Transdermal Estradiol Research Articles

Effect of menopausal hormonal therapy on cardiovascular risks in Korean postmenopausal women: A nationwide cohort study.

To evaluate the association between menopausal hormonal therapy (MHT) and the risk of cardiovascular disease (CVD), according to various regimens, dosages, routes of administration and starting ages of MHT. A population-based cohort study using the Korean National Health Insurance Services database. Nationwide health insurance database. Women who reported entering menopause at an age of ≥40 years with no history of CVD in the national health examination. The study population comprised 1 120 705 subjects enrolled between 2002 and 2019, categorised according to MHT status (MHT group, n = 319 007; non-MHT group, n = 801 698). Incidence of CVD (a composite of myocardial infarction and stroke). The incidence of CVD was 59 266 (7.4%) in the non-MHT group and 17 674 (5.5%) in the MHT group. After adjusting for confounding factors, an increased risk of CVD was observed with the administration of tibolone (hazard ratio, HR 1.143, 95% CI 1.117-1.170), oral estrogen (HR 1.246, 95% CI 1.198-1.295) or transdermal estrogen (HR 1.289, 95% CI 1.066-1.558), compared with the non-MHT group; the risk was based on an increased risk of stroke. The risk trends were consistent regardless of the age of starting MHT or the physicians' specialty. Among tibolone users, a longer period from entering menopause to taking tibolone and the use of any dosage (1.25 or 2.5 mg) were linked with a higher risk of CVD, compared with non-MHT users. This nationwide cohort study demonstrated an increased risk of CVD, driven mainly by an increased risk of stroke, among tibolone and oral or transdermal estrogen users, compared with that of non-MHT users.

The effect of estradiol add-back: a longitudinal MRI study in prostate cancer patients.

We investigated the effect of estradiol add-back therapy (EAT) on brain activation related to cognitive function and affect in addition to putative changes in gray and white matter volume in testosterone depleted participants with prostate cancer. We conducted a randomized controlled, double-blinded trial in which 40 patients received 0.9 mg of transdermal estradiol per day for 6 months or matched placebo. Anatomical MRI and three functional MRI (fMRI) scans were obtained for the emotion recognition task, verbal memory task, and visuospatial memory task. Activation in corresponding cognitive and affective brain networks was demonstrated for all tasks. Longitudinally, there was no difference in brain activation, reaction time, or accuracy in response to the fMRI tasks between the EAT group and placebo group at 6 months. In addition, there was no detectable change in whole-brain gray or white matter volume or in hippocampal volume between the two groups after 6 months. This study supports earlier findings that EAT does not improve verbal memory or affect and has no immediate effect on hippocampal volume in testosterone depleted patients with prostate cancer.

A randomized clinical trial of transdermal (gel) versus oral estrogen for endometrial preparation in frozen embryo transfer cycle.

The aim of this study was to compare endometrial thickness with the use of transdermal estrogen (gel) versus oral estrogen (pills) for endometrial preparation in the frozen embryo transfer cycle and serum estrogen concentrations during the preparation cycle, side effects, and chemical and clinical pregnancy rates. This was a prospective, randomized controlled trial of women undergoing endometrial preparation for cryopreserved blastocyst transfer. A total of 88 women were randomized, of which 82 completed the study protocol. Of this group, 44 received 6 mg/day of estradiol valerate orally (pills group) and 38 received 4.5 mg/day of estradiol hemihydrate transdermally (gel group). Endometrial thickness was measured using transvaginal ultrasound between the 7 and 10th day of the cycle. Serum estradiol concentrations were measured on the day of initiating the cycle, on control transvaginal ultrasounds, and on the day of embryo transfer. Side effects were documented at each study visit. p<0.05 were adopted as statistically significant. The groups were compared using Student's t-test for continuous variables and chi-square or Fisher's exact test for categorical variables. There were no significant group differences (p>0.05) in endometrial thickness, biochemical and clinical pregnancy rates, miscarriage rate, blood estradiol concentrations, duration of estradiol administration, or cycle cancellation rates. Endometrial preparation with transdermal estrogen yielded similar reproductive outcomes to oral estrogen with fewer side effects.

Hypertension: what's new in 2023

Highlights for 2023 include the confirmation of hypertension as a cardiovascular risk factor and the standard procedure for measuring blood pressure. Transdermal oestrogens do not appear to be associated with an increased risk of hypertension unlike oestrogen given orally. The usefulness of blood pressure measured in hospital in elderly patients and the risks of intensive treatment are reviewed. A new study suggests that we are not all equal when it comes to recommended treatments. Finally, RNA interference technology has enabled the synthesis of a new antihypertensive treatment administered every 6 months that inhibits the production of hepatic angiotensinogen with a good effect on blood pressure.

Ovarian tissue autotransplantation improves longevity in mice.

In this study, we show the improvement in life longevity in an experimental mouse model after step-by-step autologous ovarian transplantation and compare its effects with exogenic transdermal estradiol usage. This has proven to be more efficient than "traditional" hormonal replacement therapy. Despite the high speed and effectiveness of estradiol replacement deficiency in blood by its oral or transdermal use, no significant increase in the life longevity of animals and possibly in women was noted. The function of the transplanted fragment is usually limited to 6-12months. This is enough for oncofertility purposes, sometimes, but not for longevity improvement. We performed periodical tissue return (autologous transplantation), containing both the cortex and medulla in the experimental mouse model, which resulted in a statistically reliable improvement in longevity. Our experience indicates the important role of medullary ovarian factors in slowing the aging process in the body and increasing the life expectancy in the experiment. As shown, the transdermal estrogen supportive therapy for ovarian deficiency improves estrogen levels but causes much slower decreases in the follicle stimulating hormone (FSH) and luteinizing hormone (LH). Moreover, we attained the best longevity with step-by-step periodic ovarian autotransplantation, thus making "prosthetics" of ovarian function longer than it is preplanned physiologically [direct correlation between the levels of FSH and lifespan (r = 0.98)]. The experimental model we suggested could be projected to other mammals or humans as cortical transplantation provides the same results for reproduction restoration in mice and humans and even for hormone level normalization, but there is still a lack of information about anti-aging factors in the ovarian medulla and cortex. Hence, we consider that the most important factor for the anti-aging ovarian transplantation technology is to preserve and transfer both the medulla and cortex as parts of the whole ovary.

Перименопаузальные расстройства у женщин после COVID-19

Aim: to assess the health-related quality of life (HRQOL) of women with perimenopause after COVID-19 and to determine the possibilities of hormone replacement therapy (HRT) in the postcovid period. Patients and Methods: 96 female patients aged 45 to 54 years were examined. Group 1 consisted of 52 female patients who were being treated in a hospital for COVID-19 12–16 weeks before study. Group 2 (comparison group) consisted of 44 female patients without COVID-19. Further, HRT was performed in 21 female patients of group 1 without contraindications (subgroup 1A). HRT regimen: estradiol hemihydrate, 1.58 mg, transdermally sequestered and dydrogesterone, 10 mg, per os. In subgroup 1B, 31 female patients did not undergo HRT. All patients were examined, which included the following: survey, follow-up, hormone blood test and hemostasiogram. HRT efficacy was evaluated after 3 months. Results: group 1 had more significant neurovegetative, psychoemotional and metabolic disorders, as well as an increase in the frequency of menstrual disorders versus group 2. In group 1, 43/52 (82,7%) of the respondents experienced hot flashes, where 23/52 (44,2%) of female patients noted the first occurrence of hot flashes after suffering COVID-19. In group 2, 16/44 (36,3%) of patients were concerned about this symptom. In group 1, 42.3% (22/52) of patients reported menstrual disorders. In patients of subgroup 1A, the severity of neurovegetative, metabolic and psychoemotional disorders decreased after HRT versus those in subgroup 1B. Conclusion: in female patients who suffered moderate to severe COVID-19, perimenopausal disorders include more significant neurovegetative, psychoemotional and metabolic symptoms. Cyclic HRT using transdermal estrogens significantly improves the life quality of women, however, the unfavorable comorbid background observed may reduce the effect of hormone therapy KEYWORDS: perimenopause, menopausal syndrome, COVID-19, postcovid syndrome, modified Kuperman Index, hormone replacement therapy FOR CITATION: Irgasheva S.U., Nadirkhanova N.S., Azamkulova N.O. Perimenopausal disorders in women after COVID-19. Russian Journal of Woman and Child Health. 2024;7(2):110–115 (in Russ.). DOI: 10.32364/2618-8430-2024-7-2-4.

Effectiveness and Safety of Different Estradiol Regimens in Transgender Women (TREAT Study): Protocol for a Randomized Controlled Trial.

Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight the importance of investigating changes in lipoproteins, glucose, and insulin sensitivity, among other markers while receiving GAHT. This study aims to evaluate the degree of testosterone suppression achieved at 1, 6, and 12 months in treatment-naive transgender women when randomized to GAHT with estradiol and spironolactone as antiandrogens. As a secondary aim, this study will assess the treatment effect on metabolic and coagulation factors from baseline to 6 and 12 months after initiating GAHT. This is a prospective pilot, open-label, randomized clinical trial conducted at an adult transgender clinic in a tertiary medical center. The 3 treatment arms include once-daily sublingual 17-β estradiol, twice-daily sublingual 17-β estradiol, and transdermal 17-β estradiol. All participants received spironolactone as an antiandrogen. Transgender women aged 18 to 45 years who are being evaluated for the initiation of GAHT with 17-β estradiol and did not have a history of coagulopathy, cigarette smoking, liver disease, dyslipidemia requiring treatment, or use of gonadotropin-releasing hormone agonist were eligible to enroll. The main outcome is the total testosterone suppression at 1 and 6 months after the initiation of GAHT, and the secondary outcome is to assess treatment effect in a lipid panel; homeostatic model assessment for insulin resistance; coagulation factors II, IX, and XI; Von Willebrand factor; activated protein C resistance; protein C; and protein S at baseline, 6 months, and 12 months after therapy is initiated. This study was funded in March 2022, and enrollment concluded in August 2022. It was concluded in July 2023, and currently, the results are being analyzed for publication. The Transgender Estradiol Affirming Therapy (TREAT) study offers a rigorous and reproducible approach to answer important questions regarding GAHT in transgender women, specifically, the most effective 17-β estradiol regimen to suppress testosterone levels to 50 ng/dL, as currently recommended. ClinicalTrials.gov NCT05010707; https://clinicaltrials.gov/study/NCT05010707. DERR1-10.2196/53092.

Real-world Study of Transdermal Oestradiol in Metastatic Prostate Cancer

Real-world Study of Transdermal Oestradiol in Metastatic Prostate Cancer

Design, optimization, and evaluation for a long-time-released transdermal microneedle delivery system containing estradiol.

Transdermal drug delivery systems (TDDS) have drawbacks such as poor absorption, low blood concentration, and delayed effects. Dissolving microneedle has sharp tips and short length, which overcome patients' pain and improve transdermal efficiency but has low mechanical strength and drug loading capacity. This study thereby proposes a microemulsion-encapsulated and long-time-released transdermal microneedle (MN) delivery system with estradiol (Es) as the model drug. The microemulsion (ME) was optimized by utilizing the pseudo-ternary phase diagram and D-optimal mixture design. The estradiol microemulsion-encapsulated microneedle (Es-ME-MN) was optimized by Box-Behnken design and prepared by freeze-thaw method. The Es-ME-MN obtained was characterized and evaluated through a large variety of studies. Es-ME-MN had sufficient mechanical strength to pierce skin and was safe enough, the length of which was 600 μm, and the Es content was 177.12 ± 0.72 μg/patch without drug-excipient chemical interaction. In vitro permeation study showed that Es-ME-MN has a higher transdermal efficiency and lower retention capacity than commercial estradiol patch and conventional MN. Es plasma concentration began to increase at 3 h and remained at 12.98-23.52 ng/mL until 72 h by pharmacokinetic experiments in the Es-ME-MN group. Es-ME-MN rapidly achieves effective blood concentrations through needle puncture and microemulsion delivery and maintains blood concentrations through the baseplate long-time release. Microemulsion-encapsulated, organic solvent-free, and long-time-released transdermal microneedle will make progress and provide a new idea for transdermal delivery of lipophilic drugs.

#292 : Combination of Hormone Replacement Therapy and Ovarian Stimulation as Endometrial Preparation Strategy for Refractory Thin Endometrium

Background and Aims: The aim of the case study is to demonstrate that combination of hormone replacement therapy with controlled ovarian stimulation is effective to improve endometrial thickness (ET) in difficult cases of thin endometrium. Method: The patient is a 35-year-old, nulliparous with primary subfertility for six years. She had PCOS with history of right salphingo-oophorectomy done for benign serous papillary cystadenoma. The male partner had severe oligoasthenoteratozoospermia. He started on FSH injections for three months with slight improvement in sperm parameters. She then underwent an IVF cycle and obtained five blastocysts. We struggled with thin ET with one failed frozen embryo transfer (FET) and two abandoned cycles. The patient was started with hormone replacement therapy on day one menses with tablet progynova 4 mg six hourly together with estrogel 3 g eight hourly transdermally. A scan was performed on day one menses and endometrial thickness was 4.5 mm. The serum progesterone and luteinizing hormone was baseline. A repeat scan for ET was done on day seven menses and was noted to be 6.4 mm. She was given another four days of oral and transdermal estrogen and the ET remained 6.4 mm at day eleven menses. We decided to perform low dose ovarian stimulation with recombinant FSH 150 IU daily. She was then seen on day fourteen menses for repeat scan. The ET only marginally increased to 6.7 mm. We increased the injection to 225 IU daily. On day eighteen menses, her ET was 7.8 mm and we triggered with HCG 5000 IU. She had her FET done on day twenty-five menses. Results: Her BHCG two weeks later was 948.3 U/L. The pregnancy is currently ongoing at 18 weeks. Conclusion: A combination of hormone replacement therapy and ovarian stimulation enables the exogenous and endogenous estrogen to act synchronously on the endometrium to achieve better endometrial thickness for implantation.

Serum Hormone Concentrations in Transgender Youth Receiving Estradiol

ObjectiveThis study aimed to evaluate the serum estradiol levels in gender-diverse youth to compare the efficacy of different estradiol routes in achieving therapeutic blood levels and suppressing serum testosterone levels. MethodsThis was a retrospective chart review of patients who initiated estradiol at an adolescent gender clinic between 2010 and 2019. Data on the route of estradiol administration and antiandrogen use (spironolactone or gonadotropin-releasing hormone agonist) were collected, and laboratory data were analyzed. Scatterplots were used to visualize the relationship between the estradiol dose and testosterone and estradiol laboratory values. ResultsA total of 118 patients were included, with a mean (standard deviation [SD]) age of 17.2 (1.6) years. The most common route of estradiol administration was oral only (62.7%), followed by transdermal only (23.7%), multiple routes excluding subcutaneous (8.5%), and any subcutaneous (5.1%). Notable variability was observed in the serum estradiol levels, with means (SDs) of 131.9 (120.4) pg/mL for those on oral estrogen 6 to 8 mg per day, 62.6 (40.3) pg/mL for those on transdermal estrogen 0.1 to 0.15 mg every 24 hours, and 53.6 (42.4) pg/mL for those on subcutaneous estradiol. In patients who received spironolactone, transdermal estradiol was associated with lower testosterone levels than estradiol administered orally or subcutaneously. ConclusionOral, transdermal, and subcutaneous administrations of estrogen all lead to increased serum estradiol levels and are effective for use in gender-affirming care for youth. Patients on transdermal estrogen tended to have lower serum estradiol levels but also had more suppression of serum testosterone levels.

Changes in menopausal symptoms comparing oral estradiol versus transdermal estradiol

Objective This study aimed to compare the efficacy and safety of oral and transdermal estradiol in alleviating menopausal symptoms. Method A total of 257 recently menopausal women were randomized into two groups. The t-E2 group received transdermal estradiol (2.5 g per day) (n = 128) and the o-E2V group received oral estradiol valerate (2 mg per day) (n = 129) for 24 weeks; both groups received micronized progesterone (200 mg per day). The primary outcome measure is the change in the modified Kupperman Menopausal Index (KMI) after 24 weeks of treatment. Menopausal symptoms were recorded at screening and at 4, 12 and 24 weeks using both the KMI and the Menopause Rating Scale (MRS). Results Significant amelioration was observed by KMI and MRS scores for both groups after treatment (p < 0.001). The mean KMI scores showed no difference between the two groups. The mean MRS scores were similar between the two groups at baseline and after 4 weeks of treatment. The results showed statistical differences after 12 weeks and 24 weeks of treatment (p = 0.005 and p = 0.011). Both the after-treatment scores minus the baseline scores of KMI and MRS and the incidence of adverse effects showed no difference between the two groups. Conclusions This study shows that both transdermal and oral estradiol are effective in relieving menopausal symptoms, with little difference in treatment efficacy and safety. Clinical trial number ChiCTR2300073146

A Repurposing Programme Evaluating Transdermal Oestradiol Patches for the Treatment of Prostate Cancer Within the PATCH and STAMPEDE Trials: Current Results and Adapting Trial Design

AimsAndrogen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer. Materials and methodsThe PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately. ResultsRecruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of –3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3–13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80–1.53; P = 0.54). Oncological outcomes are awaited. FutureEfficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure – overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.

Comparative estrogen exposure from compounded transdermal estradiol creams and Food and Drug Administration-approved transdermal estradiol gels and patches.

The aim of this study was to evaluate the amount of estrogen exposure associated with the use of compounded transdermal estradiol (E2) creams and compare it with estrogen exposure associated with the use of Food and Drug Administration (FDA)-approved transdermal E2 patches and gels. This was a retrospective cohort study that used clinical laboratory data collected from January 1, 2016, to December 31, 2019. Participants were first divided into three groups: postmenopausal women on no menopausal hormone therapy (n = 8,720); postmenopausal women using either a transdermal E2 patch, gel, or cream (n = 1,062); and premenopausal women on no hormonal therapy (n = 16,308). The postmenopausal menopausal hormone therapy group was further subdivided by formulation (patch [n = 777], gel [n = 132], or cream [n = 153]) and dose range (low, mid, or high). The Jonckheere-Terpstra trend test was used to determine if there was a dose-dependent trend in urinary E2 with increasing dose of compounded E2 cream (dose categories for E2 cream subanalysis, <0.5 mg [n = 49], ≥0.5-≤1.0 mg [n = 50], ≥1.0-≤1.5 mg [n = 58], and >1.5-≤3.0 mg [n = 46]). Urinary E2 and other characteristics were compared across formulations (within each dose range) using Kruskal-Wallis one-way analysis of variance. A dose-dependent, ordered trend existed for urinary E2 with increasing doses of compounded E2 cream (urinary E2 medians [ng/mg-Cr], 0.80 for <0.5 mg, 0.73 for ≥0.5-≤1.0 mg, 1.39 for ≥1.0-≤1.5 mg, and 1.74 for >1.5-≤3.0 mg; Jonckheere-Terpstra trend test, P < 0.001). Significant differences in urinary E2 concentrations were observed in all three dose ranges (Kruskal-Wallis one-way analysis of variance, P = 0.013 for low dose, P < 0.001 for mid dose, P = 0.009 for high dose). Comparison of E2 concentrations of compounded creams to E2 concentrations obtained with similar doses of FDA-approved patches and gels showed that the creams had significantly lower values than the patches and gels. Estrogen exposure from compounded transdermal E2 creams increases in a dose-dependent manner; however, the amount of estrogen exposure associated with compounded creams is significantly lower than estrogen exposure associated with FDA-approved transdermal E2 patches and gels. Clinicians should be aware of the direction and magnitude of these potential differences in estrogen exposure when encountering women who have either previously used or are currently using compounded E2 creams.

FRI007 Kisspeptin Does Not Affect Food Intake In Women With Overweight Or Obesity

Abstract Disclosure: C. Izzi-Engbeaya: None. M. Choudhury: None. B. Patel: None. B. Muzi: None. A. Qayum: None. E.G. Mills: None. M. Ahsan: None. M. Phylactou: None. S. Clarke: None. L. Aslett: None. A.N. Comninos: None. A. Abbara: None. T. Tan: None. W.S. Dhillo: None. Background: Kisspeptin neurons in the hypothalamus are believed to play a role in mediating the interaction between metabolic and reproductive health. Functional neuroanatomical connections exist between kisspeptin neurons and appetite-regulating neurons in the arcuate nucleus of the hypothalamus. Female (but not male) global kisspeptin receptor knockout mice have reduced food intake compared to controls. However, studies of kisspeptin administration have yielded conflicting results, with either decreased, or unchanged food intake reported in rodent studies. Consistent with some of the literature, kisspeptin administration does not influence food intake in men. However, the effects of kisspeptin on food intake have not previously been studied in women. Research Question: What is the effect of kisspeptin administration on food intake in women? Methodology: A randomized controlled crossover study was performed in women with overweight or obesity (BMI &amp;gt;25 kg/m2) who were not in receipt of exogenous oral and/or transdermal estrogens or progestins. Each woman attended two study visits in random order following an overnight fast. During each study visit they received either a 2-hour intravenous infusion of kisspeptin-54 at a rate of 1.0 nmol/kg/hr, or a rate-matched vehicle infusion. The study was single-blinded, with participants unaware of the infusion identity. Participants were given an ad libitum meal 45 minutes after the start of each infusion. Blood samples were taken for reproductive and metabolic profiling, and visual analogue scales (VAS) to assess hunger were completed at regular intervals throughout both study visits. Data are presented as mean±SD. Results: 17 women (age 49±12 years, BMI 34±7 kg/m2) completed both study visits. As expected, LH levels were higher during kisspeptin than during vehicle infusion (p&amp;lt;0.01), confirming bioactivity of the kisspeptin dose. Pre-meal estradiol levels were similar during kisspeptin and vehicle infusions (p=0.34). There were no differences in pre-meal hunger VAS scores 30 mins after the start of the infusion (kisspeptin 5.2±2.7 vs vehicle 5.9±2.3, p=0.33) or bodyweight-adjusted food intake (kisspeptin 6.8±3.7 kcal/kg vs vehicle 6.2±2.8 kcal/kg, p=0.33). There were also no differences in glucose (p=0.97) or insulin (p=0.68) levels between kisspeptin and vehicle infusions. Conclusions: Acute intravenous administration of a biologically active dose of kisspeptin did not affect food intake or hunger in women with overweight or obesity. Furthermore, kisspeptin administration did not alter fasting or post-prandial glucose levels. This is the first study to examine the effects of kisspeptin on hunger and food intake in women and provides reassuring safety data for the ongoing development of kisspeptin-based therapeutics. Presentation: Friday, June 16, 2023

FRI556 Thyroid Autoimmunity Leading To Premature Ovarian Insufficiency (POI) In A Euthyroid Young Woman

Abstract Disclosure: P. rimal: None. M. Moeed: None. C. Musurakis: None. A. Ojha: None. W. Akhtar: None. C.P. Barsano: None. M.F. Siddiqui: None. Introduction: Premature Ovarian Insufficiency is rare in young women and affects only 0.1% before the age of 30. The causes of POI in most cases remain unidentified, with autoimmunity being responsible for 4-30% of the cases. We present the case of a young euthyroid woman who presented for the evaluation of primary amenorrhea and diagnosed with POI associated with thyroid autoimmunity. Clinical Case: A 28-year-old Afghani woman with no known co-morbidities was referred to endocrinology clinic for the work up of primary amenorrhea. She was a goitrous and had normal secondary sexual characteristics and a history of withdrawal bleeding with OCP. There was no known personal or family history of autoimmune disease. Work up revealed hypergonadotropic hypogonadism with high FSH, 55 mIU/ml[Ref range for postmenopausal woman 16.7-113], high LH, 20.28 mIU/ml [Ref range for postmenopausal woman 10.8-58.69] and low estradiol, &amp;lt;2 pg/ml. Anti-Mullerian hormone was low, &amp;lt;0.08ng/ml [RefRange 0.69-13.39] signifying inadequate ovarian reserves and pelvic ultrasound confirmed atrophic ovaries. Etiological work up revealed normal female karyotype, 46XX, and negative FMR gene mutation testing for Fragile X syndrome. Thyroid functions were normal TSH, 3.3 mIU/L (0.27-4.2) and Free T4, 1.29 ng/dl[Ref Range 0.70-2.7]. Autoimmune work up was negative for adrenal 21-OH antibody and anti-ovarian antibodies. However, patient had strongly positive thyroid peroxidase (TPO) antibodies, 613.77 mIU/L[Ref range 0.0-9.0] consistent with thyroid autoimmunity. DXA scan revealed osteopenia. Thus, the diagnosis of POI associated with thyroid autoimmunity was established. HRT with estradiol patch and progesterone was initiated. Calcium, Vitamin D supplements and fertility counseling were provided. Conclusion: Thyroid disease is the most common autoimmune disease associated with POI. Studies have shown higher risk of POI and infertility in patients with Hashimoto’s and Graves’ diseases with co-existing high titers of TPO or anti-thyroglobulin antibodies. Ovaries are subject to autoimmune attack that leads to diminished ovarian reserves. However, until now the association of isolated elevation of TPO antibodies with POI has not been established. A Study by Osuka et al. did not find any significant difference in AMH levels between TPO and non-TPO positive euthyroid women and concluded that unlike hypothyroid women, thyroid autoantibodies were not likely to influence ovarian reserves in euthyroid women. Our case is unique where POI is associated with isolated elevation of TPO antibodies in the absence of clinical thyroid disease. This signifies the possibility that ovarian failure may precede the onset of thyroid disease in patients with thyroid autoimmunity and should be suspected and treated at an early stage, before ovarian reserves are diminished. Presentation: Friday, June 16, 2023

THU445 Complicated Course And Management After Denosumab Discontinuation: A Case Report

Abstract Disclosure: I. Arora: None. L. Ceglia: None. Background: Discontinuation of denosumab (DMAb) can lead to rapid bone loss and sometimes multiple vertebral fractures (VFx). Here we present such a case and related challenges in management. Case: A 56-year-old perimenopausal female presented for management of osteoporosis (OP) complicated by multiple VFx following a missed dose of DMAb in 8/2020. Past bone health history was notable for treatment with alendronate for approximately 11 years as a premenopausal woman. During a drug “holiday” in 2015, she was found to have a decline in bone mineral density (BMD). She was advised to start treatment with DMAb in 8/2016. She was adherent to DMAb injections for 4 years but missed a dose in 8/2020 due to the COVID-19 pandemic. In 1/2021, she developed back pain with no trauma and was diagnosed with VFx of T7, T10 and T12. She underwent vertebroplasty of all 3 vertebrae by 2/2021. DMAb was resumed in 2/2021 and 8/2021. Labs were only notable for hypercalciuria for which hydrochlorothiazide (HCTZ) was initiated. In 11/2021 she presented with new symptomatic VFx of T5, T9 and T11. In 12/2021 (3 weeks post 3 new VFx), serum fasting C-telopeptide (CTX) was 79 pg/mL. Teriparatide or abaloparatide were avoided due to hypercalciuria and potential BMD losses with this transition. Thus in 1/2022, she started romosozumab (ROMO) in an attempt to prevent new VFx. CTX was initially 78 pg/mL and rose rapidly over 3 months to 325 pg/mL with new back pain in 4/2022. No new VFx were detected; however, ROMO was discontinued due to the rise in CTX level. In 5/2022, she received a dose of zoledronic acid (ZOL). It suppressed CTX from 325 to 131 pg/mL by 6/2022. She received another 2 doses of ZOL in 8/2022 and 11/2022 due to rebound rises in CTX. Of note, as she reported ongoing menopausal complaints, transdermal low-dose estradiol therapy was started in 11/2022. She has not had a new VFx in more than 1 year. Hypercalciuria persisted throughout 2022 requiring rising doses of (HCTZ). DXA in 12/2022 was stable vs. 12/2021 without evidence of significant BMD loss. Discussion: This case not only highlights the known risk for multiple VFx in a patient discontinuing long-term DMAb treatment (4 years), but also the risks for such VFx complications in women of younger age during menopausal transition and a history of vertebroplasty. In addition, this report does not support transitioning from long-term DMAb to ROMO in order to prevent a rapid increase in the bone resorption marker, CTX. Rather, treatment with ZOL every 12 weeks based on frequent CTX monitoring successfully maintained BMD stable following long-term DMAb discontinuation. Presentation: Thursday, June 15, 2023

SAT401 The Aftermath Of Pueraria mirifica: A Case Of Hypertriglyceridemia And Necrotizing Pancreatitis In A Non-binary Individual With Surreptitious Use Of Oral Estrogenic Compounds

Abstract Disclosure: S. Tobolsky: None. F.J. Hayes: None. J. Lo: None. Background Prescription of gender-affirming hormone therapy (GAHT) has become an increasingly prevalent aspect of endocrine care meriting greater attention from our specialty. We report a case where surreptitious use of an unregulated compound with estrogenic activity in a patient with gender dysphoria resulted in severe hypertriglyceridemia and necrotizing pancreatitis. The compound, Pueraria mirifica, is readily available for purchase online. CaseThe patient is a 26yo non-binary individual assigned male at birth who presented to the ED with 1.5 days of abdominal pain and vomiting. CT abdomen showed acute necrotizing pancreatitis. On arrival, serum triglycerides 2,559 mg/dl (nl 40-150 mg/dL) and lipase 481U/L (nl 13-60 U/l). The patient reported no alcohol use. Family history of unspecified hyperlipidemia in father. Patient was admitted, made NPO, and started on insulin/dextrose infusions, continued until serum triglycerides dropped to &amp;lt;1,000 mg/dL. Fenofibrate started and extensive nutritional counseling on low-carbohydrate and low-fat diet given. In absence of clear etiology for hypertriglyceridemia, patient was questioned carefully on supplement use and revealed they took 2 tablets of Pueraria mirifica daily with intent of transitioning without medical guidance given prior negative encounters with healthcare. Patient discharged on fenofibrate 200 mg, atorvastatin 20 mg and omega-3 acid ethyl esters 2 g BID, with plan for endocrinology follow-up for initiation of medically supervised GAHT. At follow-up on this regimen, LDL was 79 mg/dL and triglycerides 160 mg/dL. Goals of transition were discussed with the patient as was importance of avoiding oral estrogens, prescribed or over-the-counter. Given patient’s desire for partial transition, low dose transdermal estradiol 0.05 mg patch and spironolactone 50mg BID started. On above regimen, estradiol was 179 pg/mL and total testosterone suppressed at 72 ng/dL. The patient’s triglycerides remained &amp;lt;150 mg/dL with no further complications. ConclusionThis case highlights a potentially fatal complication of hormone use in a transgender individual with likely underlying familial hypertriglyceridemia. It also illustrates how distrust of the medical system led to surreptitious hormone use and emphasizes the need to create a safe, welcoming environment for individuals with gender dysphoria. Finally, it emphasizes the need to interrogate possible surreptitious hormone use in patients with unusual presentations and for endocrinologists to be aware of the need to avoid oral estrogen use in patients with hypertriglyceridemia. Presentation: Saturday, June 17, 2023

THU440 A Case Of Osteomalacia In A Young Adult Female With Premature Ovarian Insufficiency

Abstract Disclosure: I.H. Kasimoglu: None. T. Vu: None. J.Q. Dai-Ju: None. Background: Osteomalacia is a condition due to inadequate mineralization during the bone-remodeling process. Common causes of bone demineralization include Vitamin D deficiency and low calcium intake. Consequently, the treatment often involves both Vitamin D and calcium supplementation, corresponding dietary modifications, and adequate exposure to sunlight. Clinical Case: 34-year-old female with past medical history of sickle cell disease s/p allogenic bone marrow transplant in 11/2020, brain toxoplasmosis infection 3/2021, secondary amenorrhea due to premature ovarian insufficiency diagnosed in 12/2021, was referred to endocrinology for management of osteomalacia. Dexa Scan from 11/2021 reported lower bone density than expected compared with the same age/gender group (Z-Scores: Left Hip – 0.3, Neck –1.4, and L1-L4 –3.6). Vitamin D 25-OH level was 8.3 (n&amp;gt;30) ng/mL and serum calcium level as low as 5.8 (n8.6-10.3) mg/dL in 3/2021, PTH-I elevated to 459 (n10-68) pg/mL, alkaline phosphatase elevated to 166 (n34-104) U/L. The patient was encouraged to increase Vitamin D3 to 4000 iu daily and calcium intake to 1200 mg daily. After discussion with patient of benefits and risks of hormone replacement, patient was started on very low dose of estradiol patch (0.025mg/day) for concern of prior history of pulmonary embolism, and progesterone 100 mg oral daily 3/2022. Vitamin D 25-OH, PTH, serum and 24 hr urine calcium have been within normal range since 9/2022. Dexa Scan from 11/2022 showed significant improvement of bone density (32.0% increase of lumbar spine, 11.2% increase of left hip). This case of osteomalacia resulting from Vitamin D deficiency and subsequent secondary hyperparathyroidism demonstrates that it is imperative to recognize and treat Vitamin D deficiency because it restores bone strength and prevents fractures while simultaneously correcting biochemical abnormalities (1). This case is also interesting as the patient still carries an increased risk of bone density loss complicated by underlying premature ovarian insufficiency and hypoestrogenic state. Thus, by providing patients with the appropriate Vitamin D and calcium supplementation recommendations along with hormone replacement therapy in young adults, it is possible to rehabilitate their overall bone health as well as reduce future risks of fractures. Conclusion: Adequate Vitamin D and calcium supplementation is important for the management of osteomalacia. In patients with premature ovarian insufficiency, it is even more imperative to promote supplementations, dietary modifications, and sunlight exposure in conjunction with traditional agents of hormonal therapy to promote overall bone health. Reference: 1) Bhan A., et al. Osteomalacia as a result of vitamin D deficiency. Endocrinol Metab Clin North Am. 2010;39(2):321–331. 10.1016/j.ecl.2010.02.001 Presentation: Thursday, June 15, 2023

Improvement of positive dysphotopsia with multifocal intraocular lenses by hormone replacement therapy

Introduction: The case of a patient with positive dysphotopsia (PD) affected by hormone replacement therapy (HRT) after multifocal intraocular lens (IOL) insertion is reported. Patient and Clinical Findings: A 66-year-old woman underwent bilateral cataract surgery and multifocal IOL implantation. Postoperatively, the uncorrected distance and near visual acuity improved bilaterally. The patient experienced mild PD symptoms in the left eye. She had been using an estradiol patch for menopausal disorders. 6 months postoperatively, the use of an estradiol patch was discontinued because of dermatitis and she noticed a marked worsening of her PD. Diagnosis, Intervention, and Outcomes: With the patient's cooperation, full-field electroretinography (ERG) and contrast sensitivity tests were performed before and after estradiol discontinuation. After the discontinuation, the amplitude of both rod and cone ERGs decreased, contrast sensitivity decreased, and PD deteriorated. There were no changes in anterior-segment condition and retinal shape. Conclusions: PD symptoms worsened after the discontinuation of estrogen hormone therapy. ERG amplitude and contrast sensitivity decreased when HRT was discontinued, suggesting that retinal function in the presence of estrogen receptors may be related to the development of PD.