The elucidation of Δ9-tetrahydrocannabinol as the active principal of Cannabis sativa in 1963 initiated a fruitful half-century of scientific discovery, culminating in the identification of the endocannabinoid signaling system, a previously unknown neuromodulatory system. A primary function of the endocannabinoid signaling system is to maintain or recover homeostasis following psychological and physiological threats. We provide a brief introduction to the endocannabinoid signaling system and its role in synaptic plasticity. The majority of the article is devoted to a summary of current knowledge regarding the role of endocannabinoid signaling as both a regulator of endocrine responses to stress and as an effector of glucocorticoid and corticotrophin-releasing hormone signaling in the brain. We summarize data demonstrating that cannabinoid receptor 1 (CB1R) signaling can both inhibit and potentiate the activation of the hypothalamic-pituitary-adrenal axis by stress. We present a hypothesis that the inhibitory arm has high endocannabinoid tone and also serves to enhance recovery to baseline following stress, while the potentiating arm is not tonically active but can be activated by exogenous agonists. We discuss recent findings that corticotropin-releasing hormone in the amygdala enables hypothalamic-pituitary-adrenal axis activation via an increase in the catabolism of the endocannabinoid N-arachidonylethanolamine. We review data supporting the hypotheses that CB1R activation is required for many glucocorticoid effects, particularly feedback inhibition of hypothalamic-pituitary-adrenal axis activation, and that glucocorticoids mobilize the endocannabinoid 2-arachidonoylglycerol. These features of endocannabinoid signaling make it a tantalizing therapeutic target for treatment of stress-related disorders but to date, this promise is largely unrealized.
Introduction Current Endocrine Society guidelines recommend that transgender women taking spironolactone have their potassium levels checked every 3 months for the first year after initiating therapy and annually thereafter to monitor for hyperkalemia. The goal of this study was to assess the need for such frequent potassium monitoring and to investigate whether age plays a role in potassium abnormalities in transgender, gender diverse and non-binary (TGDNB) individuals taking spironolactone. Methods Using EPIC-Clarity, a retrospective study of healthy, adult individuals with gender identity disorder listed in their problem list and taking spironolactone was performed. We analyzed incidence of hyperkalemia in this population. Data from June 2006 through November 2021 were obtained. Exclusion criteria included: hypertension, renal failure, diabetes mellitus, heart failure and medications that affect the renin-angiotensin-aldosterone system. Results 318 healthy TGDNB individuals met our inclusion criteria. We identified 8/318 (2.5%) individuals with hyperkalemia on spironolactone. There was a significant difference in incidence of hyperkalemia events in those age >45 years and those age ≤45 years old (8.9% vs. 1.5%, p= 0.016). Conclusion Our data suggest the incidence of hyperkalemia in our TGDNB population is low, particularly in those ≤45 years old; however, this risk increases with age. These findings suggest practice guidelines may need to be adjusted to minimize unnecessary testing in this population ≤45 years old who are not plagued by co-morbidities that affect potassium handling.
Pre-menopausal women have a lower incidence of cardiovascular disease (CVD) compared to their age-matched male counterparts however this discrepancy is abolished following the transition to menopause or during low estrogen states. This, combined with a large amount of basic and preclinical data indicating that estrogen is vasculoprotective, supports the concept that hormone therapy could improve cardiovascular health. However, clinical outcomes in individuals undergoing estrogen treatment have been highly variable, challenging the current paradigm regarding the role of estrogen in the fight against heart disease. Increased risk for CVD correlates with long-term oral contraceptive use, hormone replacement therapy in older, post-menopausal cis-females, and gender affirmation treatment for trans-females. Vascular endothelial dysfunction serves as a nidus for the development of many cardiovascular diseases and is highly predictive of future CVD risk. Despite preclinical studies indicating that estrogen promotes a quiescent, functional endothelium, it still remains unclear why these observations do not translate to improved CVD outcomes. The goal of this review is to explore our current understanding of the effect of estrogen on the vasculature, with a focus on endothelial health. Following a discussion regarding the influence of estrogen on large and small artery function, critical knowledge gaps are identified. Finally, novel mechanisms and hypotheses are presented that may explain the lack of cardiovascular benefit in unique patient populations.
Hyperprolactinemia from a prolactin-secreting pituitary tumor is the most common endocrine disorder of the hypothalamic-pituitary axis. As suggested in the 2011 Endocrine Society Guidelines on Diagnosis and Treatment of Hyperprolactinemia, macroprolactin level should be assessed in patients with asymptomatic hyperprolactinemia. However, as discussed in prior studies comparing the performance of common prolactin immunoassays in a reference population of both males and females with and without known hyperprolactinemia or macroprolactinemia, there has been poor harmonization between assays and variable reactivity towards macroprolactin, resulting in significantly different normal ranges for total and monomeric prolactin between manufacturers. The goal of our analysis is to assess the concordance of the Roche and Siemens prolactin immunoassays using cases in which prolactin and macroprolactin testing was ordered on clinical indication. We hope to educate clinicians regarding potential variability between assays that may not be fully accounted for by using established, assay-specific reference ranges. We reviewed patients 18 years and older from any gender who underwent evaluation of prolactin levels as clinically indicated and had elevated serum prolactin on a Roche assay with a subsequent normal prolactin on a Siemens assay. Seven out of 18 patients had an elevated prolactin on the Roche assay and a normal prolactin on the subsequent Siemens assay that also tests for the presence of macroprolactin. The reasons for testing prolactin in the 7 patients were: secondary hypogonadism (4), pituitary microadenoma (1), oligomenorrhea (1) and baseline labs in a transgender female starting estrogen (1). Of the 7 cases we observed with discordant Roche and Siemens prolactin results, one of our 2 female patients and one of our 4 male patients would have shown concordant hyperprolactinemia results on both assays if the Siemens reference range was narrowed to align with published studies. This study demonstrates significant analytical discordance between prolactin immunoassays, leading to variable clinical interpretation regarding the presence of hyperprolactinemia. We suggest using a single prolactin immunoassay for routine measurement of prolactin as well as investigation of macroprolactin measurement to ensure comparable reactivity towards all forms of prolactin. References: (1) Vallette-Kasic et al., J Clin Endocrinol Metab. 2002 Feb;87(2):581-8. (2) Gibney et al., J Clin Endocrinol Metab. 2005 Jul;90(7):3927-32. (3) Luisa et al., Clinical chemistry 2008 Sept; 54:10 1673-1681 (4) Shlomo et al., J Clin Endocrinol Metab, February 2011, 96(2):273-288
Sublingual administration of estradiol (E2) may be a safer and more effective hormone replacement therapy (HRT) route than oral estradiol, the most commonly used formulation, but it has yet to be investigated in transgender women. Unlike oral E2, sublingual E2 is thought to bypass the first pass effect by the liver, making it less likely to impact hepatic clotting factor synthesis, and thus decreasing the risk of thromboembolic events posed by oral administration, such as VTE and ischemic stroke (1). Additionally, studies in cisgender women have demonstrated a 13-fold higher peak serum concentration and a decreased estrone (E1) to estradiol ratio with sublingual administration, suggesting that sublingual E2 is more a physiologically potent route (2). To advance the understanding of sublingual E2 as an alternative method of administration in transgender HRT, we investigated the pharmacokinetics of estradiol when administered orally versus sublingually in transgender women. Ten transgender women naïve to estrogen were provided 1.0 mg of oral estradiol. Blood samples were collected via percutaneous intravenous catheter at baseline and at T=1,2,3,4,6, and 8 hours post-dosing. After a 7-day washout period, 1.0 mg of sublingual estradiol was dosed with identical sampling over time. Analysis of serum samples was performed using LC-MS/MS and estradiol immunoassay. Initial results demonstrate a higher peak serum concentration within 8 hours with sublingual dosing in both LC-MS/MS and immunoassay quantification (178±47 and 150±31 pg/mL, respectively) compared to oral administration (36±5 and 35±4 pg/mL, respectively; N=5). Peak concentration was reached at T=1 hour for sublingual E2 in both LC-MS/MS and immunoassay analysis, whereas oral E2 reached peak serum concentration at T=8 hours in LC-MS/MS analysis and T=6 hours in immunoassay analysis. Sublingual E2 still maintained higher overall mean concentrations of estradiol across the 8 hours compared to oral E2. Importantly, subjects reported high satisfaction with sublingual administration due to rapid dissolution (<2 minutes) and minimal taste; as a result, subjects predicted high ease of adherence in future HRT, which indicates the feasibility of sublingual E2 as an alternative to oral E2. Additional analysis of half-life and oral clearance will be performed at the completion of the study, in order to further establish pharmacokinetic differences and potency between the two routes. This pharmacokinetic data will allow future studies on optimal dosing, safety, and efficacy compared to oral estradiol in hormone replacement therapy. (1) Hembree et al. J Clin Endocrinol Metab. 2017;102(11):3869-3903. (2) Price et al., Obstet Gynecol. 1997.
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