ACS Appl Mater Interfaces. 2023 Jul 25. doi: 10.1021/acsami.3c04692. Online ahead of print.

ABSTRACT

Biophysical and biochemical cues modulate mammalian cell behavior and phenotype simultaneously. Macrophages, indispensable cells in the innate immune system, respond to external threats such as bacterial infections and implanted devices, undergoing the classical M1 polarization to become a pro-inflammatory phenotype. In the study, lipopolysaccharide (LPS)-induced M1 polarization was examined using RAW264.7, THP-1, and primary human PBMCs on a family of artificial extracellular matrix (ECM), named colloidal self-assembled patterns (cSAPs). The results showed that cSAPs were biocompatible, which cannot induce M1 or M2 polarization. Interestingly, specific cSAPs (e.g., cSAP3) suppress the level of M1 polarization (i.e., reduced nitric oxide production, down-regulated gene expression of iNOS, IL-6, TNF-α, IL-1β, and TLR4, and reduced proportion of CD11b+CD86+ cells). Transcriptome analysis showed that cell adhesion and cell-ECM interaction participated in the M1 polarization, and the mechano-sensitive genes such as PIEZO1 were down-regulated on the cSAP3. More interestingly, these genes were also down-regulated under LPS stimulation, indicating that cells became insensitive to the LPS. The abovementioned results indicate that the defined physicochemical cues can govern macrophage polarization. This study illustrates a potential surface design at biointerface, which is critical in tissue engineering and materiobiology. The outcome is also inspiring in ECM-mediated immune responses.

PMID:37489656 | DOI:10.1021/acsami.3c04692

Twin Res Hum Genet. 2023 Jul 25:1-7. doi: 10.1017/thg.2023.28. Online ahead of print.

ABSTRACT

The purpose of this research was to determine the frequency of mutation of the cytochrome CYP3A5 genes and transport proteins SLCO1B1 and MDR1 in patients with coronary heart disease in the Kazakh nation. A prospective cohort clinical and genetic study was conducted. The study was conducted in 2017-2019. Medical records containing information about drug prescription conducted in hospitals and outpatient departments were carefully analyzed. In the examined group of 178 patients treated with statins, a significant frequency of genetic variants that determine the increased risk of complications of statin use was revealed. There was a tendency toward an increase in the activity of creatine phosphokinase (CPK) in the blood upon detection of the A6986G mutation of the cytochrome gene and SLCO1B1 (c.521T>C) gene of the transport protein OATP1B1. In the studied Kazakh population, the presence of a homozygous mutant SLCO1B1 gene of the transport protein can be recommended as a genetic marker for the undesirability of using antihypercholesterolemic therapy with statins, which simultaneously leads to a decrease in the effectiveness of treatment and an increase in the risk of side effects.

PMID:37489533 | DOI:10.1017/thg.2023.28

Sci Rep. 2023 Jul 24;13(1):11911. doi: 10.1038/s41598-023-39179-2.

ABSTRACT

Drug response prediction is important to establish personalized medicine for cancer therapy. Model construction for predicting drug response (i.e., cell viability half-maximal inhibitory concentration [IC50]) of an individual drug by inputting pharmacogenomics in disease models remains critical. Machine learning (ML) has been predominantly applied for prediction, despite the advent of deep learning (DL). Moreover, whether DL or traditional ML models are superior for predicting cell viability IC50s has to be established. Herein, we constructed ML and DL drug response prediction models for 24 individual drugs and compared the performance of the models by employing gene expression and mutation profiles of cancer cell lines as input. We observed no significant difference in drug response prediction performance between DL and ML models for 24 drugs [root mean squared error (RMSE) ranging from 0.284 to 3.563 for DL and from 0.274 to 2.697 for ML; R2 ranging from -7.405 to 0.331 for DL and from -8.113 to 0.470 for ML]. Among the 24 individual drugs, the ridge model of panobinostat exhibited the best performance (R2 0.470 and RMSE 0.623). Thus, we selected the ridge model of panobinostat for further application of explainable artificial intelligence (XAI). Using XAI, we further identified important genomic features for panobinostat response prediction in the ridge model, suggesting the genomic features of 22 genes. Based on our findings, results for an individual drug employing both DL and ML models were comparable. Our study confirms the applicability of drug response prediction models for individual drugs.

PMID:37488424 | DOI:10.1038/s41598-023-39179-2

NPJ Biofilms Microbiomes. 2023 Jul 24;9(1):51. doi: 10.1038/s41522-023-00419-y.

ABSTRACT

Vitamin B12 (VB12) deficiency, which may lead to hematologic and neurologic symptoms, has been associated with metformin use, but the underlying mechanism is unclear. Here we report the B. ovatus as an effective VB12 catcher which was enriched in the type 2 diabetes patients suffered from VB12 deficiency after 3 to 6 months of metformin treatment. Colonization of B. ovatus increased the plasma levels of methylmalonic acid and homocysteine in high-fat diet (HFD)-fed mice treated with metformin, and compromised the efficacy of metformin against the HFD-induced metabolic disorders. Mechanistically, metformin increased the intracellular accumulation of VB12 in B. ovatus via btuB upregulation and promoted ATP production for energy-dependent translocation of VB12 transporters at the inner membrane, leading to an enhanced colonization of B. ovatus to compete for VB12 with hosts and subsequently an aggravated VB12 deficiency in the host. Our findings illustrate a previously unappreciated mechanism of metformin leads to host VB12 deficiency by acting directly on gut bacteria to increase their VB12 uptake and consumption, and suggest that inter-host-microbe competition for nutrients may broadly impact human health and drug safety.

PMID:37488134 | DOI:10.1038/s41522-023-00419-y

Schizophr Res. 2023 Jul 22:S0920-9964(23)00228-1. doi: 10.1016/j.schres.2023.07.002. Online ahead of print.

ABSTRACT

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable.

METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study.

RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11).

CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

PMID:37487869 | DOI:10.1016/j.schres.2023.07.002

J Geriatr Oncol. 2023 Jul 22:101595. doi: 10.1016/j.jgo.2023.101595. Online ahead of print.

NO ABSTRACT

PMID:37487857 | DOI:10.1016/j.jgo.2023.101595

Clin Lung Cancer. 2023 Jul 19:S1525-7304(23)00142-0. doi: 10.1016/j.cllc.2023.07.003. Online ahead of print.

NO ABSTRACT

PMID:37487787 | DOI:10.1016/j.cllc.2023.07.003

Front Med (Lausanne). 2023 Jul 6;10:1198088. doi: 10.3389/fmed.2023.1198088. eCollection 2023.

ABSTRACT

Randomized controlled trials are considered the 'gold standard' to reduce bias by randomizing patients to an experimental intervention, versus placebo or standard of care cohort. There are inherent challenges to enrolling a standard of care or cohorts: costs, site engagement logistics, socioeconomic variability, patient willingness, ethics of placebo interventions, cannibalizing the treatment arm population, and extending study duration. The COVID-19 pandemic has magnified aspects of constraints in trial recruitment and logistics, spurring innovative approaches to reducing trial sizes, accelerating trial accrual while preserving statistical rigor. Using data from medical records and databases allows for construction of external control arms that reduce the costs of an external control arm (ECA) randomized to standard of care. Simultaneously examining covariates of the clinical outcomes in ECAs that are being measured in the interventional arm can be particularly useful in phase 2 trials to better understand social and genetic determinants of clinical outcomes that might inform pivotal trial design. The FDA and EMA have promulgated a number of publicly available guidance documents and qualification reports that inform the use of this regulatory science tool to streamline clinical development, of phase 4 surveillance, and policy aspects of clinical outcomes research. Availability and quality of real-world data (RWD) are a prevalent impediment to the use of ECAs given such data is not collected with the rigor and deliberateness that characterizes prospective interventional control arm data. Conversely, in the case of contemporary control arms, a clinical trial outcome can be compared to a contemporary standard of care in cases where the standard of care is evolving at a fast pace, such as the use of checkpoint inhibitors in cancer care. Innovative statistical methods are an essential aspect of an ECA strategy and regulatory paths for these innovative approaches have been navigated, qualified, and in some cases published.

PMID:37484840 | PMC:PMC10359981 | DOI:10.3389/fmed.2023.1198088

Heliyon. 2023 Jul 4;9(7):e17712. doi: 10.1016/j.heliyon.2023.e17712. eCollection 2023 Jul.

ABSTRACT

BACKGROUND: Cervical cancer (CC) is the second most common type of female malignancy in Bangladesh. Polymorphisms in the CYP1A1 gene have been reported to be associated with CC in different populations. This case-control study with meta-analysis was undertaken to assess the relation of CYP1A1 rs4646903 and rs1048943 polymorphisms with the susceptibility of CC.

METHODS: A total of 185 CC patients and 220 controls were recruited, and the PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism) technique was applied for genotyping. Again, 42 eligible studies (24 with rs4646903 and 18 with rs1048943) were included for meta-analysis, and RevMan 5.3 and the MetaGenyo web-based tool were used.

RESULTS: The rs4646903 polymorphism was significantly linked with CC in all association models, namely, additive 1, additive 2, dominant, recessive, overdominant, and allele models (OR = 2.41, 4.75, 2.67, 3.61, 2.13, and 2.44 with corresponding 95% CI = 1.55-3.76, 1.81-12.45, 1.75-4.07, 1.39-9.35, 1.38-3.30, and 1.71-3.48, respectively). On the contrary, rs1048943 showed no association (p > 0.05) with CC. Haplotype analysis revealed AT and AC haplotypes significantly decreased (OR = 0.45) and increased (OR = 4.86) CC risk, respectively, and SNPs are in strong linkage disequilibrium (D' = 0.912, r2 = 0.448). Again, rs4646903 carriers with a contraception history and >5 years of taking contraceptives showed an enhanced risk of CC (OR = 2.39, OR = 3.05). Besides, rs1048943 carriers aged >40 years (OR = 0.44), conceived first child aged ≤18 years (OR = 3.45), and history of contraceptives (OR = 2.18) were significantly linked with CC. Our meta-analysis found that for CYP1A1 rs4646903 codominant 1 (COD 1), codominant 2 (COD 2), codominant 3 (COD 3), dominant model (DM), recessive model (RM), and allele model (AM) in Caucasians and overdominant model (OD) in the overall population are associated with an elevated risk of CC, whereas rs1048943 is also associated with CC in overall, Caucasians and Asians in some genetic models.

CONCLUSION: Our case-control study and meta-analysis summarize that CYP1A1 rs4646903 and rs1048943 polymorphisms may be correlated with cervical cancer.

PMID:37483787 | PMC:PMC10359826 | DOI:10.1016/j.heliyon.2023.e17712

Clin Microbiol Infect. 2023 Jul 21:S1198-743X(23)00339-7. doi: 10.1016/j.cmi.2023.07.013. Online ahead of print.

ABSTRACT

BACKGROUND: Tuberculosis is a global health challenge and one of the leading causes of death worldwide. In the last decade, the tuberculosis treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, SHINE) and drug-resistant tuberculosis (STREAM, NiX-TB, ZeNix, TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs have also brought hopes of further development of safe and effective regimens. Consequently, international and World Health Organization clinical guidelines have been updated multiple times in the last years to keep pace with these advances.

OBJECTIVES: This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant tuberculosis, as well as recent trials results and an overview of ongoing clinical trials.

SOURCES: A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of tuberculosis. Ongoing clinical trials were listed according to the authors' knowledge, and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials).

CONTENT: This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetic and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research.

IMPLICATIONS: Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centered access to new treatment options for all people affected by tuberculosis.

PMID:37482332 | DOI:10.1016/j.cmi.2023.07.013

Eur J Med Chem. 2023 Jul 20;259:115666. doi: 10.1016/j.ejmech.2023.115666. Online ahead of print.

ABSTRACT

ATP-binding cassette subfamily G member 2 (ABCG2), an efflux transporter, is involved in multiple pathological processes. Ko143 is a potent ABCG2 inhibitor; however, it is quickly metabolized through carboxylesterase 1-mediated hydrolysis of its t-butyl ester moiety. The current work aimed to develop more metabolically stable ABCG2 inhibitors. Novel Ko143 analogs were designed and synthesized by replacing the unstable t-butyl ester moiety in Ko143 with an amide group. The synthesized Ko143 analogs were evaluated for their ABCG2 inhibitory activity, binding mode with ABCG2, cytotoxicity, and metabolic stability. We found that the amide modification of Ko143 led to metabolically stable ABCG2 inhibitors. Among these Ko143 analogs, K2 and K34 are promising candidates with favorable oral pharmacokinetic profiles in mice. In summary, we synthesized novel Ko143 analogs with improved metabolic stability, which can potentially be used as lead compounds for the future development of ABCG2 inhibitors.

PMID:37482017 | DOI:10.1016/j.ejmech.2023.115666

Eur J Med Res. 2023 Jul 22;28(1):248. doi: 10.1186/s40001-023-01221-4.

ABSTRACT

OBJECTIVE: The latest research proposed a novel copper-dependent programmed cell death named cuproptosis. We aimed to elucidate the influence of cuproptosis in clear cell renal cell carcinoma (ccRCC) from a multi-omic perspective.

METHODS: This study systematically assessed mRNA expression, methylation, and genetic alterations of cuproptosis genes in TCGA ccRCC samples. Through unsupervised clustering analysis, the samples were classified as different cuproptosis subtypes, which were verified through NTP method in the E-MTAB-1980 dataset. Next, the cuproptosis score (Cuscore) was computed based on cuproptosis-related genes via PCA. We also evaluated clinical and immunogenomic features, drug sensitivity, immunotherapeutic response, and post-transcriptional regulation.

RESULTS: Cuproptosis genes presented multi-layer alterations in ccRCC, and were linked with patients' survival and immune microenvironment. We defined three cuproptosis subtypes [C1 (moderate cuproptosis), C2 (low cuproptosis), and C3 (high cuproptosis)], and the robustness and reproducibility of this classification was further proven. Overall survival was best in C3, moderate in C1, and worst in C2. C1 had the highest sensitivity to pazopanib, and sorafenib, while C2 was most sensitive to sunitinib. Furthermore, C1 patients benefited more from anti-PD-1 immunotherapy. Patients with high Cuscore presented the notable survival advantage. Cuscore was highly linked with immunogenomic features, and post-transcriptional events that contributed to ccRCC development. Finally, several potential compounds and druggable targets (NMU, RARRES1) were selected for low Cuscore group.

CONCLUSION: Overall, our study revealed the non-negligible role of cuproptosis in ccRCC development. Evaluation of the cuproptosis subtypes improves our cognition of immunogenomic features and better guides personalized prognostication and precision therapy.

PMID:37481601 | DOI:10.1186/s40001-023-01221-4

J Mol Diagn. 2023 Jul 20:S1525-1578(23)00154-X. doi: 10.1016/j.jmoldx.2023.07.001. Online ahead of print.

NO ABSTRACT

PMID:37481236 | DOI:10.1016/j.jmoldx.2023.07.001

Acta Neurol Belg. 2023 Jul 22. doi: 10.1007/s13760-023-02340-9. Online ahead of print.

NO ABSTRACT

PMID:37480479 | DOI:10.1007/s13760-023-02340-9

Clin Exp Med. 2023 Jul 22. doi: 10.1007/s10238-023-01142-w. Online ahead of print.

ABSTRACT

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and multifactorial etiologies ranging from environmental to genetic. SLE is associated with dysregulated immunological reactions, with increased immune complex formation leading to end-organ damages such as lupus nephritis, cutaneous lupus, and musculoskeletal disorders. Lupus treatment aims to reduce disease activity, prevent organ damage, and improve long-term patient survival and quality of life. Antimalarial, hydroxychloroquine (HCQ) is used as a first-line systemic treatment for lupus. It has shown profound efficacy in lupus and its associated conditions. However, wide variation in terms of clinical response to this drug has been observed among this group of patients. This variability has limited the potential of HCQ to achieve absolute clinical benefits. Several factors, including genetic polymorphisms of cytochrome P450 enzymes, have been stipulated as key entities leading to this inter-individual variation. Thus, there is a need for more studies to understand the role of genetic polymorphisms in CYP450 enzymes in the clinical response to HCQ. Focusing on the role of genetic polymorphism on whole blood HCQ in lupus disorder, this review aims to highlight up-to-date pathophysiology of SLE, the mechanism of action of HCQ, and finally the role of genetic polymorphism of CYP450 enzymes on whole blood HCQ level as well as clinical response in lupus.

PMID:37480404 | DOI:10.1007/s10238-023-01142-w

Nat Commun. 2023 Jul 21;14(1):4418. doi: 10.1038/s41467-023-39996-z.

ABSTRACT

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

PMID:37479706 | DOI:10.1038/s41467-023-39996-z

Talanta. 2023 Jul 11;266(Pt 1):124936. doi: 10.1016/j.talanta.2023.124936. Online ahead of print.

ABSTRACT

DNA is an indispensable part of metabolism, which affects many important processes in the body, including gene expression, protein synthesis, and drug delivery. Surface-enhanced Raman spectroscopy (SERS) is one of the most important methods used to study the structure and function of DNA and can obtain rich DNA molecular fingerprints. However, it is still a great challenge to use SERS to directly analyze the characteristic Raman signals of the DNA molecule and achieve rapid and simple detection. Hence, a detection platform based on gold bipyramidal nanoparticles (AuNBs) self-assembly that can be directly used for the detection of DNA molecules without the need for additional aggregators and cleaning agents was designed in this study. The original hexadecyltrimethylammonium bromide (CTAB) of AuNBs can be used as the internal standard for DNA quantification without an additional standard. This is the first time that the Raman signals of the analyte molecule can be obtained directly without labels by using the interaction between the molecule and the enhanced substrate. We used this method to capture the original DNA molecules in methylated DNA, serum, and cell metabolites and obtained spectral data processing results using linear discriminant analysis (LDA). This provides new ideas for the digitization of disease treatment and the study of the metabolic processes of life.

PMID:37478765 | DOI:10.1016/j.talanta.2023.124936

Am J Health Syst Pharm. 2023 Jul 21:zxad159. doi: 10.1093/ajhp/zxad159. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: To develop a pharmacist-driven, exploratory pharmacogenomics implementation model with the goal of creating a process for pharmacists to interpret pharmacogenomics results from RIGHT 10K Study samples and provide electronic consults to providers.

SUMMARY: A train-the-trainer model program was initiated whereby pharmacogenomics pharmacists developed a documentation template and a quick reference guide as a standard guide to train other pharmacists. Pharmacists completed electronic consults (e-consults) reviewing pharmacogenomics results, with reference to drug-gene interactions, for patients with "semi-urgent" and "clinically actionable" results, defined as those indicating a potential for gene-drug interactions to cause major harm and those indicating a potential for an adverse drug reaction or reduced efficacy, respectively. Outcomes measured included the number of consults over time, number and role of pharmacists involved, average time to complete e-consults over time, and gene-drug pairs for semi-urgent consults per month. A total of 395 pharmacists were trained. The total number of e-consults completed was 2,843: 61 semi-urgent and 2,782 clinically actionable consults. The average time spent per consult was 24 minutes, and the average number of e-consults per pharmacist was 7. CYP2C19-clopidogrel was the most common gene-drug pair targeted in semi-urgent consults.

CONCLUSION: Pharmacy leaders planning to implement similar pharmacogenomics programs can utilize this data to estimate hiring needs for future pharmacogenomics implementation, while also considering the potential additional cost of developing resources.

PMID:37478473 | DOI:10.1093/ajhp/zxad159

CourseSource. 2023;10. doi: 10.24918/cs.2023.10.

ABSTRACT

Cytochrome P450 (CYP) enzymes are important regulators of drug efficacy and toxicity. Genetic variation in CYP isoforms can impact how well patients respond to medications or experience unwanted toxicities. PharmGKB is an online pharmacogenomics resource that collates the latest data and clinical guidelines on genetic variation and drug responses. The purpose of this lesson was to develop an interactive, case-based activity that demonstrated how pharmacogenetics can be used to influence the prescribing of medications. This lesson was provided to 71 students during a two-hour online interactive session. The lesson consisted of 1) a didactic lecture on pharmacogenetic principles, 2) an overview of the PharmGKB website by the instructor, and 3) patient cases that used the PharmGKB website to answer questions and make recommendations about drug therapy. Patient cases explored the impact of genetic variation in CYP enzymes on patients prescribed medications for different diseases including depression (citalopram, CYP2C19), pain (codeine, CYP2D6), organ transplantation (tacrolimus, CYP3A5), and viral infection (efavirenz, CYP2B6). Four additional cases are included in this lesson. Students reviewed the patient cases in small groups, used PharmGKB to answer questions and design treatment plans, and presented their recommendations to instructors and other students. Based on pre-/post-lesson assessment questions and student feedback, we conclude that an interactive, group-based activity can be used to teach basic principles of pharmacogenetics and connect students to online resources for drug dosing.

PMID:37476533 | PMC:PMC10357923 | DOI:10.24918/cs.2023.10

Front Endocrinol (Lausanne). 2023 Jul 4;14:1184024. doi: 10.3389/fendo.2023.1184024. eCollection 2023.

ABSTRACT

Gender dysphoria is the imparity between a person's experienced gender and their birth-assigned gender. Gender transition is the process of adapting a person's sexual characteristics to match their experienced gender. The number of adults receiving sex hormone therapy for gender dysphoria is increasingly and these pharmacotherapies are increasing being prescribed in a general practice setting. The role of hormone therapy is to reverse or reduce physical sexual characteristics of the birth-assigned gender and enhance and build characteristics aligning to the expressed gender and these therapies apply to both transgender and gender nonconforming patients. Recognizing the options and interpreting the effects of gender transition therapies are fundamental to the discussion and treatment of gender dysphoria. This review summarizes pharmacodynamics, comparative dosing, adverse effects, monitoring, and potential pharmacogenetic influence of current pharmacotherapy. These include the use of 17-beta-estradiol, spironolactone, testosterone, GnRH agonists as well as adjunctive phosphodiesterase-5 inhibitors. The article also addresses gaps within the published literature including optimal routes of administration for individual patients, risks of malignancy and dosing reductions as transgender patients age.

PMID:37476490 | PMC:PMC10355117 | DOI:10.3389/fendo.2023.1184024