Transdermal Estradiol Research Articles

The range and variation in serum estradiol concentration in perimenopausal and postmenopausal women treated with transdermal estradiol in a real-world setting: a cross-sectional study.

The aims of the study are to explore the range and variation in serum estradiol concentration, and to estimate the prevalence of "poor absorption" (women using licensed estradiol doses with subtherapeutic levels), in perimenopausal and postmenopausal women using transdermal estradiol in the real world. This is a cross-sectional analysis in a specialist menopause clinic in the UK. Serum samples were obtained from 1,508 perimenopausal and postmenopausal women. A total of 61.87% were using licensed doses. The median estradiol concentration was 355.26 pmol/L (interquartile range 198.44-646.15 pmol/L). A reference interval for the whole cohort was defined as 54.62-2,050.55 pmol/L. There was substantial interindividual variation across the dose range. Variance was greater in younger women (P = 0.002) and gel users (P = 0.002). There was a trend toward greater variance in women using higher doses, but the association failed to reach statistical significance (P = 0.074). One in four women (24.84%) using the highest licensed dose had subtherapeutic levels (<200 pmol/L). Older women (≥50 y) and patch users were more likely to have low levels (odds ratio 1.77, 95% confidence interval 1.22-2.62, P = 0.003; and odds ratio 1.51, 95% confidence interval 1.18-1.95, P = 0.001, respectively). The reference interval for perimenopausal and postmenopausal women using on-label and off-label doses of transdermal estradiol in the real world is wide, and there is considerable interindividual variation. The number of estradiol users with low estradiol levels (<200 pmol/L) is higher than previously recognized. Measurement of serum estradiol can be helpful to identify women who may benefit from an off-label dose. Dose customization is key to ensure that all women can reap the benefits of HT.

Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study.

Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial. The KEEPS-Cog (2005-2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017-2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline. In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population.

Service evaluation: HRT regimens prescribed for complex menopausal patient cases

Abstract Introduction With government and NHS drivers, there has been an increase in menopause awareness and management. The NHS Business Services Authority reported a 29% increase in hormone replacement therapy (HRT) prescribing between 2022-2023, with expectation that this would rise further with introduction of the new HRT prepayment certificate in April 20231. Partly due to celebrity sway and supported by national guidance2,3 there is patient expectation towards transdermal oestrogen with natural progesterone HRT. Older women, some years since undergoing natural menopause, are also seeking advice on HRT use (3) with referrals accepted by specialist menopause clinics. Aims This service evaluation project was undertaken to evaluate the prescribing of HRT regimens in complex patient cases seen within a specialist menopause clinic and included assessment of those advised to use natural progesterone as part of their HRT regimen, for endometrial protection2,3. Method 366 specialist menopause clinic appointments over 6 months (05.01.23-22.06.23) were retrospectively evaluated, with patients seen by a multidisciplinary team within an outpatient secondary care setting. Exclusion criteria included appointments not attended, those that were incorrectly booked or patients with inaccessible records. Data was collected using electronic patient records with results analysed using Microsoft Excel. Results Of 327 (89%) appointments evaluated, the patient age ranged between 30-84 years (median age 53). HRT was recommended for 288 (88%) patients. HRT was not recommended in cases such as antiphospholipid syndrome, breast cancer without genitourinary symptoms, in those of advanced age or in line with patient choice with patient decision not to take HRT after an individualised risk benefit evaluation. For 26 (9%) patients, only topical oestrogen treatment for localised genitourinary syndrome symptoms was advised. 171 (52%) patients were postmenopausal, 61 (19%) perimenopausal, 46 (14%) with premature ovarian insufficiency and 20 (6%) with surgical menopause. For 22 patients (7%) with Mirena intra-uterine system in situ, their menopause phase could not be accurately defined. 243 (88%) of those recommended HRT were advised a combined regime; 154 (53%) continuous combined; 67 (23%) sequential combined and 22 (9%) oestrogen with Mirena coil. For patients accepting combined HRT, one third (81) were recommended natural progesterone, with the other patients using progestogens for endometrial protection. Of these 81 patients, 77 (95%) were recommended transdermal oestrogen in combination with natural progesterone. For patients recommended natural progesterone, 68 (84%) were for doses in line with licensing and current British Menopause Society guidance. For 10 patients the off-label recommendation involved doubled doses of natural progesterone to help with control of unfavourable bleeding. Discussion For prescribing of natural progesterone, we assumed that our recommendations to the GP were enacted. With retrospective evaluation of patient letters as a limitation, this project identified that within our specialist clinic complex patient population, a recommendation for natural progesterone was made for one third of patients suitable for combined HRT use. When not prescribed in line with licensing, this was due to issues with vaginal bleeding. Acknowledgments Biranavi Kirupakaran, Sahil Misri, Hernani Almeida, Medical Students, Imperial College London for data collection.

Comparison of Combined Oral Contraceptives and a Transdermal Estrogen Patch With Oral Progesterone: Treatment of Abnormal Uterine Bleeding in Adolescents.

Objective Abnormal uterine bleeding (AUB) is a frequent complaint in adolescents. Ovulatory dysfunction (AUB-O) is the most common etiology of AUB. We aimed to compare possible treatment modalities for idiopathic AUB-O, the most common reason for AUB-O in adolescents. Methods Thirty patients who were treated with either 30 μg ethinyl estradiol/3 mg drospirenone combined oral contraceptive (group A) or 1.95 mg 17β-estradiol transdermal patch and 5 mg oral medroxyprogesterone acetate combined treatment (group B) for six months in the pediatric endocrinology department between years 2017 and 2019 were enrolled in our study retrospectively, and aquestionnaire was performed on them to assess their treatment satisfaction. Results In the first three months of treatment, four (26.6%)patients reported intermenstrual bleeding (IMB), three (20%) reported abdominal pain, two (13.3%) reported nausea-vomiting, and one (6.7%) reported headaches in group A, while eight (53.3%) patients reported IMB, six (40%) reported abdominal pain, two (13.3%) reported nausea-vomiting, and two (13.3%) reported headaches in group B. No major side effects were reported to cause cessation of treatment in any treatment group, but fewer mild side effects were reported in group A. Group A had better treatment compliance and satisfaction. Menstrual irregularity stopped after two months of treatment in both groups, but one (6.6%) and three (20.0%)patients reported that AUB repeated within three months of treatment cessation in group A and group B, respectively. Conclusion Immaturity of the hypothalamo-pituitary-ovarian axis in adolescence can present with a wide range of symptoms and proves challenging to choose the proper treatment regimen.

8483 Changes in kidney hemodynamics during gender-affirming hormone therapy in transgender individuals - findings from the KNIGHT pilot study

Abstract Disclosure: S.A. van Eeghen: None. C. Wiepjes: None. L.L. Pyle: None. M. den Heijer: Research Investigator; Self; Kyowa Kirin. Other; Self; Novartis Pharmaceuticals. P. Bjornstad: Advisory Board Member; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Novo Nordisk, XORTX. Consulting Fee; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly &amp; Company, LG Chemistry, Horizon Pharma, Novo Nordisk, Sanofi. Research Investigator; Self; AstraZeneca, Merck, Horizon Pharma. Other; Self; Bayer, Inc. D. van Raalte: Consulting Fee; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly &amp; Company, Merck, Sanofi, MSD. Research Investigator; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly &amp; Company, Merck, Sanofi, MSD. N.J. Nokoff: Consulting Fee; Self; Neurocrine Biosciences, Inc, Ionis Pharmaceuticals Inc.. Research Investigator; Self; Neurocrine Biosciences, Inc. Other; Self; World Athletics. Background: Studies in transgender individuals have shown that gender-affirming hormone therapy (GAHT) impacts estimated glomerular filtration rate (eGFR). Masculinizing hormone therapy decreases, while feminizing hormone therapy increases eGFR, based on changes in serum creatinine and cystatin C. These substantial changes suggest an effect of sex hormones on kidney hemodynamics. To investigate this, we studied kidney hemodynamic changes before and after 3 months of gender-affirming hormone therapy (GAHT) in transgender individuals. Methods: This prospective observational pilot study assessed kidney hemodynamics in 23 transgender individuals assigned male at birth receiving feminizing hormone therapy and 21 transgender individuals assigned female at birth receiving masculinizing hormone therapy. Feminizing therapy included transdermal (n=16), sublingual (n=5), or oral estradiol (n=2), in combination with an anti-androgen (n=22); intramuscular triptorelin (n=16), spironolactone (n=5) or finasteride (n=1). Masculinizing therapy involved transdermal (n=17) or injected testosterone (n=4). Measures included glomerular filtration rate (GFR; Iohexol clearance), effective renal plasma flow (ERPF; p-aminohippurate clearance), and renal vascular resistance (RVR; mean arterial pressure/renal blood flow). Glomerular hydraulic pressure (PGLO), and afferent/efferent vascular resistance (RA/RE) were estimated by Gomez equations. Linear mixed models compared baseline and three-month measurements. Results: Individuals undergoing feminizing hormone therapy [median age 21 (IQR 19-29) years, BMI median 22.9 (IQR 18.9-30.7) kg/m²] had increased GFR by 2.8 mL/min per 1.73m² (95% CI, 0.01 to 5.6) and a nonsignificant increase in ERPF (+42 mL/min per 1.73m²; 95% CI, -5 to 90). RVR and RA significantly decreased [RVR: -0.007 mmHg/L/min (95% CI, -0.015 to -0.0003), RA: -294 dyn/s per cm5 (5% CI, -568 to -21)], indicating afferent vasodilation. In contrast, individuals receiving masculinizing therapy (median age median 20 (IQR 18-23) years, BMI median 24.2 (IQR 21.1-27.3) kg/m²) showed a slight, nonsignificant decrease in GFR (-2.1 mL/min per 1.73m²; 95% CI, -4.9 to 0.8), with no changes in other kidney hemodynamic parameters. Conclusions: In this cohort of transgender individuals, GFR increased during feminizing hormone therapy, likely due to afferent vasodilatation, while during masculinizing hormone therapy GFR tended to decrease. These findings suggest an influence of sex hormones on kidney hemodynamics, especially during feminizing hormone therapy. Presentation: 6/3/2024

5158 Estrogen for Feminizing Gender Affirming Hormone Therapy: Understanding the Influence of Route of Administration and Dose on Serum Estradiol and Testosterone Levels

Abstract Disclosure: D.J. Slack: None. A. Di Via Ioschpe: None. M. Saturno: None. S. Kihuwa-Mani: None. U. Amakiri: None. S. Karim: None. D. Guerra: None. J.D. Safer: None. For feminizing gender affirming hormone therapy (GAHT), the Endocrine Society and WPATH SOC 8 suggest targeting testosterone (T) levels below 50 ng/dL and estradiol (E2) levels in the range of 100-200 pg/mL. Exogenous estrogen may be given via several routes of administration (ROA) and at a variety of doses, but little is known about how ROA and dose influence T and E2 levels. We sought to investigate the relationship between estrogen dosage, ROA, and hormonal profiles in trans feminine individuals. We conducted a chart review of patients in the Mount Sinai Health System and included all patients who had active prescriptions for feminizing GAHT with both T and E2 levels recorded (n = 585), excluding those with a history of orchiectomy. For oral (PO) estrogen, there was a negative correlation between dose and serum T (p &amp;lt; .01), LH (p &amp;lt; .05), and FSH (p &amp;lt; .05), but no correlation with E2. For transdermal (TD) estrogen, dose did not correlate with serum T, E2, LH, or FSH. For intramuscular (IM) estrogen, there was a positive correlation with serum E2 (p &amp;lt; .05), LH (p &amp;lt; .05), and FSH (p &amp;lt; .01), but no correlation with T. Individuals were then stratified into groups of T and E2 ranges that were determined via bell-curve frequency distributions. Within each group, the relative proportion of users of a given ROA, their mean dose of estrogen given via that ROA, and their resulting mean T and E2 levels were calculated. For users of IM estrogen, a significantly higher proportion of individuals had T &amp;lt; 50 ng/dL as opposed to T &amp;gt;= 50 ng/dL. IM users also much more frequently exhibited E2 &amp;gt;= 200 pg/mL than E2 &amp;lt; 200 pg/mL. For users of PO estrogen, a higher proportion of individuals had T &amp;gt;= 100 ng/dL compared to T &amp;lt; 50 ng/dL, with the proportion of those with T 50-99 ng/dL not differing from either group. A higher proportion of users of PO estrogen had E2 50 - 199 pg/mL compared to E2 &amp;lt; 25 ng/dL and E2 &amp;gt; 200 pg/mL, with the proportion of those with E2 25-49 pg/mL not differing significantly from either. For users of TD estrogen, there was a higher proportion of those with T 50 - 99 ng/dL compared to &amp;lt; 50 ng/dL and &amp;gt;= 200 ng/dL, with the proportion of those with T 100 - 199 ng/dL not differing from either group. A higher proportion of users of TD estrogen had E2 25 - 49 pg/mL compared to E2 100 - 199 pg/mL and E2 &amp;gt; 300 pg/mL, while the frequency of those with E2 &amp;lt; 25 pg/mL, 50 - 99 pg/mL, or 200 - 299 pg/mL did not differ significantly. Our results indicate a propensity for users of IM estrogen to achieve T suppression and to overshoot E2 targets, while users of PO estrogen were most likely to have E2 levels at-target but less likely to achieve T suppression. Users of TD estrogen appear least likely to achieve either target. While further research is needed to confirm and expand upon our findings, our data are an important step forward in providing clinicians with some predictive capability as to the serum E2 and T levels they might expect with the use of exogenous estrogen at a given dose and ROA. Presentation: 6/2/2024

5158 Estrogen for Feminizing Gender Affirming Hormone Therapy: Understanding the Influence of Route of Administration and Dose on Serum Estradiol and Testosterone Levels

Abstract Disclosure: D.J. Slack: None. A. Di Via Ioschpe: None. M. Saturno: None. S. Kihuwa-Mani: None. U. Amakiri: None. S. Karim: None. D. Guerra: None. J.D. Safer: None. For feminizing gender affirming hormone therapy (GAHT), the Endocrine Society and WPATH SOC 8 suggest targeting testosterone (T) levels below 50 ng/dL and estradiol (E2) levels in the range of 100-200 pg/mL. Exogenous estrogen may be given via several routes of administration (ROA) and at a variety of doses, but little is known about how ROA and dose influence T and E2 levels. We sought to investigate the relationship between estrogen dosage, ROA, and hormonal profiles in trans feminine individuals. We conducted a chart review of patients in the Mount Sinai Health System and included all patients who had active prescriptions for feminizing GAHT with both T and E2 levels recorded (n = 585), excluding those with a history of orchiectomy. For oral (PO) estrogen, there was a negative correlation between dose and serum T (p &amp;lt; .01), LH (p &amp;lt; .05), and FSH (p &amp;lt; .05), but no correlation with E2. For transdermal (TD) estrogen, dose did not correlate with serum T, E2, LH, or FSH. For intramuscular (IM) estrogen, there was a positive correlation with serum E2 (p &amp;lt; .05), LH (p &amp;lt; .05), and FSH (p &amp;lt; .01), but no correlation with T. Individuals were then stratified into groups of T and E2 ranges that were determined via bell-curve frequency distributions. Within each group, the relative proportion of users of a given ROA, their mean dose of estrogen given via that ROA, and their resulting mean T and E2 levels were calculated. For users of IM estrogen, a significantly higher proportion of individuals had T &amp;lt; 50 ng/dL as opposed to T &amp;gt;= 50 ng/dL. IM users also much more frequently exhibited E2 &amp;gt;= 200 pg/mL than E2 &amp;lt; 200 pg/mL. For users of PO estrogen, a higher proportion of individuals had T &amp;gt;= 100 ng/dL compared to T &amp;lt; 50 ng/dL, with the proportion of those with T 50-99 ng/dL not differing from either group. A higher proportion of users of PO estrogen had E2 50 - 199 pg/mL compared to E2 &amp;lt; 25 ng/dL and E2 &amp;gt; 200 pg/mL, with the proportion of those with E2 25-49 pg/mL not differing significantly from either. For users of TD estrogen, there was a higher proportion of those with T 50 - 99 ng/dL compared to &amp;lt; 50 ng/dL and &amp;gt;= 200 ng/dL, with the proportion of those with T 100 - 199 ng/dL not differing from either group. A higher proportion of users of TD estrogen had E2 25 - 49 pg/mL compared to E2 100 - 199 pg/mL and E2 &amp;gt; 300 pg/mL, while the frequency of those with E2 &amp;lt; 25 pg/mL, 50 - 99 pg/mL, or 200 - 299 pg/mL did not differ significantly. Our results indicate a propensity for users of IM estrogen to achieve T suppression and to overshoot E2 targets, while users of PO estrogen were most likely to have E2 levels at-target but less likely to achieve T suppression. Users of TD estrogen appear least likely to achieve either target. While further research is needed to confirm and expand upon our findings, our data are an important step forward in providing clinicians with some predictive capability as to the serum E2 and T levels they might expect with the use of exogenous estrogen at a given dose and ROA. Presentation: 6/2/2024

6448 Metabolic Profile and Adipose Tissue Distribution of Young Individuals with Turner Syndrome

Abstract Disclosure: V.M. Thomas: None. P.F. Backeljauw: Consulting Fee; Self; Novo Nordisk, Ascendis, Biomarin, Cavalry Biosciences, Upsher-Smith Laboratories, Tolmar. Speaker; Self; BioMarin, Ascendis.. A. Shah: None. I. Gutmark-Little: Research Investigator; Self; Novo Nordisk, Ascendis, OPKO. Introduction: Turner syndrome (TS) is the most common sex chromosome abnormality in females. Incidence of type 2 diabetes mellitus, hypertension, and dyslipidemia is high in TS. Current practice is to employ BMI as a proxy for adiposity. However, BMI is not an optimal tool due to the short stature observed in TS. Alternate methods such as the dual-energy x-ray absorptiometry (DXA) scan and bioelectrical impedance (BI) may provide more information about body composition. Objectives: The objective of this study is to assess alternative outpatient methods for body composition assessment, including adiposity in pediatric patients with TS. The secondary goal is to characterize the metabolic profile of pediatric subjects with TS compared to obese (BMI ≥95 th%ile) and lean controls (BMI: 5-85th%ile). Methods: This is a cross-sectional study. TS patients are on ≥50mcg transdermal estradiol equivalent replacement OR are self-menstruating. BI, DXA, metabolic markers, interleukin-6 (IL-6) &amp; C-reactive protein (CRP) were obtained in all 3 groups. Statistical analysis was conducted using SPSS software. Results: We present preliminary data on 15 TS, 12 obese, and 15 lean youth, aged 13-19 years. TS youth averages: Age 16.5±1.3 years; BMI 29.3±8.5 kg/m2 (z-score: 1.21±1.27). DXA visceral adiposity (DXA VA): 392±257 g; BI visceral fat (BI VF): 1300±750 cm². Elevated LDL-C&amp;gt;100 mg/dL was noted in n=5 (102-166). Elevated AST &amp;/or ALT &amp;gt;40 unit/L were found in 6 TS. 6 TS had elevated BI VF and DXA VA (&amp;gt;250g) with BMI z-score &amp;lt;2.0. Increased CRP &amp;/or IL-6 levels were noted in 4 TS (BMI z-score: 1.29-2.54), all of whom had primary ovarian failure. These 4 also had increased DXA VA (358-887 g), and BI VF (1500-2500 cm²) compared to the rest of the group. Obese youth averages: Age 16.7±1.83 years; BMI 38 kg/m2 (z-score: 2.26±0.3); DXA VA 674±226 g; BI VF 2300±390 cm². LDL-C&amp;gt;100 mg/dL noted in n=5 (102-121). AST&amp;ALT&amp;lt;35 units/L for all. Increased CRP &amp;/or IL-6 were noted in 4 study subjects (DXA VA: 474-718 g). All 4 had normal A1c, lipid, and liver profiles. Lean youth averages: Age 16.4±2.4 years, BMI 21.6 kg/m2 (z-score: 0.32±0.7); DXA VA 162±68 g; BI VF: 580±370 cm². LDL-C &amp;gt;100 mg/dL noted in n=3 (106-120); 1 subject had increased AST&amp;ALT &amp;gt;40 unit/L. All others had AST &amp; ALT&amp;lt;26 units/L. Elevated CRP/IL-6 was noted in 4 subjects, 1 of whom had increased DXA VA (367g). All subjects had normal HgA1c (≤5.6). Total mass, lean mass, and fat % from DXA and BI were compared (correlation analysis) for each subject and showed agreement throughout. Conclusion: Based on these preliminary data, BI may be a convenient and noninvasive tool to assess adiposity in the outpatient setting in TS. BI and DXA both detected increased visceral fat in TS subjects with normal BMI. BI could potentially identify TS individuals at risk for metabolic dysfunction. Further studies on larger patient numbers will be needed to confirm these preliminary findings. Presentation: 6/2/2024

7238 A rare cause of primary ovarian failure in an adolescent due to a genetic mutation in mitochondrial poly-A-polymerase (mTPAP) mRNA

Abstract Disclosure: J. Epstein: None. S. Veera: None. J. Pappas: None. B.C. Shah: None. Primary ovarian insufficiency (POI) is a dysfunction or loss of ovarian follicles with associated amenorrhea. While most causes are idiopathic, approximately 15% of POI cases are due to single gene or chromosomal abnormalities, such as X chromosome abnormalities. Many of these nuclear genes encode for proteins that function within the mitochondria. Mitochondrial disorders affect tissues with high energy demand, such as the neurological, skeletal, cardiac, and endocrine systems. Furthermore, mature ovaries have a relatively higher concentration of mitochondria, which play a role in cellular respiration along with steroidogenesis. Mutations that disrupt these pathways can therefore lead to ovarian dysfunction. We present a case of a 17-year-old female with concern for primary amenorrhea. She underwent pubarche at age 12 years and thelarche at 14 years, with slowed progression. Height Z score was -1.61 and weight Z score was -0.41. Lab work at presentation was significant for LH 18.6 IU/L (N 2.4-12.6 IU/L), FSH 43.9 IU/L (N 1.1-9.6 IU/L), low estradiol &amp;lt;2.5 pg/mL (N 30-100 pg/mL), low total testosterone 8.3 ng/dL (N 15-31 ng/dL), unremarkable HbA1C, cortisol, thyroid levels, and a 46 XX karyotype. Pelvic ultrasound showed small ovarian volumes with a 1.9 cc right ovary, 1.5 cc left ovary consistent with lack of hormonal stimulation, and uterus length of 4.9 cm (N &amp;gt; 4 cm) consistent with early hormonal stimulation. She was started on transdermal estrogen replacement. Past medical history included stable pericardial effusion, episodes of supraventricular tachycardia, pre-cataracts, speech delays, mild learning disabilities, spastic diplegia, progressive gait abnormalities, ligamentous laxity, and recurrent patellar dislocations requiring multiple orthopedic limb surgeries. Family history was significant for parental consanguinity as first cousins. As the etiology of the POI remained unknown, genetic testing was completed. Whole exome sequencing (WES) revealed a homozygous pathogenic variant in the MTPAP gene: p.(Leu495Arg) (CTG&amp;gt;CGG): c.1484 T&amp;gt;G in exon 9 on chromosome 10p11.23. MTPAP, also known as SPAX4, TENT6, or PAPD1, is a nuclear-encoded polymerase involved in synthesizing the 3’ poly(A) tail of mitochondrial transcripts as well as in mRNA degradation. She was diagnosed with autosomal recessive MTPAP-related neurodevelopmental and movement disorder. Monogenic disorders affecting mitochondrial function are rare causes of POI. A high index of suspicion should be raised when a constellation of neurological, musculoskeletal, and cardiac problems co-exist. WES can be a very useful tool for uncovering rare genetic disorders. Further studies are needed to clarify details of organ specific mitochondrial dysfunction and possible therapeutics in individuals affected with MTPAP-related neurodevelopmental and movement disorders. Presentation: 6/1/2024

7802 A Review of 21 Cases of Kallmann Syndrome

Abstract Disclosure: T. Kashima: None. M. Ishimaru: None. E. Tanimoto: None. S. Fukui: None. C. Nakamura: None. N. Ujita: None. H. Miyagi: None. M. Igarashi: None. H. Doi: None. K. Yoshii: None. Y. Naiki: None. R. Horikawa: None. Kallmann syndrome is the most common form of hypogonadotropic hypogonadism. The incidence is estimated to be 1 in 10,000 birth boys and 1 in 50,000 birth girls. The goals of treatment for childhood puberty are to induce the progression of secondary sexual characteristics close to physiological sexual maturity, to improve psychosocial problems caused by delayed puberty, and to achieve fertility. Methods.Twenty-one patients (fifteen males and six females) with a diagnosis of Kallmann syndrome who visited our Department between August 2004 and November 2023 were included in the study. The electronic medical records were reviewed retrospectively. Results.The median age at first visit was 15 years and 11 months (13 years and 3 months to 17 years and 7 months). The chief complained were secondary sexual characteristics not yet developed, olfactory disturbance, amenorrhea, decreased growth rate, and micropenis. Three adults had symptoms of Kallmann's syndrome and were seen for close examination. 6 had a history of hearing loss. Family history included 2 cases of hypogonadotropic hypogonadism and a sibling with Sjogren-Larsson syndrome. 9 cases had genetic testing, including KAL1, KAL2, FGF8, IL17D, 1 case each, and 2 gene variants of CHD2.At the time of initial examination, the median testicular volume in males was 1.0 mL (1.0-3.0 ml). Five of the six female patients had no breast enlargement.Endocrine examination revealed that the mean basic LH and LHRH test peak values were 0.25 and 3.40 mIU/mL, respectively; the mean basic FSH and peak FSH values were 0.91 and 4.47 mIU/m, respectively; the mean testosterone level in males was 0.09 ng/mL; and the mean estradiol level in females was 5.58 pg/mL.For the 20 patients, excluding children, gonadotropins (HCG+rFSH) for men and estrogen patches for women were both started at low doses and titrated up to Kaufman therapy in women. Median age at initiation of treatment was 16 years and 5 months (14 years and 1 month to 18 years and 6 months). Bone density increased after the start of treatment. One patient diagnosed with micropenis in infancy was treated with testosterone for micropenis at 2 years and 5 months. Two male patients had a baby with their partners. Discussion.The age of diagnosis (age of first examination) is considerably older than the average age of onset of secondary sexual characteristics, so it is necessary to educate the public so that patients can be examined earlier. The patient's fertility was partially confirmed, and a smooth transition to adult/reproductive medical care can be expected through earlier intervention. Presentation: 6/1/2024

Examining the Influence of the Route of Administration and Dose of Estradiol on Serum Estradiol and Testosterone Levels in Feminizing Gender-Affirming Hormone Therapy

IntroductionIndividuals may seek gender-affirming hormone therapy (GAHT) to align their physical appearance with their gender identity. Feminizing GAHT typically involves the use of estrogen. This study investigates the effect of route of administration (ROA) and dose of estradiol on estradiol (E2) and testosterone (T) levels in transfeminine individuals. MethodsWe conducted a chart review of 573 patients with an active prescription for estradiol for feminizing GAHT and serum hormone levels available. Multiple linear regression and analysis of variance were used to analyze the effect of dose and ROA of estradiol on serum E2 and T. ResultsOral estradiol was the only ROA demonstrating a linear dose-response, with each 1 mg/d increase associated with a reduction in T of 19.03 ng/dL (P = .005). Lower T levels were seen with higher doses of transdermal estradiol but a significant dose-response was not demonstrated. Intramuscular estradiol was associated with lower T and higher E2 compared to oral and transdermal ROAs (P < .001), with many achieving target hormone levels even at low doses. Higher doses of oral estradiol were associated with lower mean serum leutenizing hormone and follicle stimulating hormone levels (P < .05). ConclusionOral estradiol can be titrated to achieve a stepwise decrease in serum T. The intramuscular ROA appears to be the most potent delivery of estradiol with impact on serum hormone levels with doses on the low end of guideline-suggested ranges. Serum leutenizing hormone and follicle stimulating hormone may also help with the management of feminizing GAHT.

A multicentre, randomized, double-blind, placebo-controlled trial of topical oestradiol gel for endometrial regeneration after induced abortion.

Is topical oestradiol gel effective in promoting endometrial regeneration after a surgical abortion? Topical oestradiol gel is effective in promoting endometrial regeneration after a surgical abortion with few side-effects. Oestrogen is effective in promoting endometrial regeneration. Transdermal oestrogen has been widely used in clinical practice for endometrial regeneration after induced abortion, but high-level evidence is limited. We conducted a multicentre, superiority, randomized, double-blind, placebo-controlled trial. Between 9 March 2022 and 21 February 2023, 200 women were assigned in a 1:1 ratio to receive either oestradiol gel (treatment) and or oestradiol gel simulant (control) for 28 days. The participants were scheduled to have their endometrial thickness (mm) measured by ultrasonographic scan at 21-23 days post-abortion. The trial was blinded for participants, investigators, medical staff, and statistical analysts until final unblinding. Participants were women undergoing induced abortion within 10 weeks of gestation. A total of 200 participants were enrolled, with 100 in each group. Eighty-eight (88%) in the treatment group and 82 (82%) in the control group completed the study as per the protocol and were included in the per-protocol set (PPS). The intent-to-treat (ITT) analysis included all participants randomized to the study groups and used inverse probability weighting to account for loss to follow-up. The ITT analysis showed revealed significantly greater endometrial thickness in the treatment group (mean 8.1 ± 2.5 mm) compared to the control group (mean 6.9 ± 2.1 mm) 21-23 days postabortion (mean difference 1.2 mm, 95% CI 0.7 to 1.9; P < 0.001). The median time to menstrual return was shorter in the treatment group (34 days, inter-quartile range [IQR] 30-38) than in the control group (35 days, IQR 32-42), with a difference of -1 day (95% CI -2.3 to -0.9; P = 0.036). No differences were observed in the timing or volume of bleeding in the first post-abortion cycle. The PPS analysis mirrored the ITT findings. Adverse events were minimal (6% versus 8%), and the blood profile, liver, kidney and coagulation test results were comparable between groups (all P > 0.05). Loss to follow-up was 11% in the treatment group and 15% of controls, with no significant difference (P > 0.05). Inconsistencies in the timing of the ultrasonographic scans may have affected the accuracy of endometrial thickness measurements. Our findings suggest that topical oestrogen supplementation immediately after abortion within the first 10 weeks of gestation improves endometrial regeneration and growth, thereby potentially increasing the chances of a successful subsequent pregnancy. Clinical application of these findings may improve endometrial health management practices and provide a perspective on fertility treatment and women's reproductive health. This study was supported by a grant (FW-HKKT2021111501900) from Jianmin Pharmaceutical Group Co., Ltd (JMPG), Wuhan, Hubei, China. Both the oestradiol gel and the simulant were provided by JMPG. The funding source had no role in the study. X.Y.L. reports JMPG grant funding paid to their institutions. All other authors declare no competing interests. CHiCTR2100053565. 24 November 2021. 9 March 2022.

Evaluating the effectiveness and adverse effects of oral versus transdermal estradiol for endometrial preparation in frozen-thawed embryo transfer: a randomized controlled trial

BackgroundEndometrial preparation significantly influences the success of embryo transfer procedures. Although both oral and transdermal estradiol are common methods for endometrial priming, their efficacy and potential side effects remain uncertain. This randomized controlled trial aims to compare the effectiveness of oral and transdermal estradiol in endometrial preparation, while also evaluating their respective side effects in patients undergoing assisted reproduction treatments.MethodThis randomized clinical trial (ISRCTN15301227) was conducted at Hung Vuong Hospital between July 2020 and March 2022. Among 550 eligible patients undergoing frozen embryo transfer cycles, we included 380 patients for the study. The study protocol and all materials received approval from the Ethics Committee of Hung Vuong Hospital (1315/CN-HĐĐĐ). Participants were randomly assigned to one of two groups: Group A (n =190) received oral estradiol at an initial dose of 4 mg per day for 7 days, with the dose increased according to clinical response. Group B (n =190) received transdermal estradiol at an initial dose of 2 measures of 2.5 g estradiol gel per day for 7 days, with the dose similarly increased according to clinical response. Treatment in both groups began on days 2–3 of the menstrual cycle, with the maximum duration of estradiol administration being 27 days. We compared estradiol levels on the day of progesterone administration, duration of treatment, total estradiol dose, endometrial thickness, pregnancy outcomes, and any observed side effects between the two groups.ResultsGroup A exhibited significantly higher estradiol levels on the day of progesterone administration compared to Group B (270.5 pg/ml versus 186.5 pg/ml, p < 0.001). However, the comparison revealed no significant difference in endometrial thickness between the two groups (10.5 mm versus 10.6 mm, p = 0.85). Furthermore, pregnancy rates including positive human chorionic gonadotropin, clinical pregnancy, ongoing pregnancy, live birth, and pregnancy failure were also found to be similar between the two groups. Notably, a greater proportion of patients in Group A experienced mild side effects compared to those in Group B (20.3% versus 10.1%, respectively; n =37 versus n =18), and this discrepancy was found to be statistically significant (p = 0.007).ConclusionTransdermal estradiol offers comparable endometrial thickness and pregnancy outcomes, along with improved patient compliance and fewer side effects compared to oral estradiol.

LBA69 Prostate cancer efficacy results from a randomised phase III evaluation of transdermal oestradiol (tE2) versus luteinising hormone releasing hormone agonists (LHRHa) for androgen suppression in non-metastatic (M0) prostate cancer

LBA69 Prostate cancer efficacy results from a randomised phase III evaluation of transdermal oestradiol (tE2) versus luteinising hormone releasing hormone agonists (LHRHa) for androgen suppression in non-metastatic (M0) prostate cancer

Gender Incongruence: Prevalence and Therapeutic Options Among Transsexuals Belonging to a Single Center.

This study aimed to describe characteristics and treatment choices among AMABs (Assigned Male At Birth) and AFABs (Assigned Female At Birth) transgenders enrolled from March 2021 to July 2023 at the PTA S. Giorgio of the ASP3-Catania. A total of 145 patients were studied, and there was no prevalence of AMAB/AFAB. At first observation for AMABs, the age was 26 years and 25 years for AFABs, with 11 AMAB/AFAB declared as "non-binary" (average age 17 years). In AMAB/AFAB, we evaluated hormonal treatment, efficacy, and dosage/hormonal levels. In AMABs, oral estradiol valerate (4 mg/day) or transdermal estradiol in gel (2 mg/day) + oral cyproterone acetate (25 mg/day) for both estrogenic formulations were used. Testosterone (TE), LH, FSH, and PRL at baseline and during chronic treatment were measured. In AFABs, we used injectable TE (250 mg/3-4 weeks or 1 g/12-16 weeks) or transdermal TE (60- 80 mg/day). In these patients, we analyzed blood count, LH, FSH, and TE. Hematocrit, hemoglobin, and red blood cell count showed a modest elevation after 4-6 months of treatment. About 32% of AFABs complained of transient uterine bleeding, but no hypertension or ovarian pathology was detected. In AMABs, despite the short observation period, no patient showed an increased risk of myocardial infarction and ischemic stroke. Among AFABs, no increased risk of cardiovascular or cerebrovascular disease was observed. Furthermore, given the complexity of the phenomenon, the integration between the different professional figures who require specific and qualified skills is fundamental.</p>.

P-445 High serum estradiol on the day of frozen blastocyst transfer is associated with higher early miscarriage rates in hormonal replacement therapy cycles using transdermal estrogens

Abstract Study question Do serum estradiol(E2) levels on the day of frozen blastocyst transfer(FBT) affect the live birth rate (LBR) in hormonal replacement therapy(HRT) cycles using transdermal estrogens? Summary answer E2 levels ≥ 313 pg/mL on the day of FBT are associated with increased early miscarriage rates, but no significant impact on LBR. What is known already E2 plays a crucial role in endometrial receptivity during the periconceptional period and a massive role in placentation. However, the impact of serum E2 levels measured around the time of a FBT in HRT cycles outcomes remains controversial, with some studies showing a detrimental impact of high levels, and others underlining no difference. To this date, there is no study focusing on HRT cycles with transdermal estrogens only, though it is the safest way of estrogen administration regarding thrombo-embolic complications. Study design, size, duration Observational cohort study with 2364 patients undergoing HRT-FBT cycles at a university hospital, between January 2019 and December 2022. Women were only included once during the study period. Participants/materials, setting, methods Patients undergoing single autologous FBT under HRT using transdermal estrogens and vaginal micronized progesterone. The serum E2 level was measured in the morning of the FBT, in a single laboratory. The primary outcome was the LBR, secondary outcomes included clinical pregnancy rates, early miscarriage rates(EMR), and obstetrical outcomes. Patients were divided into three groups based on the 25th and the 75th percentiles of E2 levels and compared using univariate and multivariate logistic regression models. Main results and the role of chance A total of 2364 patients were divided into 3 groups: group A &amp;lt; 122 pg/mL (n = 590), group B 122-312 pg/mL (n = 1184), and group C ≥ 313 pg/mL (n = 590). Mean serum E2 level on the day of FBT was 247.8 pg/mL ± 209.01 pg/ml. The LBR was 32.0% (756/2364), and the early miscarriage rate was 26.3% (280/1075) in the overall population. Multivariate logistic regression showed a negative impact of high E2 levels (≥ 313 pg/mL) on EMR: an increase in the EMR was noted between group C and referent group B (30.3% versus 24.6%, OR 1.5 95%CI (1.06-2.17)). However, no significant impact of E2 levels was noted regarding the LBR (group C vs group B, adjusted OR 0.9 95%CI (0.69-1.10)), the clinical pregnancy rates, or the obstetrical outcomes (birthweight and term of delivery Limitations, reasons for caution The main limitation of our study is linked to its observational design. Extrapolation of our results to other laboratories, or other routes and/or doses of administering estrogens also needs to be validated. Wider implications of the findings Limiting high serum E2 levels on the day of FBT in HRT cycles may improve ART outcomes. Further studies are needed to evaluate if modifications of estrogen doses may improve pregnancy chances, in an approach to individualize the management of ART patients. Trial registration number not applicable

P-311 Impact of adenomyosis on reproductive outcomes applying the revised Morphological Uterus Sonographic Assessment criteria in fresh donor oocyte recipients pretreated with GnRH agonist

Abstract Study question Could the diagnosis of adenomyosis (AD) impact reproductive outcomes when applying the revised Morphological Uterus Sonographic Assessment (MUSA) criteria in fresh donor oocyte cycles? Summary answer Adenomyosis diagnosis following the revised MUSA criteria in recipients did not have adversely affect reproductive outcomes in fresh donor oocyte recipients pretreated with GnRH agonist What is known already Prior metanalysis on IVF outcomes in patients with adenomyosis suggested lower clinical pregnancy and live birth rates, and increased miscarriage rates. Some studies suggest improved pregnancy rates with ultra-long GnRH agonist pretreatment. Most studies focused on autologous embryo transfer without euploidy confirmation, and diagnostic criteria lacked consensus, in 2021 MUSA redefined criteria distinguishing direct and indirect features with different implications. Study design, size, duration A retrospective cohort study included all fresh oocyte donation cycles from January 2014 to September 2023, evaluating adenomyosis impact on implantation rate, clinical pregnancy rate, miscarriage rate, ectopic pregnancy rate. The study analyzed 252 cycles without a formal sample size calculation due to its retrospective nature. Participants/materials, setting, methods The study included 252 first fresh oocyte reception cycle with a fresh embryo transfer. Severe male factor cases were excluded. A transvaginal ultrasound (TUS) screening for adenomyosis criteria was performed, diagnosis required at least two criteria, with one being direct. Endometrial preparation involved one dose of 3,75mg triptorelin acetate intramuscularly injected in mid luteal phase, to facilitate the synchronization with donor and estradiol patches. Main results and the role of chance Adenomyosis was diagnosed in 10,7% (AD), endometriosis (END) was present in 21,8 % and 26,6% of patients presented both diagnoses. Endometriosis patients received more pre-treatment (oral contraceptive or 2-3 long-agonist doses) than those without (40,7% AD, 43,6% END vs 17,3% non-AD/END). Comparing patients with and without adenomyosis, no statistical differences were found in embryo transfer results between groups: clinical pregnancy rate (63% vs 56,9%), miscarriage rate (23,5% vs 14,1%), ectopic pregnancy rate (11,8% vs 4,7%) and live birth rate (40,7% vs 45,8%). No differences in gestational outcomes were observed in terms of the number of adenomyosis criteria present, the number of direct criteria, the type of criteria, or when differentiating between focal and diffuse adenomyosis. Similarly, there were no differences when comparing patients with both diagnoses to those with isolated adenomyosis. The most prevalent adenomyosis features reported were hyperechogenic islands (direct criteria), followed by an irregular junctional zone and asymmetrical wall thickening (indirect criteria). Finally, no differences were found in perinatal outcomes or complications during the pregnancy follow-up between groups. Limitations, reasons for caution Although this is the largest serie evaluating adenomyosisto the low adenomyosis prevalence in our population, these results should be confirmed in larger series. In our center all adenomyosis/endometriosis symptomatic patients are under medical treatment before assisted reproduction techniques, that may modify adenomyosis criteria over time and probably pregnancy outcomes. Wider implications of the findings This is the first study to characterize adenomyosis using the revised MUSA definitions in an oocyte donation programme. Applying these criteria and preparing endometrium with GnRH analog pretreatment and treating medically symptomatic patients before ART, adenomyosis did not adversely affect reproductive outcomes. Trial registration number Not applicable

P-410 A modified artificial cycle-frozen embryo transfer(mAC-FET) protocol with evidence of corpus luteum(CL) formation as determined by serum relaxin-2 in early pregnancy :a prospective proof-of-concept study

Abstract Study question Can a mAC-FET protocol for endometrial preparation in ovulatory patients lead to formation of a CL as evidenced by serum relaxin-2 in the pregnant patients? Summary answer CL forms in the mAC-FET protocol as serum relaxin-2 in early pregnancy was comparable to that in spontaneous conception.Late luteal rise of relaxin-2 wasn’t demonstrated. What is known already Clinical evidence points to increased incidence of preeclampsia in pregnancies by AC-FET cycles compared to ovulatory FET cycles-natural cycle(NC) and mNC. The absence of CL and it’s secretory products like relaxin-2 is a contributing factor. FET protocols for endometrial preparation in ovulatory patients need to be optimised. NC/mNC-FET protocols need frequent monitoring. Also there is a temporal variability between LH/hCG and progesterone levels. We studied a mAC-FET protocol in ovulatory patients with a delayed start(day3-5 of the cycle),low dose transdermal 17β estradiol gel to see the formation of CL as elucidated by the presence of serum relaxin-2 in early pregnancy. Study design, size, duration A proof-of- concept prospective study was conducted at a tertiary centre (July2023-Dec2023). Serum relaxin-2(R&amp;D/Quantikine/ELISA) was determined in 4 groups of patients- Group-A. mAC-FET(n = 34) 1.On the day of start of progesterone 2.Post-ET day5-9 (along with serum progesterone) 3.In pregnancy(6-9 weeks of gestation) Group-B. AC-FET(n = 8) 1.On the day of start of progesterone 2.In pregnancy(6-9 weeks) Group-C. Spontaneous conception (n = 9) 1.In pregnancy(6-9 weeks) Group-D. Infertility patients ( n = 24) 1.Preovulatory. All patients were ≤40 years with a BMI ≤30kg/m2. Participants/materials, setting, methods In the AC-FET cohort-oral estradiol 6mg/day was started from day1/2 of the cycle. When endometrial thickness was&amp;gt;7mm,progesterone&amp;lt;1ng/ ml then intramuscular progesterone was started- 50mg/day-3 days,100mg on day4-the day of ET(Day-3 embryos) and continued every alternate day.Progesterone gel was added post-ET. In the mAC-FET cohort-17β transdermal estradiol gel(0.06%) 3mg/day was started from day3-5,rest of the protocol was similar. Statistical analysis was performed using appropriate non-parametric tests.Pearson coefficient(r) was used to assess linear-relationship.Two-tailed P&amp;lt;.05 indicated statistical significance. Main results and the role of chance Mean age and BMI of the patients with mAC-FET was 33.3±4.7 years and 24.4±3.7 kg/ m2 which was comparable across all groups (P=.14,P=.52 respectively). Clinical pregnancy rate in the mAC-FET group was 52.94%(18/34). 3 patients had an early abortion. Baseline relaxin-2 levels, median[Interquartile range(IQR)] were comparable- AC-FET cohort-9.1pg/mL(8.6-16.8), mAC-FET cohort-11.5pg/mL(9.6-13.7) and the infertility cohort-10.9pg/mL(8.4-14.5) (P=0.74) The primary outcome was the comparable levels of serum relaxin-2, in early pregnancy in the mAC-FET group and spontaneous conception group - median (IQR) 449.8pg/mL(73.1-492.3) and 487.9pg/mL(419.1-497.8) respectively (P=.12) The relaxin-2 levels, in early pregnancy in the mAC-FET group were significantly higher than the AC-FET group median(IQR) 449.8pg/mL(73.1-492.3) and 7.9pg/mL(7.8-9.5) respectively (P=.0005). As secondary outcomes, we studied the late luteal rise of relaxin-2 in the mAC-FET group and the relationship of late luteal progesterone with relaxin-2 in early pregnancies in the mAC-FET cohort. A late luteal rise of relaxin-2 was not demonstrated in the mAC-FET cohort. The serum relaxin-2, on the day of start of progesterone and on day5-9 post ET- median(IQR) 11.5pg/mL(9.6-13.7) and 11.4pg/mL(9.0-18.5), respectively was comparable (P=.18). The relationship between serum relaxin-2 in early pregnancy and the progesterone levels on day5-9 post ET in the mAC-FET cohort was not significant r = -.059 (P=.07) Limitations, reasons for caution This was a small proof- of-concept single centre study. Due to the limited numbers and short duration of the study, we could not compare efficacy, cancellation rates and pregnancy outcomes of the mAC-FET protocol with other FET protocols. Wider implications of the findings The mAC-FET protocol studied for endometrial preparation was similar to the AC -FET protocol regarding monitoring,flexibility and consistent progesterone exposure with the added advantage of the presence of the CL.This may decrease the risk of maternal/neonatal complications. Larger studies are needed to confirm it’s efficacy and impact on pregnancy outcomes. Trial registration number Not Applicable

Effectiveness and Safety of Different Estradiol Regimens in Transgender Females: A Randomized Controlled Trial.

A goal of gender-affirming hormone therapy (GAHT) for transgender women is to use estradiol to suppress endogenous production of testosterone. However, the effects of different estradiol regimens and route of administration on testosterone suppression is unknown. This is the first open-label randomized trial comparing different GAHT regimens for optimal estradiol route and dosing. To evaluate 1 month and 6 months testosterone suppression <50 ng/dL with pulsed (once- or twice-daily sublingual 17-beta estradiol) and continuous (transdermal 17-beta estradiol) GAHT. This study was conducted at an outpatient adult transgender clinic. Thirty-nine transgender women undergoing initiation of GAHT were randomly assigned to receive either once-daily sublingual, twice-daily sublingual, or transdermal 17-beta estradiol. All participants received spironolactone as an antiandrogen. Doses were titrated at monthly intervals to achieve total testosterone suppression <50 ng/dL. Transdermal 17-beta estradiol resulted in more rapid suppression of total testosterone, lower estrone levels, with no differences in estradiol levels when compared to once-daily and twice-daily sublingual estradiol. Moreover, there was no difference in the mean estradiol dose between the once-daily and twice-daily sublingual 17-beta estradiol group. Continuous exposure with transdermal 17-beta estradiol suppressed testosterone production more effectively and with lower overall estradiol doses relative to once or twice daily sublingual estradiol. Most transgender women achieved cisgender women testosterone levels within 2 months on 1 or 2 0.1 mg/24 hours estradiol patches. Given no difference between once- or twice-daily sublingual estradiol, pulsed 17-beta estradiol likely provides no benefit for testosterone suppression.

Clinical Outcomes of Oral vs. Transdermal Estrogen for Endometrial Preparation for Frozen Thawed Embryo Transfer in HRT-FET Cycles: A Systematic Review and Meta-Analysis

Background and Purpose: Among different routes of estrogen formulations, the transdermal route has obtained popularity in recent years for endometrial preparation in hormone replacement (HRT) frozen embryo transfer (FET) cycles. However, no clear evidence is available regarding clinical outcome of the transdermal route. This meta-analysis investigated the clinical outcomes of oral versus transdermal estrogen for endometrial preparation for FET in HRT-FET cycles. Methods: A comprehensive literature search was performed for all published randomized controlled trials (RCTs) before May 30, 2022, in electronic databases, including PubMed, Cochrane Library, Embase, CINAHL, Trip Database, Worldwide Science, and Google Scholar. Outcomes, including endometrial thickness, implantation rate (IR), miscarriage rate (MR), clinical pregnancy rate (CPR), and live birth rate (LBR), were measured using pooled odds ratio (OR) or standardized mean difference (SMD) with 95% confidence intervals (CIs). Results: Seven studies involving a total of 898 IVF patients were included in the meta-analysis. In a pooled analysis, endometrial thickness (ET) was more in the transdermal group as compared to the oral estrogen group ([Formula: see text]; 95% [Formula: see text]–0.31). However, no significant association for IR ([Formula: see text]; 95% [Formula: see text]–1.38), CPR ([Formula: see text]; 95% [Formula: see text]–1.31), MR ([Formula: see text]; 95% [Formula: see text]–2.06), and LBR ([Formula: see text]; 95% [Formula: see text]–1.23) was found between oral versus transdermal estrogen groups. Conclusions: In HRT-FET cycles using oral or transdermal estrogen, no significant difference was seen in clinical outcomes of IR, CPR, and LBR rates; however, a trend for a higher endometrial thickness was noted in the transdermal group.