothers had elevated prevalence of mild depression. Overall, low SES, high testosterone non-mothers had substantially elevated depression risks compared to other women. We suggest that psychobiological profiles (e.g. a male with low testosterone) can emerge through variable psychosomatic and psychosocial pathways and the net effect of those profiles for depression are influenced by the social (e.g. partnering and parenting status; socioeconomic gradients), cultural (e.g. gender and family life domains), and ecological (e.g. the lived environment, particularly related to low SES and poverty) contexts in which individuals find themselves.
... [1][2][3] Los trastornos psiquiátricos como la depresión también se presentan o exacerban con cambios en la condición endocrina; de hecho, varios autores han encontrado una correlación negativa entre los niveles de testosterona (T) en pacientes hipogonadales y la gravedad de la sintomatología depresiva. 4,5 Una observación interesante sobre esta relación es que la terapia con andrógenos anabólicos reduce los síntomas depresivos en los pacientes hipogonadales, de manera similar a como lo hacen los fármacos antidepresivos tradicionales, [6][7][8] lo que sugiere una interacción entre los andrógenos, los circuitos cerebrales y los sistemas de neurotransmisión que participan en la regulación del estado de ánimo y los trastornos afectivos. Como una confirmación de esta idea, dos estudios han reportado que el tratamiento de restitución hormonal con T recupera el efecto antidepresivo de los inhibidores selectivos de la recaptura de serotonina (ISRS) en pacientes hipogonadales deprimidos, refractarios a dichos tratamientos. ...
Article
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It has been proposed that gonadal hormones participate in regulation of mood and emotion in men as well as in the effect of psychoactive drugs, such as antidepressants. However, evaluation of this type of interactions has been poorly studied in clinic and basic studies. The objective of the present study was to determine the role of gonadal hormones, testosterone (T) and 17 beta-estradiol (E-2), one of its main metabolites, in the effect of two antidepressant drugs: desipramine and fluoxetine. The former is a tricyclic antidepressant that inhibits noradrenaline reuptake in a preferential manner, while the second is a serotonin selective reuptake inhibitor (SSRI) and the most prescribed antidepressant. Behavioral evaluations were conducted in adult male rats, intact or orchidectomized (Orx), treated with T (0-2 mg/rata), E-2 (0-40 mu g/rata), desipramine (0-20 mg/kg), fluoxetine (0-20 mg/kg) and their combinations. Forced swimming test was used as an animal model to detect antidepressant-like effect induced by treatments, on the basis of its predictive validity. We found that desipramine and fluoxetine produced an antidepressant-like effect in gonadally intact male rats. However, the antidepressant-like effect of both treatments was cancelled in Orx males. Treatment with E-2, but not with T, produced antidepressant-like actions in Orx males. Interestingly, treatment with E-2 restored the antidepressant-like effect of desipramine and fluoxetine, while supplementation with T only reestablished the antidepressant-like action of desipramine, evidencing that gonadal hormones have a differential participation in regulation of neurotransmitter systems involving in the antidepressant effect. In conclusion, the main testicular androgen T, participates in the expression of the effect of antidepressant drugs, mainly via conversion to its estrogenic metabolite E-2. These results give support to the idea that a combined therapy of gonadal hormones and antidepressant drugs may be more convenient to treat depressive disorders in hypogonadal men resistant to conventional antidepressant drugs.
... Gonadal hormones are potent behavioral mediators, with increased testosterone expression resulting in elevated aggression [ 195,196 ] . A number of studies have reported associations between low testosterone and major depression [ 197 ] , which has been demonstrated to improve following testosterone treatment [ 198 ] . The HPG axis interacts with both the neuroimmune system and the HPA axis. ...
Article
Depression is a common comorbid condition in substance abuse disorders. In particular, comorbidity between alcoholism and depression occurs with extremely high prevalence in the general population. Early studies investigating this dual diagnosis issue reported alcohol abuse to occur in almost a quarter of patients with affective disorders [1, 2]. Prevalence rises as high as 32 % if other substance abuse disorders are included [2]. These findings made it clear that enormous challenges lie ahead in tracing the individual etiology of substance abuse and depression, let alone their interaction. Clearly, this dilemma was to produce further difficulties in providing adequate and appropriate treatment for sufferers. © 2013 Springer Science+Business Media New York. All rights are reserved.
... Although cases of major depression are not observed very often, one of the most common diseases at that age is dysthimia. Men with dysthimia have a lower testosterone level than healthy men (Schweiger et al., 1999). In studies on men who underwent chemical castration to prostate cancer, concentration and memory worsened. ...
Article
Late-onset hypogonadism: Review of the problem The study investigates late-onset hypogonadism (LOH), its influence on male joint system, build, cardiovascular system, haematopoesis, cognitive functions, and sexual function. LOH is a clinical and biochemical syndrome, which is related to aging and characterised by typical symptoms and a decreased serum testosterone level. It causes a worsened life quality, and the functions of various organs are badly affected. LOH is diagnosed when the testosterone level is below 8 nmol/l (230 ng/dl) or it is at the border-line (from 8 and 12 nmol/l) and there are LOH clinical symptoms such as a decreased libido, erectile dysfunction, reduced muscular mass and strength, increased obesity, reduced bone mineral density, osteoporosis, and depression. All patients with LOH are indicated testosterone replacement therapy (TRT). TRT is contra-indicated to patients suffering from prostate or thoracic gland carcinoma. In case of erythrocytosis (haematocrit > 52%), severe heart failure, marked prostate benign hyperplasia with the obstruction of urine pathways, and obstructive sleep apnoe syndrome, TRT is relatively contra-indicated and should not be started unless these dysfunctions are cured. The treatment of LOH requires thorough patient monitoring, which includes digital rectal examination and Prostate Specific Antigen conducted after 3-6 months and 12 months in the first treatment year. It is necessary to determine the total blood count after 3-4 and 12 months in the first treatment year and afterwards once a year.
Article
Background Depression is a common disorder that affects millions globally and is linked to reduced quality of life and mortality. Its pathophysiology is complex and there are several forms of treatment proposed in the literature with differing side effect profiles. Many patients do not respond to treatment which warrants augmentation with other treatments and the investigation of novel treatments. One of these treatments includes testosterone therapy which evidence suggests might improve depressed mood in older patients with low levels of testosterone and helps restore physical impairments caused by age-related hormonal changes. Objective The objective of this review is to synthesize information regarding clinical depression, its treatment options, and the efficacy and safety of testosterone treatment for the treatment of depression. Methods This review utilized comprehensive secondary and tertiary data analysis across many academic databases and published work pertaining to the topic of interest. Results Within some subpopulations such as men with dysthymic disorder, treatment resistant depression, or low testosterone levels, testosterone administration yielded positive results in the treatment of depression. Additionally, rodent models have shown that administering testosterone to gonadectomized male animals reduces symptoms of depression. Conversely, some studies have found no difference in depressive symptoms after treatment with testosterone when compared with placebo. It was also noted that over administration of testosterone is associated with multiple adverse effects and complications. Conclusion The current evidence provides mixed conclusions on the effectiveness of testosterone therapy for treating depression. More research is needed in adult men to see if declining testosterone levels directly influence the development of depression.
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Considerable research has shown that testosterone regulates many physiological systems, modulates clinical disorders, and contributes to health outcome. However, studies on the interaction of testosterone levels with depression and the antidepressant effect of testosterone replacement therapy in hypogonadal men with depression have been inconclusive. Current findings indicate that low circulating levels of total testosterone meeting stringent clinical criteria for hypogonadism and testosterone deficiency induced by androgen deprivation therapy are associated with increased risk for depression and current depressive symptoms. The benefits of testosterone replacement therapy in men with major depressive disorder and low testosterone levels in the clinically defined hypogonadal range remain uncertain and require further investigation. Important considerations going forward are that major depressive disorder is a heterogeneous phenotype with depressed individuals differing in inherited polygenic determinants, onset and clinical course, symptom complexes, and comorbidities that contribute to potential multifactorial differences in pathophysiology. Furthermore, polygenic mechanisms are likely to be critical to the biological heterogeneity that influences testosterone-depression interactions. A genetically informed precision medicine approach using genes regulating testosterone levels and androgen receptor sensitivity will likely be essential in gaining critical insight into the role of testosterone in depression.
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Purpose: Despite the effectiveness of androgen deprivation therapy in advanced prostate cancer, serious neuropsychiatric consequences in androgen deprivation therapy (ADT)-treated patients, mainly depression, have been concerning and gained more attention recently. This narrative review aims to shed light on the risk and pharmacological management of ADT-induced depression in PCa patients. Methods: We searched PubMed, Scopus and Google Scholar databases using MESH keywords “Prostate cancer OR prostate neoplasm” AND “Depression” AND “Androgen Deprivation Therapy” AND “antidepressants”. Search was limited to English and studies conducted on humans. Studies’ titles and abstracts were screened, and further information were obtained from the text, if necessary, to decide whether studies are to be included in this review. Results: Our review revealed 23 studies confirming the occurrence and worsening of depressive symptoms in ADT-treated patients, which frequently require pharmacological interventions; whereas 10 studies indicated otherwise. All studies were prospective, retrospective, cross-sectional or case reports. Based on the incidence of depression provided by the observational studies, the average among ADT-treated patients was 18.23% (range: 2.1–46.9%), while it was 8.42% (range: 1.4–23.3%) in the non-ADT patients. Although several treatments have been used for depression in cancer patients, current knowledge lacks observational and controlled studies as well as clinical guidelines that demonstrate efficacy and safety of antidepressants and guide clinicians to the appropriate treatment in these patients, respectively. On the other side, a few clinical studies have been published regarding the efficacy of selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors and/or saftey on other ADT associated adverse effects. Conclusions: Our work supports the recent attention towards mood issues as an adverse effect of ADT, and that greater awareness of this is warranted among clinicians. Clinical studies published regarding the use of antidepressants for other ADT associated adverse effects established the foundation that can be adopted to examine these therapies on ADT-induced depression.
Article
Objective To explore the association between depression and semen quality and the mediating role of oxidative stress. Design Cross-sectional study with repeated measures of semen quality. Setting Human Sperm Bank of Hubei Province, People’s Republic of China. Patient(s) From April 2017 to July 2018, we recruited 1,000 potential sperm donors who completed the Beck Depression Inventory questionnaire and had measures of oxidative stress biomarkers. Intervention(s) None. Main Outcome Measure(s) Severity of depression was evaluated by the Beck Depression Inventory scores (0–4, no depression; 5–13, mild depression; 14–20, moderate depression; and 21 or greater, severe depression). The urinary concentrations of 8-hydroxy-2-deoxyguanosine, 4-hydroxy-2-nonenal-mercapturic acid, and 8-iso-prostaglandin F2α (8-isoPGF2α) were measured to reflect oxidative stress status. Repeated semen quality parameters (n = 5,880) were examined by trained professional technicians according to the World Health Organization laboratory manual. Associations between depression, oxidative stress, and repeated measures of semen quality parameters were evaluated using linear or mixed-effects models with adjustment for potential confounders. Mediation analysis was performed to test the potential mediating role of oxidative stress. Result(s) A total of 391 (39.1%) men were classified as mild depression, 67 (6.7%) as moderate depression, and 19 (1.9%) as severe depression. Inverse dose–response relationships between severity of depression and semen quality parameters were found. Compared with men without depression (n = 523), those with severe depression had a 25.26% (95% confidence interval, −38.65%, −8.93%) lower semen volume, 37.04% (−55.37%, −11.20%) lower total sperm count, 13.57% (−23.17%, −2.78%) lower total motility, and 15.08% (−25.09%, −3.72%) lower progressive motility; men with moderate depression also had a 12.28% (−21.16%, −2.40%) lower semen volume and 23.56% (−36.50%, −7.97%) lower total sperm count. We found a positive dose–response relationship between severity of depression and urinary 8-isoPGF2α concentrations. However, we found no evidence that the associations between depression status and semen quality were mediated by oxidative stress markers. Conclusion(s) In the study of Chinese male sperm donors, men with depression had worse semen quality parameters, including semen volume, sperm concentration, total sperm count, total motility, and progressive motility. Although depression was positively associated with urinary 8-isoPGF2α concentrations, depression–semen quality associations were not mediated by oxidative stress.
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Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress and trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, the relationship between stress-related disorders and alcohol use is generally stronger among women leading to complex comorbidities across these disorders and alcohol misuse. This review highlights the therapeutic potential for progestogen- and androgen-derived neurosteroids, which affect both stress- and alcohol-related disorders, to target the overlapping symptoms related to negative affect. This article is part of the special issue on ‘Vulnerabilities to Substance Abuse.’
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Sexual dysfunctions are common in men with depression. As the hypothalamic-pituitary-gonadal (HPG) axis is a crucial regulator of sexual function, and also affects mood and cognition, the following question arises: Is the HPG axis altered in depressed men when compared to healthy controls? To answer this question, PubMed and PsycINFO were searched. Inclusion criteria for the systematic review and meta-analysis were: (1) case-control study including male patients with a depressive disorder and (2) assessment of follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, or testosterone. Seventeen studies were identified. Follicle-stimulating hormone and LH did not differ between patients and controls. By contrast, in patients, oestradiol was marginally increased (g = 0.52, 95% CI [−0.01, 1.04]; Z = 1.92, p = .055) and testosterone was significantly decreased (g = −0.45, 95% CI [−0.80, −0.10]; Z = −2.53, p = .012). Depressed men may be characterised by diminished testosterone and potentially elevated oestradiol, which beyond contributing to sexual dysfunction, could impact mood and cognition.
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Introducción. El suicidio es una de las principales causas de muerte. La mayor predisposición del género masculino a cometer suicidio sugiere la participación de las hormonas gonadales. La testosterona parece influir en la impulsividad; la progesterona y el estradiol ejercen acciones ansiolíticas y antidepresivas; sin embargo, la relación entre estas hormonas y la violencia, es aún controversial. Objetivo. Comparar los niveles séricos de testosterona, progesterona y estradiol en hombres víctimas de suicidio, deceso con violencia y controles vivos. Material y métodos. La testosterona fue determinada por el método de ensayo inmunoenzimático de competencia (ELISA). La progesterona y el estradiol por ensayo inmunoenzimático de micropartículas (MEIA). Resultados. Los niveles séricos de testosterona fueron significativamente [F 2, 30= 5.28, p‹ 0.01] mayores en los suicidas (8.5±1.30 ng/mL) con respecto al grupo de deceso con violencia (2.3±1.54 ng/mL) y los controles vivos (4.5±0.98 ng/mL), no hubo diferencias entre estos dos últimos grupos. El nivel sérico de estradiol más alto, se encontró en el grupo suicida (92.6±16.21 pg/mL); mientras que en los controles (45.0±3.10 pg/mL) los valores fueron intermedios y los niveles significativamente [F 2, 31= 16.05, p‹ 0.001] más bajos, se encontraron entre quienes fallecieron con violencia (13.5±3.04 pg/mL). No se encontraron diferencias entre los grupos en los niveles séricos de progesterona [F 2, 31= 0.81, p= 0.45]. Conclusiones. El suicidio podría caracterizarse por niveles elevados de testosterona y estradiol, que a su vez podrían relacionarse con un grado alto de impulsividad.
Article
Major depressive disorder (MDD) is a severe mood disorder that may lead to use of drugs, alcohol, and even suicide in acute cases. It has been shown that neurotransmitters and hormones have the same receptors and pathways in the mood area of the brain. Therefore, metabolic and biochemical changes are expected in MDD and, in such diseases, understanding the hormonal alterations would be extremely helpful in the management or treatment with hormone replacement therapy. We evaluated levels of cortisol, adrenocorticotropic hormone (ACTH), testosterone, thyroid‐stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3), free thyroxine index (FT4I), T3 resin uptake (T3RU), and dehydroepiandrosterone sulfate (DHEA‐S) in 79 patients suffering from MDD and 71 healthy controls. The existence of MDD was confirmed by a face‐to‐face structured clinical interview. We started the investigation by taking a blood sample from the study population. Then, hormone levels were measured by enzyme‐linked immunosorbent assay. Significant differences were found between TSH, FT4I, DHEA‐S, ACTH, testosterone, and cortisol/DHEA‐S ratio in MDD patients compared to the healthy controls. We also demonstrated a correlation between MDD recurrence and FT4I index and TSH, respectively. Regarding some hormonal changes in patients with MDD, hormonal shifts should be considered in the treatment or management of MDD patients.
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Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with age and featured by typical symptoms and reduced blood testosterone level. Among males aged over 30 years, the incidence of androgen deficiency is 7 to 30%. The aim of this study was to investigate the incidence of hypogonadism in patients aged over 40 years with an underlying condition and/or a comorbidity, such as arterial hypertension, Chronic obstructive pulmonary disease (COPD), metabolic syndrome, Type 2 of diabetes mellitus, dyslipidaemia, adiposity in various General practice (GP) and physician-sexologists’ offices in Latvia, and to determine the influence of chronic diseases on the development of hypogonadism. Males aged 39 years who turned to family doctors at nine GP were offered to fill in Aging Male Study (AMS) questionnaires used for the diagnostics of late-onset hypogonadism. Males aged 40 years who visited the office of the physician sexologist Anatolijs Požarskis were offered to fill in the same questionnaires. After compiling the data from AMS questionnaires, a group of males exhibiting signs of LOH were isolated (in total 1222 persons). In these patients, we determined blood testosterone and sex-hormone binding globulin (SHBG) levels. Chronic diseases were found in these men in data evaluation of patient medical records, and after performing physical and laboratory examinations. Late-onset hypogonadism was laboratory-diagnosed in 79% of patients with signs of late-onset hypogonadism in accordance with the AMS questionnaires and with concomitant diseases and in 4.7% of patients with signs of late-onset hypogonadism in accordance with the AMS questionnaires and without the aforementioned concomitant diseases. Persons with arterial hypertension, dyslipidaemia, adiposity, metabolic syndrome, COPD and Type 2 of diabetes mellitus had higher chance of developing hypogonadism ( p < 0.001). Arterial hypertension, dyslipidaemia, adiposity, metabolic syndrome, COPD statistically significantly ( p < 0.001) decreased the level of total testosterone by 0.47, 1.18, 0.36, 0.67, and 0.18 ng/ml, respectively, and decreased the level of free testosterone by 2.52, 2.71, 1,69, 6.77, and 4.58 pg/ml, respectively. Type 2 diabetes mellitus had no statistically significant effect on the level of total and free testosterone ( p = 0.95, p = 0.10). The most significant decrease in the level of testosterone was observed in cases of dyslipidemia, COPD and metabolic syndrome. General physicians should pay special attention to patients with this disease, as these patients belong to a group with a high risk of development of expressed LOH syndrome.
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Importance: Countering depressive disorders is a public health priority. Currently, antidepressants are the first-line treatment, although they show modest effects. In men, testosterone treatment is a controversial alternative or adjunct treatment option. Objectives: To examine the association of testosterone treatment with alleviation of depressive symptoms in men and to clarify moderating effects of testosterone status, depression status, age, treatment duration, and dosage. Data Sources: English-language studies published in peer-reviewed journals identified from PubMed/Medline, Embase, Scopus, PsychINFO, and the Cochrane Controlled Trials Register from database inception to March 5, 2018, using the search terms testosterone, mood, administration, dosage, adverse effects, deficiency, standards, therapeutic use, therapy, treatment, and supplementation. Study Selection: Randomized placebo-controlled clinical trials (RCTs) of testosterone treatment that together cover a broad age range and hypogonadal or eugonadal men reporting depressive symptoms on psychometrically validated depression scales. Data Extraction and Synthesis: Of 7690 identified records, 469 were evaluated against full study inclusion criteria after removing duplicates, reviews, and studies that did not examine male patients or testosterone. Quality assessment and data extraction from the remaining 27 RCTs were performed. Main Outcomes and Measures: Primary outcomes were testosterone treatment effectiveness (standardized score difference after treatment), efficacy (proportion of patients who responded to testosterone treatment with a score reduction of 50% or greater), and acceptability (proportion of patients who withdrew for any reason). Results: Random-effects meta-analysis of 27 RCTs including 1890 men suggested that testosterone treatment is associated with a significant reduction in depressive symptoms compared with placebo (Hedges g, 0.21; 95% CI, 0.10-0.32), showing an efficacy of odds ratio (OR), 2.30 (95% CI, 1.30-4.06). There was no significant difference between acceptability of testosterone treatment and placebo (OR, 0.79; 95% CI, 0.61-1.01). Meta-regression models suggested significant interactions for testosterone treatment with dosage and symptom variability at baseline. In the most conservative bias scenario, testosterone treatment remained significant whenever dosages greater than 0.5 g/wk were administered and symptom variability was kept low. Conclusions and Relevance: Testosterone treatment appears to be effective and efficacious in reducing depressive symptoms in men, particularly when higher-dosage regimens were applied in carefully selected samples. However, given the heterogeneity of the included RCTs, more preregistered trials are needed that explicitly examine depression as the primary end point and consider relevant moderators.
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Following the birth of an infant, decreases in testosterone and increases in depressive symptoms have been observed in fathers. Paternal testosterone may reflect fathers' investment in pair-bonding and paternal caregiving and, as such, may be associated with maternal and familial well-being. This study tests associations between paternal testosterone, paternal and maternal postpartum depressive symptoms, and subsequent family functioning. Within 149 couples, fathers provided testosterone samples when infants were approximately nine months old and both parents reported on postpartum depressive symptoms at two, nine, and 15 months postpartum. Fathers with lower aggregate testosterone reported more depressive symptoms at two and nine months postpartum. Mothers whose partners had higher evening testosterone reported more depressive symptoms at nine and 15 months postpartum. Maternal relationship satisfaction mediated this effect, such that mothers with higher testosterone partners reported more relationship dissatisfaction, which in turn predicted more maternal depressive symptoms. Higher paternal testosterone and paternal depressive symptoms at nine months postpartum each independently predicted greater fathering stress at 15 months postpartum. Higher paternal testosterone also predicted more mother-reported intimate partner aggression at 15 months postpartum. In addition to linear relationships between testosterone and depression, curvilinear relationships emerged such that fathers with both low and high testosterone at nine months postpartum reported more subsequent (15-month) depressive symptoms and fathering stress. In conclusion, whereas higher paternal testosterone may protect against paternal depression, it contributed to maternal distress and suboptimal family outcomes in our sample. Interventions that supplement or alter men's testosterone may have unintended consequences for family well-being.
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Depressive Disorders in the DSM-5 include Major Depressive Disorder, Persistent Depressive Disorder, Disruptive Mood Dysregulation Disorder, and Premenstrual Dysphoric Disorder, along with unspecified and secondary depressive conditions. This chapter mostly focuses on practical considerations in pharmacotherapy. It also focuses on topics of clinical importance when using conventional antidepressants to treat major depressive disorder: efficacy, overdose potential, treatment-emergent suicidality, therapeutic monitoring and drug–drug interactions, discontinuation syndromes, side effects and adverse events. Major psychological issues that arise in the treatment of depression are also discussed here. Successful treatment of depression is a collaborative effort involving patient, family, clinician (and associates). Faith is needed, and so persuasion and the support of others surrounding the patient can have greater influence on treatment outcome than does the particular choice of pharmaceuticals or psychotherapeutic method.
Chapter
The reproductive glands are an essential part of the human body. Extensive changes occur as we develop in the womb, to the period of puberty, and then as we age. Through out this time, intricate and timely hormonal changes occur in a unique manner that allow these changes to occur. As the process unwinds our aging body reflects the decades of repetitive assimilation and protection of the germ lines, as well as hormonal decline that affects every male. The revolution of science has allowed us to better understand the aging process so that maintenance of well being and functionality can be preserved. Hopefully, better understanding of this process will allow us to promote successful aging.
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Severe oligoasthenospermia seems to be a more crucial aspect than moderate dyspermia in the restoration of couple fertility. Female age is a further critical aspect in the correction of male factor infertility. Many lifestyle factors such as vigorous exercise, psychological stress, cigarette smoking, illicit drug use, and alcohol negatively influence fertility, whereas others such as Mediterranean diet and moderate exercise may be beneficial.
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The final biological steps in the cellular cascade of normal male sexual differentiation are initiated by the molecular action of androgens in androgen-responsive target tissues. Lack of androgenic steroids leads to defective sexual differentiation in embryos with 46, XY karyotype; while their excess is associated with virilization in 46, XX children. Furthermore, androgens lead to specific changes during male puberty and are required for male fertility. A key player in the translation of androgen action is the androgen receptor (AR), a nuclear transcription factor which can bind various androgenic steroids as ligands and then act via differential DNA targeting and genetic control. With the elucidation of the X-chromosomal localization and the genetic structure of the AR more than 20 years ago (Fig. 3.1), it was thought that most 46, XY patients with presumed defects of androgen action would carry mutations in the coding regions of the AR gene. While this holds true for the majority of patients with complete androgen insensitivity syndrome (CAIS), to an increasing proportion patients clinically assigned as partial (PAIS) or minimal androgen insensitivity syndrome (MAIS) do not carry relevant mutations in the AR. Therefore the clarification of the time- and cell-specific mechanisms of androgen action and the factors acting in concert with the AR is of utmost importance. They lead to the cell-specific modulation of androgen-dependent transcription of several hundred target genes (Holterhus et al. 2003; 2007).
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Introduction: Bipolar disorder is affected by variables that modulate circadian rhythm, including seasonal variations. There is evidence of a seasonal pattern of admissions of mania in various geographical settings, though its timing varies by region and climate. Variables such as age and gender have been shown to affect seasonality in some studies. Methodology: Data on monthly admission patterns for mania at a general hospital psychiatry unit in Pondicherry, India, were collected for 4 years (2010–2013) and analyzed for seasonality and seasonal peaks. The effects of age and gender were analyzed separately. Results: There was overall evidence of a seasonal pattern of admissions for mania (P < .01, Friedman test for seasonality), with a peak beginning during the rainy season and ending before summer (P < .0.1, Ratchet circular scan test). Male sex (P < .005, Ratchet circular scan test) and age > 25 years (P < .005, Ratchet circular scan test) were specifically associated with this seasonal peak. Discussion: The effect of seasons on mania is complex and is modulated by a variety of variables. Our study is consistent with earlier research findings: a greater degree of seasonality for mania in men. It is possible that climatic and individual variables interact to determine seasonal patterns in bipolar disorder in a given setting.
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To enhance diagnostic assessment in routine clinical care, the Munich Diagnostic Checklists have been developed for a systematic criteria-related evaluation of the most common psychiatric disorders according to DSM-III-R. Design, concept, and areas of application of the instrument are described. An initial test-retest study showed that satisfactory to excellent diagnostic agreement can be reached.
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Major depression is associated with hypercorticoidism, a risk factor for osteoporosis. However, it is unknown whether depressive disorders are associated with alterations in bone mineral density. The authors measured the density of trabecular bone from the first to the third lumbar vertebra by quantitative computerized tomography in 80 depressed inpatients older than 40 years and in 57 healthy comparison subjects. An analysis of covariance model with age as a covariate showed a significant effect of diagnosis on the dependent variable spinal bone mineral density: depressed patients had lower values. Other factors could not explain the finding. The authors conclude that major depression is a significant risk factor for osteoporosis.
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• To enhance diagnostic assessment in routine clinical care, the Munich Diagnostic Checklists have been developed for a systematic criteria-related evaluation of the most common psychiatric disorders according to DSM-III-R. Design, concept, and areas of application of the instrument are described. An initial test-retest study showed that satisfactory to excellent diagnostic agreement can be reached.
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Socially dominant male sugar gliders are heavier than socially subordinate males, have higher plasma testosterone and lower cortisol concentrations, win more social encounters, scan the arena more, scent-mark more, and are more active and move more quickly, even though they spend more time in the colony nesting box. When they are transferred into a foreign stable colony there is an impressive reversal of behavioral measures and a concomitant decrease in concentration of plasma testosterone and rise in cortisol that is apparent over the first 3 weeks of observation.
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This chapter discusses the accumulated data. A broad concept of the role of corticotropin-releasing hormone (CRH) as a mediator of adaptive response to all forms of stress has now emerged. The evidence presented in the chapter proposes that: (1) CRH integrates not only the hormonal but also the physiological and behavioral pattern in response to environmental and endogenous challenges perceived as stress and (2) continuous alterations in the fine-tuned neuro-endocrine pathways result in overt psychopathology, perpetuate clinical symptoms, and may lower the threshold for the development of full-blown clinical syndromes in individuals carrying a genetic risk for psychiatric disorders. The neuroendocrine and behavioral systems are inextricably intertwined. Given this bidirectional loop, distinctions between cause and effect are clearly only useful within a limited experimental context. Keeping this in mind, the ambitious goal of understanding how neural and endocrine systems regulate behavior and how psychopathology develops may yet be achieved.
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Twenty-two normal weight women with bulimia nervosa (BN) were studied (mean age, 25 +/- 5 yr; body mass index, 20.2 +/- 2.6 kg/m2). Sixteen of them reported menstrual cycles in the range of 21-42 days, and 6 had experienced absence of menstruation for at least 3 months. Twenty-one healthy women with regular menstrual cycles (mean age, 23 +/- 2 yr; body mass index, 20.7 +/- 1.4) served as the control subjects. Frequent morning blood samples for estradiol (E2) and progesterone (P4) determinations were obtained for the duration of 1 menstrual cycle or for 6 weeks in the case of amenorrhea. LH, FSH, cortisol, and insulin secretion were studied on day 3, 4, or 5 after the onset of a menstrual cycle or on a random day in the 6 BN women with amenorrhea. Blood samples were collected at 15-min intervals from 1800-0600 h for LH and FSH and at 30-min intervals from 2400-0600 h for cortisol and insulin. Nineteen of the 21 controls, but only 10 of the 22 BN women, fulfilled the following standard criteria: maximum E2 above 440 pmol/L, maximum P4 above 19 nmol/L, and luteal phase length of 9 days or more. The 10 BN women with normal menstrual cycles had lower mean insulin concentrations than the controls (70 +/- 20 vs. 120 +/- 30 pmol/L; P less than 0.01), but gonadotropin secretion, cortisol, and T3 concentrations were similar. The 8 BN women with amenorrhea or ovulatory dysfunction (maximum E2, less than 440 pmol/L; maximum P4, less than 6 nmol/L) displayed decreased mean LH pulse frequency (2.6 +/- 2.4 vs. 5.7 +/- 2.0 pulses/12 h; P less than 0.01), increased mean cortisol (120 +/- 40 vs. 80 +/- 20 nmol/L; P less than 0.01), decreased mean insulin (90 +/- 40 vs. 120 +/- 30 pmol/L; P less than 0.05), and decreased mean T3 concentrations (1.5 +/- 0.3 vs. 1.8 +/- 0.2 nmol/L; P less than 0.01). The data suggest that BN in normal weight women is associated with an increased rate of ovarian dysfunction; decreased pulsatile LH secretion seems to be an important mechanism. Increased cortisol in the disturbed subgroup indicates that activation of the hypothalamic-pituitary-adrenal axis may play a role in the pathogenesis of gonadal dysfunction in bulimia nervosa.
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We investigated the effects of age on pituitary-adrenocortical function in healthy young (21-38 yr, n = 11) vs. old (66-78 yr, n = 11) men by drawing frequent serial basal blood samples from 2000-0800 h for measurement of ACTH and cortisol, followed by an iv ovine CRH (oCRH) stimulation test. Subjects were readmitted at intervals and given increasing doses of oral dexamethasone (0.15, 0.3, 0.6, 1 mg) at midnight, followed by repeat blood sampling from 0400-0800 h and oCRH testing. We compared mean hormone levels for the entire 12-h and three component 4-h periods of the basal visit, and for each 4-h dexamethasone visit using the Mann-Whitney U test and repeated measures analysis of variance. Pulsatile secretion was characterized using the Pulsar computer program. Basal mean 12-h and 4-h ACTH and cortisol values did not differ with age (P greater than 0.1). Pulse analysis revealed no age change in the corresponding values for peak frequency, amplitude, or duration for either hormone examined. Increasing doses of dexamethasone produced progressive inhibition of mean ACTH and cortisol levels (P less than 0.001) as well as decreased (P less than 0.01) pulse frequency, amplitude, and duration with no age differences (P greater than 0.1). ACTH and cortisol responses to oCRH were progressively suppressed by increasing doses of dexamethasone (P less than 0.02) and did not differ between age groups (P greater than 0.3) except for a slightly higher peak cortisol response (P = 0.05) in the older men at the 0.3 mg dexamethasone dose. We conclude that basal and oCRH-stimulated ACTH and cortisol secretion, as well as sensitivity of the ACTH-cortisol axis to glucocorticoid feedback suppression, are essentially unaltered with age in healthy men.
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This article reviews the mechanisms believed to mediate stress-induced inhibition of reproductive functions and the anatomical sites at which these effects take place. Particular emphasis is placed on the potential modulating role of hormones or neurotransmitters released during stress. At the level of the gonads, adrenal corticoids, pro-opiomelanocortin (POMC)-like peptides, and corticotropin-releasing factor (CRF) are reported to interfere with the stimulatory action of gonadotropins on sex steroid-producing cells. Increased circulating corticosteroid levels may also decrease pituitary responsiveness to GnRH. There is, however, increasing evidence that these mechanisms are primarily involved in mediating the effects of prolonged stress, but not those of an acute stimulus. In contrast, a variety of hormones or neurotransmitters, including CRF, POMC peptides, and biogenic amines act within the brain to mediate the inhibitory influence of both acute and prolonged stresses on reproductive function.
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Sleep EEG and the nocturnal secretion of cortisol and testosterone in 12 male patients (mean age 46.4 +/- 11.26 years) with major endogenous depression were investigated concomitantly during acute depression, before treatment and after recovery and drug cessation. Testosterone concentration increased after remission, while cortisol secretion decreased. Sleep EEG disturbances remained unchanged in remitted patients. The data suggest that a blunted testosterone and an elevated cortisol secretion are state markers of acute depression, which normalize independently from sleep structure. An interaction between the hypothalamic-pituitary-gonadal axis and the limbic-hypothalamic-pituitary-adrenocortical axis appears likely.
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Baseline follicle stimulating hormone (FSH) and luteinizing hormone (LH) plasma levels and their responses to luteinizing hormone releasing hormone (LHRH) stimulation were investigated in 72 patients who met Research Diagnostic Criteria for affective disorders and in 72 healthy volunteers. Fifty-six patients were examined during a depressive phase and 16 during a normothymic phase. LH-FSH basal levels were significantly lower in postmenopausal depressed and normothymic women than in controls. In fertile women and men, concentrations of the two gonadotropins were also lower in patients than in controls, but the phenomenon did not generally reach statistical significance. LHRH-induced LH rises were lower in postmenopausal and fertile depressed and normothymic women than in controls, while FSH rises were reduced only in postmenopausal depressive women in both depressed and normothymic phases. The impairment underlying the gonadotropin secretory deficiency remains to be elucidated.
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Hypothalamic amenorrhea (HA) is a common disorder associated with hypoestrogenemia and has adverse effects. The mechanism of GnRH deficiency in these women is not yet known. To investigate the role of the hypothalamic-pituitary-adrenal axis in HA, we studied 10 women [mean age, 29 +/- 7 (+/- SD) yr] with 0.5-13 yr of amenorrhea (mean, 4.3 +/- 3.7 yr) related to simple weight loss or psychological stress. We investigated cortisol and ACTH responses to a bolus of ovine CRH, 24-h plasma cortisol levels obtained every 10 min, and urinary free cortisol levels in these patients. Results were compared with those obtained in normal women during all phases of the menstrual cycle. We found that mean basal concentrations of cortisol were significantly higher (P = 0.03) in the HA patients (mean, 210 +/- 130 nmol/L) than in the normal women (100 +/- 30 nmol/L). The delta (peak - basal) cortisol was significantly lower (P = 0.004) in the HA patients than in the normal women (320 +/- 100 vs. 440 +/- 90 nmol/L, respectively). ACTH responses to CRH did not differ between HA patients and normal women. The 24-h mean cortisol was significantly higher (P = 0.006) in the HA patients than in the normal controls (280 +/- 50 and 220 +/- 50 nmol/L, respectively), due to higher cortisol levels at night. The urinary free cortisol level was significantly higher (P = 0.005) in the HA patients (230 +/- 70 nmol/day) than in normal women (150 +/- 40 nmol/day). We conclude that women with HA have a blunted cortisol response to CRH administration. In addition, they have hypercortisolism, as demonstrated by elevated 24-h mean serum cortisol levels and urinary free cortisol values. This hypothalamic-pituitary-adrenal axis activation in patients with stress or weight loss may be a mechanism in the development of amenorrhea and may relate to other potential adverse effects of HA.
Article
To further elucidate the neuroendocrine regulation of anterior pituitary function in women with functional hypothalamic amenorrhea (FHA), we measured serum LH, FSH, cortisol, GH, PRL, TSH concentrations simultaneously at frequent intervals for 24 h in 10 women with FHA and in 10 normal women in the early follicular phase (NC). Using the same data, we separately analyzed the cortisol-PRL responses to meals in these women. In addition, the pituitary responses to the simultaneous administration of GnRH, CRH, GHRH, and TRH were assessed in 6 FHA and 6 normal women. The 24-h secretory pattern of each hormone except TSH was altered in the women with FHA. Compared to normal women, the women with FHA had a 53% reduction in LH pulse frequency (P less than 0.0001) and an increase in the mean LH interpulse interval (P less than 0.01); LH pulse amplitude was similar. The 24-h integrated LH and FSH concentrations were reduced 30% (P = 0.01) and 19% (P less than 0.05), respectively. The mean cortisol pulse frequency, amplitude, interpulse interval, and duration were similar in the two groups, but integrated 24-h cortisol secretion was 17% higher in the women with FHA (P less than 0.05). This increase was greatest from 0800-1600 h, but also was present from 2400-0800 h. Cortisol levels were similar in the two groups from 1600-2400 h, resulting in an amplified circadian excursion. In contrast, the 24-h serum PRL levels were markedly lower at all times (P less than 0.0001), the sleep-associated nocturnal elevation of PRL was proportionately greater (P less than 0.05), and serum GH levels were increased at night in the women with FHA (P less than 0.05). Although 24-h serum TSH levels were similar at all times, T3 (P less than 0.05) and T4 (P less than 0.01) levels were lower in the FHA women. The responses of serum cortisol to lunch (P less than 0.01) and dinner (P less than 0.05) and those of serum PRL to lunch (P less than 0.05) and dinner (P = 0.08) were blunted in the women with FHA. Pituitary hormone increments in response to the simultaneous iv administration of GnRH, CRH, GHRH, and TRH were similar in the two groups, except for a blunted PRL response to TRH in the women with FHA (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
To determine the extent of hypothalamo-pituitary-gonadal (HPG) axis dysfunction in endogenous depressed men, we measured nocturnal and diurnal serum luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), and estradiol (E2) concentrations, and their responses to gonadotropin releasing hormone (LHRH) and dexamethasone administration, in 16 Research Diagnostic Criteria primary, definite endogenous male depressives and 16 individually matched male normal controls. Compared to their controls, the patients showed no differences in basal nocturnal or diurnal gonadotropin or gonadal steroid hormone concentrations, and no differences in hormone concentrations either post-LHRH or post-dexamethasone. Age was negatively correlated with baseline serum T in the patients but not in the controls, and it was modestly positively correlated with baseline serum LH in both groups of subjects. In the patients, the presence of DSM-III melancholia was modestly negatively correlated with baseline and post-LHRH concentrations of both LH and FSH and was positively correlated with baseline serum T, but it bore no relation to serum E2. None of the other subject characteristics or specific dimensions of depressive symptomatology were significantly related to the HPG axis measures. The HPG axis measures also were unrelated to pre- and post-dexamethasone cortisol concentrations in both groups of subjects. The results of this study suggest that, in contrast to the hypothalamo-pituitary-adrenal cortical and thyroid axis abnormalities frequently found in endogenous depressives, HPG axis function in male depressives is relatively normal.
Article
The baseline LH, FSH and testosterone levels and the LH and FSH response to TRH-LHRH administration (delta LH, delta FSH) were investigated in 28 patients meeting the RDC criteria for an acute major depressive disorder, and in 20 healthy persons. Twenty-two patients were also reinvestigated in a state of complete or partial clinical remission. Cross-sectional and longitudinal comparisons were made between the groups divided according to sex and menopausal status. After mathematical correction for age differences, the depressed males with an abnormal DST response showed significantly (P less than 0.03) higher delta FSH in the acute state compared to the controls. No relation could be established between the HPG axis hormone levels and the nocturnal serum melatonin levels or the PRL or TSH response to TRH-LHRH administration. In the longitudinal part of the study, the depressed males with an abnormal DST response showed decreased (P less than 0.03) testosterone levels and increased delta FSH (n.s.) in the acute state compared to remission, in contrast to the males with a normal DST. The present results do not support a hypothesis regarding a stimulus-induced down-regulation of the pituitary LHRH receptors in our patients. The possible mechanisms by which HPA axis activation (as revealed by an abnormal DST response) could influence the HPG axis in depressed patients remain to be elucidated.
Article
Electron microscopic double-label immunostaining with peroxidase and avidin-ferritin was used to study connections between corticotrophin-releasing factor (CRF) and gonadotrophin-releasing hormone (GnRH) immunoreactive elements in the medial preoptic area of the rat. Synaptic contacts were observed between CRF-immunoreactive axon terminals and the dendrites of GnRH-immunopositive neurons. These results suggest that the inhibitory effects of stress-induced CRF release on reproductive function may involve a direct CRF input to the GnRH-producing cells.
Article
Total and free testosterone, estradiol and cortisol were measured in 12 depressed males and 12 age-matched normal volunteers. There was no significant difference in any of the hormone levels between the patient and control group. Total testosterone was negatively correlated with age in the depressed group, but not with severity of depression.
Article
To examine both predexamethasone and postdexamethasone cortisol measures in depression, we determined circadian serum cortisol patterns, cortisol responses to dexamethasone, and 24-hour urinary free cortisol excretion before and after dexamethasone administration in 40 patients with primary, definite endogenous depression diagnosed by Research Diagnostic Criteria and in 40 individually matched normal control subjects. Fifteen patients (38%) were dexamethasone nonsuppressors; they had significantly higher predexamethasone serum and urine cortisol measures than both their matched controls and the 25 suppressor patients. Both the predexamethasone and postdexamethasone cortisol measures were unimodally distributed across the patients and the controls. Circadian cortisol rhythms of similar magnitude occurred in both groups. The cortisol measures before and after dexamethasone administration were positively correlated to a similar degree in the patients and their controls, suggesting that predexamethasone hypothalamic-pituitary-adrenocortical hyperactivity and postdexamethasone cortisol nonsuppression are not independently determined in endogenous depression.
Article
Tested the hypotheses that (1) testosterone levels in depressives are reduced relative to the severity of depression when controlled for age and that (2) lower plasma testosterone levels in depressives correlate with severity of sexual dysfunction when controlled for age and severity of depression in a study with 18 endogenously depressed (Research Diagnostic Criteria) males. Results support the 1st hypothesis. When controlled for age and the Hamilton Rating Scale for Depression scores, the relationship between testosterone level and sexual activity in Ss is not significant, indicating that reduced testosterone levels are not likely to be responsible for most cases of sexual dysfunction in depression. (11 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
Plasma testosterone concentration was determined at 8 am in 15 depressed men, ages 46 to 78, during illness and after recovery. There was no meaningful change for the group and in 11 cases illness and recovery values were essentially the same. Urinary testosterone excretion was also measured in seven of the men and there was no significant change for the group before and after recovery.
Article
The acute administration of 0.015-1.5 nmol ovine corticotropin-releasing factor (CRF) into the lateral ventricle of gonadectomized (or gonadectomized/adrenalectomized) female rats caused a rapid and prolonged dose-related inhibition of LH (but not FSH) secretion. By contrast, the acute peripheral injection of up to 15 nmol CRF was without effect in the same animal preparations. In cycling intact female rats, injection of 1.5 nmol CRF into the brain or of 75 nmol CRF sc inhibited ovulation and blocked the proestrous LH surge in about 50% of the animals. Lower doses of peripherally administered CRF were ineffective. Finally, CRF injected daily sc (15 nmol/day) to female rats during the first 12 days after mating caused a 40% disruption of pregnancy. These results indicate that CRF will lower plasma LH levels and can exert this effect in the absence of circulating steroids of either adrenal or gonadal origin. CRF inhibition of LH secretion, which we have previously reported to be absent in vitro, was unaltered by the opiate receptor antagonist naltrexone or by the ganglionic blocker chlorisondamine. Furthermore, blockade of CRF-induced beta-endorphin or ACTH release into the general circulation by dexamethasone did not interfere with the inhibitory effect of CRF on LH secretion. Such observations suggest that CRF exerts deleterious actions on reproductive functions through brain sites of action which, at least under the experimental mental design used, do not appear to directly involve opiate or peripheral catecholaminergic pathways.
Article
Considerable attention has been paid to studies of hormonal response abnormalities in depressed patients, and functional changes have been demonstrated in a number of neuroendocrine axes. The findings from the present study extend the results of previous investigations but demonstrate a functionally intact HPG axis in depressed patients. A number of statements can be made concerning the gonadotropin-releasing hormone (GnRH) strategy: (1) Previous studies utilizing GnRH challenge have been limited in number and poorly controlled. (2) We chose to utilize our normative data because standard gonadotropin response ranges to GnRH have not previously been established in studies with depressed patients. Moreover, hormonal responses may be affected by age, sex, menstrual status, dose, and method and rate of GnRH administration. The assessment of the hormonal responses to GnRH in depressed patients and healthy controls studied under identical conditions provides the most accurate basis for comparison. (3) The incidence of abnormal LH and FSH release in depressed subjects was similar to controls, in contrast to response abnormalities found with other neuroendocrine axes. (4) Alterations in gonadotropin were limited to FSH, were sporadic, and did not differ significantly from controls. This finding is of interest and suggests that neuroendocrine alterations in depression do not necessarily affect all neuroendocrine axes.
Article
There is no generally accepted procedure for identifying ultradian pulsations in hormonal time series. We suggest an approach based on removing long-term trends, such as diurnal rhythms, from the series of observations; identifying peaks in the residual series; and resolving each peak, if appropriate, into overlapping secretory episodes. The first step uses a robust smoothing technique to generate a smoothed series that omits peaks or trends with time constants less than 6--12 h. The smoothed series is subtracted from the original, and in the second step their difference, the residual series, is examined for the presence of peaks. The standard deviation of the assay is calculated at each point, and the residuals are rescaled in terms of this unit. Peaks are identified as individual subseries elevated above the base line of duration n, all the points in which have magnitude at least G(n), where the values of G are cut-off criteria based on the width of the peak. Thus the algorithm selects both narrow high peaks and broader peaks that may be lower. The user selects the G(n) for each hormone based on theoretical considerations or a set of calibration data series. Points that meet these criteria are identified as belonging to peaks and flagged. To assure that the smoothing process is not influenced by runs of closely spaced peaks, these flagged points are then assigned a reduced weight, and the smoothing is repeated; the revised residuals are then reexamined. After these two steps are iterated until there are no further changes, each peak is examined once more to determine whether it can be resolved into more than one overlapping peak. Finally, the process collects statistics on the average frequency and amplitude of the peaks. We have developed computer programs to carry out these algorithms.
Article
In distinction to the course of reproductive ageing in women, men do not experience a rapid decline of Leydig cell function or irreversible arrest of reproductive capacity in old age. Hence, strictu sensu, the andropause does not exist. Nevertheless, both spermatogenesis and fertility as well as Leydig cell function do decline with age, as shown by a decrease of +/- 35% of total and of 50% of free testosterone levels between the age of 20 and 80 years. The origin of this decline of Leydig cell function resides on the one hand in the testes, and is essentially characterized by a decreased number of Leydig (and Sertoli) cells and on the other hand in the hypothalamo-pituitary complex characterized by a decreased luteinzing hormone (LH) pulse amplitude, LH pulse frequency being maintained. As the responsiveness of the gonadotrophs to gonadotropin-releasing hormone (GnRH) remains unimpaired, one may assume that the amount of GnRH released at each pulse is also reduced, possibly as the consequence of a reduction of the cellular mass of GnRH neurones. Plasma levels of testosterone below the lower normal limit occur, however, only in a minority of elderly men from 7% in the age group 40-60, to 20% in the age group 60-80 and 35% in the age group over 80 years old. Factors influencing testosterone levels in elderly men are multiple: hereditary, environmental (obesity, stress), psychosocial (depression, smoking, drugs) or socioeconomical (diet, hygiene). Whether these elderly men should be substituted with androgens remains controversial.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Opstad PK. Circadian rhythm of hormones is extinguished during prolonged physical stress, sleep and energy deficiency in young men. Eur J Endocrinol 1994:131:56–66. ISSN 0804–4643 The circadian rhythm of hormones (N = 10) and mental performance (N = 18) was investigated in male cadets during a 5-day military training course with continuous heavy physical activities corresponding to 35% of the maximal oxygen uptake, with almost total lack of food and sleep. The 24-h means for androstenedione, dihydroepiandrosterone (DHEA), 17α-hydroxyprogesterone, testosterone and thyroid-stimulating hormone decreased strongly during the course, and the circadian rhythm was extinguished below the minimum levels measured during the control experiment. The 24-h means for cortisol, dihydroepiandrosterone sulfate (DHEA-S) and progesterone increased during the course, and the circadian rhythm was abolished above the maximum levels of the control experiment. A gradual increase was found in thyroxine, free thryoxine and triiodothyronine during the first 12 h of activities, followed by a constant decrease for the rest of the course. Mental performance decreased during the course and the amplitude of its circadian rhythm increased from ±10% to ±30% of the 24-h mean. The circadian rhythms investigated were almost normalized after 4–5 days of rest. However, the nocturnal rise for cortisol, androstenedione and DHEA appeared earlier, and the plasma levels of thyroid hormones, estradiol and DHEA-S were lower during the recovery experiment than in the control experiment. The responses to stress of the circadian rhythm for mental performance and steroid hormones during the course indicate a differential regulation. Per Kristian Opstad, Norwegian Defence Research Establishment, N-2007 Kjeller, Norway
Article
The results of recent studies suggest that a relative hypogonadism in men is associated with several established risk factors for prevalent diseases. Therefore, we determined total and free testosterone, luteinizing hormone (LH), and sex-hormone binding globulin (SHBG) in a cohort of randomly selected men (n = 659) at 67 years of age. These data were analyzed cross-sectionally in relation to blood glucose and serum insulin, which were measured while fasting and after an oral glucose tolerance test, in addition to plasma lipids and blood pressure. The data were also analyzed in relation to impaired glucose tolerance (IGT) and diabetes, which were discovered at examination or earlier diagnosis. Risk factors for the development of diabetes up to 80 years of age were analyzed with univariate and multivariate statistics. Total and free testosterone and SHBG concentrations correlated negatively with glucose and insulin values; total testosterone and SHBG, with triglycerides; and SHBG, with blood pressure (from P < 0.05 to P < 0.01). Men with IGT or newly diagnosed diabetes had higher BMI values (26.2 +/- 0.31 and 27.0 +/- 0.59 [mean +/- SE], respectively) and waist circumference (99.0 +/- 1.03 and 100.5 +/- 1.57) than nondiabetic men (BMI, 25.1 +/- 0.14; waist circumference, 95.4 +/- 0.47; P < 0.05), indicating abdominal obesity. Such men and men with previously diagnosed diabetes had, in general, lower total and free testosterone and SHBG levels, while those for LH were not different. In multivariate analyses that included BMI, waist-to-hip ratio, total and free testosterone, and SHBG, the remaining independent predictors for the development of diabetes were low total testosterone (P = 0.015) and, on the borderline, low SHBG (P = 0.053). In relation to nondiabetic men, the risk ratio for mortality, myocardial infarction, and stroke increased gradually and significantly from 1.18 to 1.68, from 1.51 to 1.78, and from 1.72 to 2.46 in men with IGT, newly diagnosed diabetes, and previously known diabetes, respectively. It was concluded that low testosterone and SHBG concentrations in elderly men are associated with established risk factors for diabetes and in established diabetes. Moreover, low testosterone levels independently predict the risk of developing diabetes. In different degrees of expression, the diabetic state predicts strongly (and gradually mortality from) myocardial infarction and stroke. It has been suggested that a relative hypogonadism might be a primary event, because other studies have shown that testosterone deficiency is followed by insulin resistance, which is ameliorated by testosterone substitution. The data suggest that the relative hypogonadism involved might be of both central and peripheral origin.
Behavioral and endocrinological correlates of social status in the male sugar glider
  • J Mallick
  • Dm Stoddart
  • I Jones
  • Aj Bradley
Mallick J, Stoddart DM, Jones I, Bradley AJ. Behavioral and endocrinological correlates of social status in the male sugar glider. Physiol Behav 1994;55:1131– 4.
  • Tibblin
  • Biller