Cardiovascular disease in transgendered people: A review of the literature and discussion of risk.

This review examines the impact of gender affirming hormone therapy used in the transgendered and non-binary populations on cardiovascular outcomes and surrogate markers of cardiovascular health. Current evidence suggests that hormonal therapy for transgendered women decreases or is neutral regarding myocardial infarction risk. There is an increased incidence of venous thromboembolism (VTE), but newer studies suggest that the risk is significantly lower than previously described. For transgendered men, there appears to be an adverse effect on lipid parameters but this does not translate into an increased risk of cardiovascular disease above that of general male population. In all transgendered people, risk factor interventions such as smoking cessation, weight management and treatment of co-morbid conditions are important in optimising cardiovascular health. The effect of gender affirming hormonal therapy in transgendered people is difficult to interpret due to the variety of hormone regimens used, the relative brevity of the periods of observation and the influence of confounding factors such as the historical use of less physiological, oestrogens such as conjugated equine oestrogen and ethinylestradiol which are more pro-thrombotic than the 17ß oestradiol that is used in modern practice.

A review of the physical and metabolic effects of cross-sex hormonal therapy in the treatment of gender dysphoria.

This review focuses on the effect that cross-gender sex steroid therapy has on metabolic and hormonal parameters. There is an emphasis on those changes that result in significant clinical effects such as the positive effects of the development of secondary sexual characteristics and negative effects such as haemostatic effects and thromboembolism in transwomen or dyslipidaemia in transmen. There is also a description of the current hormonal regimens used at the largest UK gender identity clinic. The overall safety of these treatments in the context of long-term outcome data is reviewed.

Identification of hypothalamic nuclei involved in the orexigenic effect of melanin-concentrating hormone.

The hypothalamic neuropeptide melanin-concentrating hormone (MCH) increases feeding when injected intracerebroventricularly in rats. To identify the hypothalamic nuclei responsible for the orexigenic effect, we injected the peptide into discrete hypothalamic nuclei known to express the MCH receptor, MCH1R. MCH (0.6 nmol) elicited a rapid and significant increase in feeding in satiated rats following injection into the arcuate nucleus (0-1 h: 421 +/- 60%; P < 0.01). An elevation in feeding was also observed following injection into the paraventricular nucleus, which was sustained up to 4 h post injection (0-4 h: 218 +/- 29%; P < 0.01). A significant increase in feeding during this time period was also observed following injection into the dorsomedial nucleus (0-4 h: 155 +/- 12%; P < 0.05). No significant alteration in feeding was observed following injection into the supraoptic nucleus, lateral hypothalamic area, medial preoptic area, anterior hypothalamic area, or ventromedial nucleus of the hypothalamus. To identify the neurotransmitters that may be potentially involved in this effect, we examined their release from hypothalamic explants in vitro following exogenous MCH administration. MCH (1 micro M) increased the release of the orexigenic neurotransmitters neuropeptide Y (37.8 +/- 6.0 fmol/explant vs. basal 30.2 +/- 4.3 fmol/explant; P < 0.05) and agouti-related peptide (4.1 +/- 0.6 fmol/explant vs. basal 2.4 +/- 0.2 fmol/explant; P < 0.05) and decreased the release of the anorectic neurotransmitters alpha-MSH (41.7 +/- 6.8 fmol/explant vs. basal 65.9 +/- 11.0 fmol/explant; P < 0.01) and cocaine- and amphetamine-regulated transcript (112.3 +/- 12.4 fmol/explant vs. basal 167.4 +/- 13.0 fmol/explant; P < 0.001). These studies suggest that the orexigenic effect of MCH may be mediated via activation or inhibition of these feeding circuits within the arcuate nucleus and paraventricular nucleus of the hypothalamus.

The hypothalamic mechanisms of the hypophysiotropic action of ghrelin.

Ghrelin is an endogenous ligand for the growth hormone secretagogue (GHS) receptor, expressed in the hypothalamus and pituitary. Ghrelin, like synthetic GHSs, stimulates food intake and growth hormone (GH) release following systemic or intracerebroventricular administration. In addition to GH stimulation, ghrelin and synthetic GHSs are reported to stimulate the hypothalamo-pituitary-adrenal (HPA) axis in vivo. The aims of this study were to elucidate the hypothalamic mechanisms of the hypophysiotropic actions of ghrelin in vitro and to assess the relative contribution of hypothalamic and systemic actions of ghrelin on the HPA axis in vivo. Ghrelin (100 and 1,000 nM) stimulated significant release of GH-releasing hormone (GHRH) from hypothalamic explants (100 nM: 39.4 +/- 8.3 vs. basal 18.3 +/- 3.5 fmol/explant, n = 49, p < 0.05) but did not affect either basal or 28 mM KCl-stimulated somatostatin release. Ghrelin (10, 100 and 1,000 nM) stimulated the release of both corticotropin-releasing hormone (CRH) (100 nM: 6.0 +/- 0.8 vs. basal 4.2 +/- 0.5 pmol/explant, n = 49, p < 0.05) and arginine vasopressin (AVP) (100 nM: 49.2 +/- 5.9 vs. basal 35.0 +/- 3.3 fmol/explant, n = 48, p < 0.05), whilst ghrelin (100 and 1,000 nM) also stimulated the release of neuropeptide Y (NPY) (100 nM: 111.4 +/- 25.0 vs. basal 54.4 +/- 9.0 fmol/explant, n = 26, p < 0.05) from hypothalamic explants in vitro. The HPA axis was stimulated in vivo following acute intracerebroventricular administration of ghrelin 2 nmol [adrenocorticotropic hormone (ACTH) 38.2 +/- 3.9 vs. saline 18.2 +/- 2.0 pg/ml, p < 0.01; corticosterone 310.1 +/- 32.8 ng/ml vs. saline 167.4 +/- 40.7 ng/ml, p < 0.05], but not following intraperitoneal administration of ghrelin 30 nmol, suggesting a hypothalamic site of action. These data suggest that the mechanisms of GH and ACTH regulation by ghrelin may include hypothalamic release of GHRH, CRH, AVP and NPY.

Prolactin-releasing peptide releases corticotropin-releasing hormone and increases plasma adrenocorticotropin via the paraventricular nucleus of the hypothalamus.

Intracerebroventricular (ICV) injection of prolactin-releasing peptide (PrRP) is known to increase plasma adrenocorticotropin (ACTH) and cause c-fos expression in the hypothalamic paraventricular nucleus (PVN). We hypothesize that this is the site at which PrRP acts to increase plasma ACTH. We have used ICV injection and direct intranuclear injection of PrRP into the PVN to investigate the sites important in the stimulation of ACTH release in vivo. To investigate the mechanism of action by which PrRP increases ACTH, we have used primary culture of pituitary cells and measured neuropeptide release from in vitro hypothalamic incubations. ICV administration of PrRP increased plasma ACTH 10 min post-injection (PrRP 5 nmol 81.0 +/- 23.5 pg/ml vs. saline 16.8 +/- 14.1 pg/ml, p < 0.05). Intra-PVN injection of PrRP increased ACTH 5 min post-injection (PrRP 1 nmol 22.9 +/- 5.0 pg/ml vs. saline 10.3 +/- 1.4 pg/ml, p < 0.05). This effect continued until 40 min post-injection (PrRP 1 nmol 9.9 +/- 1.5 pg/ml vs. saline 6.2 +/- 0.5 pg/ml, p < 0.05). In vitro PrRP (1-100 nmol/l) did not effect basal or corticotropin-releasing hormone (CRH)-stimulated ACTH release from dispersed anterior pituitary cells. PrRP increased hypothalamic release of CRH (PrRP 100 nmol/l 1.4 +/- 0.2 nmol/explant vs. the basal 1.1 +/- 0.2 nmol/explant, p < 0.05) but not arginine vasopressin. PrRP also stimulated neuropeptide Y release (PrRP 100 nmol/l 56.5 +/- 11.8 pmol/explant vs. basal 24.0 +/- 1.9 pmol/explant, p < 0.01), a neuropeptide known to stimulate the hypothalamo-pituitary-adrenal axis. Our data suggest that in vitro PrRP does not have a direct action on the corticotrope but increases plasma ACTH via the PVN and this effect involves the release of hypothalamic neuropeptides including CRH and neuropeptide Y.

The hypothalamic melanocortin system stimulates the hypothalamo-pituitary-adrenal axis in vitro and in vivo in male rats.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is an agonist, and agouti-related protein (Agrp) an endogenous antagonist at the melanocortin 3 and 4 receptors which are found in the central nervous system (CNS). We have examined the effect of alpha-MSH and Agrp on the hypothalamo-pituitary-adrenal (HPA) axis in vitro and in vivo in male rats. Intraparaventricular nuclear (iPVN) injection of [Nle(4),D-Phe(7)]-alpha-MSH (NDP-MSH) (a long-acting alpha-MSH analogue) increased plasma adrenocorticotropic hormone (ACTH) (10 min post-injection: 25.0 +/- 3.9 vs. saline 10.9 +/- 2.0, p < 0.05) and plasma corticosterone (10 min post-injection: 174.1 +/- 14.2 vs. saline 124.7 +/- 16.3 ng/ml, p < 0.05). iPVN injection of Agrp(83-132) increased plasma ACTH (24.2 +/- 4.0 vs. saline 10.1 +/- 1.0 pg/ml, p < 0.01). The combination of NDP-MSH and Agrp(83-132) administered iPVN significantly increased plasma ACTH (10 min post-injection: 21.3 +/- 3.8 vs. 10.9 +/- 2.0, p < 0.05) and plasma corticosterone (10 min post-injection: 169.0 +/- 15.1 vs. saline 124.7 +/- 16.3 ng/ml, p < 0.05), but there was no additive effect. Hypothalamic explants treated with alpha-MSH (100 nM) resulted in a 159 +/- 23% increase in corticotropin-releasing hormone (CRH) release (p < 0.01) and 175 +/- 12% increase in arginine vasopressin (AVP) release (p < 0.001) compared to basal. Agrp(83-132) (100 nM) administered to hypothalamic explants resulted in a 161 +/- 20% increase in CRH (p < 0.01) and 174 +/- 13% increase in AVP release (p < 0.001) compared to basal. Hypothalamic explants treated with the combination of alpha-MSH and Agrp(83-132) (100 nM) resulted in a 179 +/- 31% increase in CRH release (p < 0.01) and 130 +/- 9% increase in AVP release (p < 0.01) compared to basal, but there was no additive effect. This is the first report that both alpha-MSH and Agrp(83-132) stimulate the HPA axis. The combination of alpha-MSH and Agrp(83-132) has no additive effect in vitro and in vivo in male rats. These results suggest that there may be another receptor independent of the known melanocortin receptors at which Agrp is acting.