SUN-LB9 Pharmacokinetics of Sublingual Versus Oral Estradiol in Transgender Women

Abstract

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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“…Compared to oral formulations, transdermal estrogens provide more stable bioavailability, have reduced thrombotic risk by avoiding first-pass metabolism, and are preferred in patients with a history of unprovoked thrombosis or clotting disorders [ 37 , 38 ]. However, estrogen patches are more expensive than oral estrogen and not covered by some insurance [ 32 , 33 ].…”

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