Cardiovascular risk with androgen deprivation therapy for prostate cancer: Potential mechanisms.

Androgen deprivation therapy (ADT) is frequently used for the treatment of advanced prostate cancer. ADT is associated with numerous side effects related to its mode of action, namely the suppression of testosterone to castrate levels. Recently, several large retrospective studies have also reported an increased risk of diabetes and cardiovascular disease in men receiving ADT, although these risks have not been confirmed by prospective randomized trials. We review the literature to consider the risk of cardiovascular disease with different forms of ADT and examine in detail potential mechanisms by which any such risk could be mediated. Mechanisms discussed include the metabolic syndrome resulting from low testosterone level and the potential roles of testosterone flare, gonadotropin-releasing hormone receptors outside the pituitary gland, and altered levels of follicle-stimulating hormone. Finally, the clinical implications for men prescribed ADT for the treatment of advanced prostate cancer are considered

Low Progesterone and Low Estradiol Levels Associate with Abdominal Aortic Aneurysms in Men

Context Male sex is a major risk factor for abdominal aortic aneurysms (AAA) but few studies have addressed associations between sex hormone levels and AAA.ObjectiveTo describe the associations between serum sex steroids and early, screening-detected AAA in men.MethodsWe validated a high-sensitivity liquid chromatography-tandem mass spectrometry assay for comprehensive serum sex hormone profiling. This assay was then employed in a case-control study including 147 men with AAA (infrarenal aorta ≥30 mm) and 251 AAA-free controls recruited at the general population-based ultrasound screening for AAA in 65-year-old Swedish men.Outcomes includedAssociations between dehydroepiandrosterone, progesterone, 17α-hydroxyprogesterone, androstenedione, estrone, testosterone, dihydrotestosterone, and estradiol and AAA presence.ResultsDehydroepiandrosterone, progesterone, 17α-hydroxyprogesterone, testosterone, and estradiol, but not the other hormones, were lower in men with AAA. In models with adjustments for known AAA risk factors and comorbidity, only progesterone (odds ratio per SD decrease 1.62 [95% CI 1.18-2.22]) and estradiol (1.40 [95% CI 1.04-1.87]) remained inversely associated with the presence of AAA. Progesterone and estradiol contributed with independent additive information for prediction of AAA presence; compared with men with high (above median) levels, men with low (below median) levels of both hormones had a 4-fold increased odds ratio for AAA (4.06 [95% CI 2.25-7.31]).​​​​​​​ConclusionMeasured by a high-performance sex steroid assay, progesterone and estradiol are inversely associated with AAA in men, independently of known risk factors. Future studies should explore whether progesterone and estradiol, which are important reproductive hormones in women, are protective in human AAA.</p

Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

Aims: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.Methods and results: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.Conclusions: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.</p

Cardiovascular effects of growth hormone, IGF-I and growth hormone secretagogues

Growth hormone (GH) may exert direct growth-promoting and metabolic actions on target tissues, but most of its effects are mediated by circulating (endocrine) or local (auto-/paracrine) insulin-like growth factor-I (IGF-I). The GH/IGF-I system has an important role during cardiac development and for maintaining the structure and function of the heart. Attention has recently been focused on the endogenous GH secretagogue ghrelin, which, besides amplification of GH secretion, has metabolic and possibly also cardiovascular effects. The aim of this thesis was to elucidate the relative importance of circulating IGF-I for cardiovascular function, to elucidate which genes are involved in the cardiac effects of GH, and to examine the cardiovascular effects of natural (ghrelin) and synthetic (hexarelin) GH secretagogues. We found that similar hemodynamic effects were evoked by GH and IGF-I in rats 4 weeks after myocardial infarction, including increased stroke volume and reduced peripheral resistance, supporting the notion of a role of IGF-I in mediating the cardiovascular actions of GH. Cardiovascular phenotyping of transgenic mice with liver-specific deletion of IGF-I (LI-IGF-I-/- mice) and approximately 80 per cent reduction of IGF-I levels in serum revealed that these mice have increased systolic blood pressure levels and impaired endothelium-dependent relaxation in resistance vessels. LI-IGF-I-/- mice also had reduced cardiac output and increased wall thickness of the heart, which probably reflects adaptations to the increased blood pressure. Two weeks of GH treatment in hypophysectomised rats increased circulating IGF-I, heart weight and stroke volume. When global gene expression of the GH-regulated genes (quantified in microarray) was correlated to stroke volume, genes involved in cardiac calcium-handling, hypertrophy and turnover of extracellular matrix showed the highest correlation coefficients. In particular, down-regulation of Na+/K+-ATPase and up-regulation of Na+/Ca2+-Exchanger by GH may contribute to increase cardiac contractility and/or hypertrophy. The synthetic GH secretagogue hexarelin decreased total peripheral peripheral resistance and increased cardiac output to a similar extent as GH in the rat model of myocardial infarction, despite unchanged body weight gain and levels of serum IGF-I. GH-independent cardiovascular effects of ghrelin were studied in hypophysectomised rats, showing that ghrelin decreased blood pressure but had no effects on cardiac output or gene regulation. In conclusion, the results presented in this thesis show that both circulating, liver-derived IGF-I and natural as well as synthetic GH secretagogues are major regulators of peripheral resistance. In contrast to its vascular actions, the cardiac effects of ghrelin seem to be dependent on its ability to release GH. Furthermore, we show that GH increases the mRNA expression of a broad range of genes in the heart in order to increase cardiac performance

Sex hormone-dependent and-independent regulation of serum BAFF and TNF in cohorts of transgender and cisgender men and women

Background: The risk of inflammatory diseases is sex-dependent, but it remains unknown whether this is due to the impact of sex hormones or sex chromosomes. Transgender individuals represent a unique cohort for studying the relative influence of endocrine and chromosomal factors. Here we compared serum levels of B-cell activating-factor (BAFF) and tumor necrosis factor (TNF) in transgender men (TM), transgender women (TW), cisgender women (CW) and cisgender men (CM). Methods: BAFF and TNF were measured in the serum of 26 CW, 30 CM, 27 TM and 16 TW individuals. To determine the responsiveness of immune cells, TNF was measured in bacterial lipopolysaccharide (LPS)-treated peripheral leukocytes. Results: BAFF was higher in CF (998 pg/mL) and TW (973 pg/mL) compared to CM (551 pg/mL) (P < 0.0001) and TM (726 pg/mL) (P < 0.0001). No difference in BAFF levels was shown between subjects grouped according to the number of X chromosomes. TNF was higher in CM (174 pg/mL) than TW (2.3 pg/mL) (P = 0.027) and TM (27.4 pg/mL) (P = 0.028). LPS-induced TNF was higher in CM (2524 pg/mL) and TM (2078 pg/mL) than in CW (1332 pg/mL) (both P < 0.0001) and TW (1602 pg/mL) (both P = 0.009). Discussion: Sex hormones and sex chromosomes have different impacts on cytokines involved in the sex-dependent inflammatory response. The concentration of BAFF and LPS-stimulated TNF secretion depended on sex hormone levels, whereas basal TNF was regulated by both sex hormone-dependent and-independent factors

Umbilical cord blood androgen levels in girls and boys assessed by gas chromatography-tandem mass spectrometry

Androgen exposure of the fetus during gestation plays an important role in human physiology and pathophysiology, but assessment of androgens, in particular dihydrotestosterone (DHT), in human umbilical cord blood is technically challenging. The aim of this study was to assess umbilical cord androgen levels, including DHT, at birth by a highly sensitive assay, and study their association with sex of the infant, sex-hormone-binding globulin (SHBG) levels, and gestational age at delivery. Swedish infants (27 girls, 26 boys) were recruited at maternity care clinics in Southern Sweden. Umbilical cord blood levels of dehydroepiandrosterone (DHEA), androstenedione, testosterone and DHT at delivery were assessed by a gas chromatography–tandem mass spectrometry assay. Cord blood levels of DHT were 2.4-fold higher in boys (median 27.8 pg/mL) than in girls (11.5 pg/mL), while the sex difference was less pronounced for testosterone (1.3-fold higher in boys) and non-significant for DHEA and androstenedione. Gestational age at delivery associated inversely with DHT levels in boys and with DHEA levels in girls. There was a strong inverse correlation between SHBG and DHEA in both sexes, while there were no associations between SHBG and testosterone or DHT levels. In conclusion, using state of the art technology, we report that there is a pronounced sexual dimorphism in human umbilical cord blood DHT levels. The possibility to assess a complete androgen profile in human cord blood opens up for future increased understanding of the biological impact of the fetal androgen milieu