Transdermal Research Articles

Gelatin-PVP dissolving microneedle-mediated therapy for controlled delivery of nifedipine for rapid antihypertension treatment.

Nifedipine has exhibited to be the oldest primary drug having promising therapeutic potential for hypertension, angina pectoris, and pre-eclampsia treatment which are the most emergency serious complications worldwide. Moreover, for long-term treatment transdermal route of delivery using polymeric dissolving microneedles (DMNs) patches has shown greater advantages, thus enhancing treatment compliance, painless, reducing the daily number of doses, prolonged release in a controlled manner, and variable bioavailability making this an ideal candidate for the transdermal therapeutic system. Here, we fabricated DMN patches made of gelatin and PVP using PDMS molds loaded with nifedipine drugs for a controlled painless delivery for a longer stable duration. The prepared gelatin-PVP (gel-PVP) DMN patches loaded with nifedipine were fabricated by centrifugation casting method. The characterization results displayed excellent mechanical strength of the needles to penetrate the skin. SEM and confocal microscopy showed penetration of the needles up to 567-600 µm using rhodamine B applied to the hairless punctured skin site. FTIR study exhibited no degradation of the drug was observed while fabricating the DMNs patch at different pH 7.4 and 4. Skin resealing test proved that there was immediate resealing of the skin observed within 10-15 min. Further in-vitro drug release profile study was carried out by dissolution method at different pH 7.4 and 4 showed sustained release of the drug up to 96 ± 2% till 48-72 h avoiding polymer or drug loss which was quantified by UV vis spectrophotometer at 235 nm absorbance showed stable release of the drug upto 48-72 h. A stability study carried out by the HPLC method showed the DMN patches loaded with the drug were found to be stable for up to 30 days at 25 °C. This novel preliminary data are the first study to our knowledge introducing these fabricated nifedipine gel-PVP DMN patches were found to be very efficient and showed prolonged controlled release up to 48-72 h thereby treating hypertension in a convenient, painless manner. This DMN patch-formulated design might act as a potential approach leading to a controllable, self-administrative, and rapid transdermal delivery system.

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.

Skin irritation assessment and potential mechanism of Capparis spinosa L. fruits

Ethnopharmacological relevanceIn China, Capparis spinosa L. fruits (CSF) are often used topically in Uyghur folk medicine in treating rheumatic diseases with remarkable efficacy. However, it has noticed severe skin irritation after a short time application with high dose of CSF, which limited long-term clinical use. To date, there is almost no research related to skin irritation of CSF.Aim of the study: This study was intended to perform the first systematic assessment of morphological and histological changes in skin after stimulation with CSF. Furthermore, potential irritant components in CSF and related mechanisms were explored by in vitro transdermal techniques, network pharmacology, molecular docking, and experimental validation. Materials and methodsSkin changes after single and multiple stimulations with CSF were observed and subjected to skin irritation response scoring, irritation strength assessment, and histopathological analysis. In addition, in vitro transdermal technology, liquid chromatography-mass spectrometry (LC-MS) method, network pharmacology, molecular docking, and experimental validation were used to further exploit underlying skin irritant components and possible mechanisms of action. ResultsCSF induced significant morphological (erythema and edema) and histological (epidermal thickening and inflammatory infiltration) changes in skin of mice, which were similar to the clinical presentation of irritation contact dermatitis (ICD). The ethyl acetate fraction of CSF (CFEAF) was the main source of CSF-induced skin irritation. Kaempferol, flazin, and gallic acid were potential major irritant compounds. Moreover, CFEAF, kaempferol, flazin, and gallic acid could increase the levels of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and interleukin-17A (IL-17A) to promote skin inflammation. The potential mechanism of CSF-induced skin irritation may be activation of the nuclear factor kappa-B (NF-κB) signaling pathway, including phosphorylation of NF-κB p65 (p65) and nuclear factor-kappa B inhibitor alpha (IκBα). ConclusionKaempferol, flazin, and gallic acid are potential skin irritant components from CSF. Altogether, they induce skin irritation responses through promoting the release of the inflammatory factors TNF-α and ICAM-1, as well as activating the NF-κB signaling pathway. In addition, IL-17A may be an important pro-inflammatory factor in skin irritation.

Raloxifene encapsulated spanlastic nanogel for the prevention of bone fracture risk via transdermal administration: Pharmacokinetic and efficacy study in animal model.

This research work is to evaluate spanlastic-loaded raloxifene (RLX) nanogel administration via the transdermal route to avoid its hepatic metabolism and to enhance the bioavailability for better management of osteoporosis. RLX-loaded spanlastic nanogel was prepared and characterized for its viscosity, pH, spreadability, and texture profile. The formulation was applied on the skin surface of the animal for pharmacokinetic evaluation, and later, the efficacy of the formulation was assessed in ovariectomized female Wistar rats.The nanogel was obtained with a viscosity (2552.66 ± 30.61 cP), pH (7.1 ± 0.1), and spreadability (7.1 ± 0.2cm). The texture properties, cohesiveness, and adhesiveness of the nanogel showed its suitability for transdermal application. Nanogel showed no sign of edema and erythema in the skin irritation test which revealed its safety for transdermal application. The t1/2 obtained for RLX-spanlastic nanogel (37.02 ± 0.59h) was much higher than that obtained for RLX-oral suspension (14.43h). The relative bioavailability was found to be 215.96% for RLX-spanlastic nanogel, and the drug and formulation did not show any toxicity in any of the vital organs, as well as no hematological changes occurring in blood samples. In microarchitectural measurement, RLX-spanlastic nanogel exhibited no unambiguous deviations along with improved bone mineral density compared to the RLX suspension treated group. Transdermal administration of RLX-spanlastic nanogel showed significant improvement of drug bioavailability (approx. twice to oral administration) without any toxic effect in the treated rats. Hence, spanlastic nanogel could be a better approach to deliver RLX via transdermal route for the management of osteoporosis.

Investigating the Effect of Transdermal Testosterone Gel Administration on Ovarian Response Rate in Infertile Women with Poor Response to Conventional Assisted Reproductive Methods

Investigating the Effect of Transdermal Testosterone Gel Administration on Ovarian Response Rate in Infertile Women with Poor Response to Conventional Assisted Reproductive Methods

Transdermal Therapeutic Systems for the Treatment of Alzheimer's Disease: A Patent Review.

Two classes of medications are used to treat Alzheimer's disease (AD); donepezil, galantamine, and rivastigmine are acetylcholinesterase inhibitors, and memantine is a non-competitive antagonist of the N-methyl-D-aspartate receptor. Although these are typically taken orally, there are transdermal therapeutic systems (TTSs) commercially available for rivastigmine and donepezil. The transdermal route has been preferable for guardians/caregivers due to ease of use, reduced side effects, and improved adherence to therapy. The study aimed to obtain knowledge of the properties of these drugs and to search for patents relating to the TTS for AD using the Espacenet platform. The search terms were "rivastigmine AND transdermal AND skin delivery AND Alzheimer's", changing the drugs "memantine", "donepezil", and "galantamine", between January 2015 and January 2022. Title and abstract were used to choose patents. TTSs present some limit factors in terms of absorption due to skin physiology and the size of the molecules with established limits of percutaneous penetration (molecular mass of 500 g/mol and log P of 5). We found 1, 4, 4, and 2 patents for galantamine, rivastigmine, donepezil, and memantine, respectively. Galantamine TTS seems to be more challenging due to the molecular mass of 287.35 g/mol and logP of 1.8. The permeator of absorption is necessary. Memantine, rivastigmine, and donepezil present logP of 3.28, 2.3, and 4.27 and molecular weights of 179.30, 250.34, and 415.96 g/mol, respectively. TTSs are primarily effective for delivering small molecules. The use of absorption enhancers and irritation mitigators can be necessary to enhance the performance. The development of these technologies is essential for the convenience of patients and caregivers.

An Ultraswelling Microneedle Device for Facile and Efficient Drug Loading and Transdermal Delivery.

The advancement and extensive demand for transdermal therapies can benefit from a safe, and efficient and user-friendly transdermal technology with broad applicability in delivering various hydrophilic drugs. Here the design and proof of concept applications of an ultraswelling microneedle device that enables the facile and efficient loading and transdermal delivery of hydrophilic drugs with different molecular weights is reported. The device consists of a super-hydrophilic hydrogel microneedle array and a resin base substrate. Using a special micromolding technique that involves hydrated crosslinking and cryogenic-demolding, the microneedle part displays a rapid swelling ratio of ≈3800%, enabling the loading of drugs up to 500kDa in molecular weight. The drug loading process using the device just involves incubating the microneedle part in a drug solution for 1min, followed by 15min of drying. The microneedles can easily penetrate the skin under press and detach from the base substrate under shear, thereby releasing the payload. Administration of desired therapeutic agents using the device outperformed conventional administration methods in mitigating psoriasis and eliciting immunity. This biocompatible device, capable of withstanding ethylene oxide sterilization, can enhance the efficacy and accessibility of transdermal therapies in research institutes, hospitals, and even home settings.

Smart Responsive Microneedles for Controlled Drug Delivery.

As an emerging technology, microneedles offer advantages such as painless administration, good biocompatibility, and ease of self-administration, so as to effectively treat various diseases, such as diabetes, wound repair, tumor treatment and so on. How to regulate the release behavior of loaded drugs in polymer microneedles is the core element of transdermal drug delivery. As an emerging on-demand drug-delivery technology, intelligent responsive microneedles can achieve local accurate release of drugs according to external stimuli or internal physiological environment changes. This review focuses on the research efforts in smart responsive polymer microneedles at home and abroad in recent years. It summarizes the response mechanisms based on various stimuli and their respective application scenarios. Utilizing innovative, responsive microneedle systems offers a convenient and precise targeted drug delivery method, holding significant research implications in transdermal drug administration. Safety and efficacy will remain the key areas of continuous efforts for research scholars in the future.

Increasing Efficiency of Transdermal Drug Delivery Systems Using Some Novel Penetration Enhancement Techniques - A Critical Review

The transdermal route has drawn considerable attention and has emerged as a solid alternative to mimic the drawbacks of drugdelivery through the oral and parenteral routes. However, the effectiveness of TDDS is often limited by the skin's outermost layer, the stratumcorneum (SC), which acts as a barrier to drug diffusion. In addition, the drug molecule's molecular weight, hydrophilicity, and ionic nature canalso impact its transdermal delivery. Various methods have been developed to overcome these limitations to facilitate drug penetration acrossthe SC, including nano-carriers, wearable delivery systems, and combination-based approaches. The use of nano-carriers, such as dendrimers,liposomes, niosomes, and micro sponges, has shown promise in enhancing the efficacy of TDDS. Another emerging innovation for TDDS iswearable delivery systems, which offer non-invasive, convenient, and extended drug administration. Additionally, combination-based approaches,such as ultrasound and microneedle-based systems or ultrasound and electrical-based techniques, are also being investigated and are the centerof attraction in the research of TDDS approaches. This review summarizes a combination of all different novel penetration enhancementtechniques used to enhance the efficacy of transdermal drug delivery systems that were not precisely captured by other review articles. Most ofthe review articles emphasized these penetration enhancement techniques separately. However, a careful review of all the penetrationenhancement techniques in one article is missing. Thus, the purpose of this article is to comprehensively review and summarize the recentlyused penetration enhancement techniques along with the possible mechanism of action in a single article. Our primary aim is to collect relevantreviews and research articles by searching various databases to provide a comprehensive overview of the field. By providing a comprehensiveoverview of the available techniques, this review article will help students and researchers stay up-to-date with the latest developments in thefield of novel penetration enhancement techniques used to increase the efficiency of TDDS.

Recent Nanoscale Carriers for Therapy of Alzheimer's Disease: Current Strategies and Perspectives.

This review covers nanotherapeutic strategies for solving the global problems associated with Alzheimer's disease (AD). The most dramatic factor contributing humanistic, social and economic urgency of the situation is the incurability of the disease, with the drug intervention addressing only AD symptoms and retarding their progress. Key sources behind these challenges are the inability of the early diagnosis of AD, the lack of comprehensive information on the molecular mechanism of the pathogenesis, the bloodbrain barrier obstacles, and the insufficient effectiveness of currently available drugs and therapeutic strategies. The application of nanocarriers allows part of these problems to be solved, together with the improvement of drug bioavailability, prolonged circulation, and overcoming/bypassing the biological barriers. To this date, numerous types and subtypes of nanocarriers are developed and reviewed, the majority of which can be adapted for the treatment of various diseases. Therefore, herein, nanotherapy strategies are specifically categorized in term of the administration routes of AD medicines, with the noninvasive, i.e., transdermal, oral, and intranasal routes emphasized. Further, benefits/ limitations of various nanocarriers are discussed, and perspectives of their application are highlighted.

The novel design of an intelligent anti-depression transdermal drug delivery system

Depression is a type of mental disorder with a significant and persistent low mood as the main clinical feature. It is often accompanied by symptoms such as slow thinking, decreased will, loss of appetite, and weight loss. The current treatment methods for depression are mainly medical treatment, psychotherapy, and physical therapy. These treatments are dependent on the patient's autonomy and the patients may suspend treatment due to forgetting or refusing. Therefore, an anti-depressant intelligent drug release system was designed, which can achieve autonomously controlled doses for the treatment of depression by transdermal drug delivery system. The work of this study is as follows:(1) The first module: the electrothermal material heating layer. Several preparation methods were screened, and multiple sets of graphene (GE) electric thermogenic layers were successfully prepared. After increasing the actual energization area to 1 cm × 1 cm, the GE electric thermogenic layer is used as the heating layer of the electrothermal material of the system, and can reach a uniform surface temperature of (45 ± 0.5) °C within 15 s at a voltage of 6 V keeping the temperature fluctuation range not exceeding ±0.03 °C, and the resistance fluctuation range not exceeding ±20 Ω, which plays a role in controlling the temperature and heat treatment of the drug loaded gel layer.(2) The second module: the drug-loaded gel layer. Based on the L16 (45) orthogonal test, the best formulation and process of N-Isopropyl acrylamide-Acrylamide copolymer (P(NIPAAm-co-AAm)) hydrogel was determined. Then, the percutaneous permeability of Selegiline liposome was studied in vitro.(3) A rat model of depression was established using chronic unpredictable mild stress (CUMS) combined with separation. From the aspects of behavior (body weight, sucrose preference test, forced swimming test, open field test) and biochemical indexes (serum proinflammatory cytokines (IL-1β, TNF-α), hippocampus HE staining observation), the therapeutic effect of hyperthermia, Selegiline oral administration and transdermal administration was discussed.

Permeation Enhancers for Transdermal Drug Delivery: Strategies and Advancements Focusing Macromolecules

The various transdermal drug delivery method, allows medications to cross the biological barriers and enter the bloodstream to elicit desired pharmacological response. The relevant article focuses on the numerous biological and other macromolecule-based permeation enhancers including carbohydrates, protein-peptides and lipids used in transdermal drug delivery. Though the focus of the study is on role of macromolecule, as well as their mechanisms and modes of action for efficient transdermal drug delivery, it also concentrates on the recent developments in various permeation enhancement techniques. Transdermal administration of weakly permeable medications with shorter biological half-lives typically makes use of the permeation augmentation techniques and agents, which should not have any explicit toxicological implications and incompatibility within the formulations. In this review, limelight has been given to the promising permeation enhancers of current scenario which consist of various macromolecules.

Microneedle-mediated transdermal delivery of N-acetyl cysteine as a potential antidote for lewisite injury

Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister formation. N-acetyl cysteine (NAC) is an FDA-approved drug for acetaminophen toxicity, identified as a potential antidote against lewisite. In the present study, we have explored the feasibility of rapid NAC delivery through transdermal route for potentially treating chemical warfare toxicity. NAC is a small, hydrophilic molecule with limited passive delivery through the skin. Using skin microporation with dissolving microneedles significantly enhanced the delivery of NAC into and across dermatomed human skin in our studies. Microporation followed by application of solution (poke-and-solution) resulted in the highest in vitro delivery (509.84 ± 155.04 µg/sq·cm) as compared to poke-and-gel approach (474.91 ± 70.09 µg/sq·cm) and drug-loaded microneedles (226.89 ± 33.41 µg/sq·cm). The lag time for NAC delivery through poke-and-solution approach (0.23 ± 0.04 h) was close to gel application (0.25 ± 0.02 h), with the highest for drug-loaded microneedles (1.27 ± 1.16 h). Thus, we successfully demonstrated the feasibility of rapid NAC delivery using various skin microporation approaches for potential treatment against lewisite-mediated skin toxicity.

Freeze-Dried Camelina Lipid Droplets Loaded with Human Basic Fibroblast Growth Factor-2 Formulation for Transdermal Delivery: Breaking through the Cuticle Barrier to Accelerate Deep Second-Degree Burn Healing.

Transdermal administration of chemo therapeutics into burn healing may be an effective treatment to reduce toxic side effects and improve patient compliance for burns. As a transdermal delivery system, Camelina lipid droplets (CLDs) have received great attention due to their biocompatibility, high drug payload, and rapid absorption. However, the absorbed-related mechanisms of Camelina lipid droplets have not yet been reported. Thus, this paper not only demonstrated that CLD can accelerate skin burn healing through promoting hFGF2 absorption, but also elucidated the mechanism between the skin tissue and keratinocytes using Franz, HE staining, DSC, FTIR spectroscopy, and atomic force microscopy with the presence of CLD-hFGF2 freeze-dried powder. We found that the cumulative release rate of CLD-hFGF2 freeze-dried powder was significantly higher than that of free hFGF2 freeze-dried powder into the skin. At the same time, CLD can change the structure and content of lipids and keratin to increase the permeability of hFGF2 freeze-dried powder in skin tissue. Unlike the free state of hFGF2, the biophysical properties of single cells, including height and adhesion force, were changed under CLD-hFGF2 freeze-dried powder treatment. Meanwhile, CLD-hFGF2 freeze-dried powder was more easily taken up through keratinocytes without damaging cell integrity, which provided a new viewpoint for understanding the absorption mechanism with the CLD system for cellular physiology characteristics. Overall, our findings demonstrated that CLD could break through the stratum corneum (SC) barrier and elucidated the transport mechanism of lipid droplets in skin tissue, which provides a crucial guideline in drug delivery applications for future engineering.

Immuno-modulation of tumor and tumor draining lymph nodes through enhanced immunogenic chemotherapy by nano-complexed hyaluronic acid/polyvinyl alcohol microneedle

Certain chemo-drugs could induce immunogenic cell death (ICD) activating T cell antitumor immunity while trigger indoleamine-2,3-dioxygenase (IDO) upregulation suppressing immune responses. Moreover, to achieve therapeutic efficacies on both primary tumors and tumor draining lymph nodes (TDLNs) in the meantime is still a big challenge. In this study, transfersomes functionalized with a tumor targeting, cell penetrating peptide tLyp1 (CGNKRTR) was developed to co-encapsulate doxorubicin (DOX, ICD inducer) and 1MT (IDO inhibitor). The functionalized transfersomes were complexed with microneedles (MNs) to realize co-delivery towards primary tumors and TDLNs via transdermal administration. The transfersomes were concentrated in the needles of MNs and released with needle dissolution after insertion into skin. After being internalized by cells, DOX induced tumor ICD effect to promote DCs maturation and dramatically activated cytotoxic T lymphocytes (CD8+ T), while 1MT inhibited IDO activity in DCs and reduced the immunosuppressive Tregs, thus mitigating tumor suppressive microenvironment. The nano-complexed microneedles exhibited 2.2-fold suppression in tumor growth compared with the I.V. group, which significantly enhanced anti-tumor effect.

Melatonin Modulates the SIRT1-Related Pathways via Transdermal Cryopass-Laser Administration in Prostate Tumor Xenograft.

Melatonin displays antitumor activity in several types of malignancies; however, the best delivery route and the underlying mechanisms are still unclear. Alternative non-invasive delivery route based on transdermal administration of melatonin by cryopass-laser treatment demonstrated efficiency in reducing the progression of LNCaP prostate tumor cells xenografted into nude mice by impairing the biochemical pathways affecting redox balance. Here, we investigated the impact of transdermal melatonin on the tumor dimension, microenvironment structure, and SIRT1-modulated pathways. Two groups (vehicle cryopass-laser and melatonin cryopass-laser) were treated for 6 weeks (3 treatments per week), and the tumors collected were analyzed for hematoxylin eosin staining, sirius red, and SIRT1 modulated proteins such as PGC-1α, PPARγ, and NFkB. Melatonin in addition to simple laser treatment was able to boost the antitumor cancer activity impairing the tumor microenvironment, increasing the collagen structure around the tumor, and modulating the altered SIRT1 pathways. Transdermal application is effective, safe, and feasible in humans as well, and the significance of these findings necessitates further studies on the antitumor mechanisms exerted by melatonin.

Effect of Addition a Sodium Deoxycholate as an Edge Activator -for Preparation of Ondansetron HCl Tansfersomal Dispersion

In ordinary clinical practice, poor patient compliance with oral and parenteral drug administration modalities is a prevalent problem. As a result, pharmaceutical research has developed a strong interest in the transdermal route of drug delivery.
 They are non-invasive that can improve patient compliance, however, The barrier function of the skin's top layer presents the biggest challenge for transdermal delivery systems. Transfersomes are vesicles composed of phospholipids and edge activators, used to transport drug from outer skin layer into the systematic circulation through semipermeable membrane. Ondansetron is an anti-emetic medication that has been given parenterally and orally. Formulating this medication as transdermal transfersomes may provoke a great advantage in medical adherence.
 Conclusion; Ondansetron has been successfully delivered transdermally by Using a transfersomal gel formulation by vortexing sonication method.

Liposome-Derived Nanosystems for the Treatment of Behavioral and Neurodegenerative Diseases: The Promise of Niosomes, Transfersomes, and Ethosomes for Increased Brain Drug Bioavailability.

Psychiatric and neurodegenerative disorders are amongst the most prevalent and debilitating diseases, but current treatments either have low success rates, greatly due to the low permeability of the blood-brain barrier, and/or are connected to severe side effects. Hence, new strategies are extremely important, and here is where liposome-derived nanosystems come in. Niosomes, transfersomes, and ethosomes are nanometric vesicular structures that allow drug encapsulation, protecting them from degradation, and increasing their solubility, permeability, brain targeting, and bioavailability. This review highlighted the great potential of these nanosystems for the treatment of Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorder, anxiety, and depression. Studies regarding the encapsulation of synthetic and natural-derived molecules in these systems, for intravenous, oral, transdermal, or intranasal administration, have led to an increased brain bioavailability when compared to conventional pharmaceutical forms. Moreover, the developed formulations proved to have neuroprotective, anti-inflammatory, and antioxidant effects, including brain neurotransmitter level restoration and brain oxidative status improvement, and improved locomotor activity or enhancement of recognition and working memories in animal models. Hence, albeit being relatively new technologies, niosomes, transfersomes, and ethosomes have already proven to increase the brain bioavailability of psychoactive drugs, leading to increased effectiveness and decreased side effects, showing promise as future therapeutics.

OR31-06 Gender-Affirming Hormone Therapy Affects Serum Cystatin C-based eGFR In Transgender Individuals

Abstract Disclosure: S.A. van Eeghen: None. C. Wiepjes: None. N. Nokoff: None. P. Bjornstad: None. M. Den Heijer: None. D. van Raalte: None. Background: Previous studies in transgender individuals have shown that masculinizing (testosterone) hormone therapy increases and feminizing (estradiol combined with anti-androgen) hormone therapy decreases serum creatinine. Translating this into estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, eGFR increases in transwomen and decreases in transmen during gender-affirming hormone therapy (GAHT). However, serum creatinine is significantly correlated with lean body mass (LBM), which also changes during GAHT, with transmen gaining and transwomen loosing muscle mass. Thus changes in creatinine-derived eGFR during hormone therapy may not reflect true changes in GFR. Another manner to estimate GFR, which is not affected by body composition, is by measuring plasma cystatin C concentrations. Therefore, we studied the effects of GAHT on serum cystatin C, a sex-independent marker for GFR. Methods: In this prospective, observational sub study of the European Network for the Investigation of Gender Incongruence (ENIGI), serum cystatin C was measured in 266 transwomen and 285 transmen before and at 12 months of GAHT. Transwomen received feminizing hormone therapy, consisting of oral (n= 122) or transdermal administration (n= 144) of estrogen in combination with the oral anti-androgen cyproteroneacetate. Transmen received masculinizing hormone therapy, which consisted of intramuscular (n= 144) or transdermal (n= 141) administration of testosterone. Serum cystatin C-based eGFR was calculated according to the full-age-spectrum equation (FAScysC; mL/min/1.73m2). Linear regression was used to assess the means. Results: In transwomen (baseline characteristics; median age 29 (IQR 23-43) years; median BMI 22.9 (IQR 20.8-26.4) kg/m2; creatinine 78.6 ± 9.9 μmol/L; creatinine-based CKD-EPI eGFR 110 ± 14 mL/min/1.73m2), cystatin C decreased by 0.07 (95% CI, 0.05 to 0.09) mg/L; from 0.94 ± 0.17 mg/L before GAHT to 0.87 ± 0.15 mg/L during GAHT. This corresponds with an increase in FAScysC of 7 (95% CI, 5 to 9) mL/min/1.73m2; from 93 ± 17 to 100 ± 18 mL/min/1.73m2. On the contrary, in transmen (baseline characteristics; median age 22 (IQR 20-28) years; median BMI 24.7 (IQR 21.4-30.1) kg/m2; creatinine 66.8 ± 9.3 μmol/L; creatinine-based CKD-EPI eGFR 110 ± 15 mL/min/1.73m2) cystatin C increased by 0.05 (95% CI, 0.03 to 0.07) mg/L; from 0.89 ± 0.17 mg/L before GAHT to 0.95 ± 0.16 mg/L during 12 months of GAHT. This is consistent with a decrease in FASCysC of 6 (95% CI, 4 to 8) mL/min/1.73m2; from 101 ± 19 to 94 ± 15 mL/min/1.73m2. Conclusions: In this large-sized cohort of transgender individuals, cystatin C-based eGFR increased with feminizing hormone therapy and decreased with masculinizing hormone therapy, indicating true biological effects of sex hormones on kidney physiology, which warrants further investigation. Presentation: Sunday, June 18, 2023

FRI436 Design Of An International Male Contraceptive Efficacy Trial Using A Self-administered Daily Topical Gel Containing Testosterone And Nestorone™

Abstract Disclosure: S.T. Page: None. Support: Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) through the Contraceptive Development Program’s Contraceptive Clinical Trials Network and by the Population Council. Background: A self-administered male hormonal contraceptive might be very useful to prevent unintended pregnancy. Prior efficacy studies of male hormonal contraceptives have relied on injections or implants of hormones by medical personnel. Transdermal testosterone gels are widely used to treat hypogonadism. Transdermal administration may have utility for male contraception as well; however, no contraceptive efficacy data from the use of a self-administered transdermal male hormonal contraceptive gel are available. Survey data suggests that men are not only interested in male contraception but that a self-administered transdermal gel is desired by many men as an optimal form of contraceptive delivery. A transdermal male contraceptive raises novel considerations regarding compliance with and absorption of the gel in men as well as concern regarding the potential cutaneous transfer of the hormones to the female partner. Previous studies in men have demonstrated that a combined Nestorone-(segesterone acetate) testosterone transdermal gel is well tolerated, and that it safely and effectively suppresses sperm production to contraceptive levels in men who apply it daily. Here we describe the design of an ongoing Phase 2b safety and efficacy trial of this transdermal male contraceptive gel. We discuss the novel aspects and challenges in the design and evaluation of an international transdermal male contraceptive efficacy study that was conducted during a global pandemic. Methods: We are conducting an international, single-arm, open-label study of self-administration of a daily combined Nestorone (segesterone acetate)-testosterone gel for male contraception. Couples are eligible for the study if they are in a committed relationship, at risk for unintended pregnancy and the men have normal spermatogenesis and are in good health. The primary outcome is the rate of pregnancy in couples during the 52-week efficacy phase of the study. Secondary endpoints include the proportion of men suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in both men and their female partners, sexual function, urinary symptoms, and regimen acceptability for the men and their female partners. ClinicalTrials.gov: NCT03452111. Results: Approximately 460 couples have been enrolled at 17 sites internationally including sites in North and South America, Europe and Africa. The study is now closed to enrollment. Conclusions: We present the design of the first study to examine contraceptive efficacy, side effect profile and acceptability of a self-administered, reversible, male hormonal contraceptive product. Presentation: Friday, June 16, 2023