E2 Valerate Research Articles

6898 A Case Report Of Drug-Induced Liver Injury Secondary To Sublingual Estradiol In A Transgender Woman

Abstract Disclosure: F. Manas: None. E. Davydov: None. A. Caines: None. K. Estrada: None. J.E. Shill: None. Drug-induced liver injury (DILI), the leading cause of acute liver failure in the United States, occurs in response to a medication or natural compound. Estrogens can lead to idiosyncratic DILI. According to LiverTox [livertox.nih.gov], estrogen has a likelihood score of A (highly likely) to cause DILI, whereas spironolactone has a likelihood score of D (rare). The current formulations of estrogens usually produce a mixed or cholestatic pattern of liver enzyme elevations, however very early, the ALT levels can be markedly elevated (5- to 20-fold). One can be asymptomatic. Often the liver injury resolves after removing the offending agent. We present a case of DILI with elevations of both alanine transferase (ALT) and aspartate transferase (AST), secondary to sublingual estradiol (E2). A 23-year-old transgender female presented for feminizing gender-affirming care. She was started on sublingual E2 2 mg once daily and spironolactone 100 mg orally twice daily. Approximately 14 weeks later, sublingual E2 was increased to 2 mg twice daily for a below-target E2 level, and spironolactone was decreased to 50 mg twice daily due to gas and nausea. Routine blood work three weeks later showed elevated liver function tests (LFTs) in a hepatocellular pattern with ALT of 216 IU/L (normal:<52IU/L), AST of 223 IU/L (normal:<35 IU/L), with normal total bilirubin and alkaline phosphatase. LFTs were normal six months prior. At the time of liver injury, she had consumed six alcoholic beverages in the previous fourteen days, and two doses of acetaminophen. She had no personal history of autoimmunity and no family history of liver disease. Acute hepatitis screen was normal. Abdominal US with liver Doppler was unremarkable. E2 and spironolactone were discontinued. Evaluation by hepatology lead to a diagnosis of DILI from sublingual E2, based on the temporal relationship between initiation of E2 and LFT elevation. Other potential causes of elevated LFTs were excluded. Although she reported alcohol use, the AST/ALT elevation was not in a classic 2:1 pattern. Three weeks after cessation of E2 and spironolactone, her LFTs normalized. Spironolactone was resumed along with E2 by patch, but due to skin-adherence issues she was transitioned to injectable E2 valerate. Her LFTs have remained normal since. This case illustrates a rare but potentially dangerous adverse event of DILI secondary to sublingual E2. Due to the low incidence of liver injury in various studies of individuals with gender incongruence on hormone therapy, current evidence does not support routine liver enzyme monitoring. Clinicians should be aware of the potential risk of liver injury and counsel patients accordingly. As in this case, patients may be successfully rechallenged with the offending DILI medication. Further studies on different formulations of hormone therapy and their effects on the liver would be beneficial in this unique population. Presentation: 6/2/2024

9224 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

6961 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

9224 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

6961 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

Estradiol modulates changes in effective connectivity in emotion regulation networks

Hormonal changes in ovarian hormones like estradiol (E2) during the menstrual cycle affect emotional processes, including emotion recognition, memory, and regulation. So far, the neural underpinnings of the effect of E2 on emotional experience have been investigated using task-based functional magnetic resonance imaging (fMRI) and functional connectivity. In the present study, we examined whether the intrinsic network dynamics at rest (i.e., directed effective connectivity) related to emotion regulation are (1) modulated by E2 levels and (2) linked to behavioral emotion regulation ability. Hence, 29 naturally cycling women participated in two resting-state fMRI scans in their early follicular phase after being administered a placebo or an E2 valerate, respectively. Emotion regulation ability was assessed using a standard emotion regulation task in which participants were asked to down-regulate their emotions in response to negative images. The regions of two functionally predefined neural networks related to emotional down-regulation and reactivity were used to investigate effective connectivity at rest using spectral dynamic causal modelling. We found that E2, compared to placebo, resulted in changes in effective connectivity in both networks. In the regulation network, prefrontal regions showed distinct connectivity in the E2 compared to the placebo condition, while mixed results evolved in the emotional reactivity network. Stepwise regressions revealed that in the E2 condition a connection from the parietal to the prefrontal cortex predicted regulation ability. Our results demonstrate that E2 levels influence effective connectivity in networks underlying emotion regulation and emotional reactivity. Thus, E2 and its potential modification via hormonal administration may play a supporting role in the treatment of mental disorders that show a dysregulation of emotions.

Bleeding Patterns of Oral Contraceptives with a Cyclic Dosing Regimen: An Overview.

Bleeding irregularities are one of the major reasons for discontinuation of oral contraceptives (OCs), and therefore clinicians need to set expectations during consultations. In this review we provide an overview of bleeding data of recently marketed cyclic combined OCs (COCs) and one progestin-only pill (POP). We evaluated data from phase 3 trials (≥12 months) used to gain regulatory approval. Overall, each type of OC has its own specific bleeding pattern. These patterns however were assessed by using different bleeding definitions, which hampers comparisons between products. In COCs, the estrogen balances the effects of the progestin on the endometrium, resulting in a regular bleeding pattern. However, this balance seems lost if a too low dose of ethinylestradiol (EE) (e.g., 10 µg in EE/norethindrone acetate 1 mg) is used in an attempt to lower the risk of venous thromboembolism. Replacement of EE by 17β-estradiol (E2) or E2 valerate could lead to suboptimal bleeding profile due to destabilization of the endometrium. Replacement of EE with estetrol (E4) 15 mg in the combination with drospirenone (DRSP) 3 mg is associated with a predictable and regular scheduled bleeding profile, while the POP containing DRSP 4 mg in a 24/4 regimen is associated with a higher rate of unscheduled and absence of scheduled bleeding than combined products.

Pregnancy and brain architecture: Associations with hormones, cognition and affect.

Sex hormones such as estradiol (E2) have long-lasting influence on brain architecture. Recent studies indicate further structural changes during hormonal transition periods including pregnancy, when women experience the greatest increase in sex hormone levels across their life span. In the present study, three groups of women (n=44) with different levels of E2 underwent structural magnetic resonance imaging: (1) first-time pregnant women (n=13, 'extreme E2group'); (2), nulliparous, naturally cycling women who received 12mg of E2valerate (n=16, 'high E2group'); and (3) nulliparous, naturally cycling women receiving a placebo and hence low E2 (n=15, 'low E2group'). Blood samples were taken to assess hormonal levels. Moreover, parameters for cognition, emotion regulation and affect were assessed. On the neuronal level, the extreme E2 compared to the high E2group showed a reduced gray matter volume in the left putamen. However, no significant differences were found between the low vs. high E2 groups, nor between the low E2 and extreme E2groups. Cognitive performance was reduced in the extreme E2group, although a positive affect was increased compared to the high E2 and low E2groups. Furthermore, regression analyses revealed several associations between cognition, subjective measures of affect, emotion regulation and gray matter volume. A volume reduction of the left putamen during pregnancy further supports the notion that the female brain is shaped by hormonal transition phases, possibly preparing women for their future roles (e.g., pregnant women for their role as mothers).

Estradiol administration modulates neural emotion regulation

Variations of sex hormones during the menstrual cycle can lead to changes in emotion processing. The ability to successfully regulate one’s emotions is associated with better social abilities and mental health. While women show better performance in fear extinction learning under high estradiol (E2) compared to women under low E2 levels, little is known about the effect of E2 on emotion regulation. We explored whether E2 modulates emotion regulation in a functional magnetic resonance imaging paradigm and administered E2 valerate to 32 young naturally cycling women during their early follicular phase in a double-blind, placebo-controlled within-subject design. This standardized experimental control allowed us to explore the specific effect of E2 on emotion regulation while controlling for other hormones varying throughout the menstrual cycle. Behaviorally, no difference between conditions appeared. However, on the neural level, E2 administration was associated with lower activation in the right lingual- and left calcarine gyrus, right orbitofrontal cortex and left hippocampus relative to placebo. With respect to the main effect of down-regulation higher activation of the right superior frontal gyrus and left dorsomedial prefrontal cortex was seen; which is in accordance to previous literature. An interaction between drug condition and emotion regulation appeared for the left inferior frontal gyrus extending into the middle frontal gyrus indicating lower activation during down-regulation in the E2 condition than the placebo condition. On the behavioral level, women reported less negative affect in the E2 condition. The results fit well to a previously described psychoneuroendocrinological model in which E2 plays an important modulatory role on emotional processes and risk factors of mental health in women.

Use of steroid pre-treatments in IVF-ICSI cycles with GnRH antagonist protocol and their impact on gestational outcomes

Different steroid pre-treatments have been used to schedule the start of the ovarian stimulation in IVF cycles. Currently, there is controversy about their effects on gestational outcomes. We designed a three-armed randomised controlled trial (RCT). Eighty-six normoresponder patients undergoing IVF treatment with antagonist GnRH protocol were allocated to three different groups. In the group 1, 34 patients received oral contraceptive pill (OCP) from the first day of the cycle to five days before starting ovarian stimulation, in the group 2, 25 patients received 2 mg/12 hours of oral E2 valerate from day 25 of the previous cycle until the day before starting stimulation, and finally, in the group 3, 27 patients did not receive any treatment. There are no statistically significant differences neither in clinical pregnancy rate (CPR) (40.9% OCP vs. 28.6% E2 vs. 53.3% no treatment group, p=.388) nor live birth rate (LBR) (31.8% OCP vs. 28.6% E2 vs. 46.7% no treatment group, p=.537) between groups in fresh embryo transfer. Likewise, no differences were found in the cumulative CPR, nor in cumulative LBR. However, there is a tendency to worst outcomes in the E2 group. In this E2 group, we observed better results with longer exposition, although no significant differences are reached (E2 mean days in the pregnant group 8.29 vs. 6.83 in the non-pregnant group, p=.08). Our study shows no significant differences in pregnancy rates between groups, but the E2 group is trending at worse gestational results. Trial registration number: Eudra-CT registration number is 2014-001809-40. Impact Statement What is already known on this subject? Nowadays, there is much controversy about how pregnancy rates could be affected by the selection of steroid pre-treatments used in order to schedule IVF cycles. However, these treatments are widely utilised in clinical practice. What the results of this study add? The results support the clinical findings of most of the studies previously published. No significant differences in gestational outcomes were found between the groups treated with steroid pre-treatments and the control group. Additionally, oestrogen pre-treatment seems to be related to better pregnancy outcomes when the exposition is longer. Thus, an earlier start of this treatment in the luteal phase could be the optimal approach. What the implications are of these findings for clinical practice and/or further research? This study pretends to provide clarity about the treatment guidelines of steroid pre-treatments to schedule the clinical work without impact on gestational outcomes.

A Comparison Between the Effect of Vaginal Sildenafil Versus Oral Estradiol Valerate on Ultrasound Parameters of Endometrial Receptivity and Follicular Growth in Iraqi Females Receiving Letrozole for Induction of Ovulation

Endometrial thickness (ET) is one of the best predictors of implantation rate and pregnancy success rate because endometrial growth depends on hormones. Estrogen regulates the proliferative phase, endometrial proliferation induced by estrogen after menstruation is largely dependent on blood flow to the basal endometrium that produces progesterone receptors which are required for progesterone-regulated endometrial growth in the secretory process. To compare the effect of estradiol valerate vs. sildenafil citrate on endometrial receptivity and subsequent pregnancy outcome in unexplained infertility patients receiving letrozole for ovulation induction. Herein, 21 patients with unexplained infertility underwent ovulation induction by letrozole (2.5 mg). Patients were divided into 2 groups; group A (10 patients) were given sildenafil tablets vaginally (25 mg) four times daily and group B (11 patients) were treated with estradiol valerate tablet 2 mg/12 hours. Patients were evaluated by transvaginal ultrasonography (TVS) to determine endometrial thickness, pattern, size, and the number of the dominant follicles, serum assessment of Vascular Endothelial Growth Factor (VEGF) level at trigger day, and chemical pregnancy outcome 14 days later. Results showed that the endometrial thickness, patterns of the endometrium, VEGF, size of the dominant follicle at the trigger day, and pregnancy rates were not significantly different between the two groups. However, the difference in the number of the dominant follicles at trigger day was statistically significant which is more in the sildenafil treated group. The present study confirmed the findings of both Sildenafil and E2 valerate to boost endometrial receptivity and pregnancy rate.

INITIAL EVALUATION OF SAFETY AND EFFICACY OF ADMINISTRATION OF ESTRADIOL (E2) BY SUBCUTANEOUS (SC) INJECTIONS TO MALE-TO-FEMALE (MTF) TRANSGENDER PATIENTS

The primary aim of this study was to determine if SC injection of E2 valerate could produce serum E2 levels within our clinic’s target therapeutic range for MTF patients (75-200 pg/mL) without causing significant adverse effects. Secondary aims were to assess: 1) if SC E2 can suppress serum total testosterone (T) levels (<50 ng/dL) as effectively as oral (PO) E2 , 2) if SC administration has less of a hepatic effect than PO, 3) if serum E2 levels remain within the target range between weekly injections and 4) if SC E2 is acceptable to patients. Retrospective chart review of MTF patients treated in Maine Medical Center Reproductive Endocrinology clinic. All charts of MTF patients seen from 2011-2020 were reviewed. Patients were allowed to choose PO, SC or transdermal (TD) administration. Inclusion criteria were age 18-79 years, PO or SC E2 therapy, and serum E2 and T levels measured by LabCorp (Calabasas CA). E2 valerate was injected SC using a 5/8’ 25g needle. 17β-E2 was administered orally. Serum E2, T, estrone (E1), and sex hormone binding globulin (SHBG) levels and fasting lipid panels were measured in SC and PO patients and values compared by Mann Whitney U test. Peak and nadir serum E2 concentrations were measured in a subgroup of SC patients. Serum sex steroid concentrations were measured by liquid chromatography/mass spectrometry. Local and systemic adverse effects were assessed by history and physical exam. The study was approved by the Maine Medical Center IRB. 102 charts were reviewed. Of 65 patients who were offered PO, TD or SC therapy (the SC option became available in May 2017), 23 choose SC. 61 patients were included in the final analysis, 23 in the SC group and 38 in the PO group. Median dose of E2 for the PO group was 4 mg/day [full range=1-12]; for SC E2 it was 4 mg/week [full range=2-6]. For the SC and PO groups the median E2 were 155.5 [75-291] (n=18) and 122 [76-208] pg/mL (n=38) respectively. Median and range of serum T levels in the SC and PO groups were 16 [4.5-82] (n=14) and 13 [4.8-515] (n=38) ng/dL respectively. E1 serum levels in the SC and PO groups were 49.0 [31.0-104.0] (n=10) and 495 [198-926] (n=12) pg/mL (p=0.003). SHBG and lipid levels did not vary significantly between the two groups (not shown). In a subgroup of SC patients, the median serum E2 decreased from 212 [158-245] to 112 [87-150] pg/mL from the day after to the day before an injection (n=12). 22/23 patients in the SC group chose to continue this method, 0/23 patients experienced a systemic reaction and 1/23 experienced a local site reaction. These preliminary data suggest that SC E2 injection is a safe and effective option for administration of E2 that appears to be well accepted by patients. It is well absorbed with minimal adverse effects and suppresses serum T levels as effectively as PO E2. SC E2 has less hepatic effect as reflected by serum E1 levels (but not SHBG or lipids in this small sample size). Serum E2 levels decrease between weekly injections and additional studies are required to refine dosing to maintain E2 values within the target range. Additional pharmacodynamic studies are also indicated.

Varying levels of serum estradiol do not alter the timing of the early endometrial secretory transformation.

Do supraphysiologic estradiol (E2) levels in the ranges attained during normal and high response superovulation cycles modify the onset of endometrial secretory transformation? Highly supraphysiologic levels of E2 do not alter the ability of physiologic levels of progesterone (P4) to induce secretory transformation. Previous studies have demonstrated that premature P4 elevations during IVF cycles are associated with a decrement in clinical pregnancy rates after fresh embryo transfer due to shifts in the window of implantation (WOI). However, alterations in the onset of secretory transformation may not apply uniformly to all patients. High responders with supraphysiologic E2 levels accompanied by similar subtle increases in P4 have not been shown to have decreased sustained implantation rates. This prospective investigation in which whole-genome transcriptomic and methylomic analysis of the endometrium is performed for individual patients under a range of E2 concentrations brings clarity to a long-debated issue. A randomized, prospective and paired trial was conducted in which 10 participants were enrolled and randomized to the order in which they completed three distinct uterine stimulation cycles, each at a specific E2 concentration: physiologic (∼180 pg/ml), moderately supraphysiologic (600-800 pg/ml) or supraphysiologic (2000 pg/ml). Target E2 ranges were selected to mimic those seen in natural, controlled ovarian stimulation and IVF cycles. E2 valerate was administered in order to maintain stable E2 levels for 12 days followed by intramuscular P4 in oil 10 mg/day for two doses, after which an endometrial biopsy was performed. A total of 30 endometrial biopsies were included in a whole-genome transcriptomic and methylomic analysis. Healthy volunteers without a history of infertility were included in this study at a single large infertility center. DNA was isolated from the endometrial biopsy specimens and bisulfite sequencing was performed to construct a methylation array. Differential methylation analysis was conducted based on differences in M-values of individuals across treatment groups for each probe as well as carrying out t-tests. RNA was isolated for RNA-Seq analysis and gene expression values were compared using DESeq2. All analyses were performed in a pairwise fashion to compare among the three stimulation cycles within individuals and secondarily to compare all participants in each of the cycles. The mean peak E2 and P4 levels were 275 pg/ml and 4.17 ng/ml in the physiologic group, 910 pg/ml and 2.69 ng/ml in the moderate group was, and 2043 pg/ml and 2.64 ng/ml in the supraphysiologic group, respectively. Principal component analysis of 834913 CpG sites was performed on M-values of individuals within the low, moderate and supraphysiologic conditions in a paired approach. There were no differences in genome-wide methylation within participants across E2 groups. A paired analysis revealed that gene expression profiles did not differ within the same individual at each of the three E2 levels. No significant alterations in gene expression as related to endometrial physiology were identified between the low, moderate and supraphysiologic groups in an inter-participant analysis. Although each participant completed a physiologic cycle in which E2 levels were maintained in a range that would simulate a natural cycle, our findings are limited by lack of an unmedicated control to assess if there was a potential effect from E2V. Additionally, our results were obtained in fertile individuals, who may have a different endometrial response compared to an infertile population. Despite the whole genomic endometrial assessment and rigorous, paired study design, the sample size was limited. Given that the endometrial response to P4 is unaffected by E2 levels in the supraphysiologic range, diminutions in implantation seen in stimulated cycles may result from embryonic-endometrial dyssynchrony following early P4 elevations or slowly blastulating embryos, which occur independently of the magnitude of the E2 rise. This study was funded by the Foundation for Embryonic Competence, Basking Ridge, NJ, USA. Dr E.S. reports consultancy work for The Foundation for Embryonic Competence, Basking Ridge, NJ, USA. The other authors declare no conflict of interests related to this topic. NCT02458404.

Drug-drug Interactions Among Thai Transgender Women Living with Human Immunodeficiency Undergoing Feminizing Hormone Therapy and Antiretroviral Therapy: The iFACT Study.

Drug-drug interactions between feminizing hormone therapy (FHT) and antiretroviral therapy (ART) are a major concern among transgender women (TGW), which may lead to suboptimal ART adherence and inappropriate FHT dosage. To evaluate potential drug-drug interactions between FHT and ART, we performed intensive measurements of the pharmacokinetic (PK) parameters of blood tenofovir (TFV), efavirenz (EFV), and estradiol (E2). Twenty TGW with newly diagnosed human immunodeficiency virus (HIV) infection were enrolled. FHT (E2 valerate 2 mg/d and cyproterone acetate 25 mg/d) was prescribed at baseline until week 5 and restarted at week 8. ART (TFV disoproxil fumarate/emtricitabine/EFV at 300/200/600 mg) was initiated at week 3. The E2 PK parameters were measured intensively at weeks 3 (without ART) and 5 (with ART), and TFV and EFV PK parameters were measured intensively at weeks 5 (with FHT) and 8 (without FHT). The median (interquartile range) age and body mass index were 25.5 (22.5-31.0) years and 20.6 (19.3-23.1) kg/m2, respectively. The differences in geometric mean ratios between weeks 3 and 5 were as follows for E2 area under the curve, maximum concentration, and concentration at 24 hours (C24), respectively: 0.72 (90% confidence interval, .64-.81; P < .001), 0.81 (.72-.92; P = .006), and 0.64 (.50-.83; P = .004). The differences in geometric mean ratios between weeks 5 and 8 were as follows for TFV AUC, TFV C24, and EFV C24: 0.86 (90% confidence interval, .80-.93; P = .002), 0.83 (.75-.93; P = .006), and 0.91 (.85-.97; P = .02). Among HIV-positive TGW, E2 PK parameters were significantly lower in the presence of TFV disoproxil fumarate/emtricitabine/EFV, and some TFV and EFV PK parameters were lower in the presence of FHT. Further studies should determine whether these reductions are clinically significant and whether they occur with other FHT or ART regimens.

Dose-dependent effects of estrogen on prediction error related neural activity in the nucleus accumbens of healthy young women.

Whereas the effect of the sex steroid 17-beta-estradiol (E2) on dopaminergic (DA) transmission in the nucleus accumbens (NAc) is well evidenced in female rats, studies in humans are inconsistent. Moreover, linear and inverted u-shaped dose response curves have been observed for E2's effects on hippocampal plasticity, but the shape of dose response curves for E2's effects on the NAc is much less characterized. Investigation of dose response curves for E2's effects on DA-related neural activity in the human NAc. Placebo or E2 valerate in doses of 2, 4, 6 or 12 mg was orally administered to 125 naturally cycling young women during the low-hormone menstruation phase on two consecutive days using a randomized, double-blinded design. The E2 treatment regimen induced a wide range of E2 levels, from physiological (2- and 4-mg groups; equivalent to cycle peak) to supraphysiological levels (6- and 12-mg groups; equivalent to early pregnancy). This made it possible to study different dose response functions for E2's effects on NAc activity. During E2 peak, participants performed a well-established reversal learning paradigm. We used trial-wise prediction errors (PE) estimated via a computational reinforcement learning model as a proxy for dopaminergic activity. Linear and quadratic regression analyses predicting PE-related NAc activity from salivary E2 levels were calculated. There was a positive linear relationship between PE-associated NAc activity and salivary E2 increases. The randomized, placebo-controlled elevation of E2 levels stimulates NAc activity in the human brain, likely mediated by dopaminergic processes.

Drug-drug interactions between feminizing hormone therapy and pre-exposure prophylaxis among transgender women: the iFACT study.

IntroductionConcerns over potential drug‐drug interactions (DDI) between feminizing hormone therapy (FHT) and pre‐exposure prophylaxis (PrEP) have hampered uptake and adherence of PrEP among transgender women (TGW). To determine DDI between FHT and PrEP, we measured the pharmacokinetic (PK) parameters of blood plasma estradiol (E2) and tenofovir (TFV) in Thai TGW.MethodsTwenty TGW who never underwent orchiectomy and had not received injectable FHT within six months were enrolled between January and March 2018. FHT (E2 valerate and cyproterone acetate) were prescribed to participants at baseline until week 5, and then from week 8 until the end of study. Daily PrEP (tenofovir disoproxil fumarate/emtricitabine) was initiated at week 3 and continued without interruption. Intensive E2 PK parameters and testosterone concentration at 24 hours (C24) were measured at weeks 3 (without PrEP) and 5 (with PrEP), and intensive TFV PK parameters were measured at weeks 5 (with FHT) and 8 (without FHT).ResultsMedian (interquartile range) age, body mass index, and creatinine clearance were 21.5 (21–26) years, 20.6 (19.0‐22.4) kg/m2, and 116 (101‐126.5) mL/min, respectively. The geometric mean (%CV) of area under curve from time zero to 24 hours (AUC0‐24), maximum concentration (Cmax), and C24 of E2 at weeks 3 and 5 were 775.13 (26.2) pg h/mL, 51.47 (26.9) pg/mL, and 15.15 (42.0) pg/mL; and 782.84 (39.6), 55.76 (32.9), and 14.32 (67.4), respectively. The geometric mean (%CV) of TFV AUC0‐24, Cmax, and C24 at weeks 5 and 8 were 2242.1 (26.5) ng h/mL, 353.9 (34.0) ng/mL, and 40.9 (31.4) ng/mL; and 2530.2 (31.3), 311.4 (30.0), and 49.8 (29.6), respectively. The geometric mean of TFV AUC0‐24 and C24 at week 5 were significantly less than that at week 8 by 12% (p = 0.03) and 18% (p < 0.001), respectively. There were no significant changes in E2 PK parameters and median C24 of bioavailable testosterone between week 3 and week 5.ConclusionsOur study demonstrated lower blood plasma TFV exposure in the presence of FHT, suggesting that FHT may potentially affect PrEP efficacy among TGW; but E2 exposure was not affected by PrEP. Further studies are warranted to determine whether these reductions in TFV are clinically significant.Clinical Trial Number: NCT03620734.

Hormonal contraception and thrombosis.

The safety of combined hormonal contraceptives (CHCs) has been documented by years of follow-up, and the occurrence of venous thromboembolism (VTE) possibly related to their use is rare in the young population exposed to these agents. The balance between the benefits and risks of contraceptive steroids is generally positive, in particular when compared with pregnancy's risks. Epidemiological studies led to different results showing either no difference in VTE risk between CHCs (active surveillance prospective studies) or an increase in risk (observational or database studies). The discrepancy may be explained by different study designs and the fact that important risk factors such as overweight, family history of thrombosis, and smoking were not adjusted for in some observational studies. To improve the safety of CHC, modifying the estrogen dose and type, selecting newer progestins, and alternative routes of delivery were implemented. Ethinyl- E2 (EE) exerts a stronger effect than E2 on estrogen-dependent markers such as liver proteins and coagulation factors. To circumvent the metabolic changes induced by EE, more natural compounds such as E2 and E2 valerate (E2V) were developed, as well as new progestins structurally closer to P. Progestins when given alone do not increase VTE risk, and their risks and benefits depend upon their chemical structure, the type and dose of combined estrogen, and the delivery route. The lower impact of E2-based CHCs on metabolic markers may result in an improved safety profile. A recent study on clinical outcomes supports this hypothesis. In conclusion, CHCs remain a safe and effective choice to prevent unwanted pregnancy, and the risk of VTE is in general low. Careful consideration of individual risk factors should be given before prescribing to avoid cumulative risks and minimize the occurrence of unwanted events.

Pelvic pain and quality of life of women with endometriosis during quadriphasic estradiol valerate/dienogest oral contraceptive: a patient-preference prospective 24-week pilot study.

The progestin dienogest (DNG) given alone effectively reduces pelvic pain of women with endometriosis. It is not clear whether the same occurs when DNG is associated with estradiol (E2). Patient preference prospective observational study. Outpatient centre of university hospital. 40 patients with endometriosis and menstrual pain. 24-week treatment with a quadriphasic association of E2 valerate (E2V) and DNG or a nonsteroidal anti-inflammatory drug (NSAID) to be used only in case of pain (ketoprofene 200-mg tablets). Menstrual pain and, when present, intermenstrual pain, and dyspareunia were investigated by means of a 10-cm visual analogue scale (VAS). Quality of life was investigated by the short form 36 (SF-36) of the health-related quality of life questionnaire. Final study group consists of 34 patients, 19 in the E2V/DNG group and 15 in the NSAID group. After 24 weeks, no significant modification of menstrual pain, intermenstrual pain, dyspareunia, or SF-36 score was observed in the NSAID group. Treatment with E2V/DNG reduced the VAS score of menstrual pain by 61% (P < .0001). In the subgroups of women with intermenstrual pain or dyspareunia, E2V/DNG reduced these complaints by 65% (P = .013) and 52% (P = .016), respectively. The reduction in menstrual (P = .0001) and intermenstrual pain (p = 0.03) was significantly greater during E2V/DNG than NSAID. Quality of life improved during E2V/DNG (P = .0002), both in physical (P = .0003) and mental domains (P = .0065). Only a few minor adverse effects were described during E2V/DNG, and none caused withdrawal from treatment. In patients with endometriosis and pelvic pain, the 24-week administration of the quadriphasic association of E2V/DNG decreases pelvic pain and improves quality of life.

Prospective measurement of blood pressure and heart rate over 24 h in women using combined oral contraceptives with estradiol

ObjectiveCombined oral contraceptives (COCs) containing ethinyl-estradiol are known to increase blood pressure (BP). We evaluated whether COCs containing estradiol (E2) influence 24-h ambulatory BP and heart rate (HR) in normotensive and normal-weight women. Study designTwenty-four-hour BP and HR were measured every 30 min with an ambulatory BP device in 18 normotensive healthy non-smoking women prior to (Days 3–6 of menstrual cycle) and after 6 months of use (Days 20–24 of cycle 6) of a COC containing either a quadriphasic combination of E2 valerate plus dienogest (n=11) or a monophasic association of micronized E2 plus nomegestrol acetate (n=7). ResultsMean age and body mass index of the final sample were 32.50±7.49 years and 22.87±4.08, respectively. E2-based COCs induced no modification of 24-h systolic BP (+1.65±8.34 mmHg; p=.41), diastolic BP (+0.04±7.36 mmHg; p=.98), mean BP (+0.64±6.42 mmHg; p=.68) or HR (−0.72±5.86 beats/min; p=.61). Differences were not observed even when daytime or nighttime values were separately considered. Though this was not a comparative study, we did not find differences between the effects of the two formulations (24-h mean BP; p=.699). ConclusionsThese data suggest a neutral effect of estradiol-based COCs on independent risk factors for cardiovascular diseases such as BP or HR. ImplicationsBP and HR of normotensive women are not increased by E2-based COCs.

Cycle scheduling for in vitro fertilization with oral contraceptive pills versus oral estradiol valerate: a randomized, controlled trial

BackgroundBoth oral contraceptive pills (OCPs) and estradiol (E2) valerate have been used to schedule gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization (IVF) cycles and, consequently, laboratory activities. However, there are no studies comparing treatment outcomes directly between these two pretreatment methods. This randomized controlled trial was aimed at finding differences in ongoing pregnancy rates between GnRH antagonist IVF cycles scheduled with OCPs or E2 valerate.MethodsBetween January and May 2012, one hundred consecutive patients (nonobese, regularly cycling women 18–38 years with normal day 3 hormone levels and <3 previous IVF/ICSI attempts) undergoing IVF with the GnRH antagonist protocol were randomized to either the OCP or E2 pretreatment arms, with no restrictions such as blocking or stratification. Authors involved in data collection and analysis were blinded to group assignment. Fifty patients received OCP (30 μg ethinyl E2/150 μg levonorgestrel) for 12–16 days from day 1 or 2, and stimulation was started 5 days after stopping OCP. Similarly, 50 patients received 4 mg/day oral E2 valerate from day 20 for 5–12 days, until the day before starting stimulation.ResultsPretreatment with OCP (mean±SD, 14.5±1.7 days) was significantly longer than with E2 (7.8±1.9 days). Stimulation and embryological characteristics were similar. Ongoing pregnancy rates (46.0% vs. 44.0%; risk difference, –2.0% [95% CI –21.2% to 17.3%]), as well as implantation (43.5% vs. 47.4%), clinical pregnancy (50.0% vs. 48.0%), clinical miscarriage (7.1% vs. 7.7%), and live birth (42.0% vs. 40.0%) rates were comparable between groups.ConclusionsThis is the first study to directly compare these two methods of cycle scheduling in GnRH antagonist cycles. Our results fail to show statistically significant differences in ongoing pregnancy rates between pretreatment with OCP and E2 for IVF with the GnRH antagonist protocol. Although the study is limited by its sample size, our results may contribute to a future meta-analysis. An interesting future direction would be to extend our study to women with decreased ovarian reserve, as these are the patients in whom an increase in oocyte yield—due to the hypothetical beneficial effect of steroid pretreatment on follicular synchronization—could more easily be demonstrated.Trial registrationClinicalTrials.gov http://NCT01501448.