madman
Super Moderator
Comparison of Subcutaneous and Intramuscular Estradiol Regimens as part of Gender-Affirming Hormone Therapy (2023)
Justine S Herndon, PA-C, Arvind K Maheshwari, MBBS, Todd B Nippoldt, MD, Sara J Carlson, RN CDE, Caroline J Davidge-Pitts, MBBCh, Alice Y Chang, MD
Abstract
Objective: Gender-affirming hormone therapy (GAHT) guidelines describe estradiol doses for intramuscular (IM), but not subcutaneous (SC) routes. The objective was to compare SC and IM estradiol doses and hormone concentrations in transgender and gender-diverse (TGD) individuals.
Methods: Retrospective cohort study at a single-site tertiary care referral center. Patients were TGD individuals receiving injectable estradiol with at least 2 estradiol measurements. The main outcomes were median doses and achieved serum hormone concentrations between SC and IM routes.
Results: There was no statistical difference in age, BMI, or anti-androgen use between patients on SC estradiol (n = 74) vs IM estradiol (n = 56). Median weekly doses of SC estradiol, 3.75 mg [IQR 3-4 mg] were statistically significantly lower than IM estradiol, 4 mg [IQR 3-5.15 mg] (p = 0.005), but estradiol concentrations achieved by both groups were not significantly different, (p = 0.69) and median testosterone concentrations were in the cisgender female range and were not significantly different between routes (p = 0.92). Subgroup analysis demonstrated significantly higher doses in the IM group when estradiol > 100 pg/mL, testosterone < 50 ng/dL, with gonads present, or the use of anti-androgens. Multiple Regression Analysis demonstrated that estradiol dose was significantly associated with estradiol concentrations after adjusting for injection route, BMI, anti-androgen use, and gonadectomy status.
Conclusions: Both SC and IM estradiol GAHT achieve therapeutic estradiol concentrations without a meaningful difference in estradiol dose (3.75 vs 4 mg). SC use may require lower doses than IM to achieve therapeutic concentration.
Introduction
Gender-affirming hormone therapy (GAHT) for transgender and gender diverse (TGD) individuals may consist of estradiol and anti-androgen therapy to align physical appearance with gender identity [1]. The current practice places emphasis on the use of 17-beta estradiol in various preparations (parenteral, oral, and transdermal),., moving away from the historical use of ethinyl estradiol and conjugated estrogens due to concerns of an increased adverse risk profile [1, 2]. Doses recommended to achieve premenopausal estradiol concentrations that also suppress the pituitary/gonadal axis for GAHT might be higher and more frequent than the current FDA-approved indications for cisgender female estrogen deficiency [1].
When used for GAHT, estradiol formulation, dosing, and route might depend on multiple factors, including geographic variation and availability, insurance coverage and financial affordability, patient preference, and concern for route-specific adverse effects [3, 4]. Prior studies have shown that parenteral estradiol use varies greatly between practices, with some studies reporting minimal use in TGD individuals [5, 6]. Parenteral estradiol is available in various esters, most commonly as valerate and cypionate. Pharmacokinetics vary depending on the specific ester with a duration lasting between 4 to 14 days, and peak estradiol level achieved 2-3 days after injection [7-10]. Existing recommendations for GAHT suggest IM doses of 2-10 mg every week or 5-30 mg every 2 weeks [1, 2]. As opposed to data and guideline recommendations about subcutaneous (SC) testosterone for GAHT in TGD individuals, there is little data to support SC estradiol recommendations to date [1]. In studies directly comparing IM and SC testosterone in transgender men, there was a clear patient preference for the SC route, with patients reporting increased tolerability and less injection site-related pain [11, 12]. When compared, most transgender men in these studies achieved cisgender male testosterone concentrations and achieved menstrual cessation with no difference between those on SC and those on IM testosterone. [11-14].
In initial studies, SC estradiol was reported to be well tolerated with fewer local side effects as compared to IM estradiol, and without any difference in feminization [15]. The recommended dosing ranges specifically for the SC route of estradiol are not widely available in current publications [16, 17]. Based on a few high-quality studies with limited sample sizes, current recommended SC estradiol doses equate to those of IM estradiol, though few studies directly compare these two parenteral routes. Studies in cisgender women show equivalent pharmacokinetic profiles between SC and IM estradiol, though parenteral use is minimal in this population compared to TGD individuals [7, 18, 19].
In this study, we sought to directly compare parenteral routes of estradiol administration as part of GAHT. The primary aim was to compare doses between SC and IM routes and the serum estradiol and testosterone concentrations in TGD individuals. Secondary goals included comparing the effect of anti-androgens, gonadectomy status, and use of estradiol cypionate vs valerate on doses between SC and IM administration.
Methods
*Available estradiol concentrations were measured using Liquid Chromatography-Tandem Mass Spectrometry, high accuracy (% bias <4), and precision (% CV <7.5) at broad linear dynamic ranges (0.005-20 ng/mL) [20]. No radioimmunoassay estradiol concentrations were included in this study.
Discussion
In this study, we compared SC versus IM routes of injection as a part of GAHT in TGD individuals. There were no significant differences in demographic or baseline characteristics between the cohorts except for a statistical difference in the number of patients who had gonadectomy in the IM group. Statistically significantly lower median weekly doses of SC estradiol were observed while achieving target estradiol concentrations, SC 3.75 mg [IQR 3-4 mg] versus IM estradiol, 4 mg [IQR 3-5.15 mg]. In Figure 1B, more individuals using the IM route clustered into a higher range of doses than the SC group. Subgroup analysis showed the groups who achieved therapeutic estradiol concentrations, testosterone concentrations < 50 ng/dL, patients with gonads present, and patients on anti-androgens had statistically greater median IM estradiol doses, but those patients with estradiol concentrations < 100 pg/mL, patients who had undergone gonadectomy, and patients not using anti-androgen groups did not. This is the first study directly comparing these two routes, and more importantly, it gives further direction on doses of parenteral estradiol for our TGD individuals.
Strengths & Limitations
To date, this study includes the largest number of patients on parenteral estradiol as compared to previous studies. The inclusion criteria, such as more than one documented estradiol level and multiple clinical visits, suggest that hormone dosing details are more reflective of adequate maintenance dosing and expected feminization. Additionally, only liquid chromatography-mass spectrometry-derived estradiol concentrations were analyzed in this study, which has a higher accuracy and precision than those concentrations derived from a radioimmunoassay method.
Limitations include the retrospective nature of this study and the individualized approach to the use of parenteral estradiol by the prescribing providers. In our practice, although estradiol concentrations were generally checked midway through the injection cycle, we were unable to document with certainty the timing of the estradiol lab testing which may have influenced the results and/or the outliers. Testosterone concentrations did not always coincide, in terms of timing of blood draw, with estradiol concentrations; however, this was infrequent, involving only 23 patients. Most recent estradiol and testosterone concentrations were collected, and some results may have been influenced by earlier GAHT users. For local injection site reactions, documentation is typically done if there is a patient-reported concern, but milder or unreported symptoms (if not bothersome) may not have been captured. Finally, there are electronic medical record-related limitations when collecting data - all patients may not have been captured and abstracted data was contingent on appropriate and accurate clinical documentation. For example, doses from clinical notes may not match the electronic prescription details, among others.
Conclusion
In conclusion, the use of subcutaneous or intramuscular estradiol for TGD individuals is an effective route for GAHT. Although median subcutaneous dosing was statistically significantly lower than intramuscular doses, doses were not meaningfully different in terms of guiding initial dose selection. Lower doses of parenteral injections than previously described in clinical practice guidelines achieved therapeutic estradiol concentrations. Our data can serve as a dosing guide for the initial and maintenance use of parenteral estradiol, which is different than what has been previously described. Therefore, initiation of estradiol GAHT in TGD individuals considerations of different routes after initiation should include a discussion of both SC and IM parenteral preparations to individualize treatments for each patient. Further studies are needed to analyze clinical outcomes and achievement of feminization in comparison to other preparations of estradiol, as well as additional risks versus benefits.
Justine S Herndon, PA-C, Arvind K Maheshwari, MBBS, Todd B Nippoldt, MD, Sara J Carlson, RN CDE, Caroline J Davidge-Pitts, MBBCh, Alice Y Chang, MD
Abstract
Objective: Gender-affirming hormone therapy (GAHT) guidelines describe estradiol doses for intramuscular (IM), but not subcutaneous (SC) routes. The objective was to compare SC and IM estradiol doses and hormone concentrations in transgender and gender-diverse (TGD) individuals.
Methods: Retrospective cohort study at a single-site tertiary care referral center. Patients were TGD individuals receiving injectable estradiol with at least 2 estradiol measurements. The main outcomes were median doses and achieved serum hormone concentrations between SC and IM routes.
Results: There was no statistical difference in age, BMI, or anti-androgen use between patients on SC estradiol (n = 74) vs IM estradiol (n = 56). Median weekly doses of SC estradiol, 3.75 mg [IQR 3-4 mg] were statistically significantly lower than IM estradiol, 4 mg [IQR 3-5.15 mg] (p = 0.005), but estradiol concentrations achieved by both groups were not significantly different, (p = 0.69) and median testosterone concentrations were in the cisgender female range and were not significantly different between routes (p = 0.92). Subgroup analysis demonstrated significantly higher doses in the IM group when estradiol > 100 pg/mL, testosterone < 50 ng/dL, with gonads present, or the use of anti-androgens. Multiple Regression Analysis demonstrated that estradiol dose was significantly associated with estradiol concentrations after adjusting for injection route, BMI, anti-androgen use, and gonadectomy status.
Conclusions: Both SC and IM estradiol GAHT achieve therapeutic estradiol concentrations without a meaningful difference in estradiol dose (3.75 vs 4 mg). SC use may require lower doses than IM to achieve therapeutic concentration.
Introduction
Gender-affirming hormone therapy (GAHT) for transgender and gender diverse (TGD) individuals may consist of estradiol and anti-androgen therapy to align physical appearance with gender identity [1]. The current practice places emphasis on the use of 17-beta estradiol in various preparations (parenteral, oral, and transdermal),., moving away from the historical use of ethinyl estradiol and conjugated estrogens due to concerns of an increased adverse risk profile [1, 2]. Doses recommended to achieve premenopausal estradiol concentrations that also suppress the pituitary/gonadal axis for GAHT might be higher and more frequent than the current FDA-approved indications for cisgender female estrogen deficiency [1].
When used for GAHT, estradiol formulation, dosing, and route might depend on multiple factors, including geographic variation and availability, insurance coverage and financial affordability, patient preference, and concern for route-specific adverse effects [3, 4]. Prior studies have shown that parenteral estradiol use varies greatly between practices, with some studies reporting minimal use in TGD individuals [5, 6]. Parenteral estradiol is available in various esters, most commonly as valerate and cypionate. Pharmacokinetics vary depending on the specific ester with a duration lasting between 4 to 14 days, and peak estradiol level achieved 2-3 days after injection [7-10]. Existing recommendations for GAHT suggest IM doses of 2-10 mg every week or 5-30 mg every 2 weeks [1, 2]. As opposed to data and guideline recommendations about subcutaneous (SC) testosterone for GAHT in TGD individuals, there is little data to support SC estradiol recommendations to date [1]. In studies directly comparing IM and SC testosterone in transgender men, there was a clear patient preference for the SC route, with patients reporting increased tolerability and less injection site-related pain [11, 12]. When compared, most transgender men in these studies achieved cisgender male testosterone concentrations and achieved menstrual cessation with no difference between those on SC and those on IM testosterone. [11-14].
In initial studies, SC estradiol was reported to be well tolerated with fewer local side effects as compared to IM estradiol, and without any difference in feminization [15]. The recommended dosing ranges specifically for the SC route of estradiol are not widely available in current publications [16, 17]. Based on a few high-quality studies with limited sample sizes, current recommended SC estradiol doses equate to those of IM estradiol, though few studies directly compare these two parenteral routes. Studies in cisgender women show equivalent pharmacokinetic profiles between SC and IM estradiol, though parenteral use is minimal in this population compared to TGD individuals [7, 18, 19].
In this study, we sought to directly compare parenteral routes of estradiol administration as part of GAHT. The primary aim was to compare doses between SC and IM routes and the serum estradiol and testosterone concentrations in TGD individuals. Secondary goals included comparing the effect of anti-androgens, gonadectomy status, and use of estradiol cypionate vs valerate on doses between SC and IM administration.
Methods
*Available estradiol concentrations were measured using Liquid Chromatography-Tandem Mass Spectrometry, high accuracy (% bias <4), and precision (% CV <7.5) at broad linear dynamic ranges (0.005-20 ng/mL) [20]. No radioimmunoassay estradiol concentrations were included in this study.
Discussion
In this study, we compared SC versus IM routes of injection as a part of GAHT in TGD individuals. There were no significant differences in demographic or baseline characteristics between the cohorts except for a statistical difference in the number of patients who had gonadectomy in the IM group. Statistically significantly lower median weekly doses of SC estradiol were observed while achieving target estradiol concentrations, SC 3.75 mg [IQR 3-4 mg] versus IM estradiol, 4 mg [IQR 3-5.15 mg]. In Figure 1B, more individuals using the IM route clustered into a higher range of doses than the SC group. Subgroup analysis showed the groups who achieved therapeutic estradiol concentrations, testosterone concentrations < 50 ng/dL, patients with gonads present, and patients on anti-androgens had statistically greater median IM estradiol doses, but those patients with estradiol concentrations < 100 pg/mL, patients who had undergone gonadectomy, and patients not using anti-androgen groups did not. This is the first study directly comparing these two routes, and more importantly, it gives further direction on doses of parenteral estradiol for our TGD individuals.
Strengths & Limitations
To date, this study includes the largest number of patients on parenteral estradiol as compared to previous studies. The inclusion criteria, such as more than one documented estradiol level and multiple clinical visits, suggest that hormone dosing details are more reflective of adequate maintenance dosing and expected feminization. Additionally, only liquid chromatography-mass spectrometry-derived estradiol concentrations were analyzed in this study, which has a higher accuracy and precision than those concentrations derived from a radioimmunoassay method.
Limitations include the retrospective nature of this study and the individualized approach to the use of parenteral estradiol by the prescribing providers. In our practice, although estradiol concentrations were generally checked midway through the injection cycle, we were unable to document with certainty the timing of the estradiol lab testing which may have influenced the results and/or the outliers. Testosterone concentrations did not always coincide, in terms of timing of blood draw, with estradiol concentrations; however, this was infrequent, involving only 23 patients. Most recent estradiol and testosterone concentrations were collected, and some results may have been influenced by earlier GAHT users. For local injection site reactions, documentation is typically done if there is a patient-reported concern, but milder or unreported symptoms (if not bothersome) may not have been captured. Finally, there are electronic medical record-related limitations when collecting data - all patients may not have been captured and abstracted data was contingent on appropriate and accurate clinical documentation. For example, doses from clinical notes may not match the electronic prescription details, among others.
Conclusion
In conclusion, the use of subcutaneous or intramuscular estradiol for TGD individuals is an effective route for GAHT. Although median subcutaneous dosing was statistically significantly lower than intramuscular doses, doses were not meaningfully different in terms of guiding initial dose selection. Lower doses of parenteral injections than previously described in clinical practice guidelines achieved therapeutic estradiol concentrations. Our data can serve as a dosing guide for the initial and maintenance use of parenteral estradiol, which is different than what has been previously described. Therefore, initiation of estradiol GAHT in TGD individuals considerations of different routes after initiation should include a discussion of both SC and IM parenteral preparations to individualize treatments for each patient. Further studies are needed to analyze clinical outcomes and achievement of feminization in comparison to other preparations of estradiol, as well as additional risks versus benefits.
