Biomedicines

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Open AccessEditorial

Gender Medicine and Pharmacology

by Sarah Allegra, Francesco Chiara and Silvia De Francia

Biomedicines 2024, 12(2), 265; https://doi.org/10.3390/biomedicines12020265 - 24 Jan 2024

Cited by 2 | Viewed by 1392

Abstract

Gender-specific medicine consists of a transversal methodological approach that aims to study the influence of sex and gender on diseases [...] Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

Research

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14 pages, 645 KiB

Open AccessArticle

Sex Differences in Oxycodone/Naloxone vs. Tapentadol in Chronic Non-Cancer Pain: An Observational Real-World Study

by Jordi Barrachina, Cesar Margarit, Javier Muriel, Vicente López-Gil, Santiago López-Gil, Pura Ballester, Laura Mira-Lorente, Laura Agulló and Ana M. Peiró

Biomedicines 2022, 10(10), 2468; https://doi.org/10.3390/biomedicines10102468 - 2 Oct 2022

Cited by 6 | Viewed by 3141

Abstract

Despite the large body of research on sex differences in pain, there is a lack of translation to real-world pain management. Our aim was to analyse the sex differences in the analgesic response to oxycodone/naloxone (OXN) and tapentadol (TAP), in comparison with other [...] Read more.

Despite the large body of research on sex differences in pain, there is a lack of translation to real-world pain management. Our aim was to analyse the sex differences in the analgesic response to oxycodone/naloxone (OXN) and tapentadol (TAP), in comparison with other opioids (OPO) commonly prescribed for chronic non-cancer pain (CNCP). An observational and cross-sectional study was conducted on ambulatory CNCP patients (n = 571). Sociodemographic, clinical (pain intensity, relief, and quality of life), safety (adverse events (AEs), adverse drug reactions), hospital frequentations and pharmacological (morphine equivalent daily dose (MEDD)) variables were collected. Multiple linear regressions were carried out to assess the association between sex and outcomes. Sex differences were observed, with lower female tolerability and higher hospital frequentation, especially in the OXN group (OR AEs report = 2.8 [1.8–4.4], p < 0.001). Here, females showed higher hospital use (23% hospital admission, 30% prescription change, p < 0.05), requiring a higher MEDD (127 ± 103 mg/day, p < 0.05), compared to OXN men. Regardless of the opioid group, CNCP women were significantly older than men (three years), with significantly higher benzodiazepine use (OR = 1.6 [1.1–2.3]), more constipation (OR = 1.34 [0.93–1.90]) and headache (OR = 1.45 [0.99–2.13]) AEs, than men who were more likely to refer sexual dysfunction (OR = 2.77 [1.53–5.01]), and loss of libido (OR = 1.93 [1.22–3.04]). Sex-differences were found related to poorer female drug tolerability and higher hospital resources, even worst in OXN female users. Other differences related to older female ages and benzodiazepine prescription, need to be further analysed from a gender perspective. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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11 pages, 859 KiB

Open AccessArticle

Sex-Differences in Pain and Opioid Use Disorder Management: A Cross-Sectional Real-World Study

by Mónica Escorial, Javier Muriel, César Margarit, Laura Agulló, Domingo Morales and Ana M. Peiró Peiró

Biomedicines 2022, 10(9), 2302; https://doi.org/10.3390/biomedicines10092302 - 16 Sep 2022

Cited by 5 | Viewed by 2844

Abstract

(1) Background: It is essential to focus attention on sex-specific factors which are clinically relevant in pain management, especially with regards to opioid use disorder (OUD) risk. The aim of this study was to explore potential sex-differences in chronic non-cancer pain (CNCP) outpatients. [...] Read more.

(1) Background: It is essential to focus attention on sex-specific factors which are clinically relevant in pain management, especially with regards to opioid use disorder (OUD) risk. The aim of this study was to explore potential sex-differences in chronic non-cancer pain (CNCP) outpatients. (2) Methods: An observational cross-sectional study was conducted under CNCP outpatients with long-term prescribed opioids (n = 806), wherein 137 patients had an OUD diagnosis (cases, 64% females) and 669 did not (controls, 66% females). Socio-demographic, clinical, and pharmacological outcomes were analyzed. (3) Results: Female controls presented an older age and less intensive pain therapy but higher psychotropic prescriptions and emergency department visits compared to male controls. Meanwhile, cases demonstrated a younger age, higher work disability, double morphine equivalent daily dose, and benzodiazepine use compared with controls. Here, female cases showed an 8% greater substance use disorder (OR 2.04 [1.11–3.76]) and 24% lower tramadol use, while male cases presented a 22% higher fentanyl use (OR 2.97 [1.52–5.81]) and reported the highest number of adverse drug reactions (24%, OR 2.40 [1.12–5.16]) compared with controls. (4) Conclusions: An OUD individual risk profile was evidenced with sex-differences to take into consideration to design equal prevention programs. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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13 pages, 2258 KiB

Open AccessArticle

Sex-Based Evaluation of Lipid Profile in Postoperative Adjuvant Mitotane Treatment for Adrenocortical Carcinoma

by Sarah Allegra, Soraya Puglisi, Chiara Borin, Francesco Chiara, Vittoria Basile, Anna Calabrese, Giuseppe Reimondo and Silvia De Francia

Biomedicines 2022, 10(8), 1873; https://doi.org/10.3390/biomedicines10081873 - 3 Aug 2022

Viewed by 1765

Abstract

Background: A wide interindividual variability in mitotane concentrations and treatment-related dyslipidemia have been reported. Here, we aimed to underline the sex-related differences in the lipid profile in patients that underwent radical surgery of adrenocortical carcinoma during treatment with adjuvant mitotane. Methods: A chromatographic [...] Read more.

Background: A wide interindividual variability in mitotane concentrations and treatment-related dyslipidemia have been reported. Here, we aimed to underline the sex-related differences in the lipid profile in patients that underwent radical surgery of adrenocortical carcinoma during treatment with adjuvant mitotane. Methods: A chromatographic method was used to quantify the drug in plasma collected from adult patients with complete tumor resection, also considering active metabolite o,p’-DDE. Results: We observed different lipid profiles between males and females and between pre- and post-menopausal women. Considering the mitotane-related effects on lipid levels, we observed that higher drug concentrations were correlated with higher HDL in all the considered groups (p < 0.001), with total cholesterol both in males (p = 0.005) and females (p = 0.036), with triglycerides in postmenopausal females (p = 0.002) and with LDL in male patients (p < 0.001). Increases in o,p’-DDE were positively correlated with HDL levels in all the groups (p < 0.001) and negatively with LDL in all the groups (males p = 0.008, pre- and post-menopausal females p < 0.001), with total cholesterol in pre- (p = 0.016) and post-menopausal women (p = 0.01) and with triglycerides in premenopausal females (p = 0.005). Conclusions: This is the first study designed to evaluate sex differences in lipoprotein and lipid levels during mitotane adjuvant treatment; the results suggest that a gender and personalized approach could be useful to prevent and manage alterations in the lipid profile. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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14 pages, 1670 KiB

Open AccessArticle

Bone Mineral Density Is a Predictor of Mortality in Female Patients with Cholangiocellular Carcinoma Undergoing Palliative Treatment

by Markus S. Jördens, Linda Wittig, Christina Loberg, Lisa Heinrichs, Verena Keitel, Maximilian Schulze-Hagen, Gerald Antoch, Wolfram T. Knoefel, Georg Fluegen, Sven H. Loosen, Christoph Roderburg and Tom Luedde

Biomedicines 2022, 10(7), 1660; https://doi.org/10.3390/biomedicines10071660 - 11 Jul 2022

Cited by 4 | Viewed by 1663

Abstract

Background: Cholangiocellular adenocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts. Its general prognosis is poor as therapeutic options are limited. Many patients present with advanced stages of disease, and palliative chemotherapy remains the only treatment option. Prognostic markers [...] Read more.

Background: Cholangiocellular adenocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts. Its general prognosis is poor as therapeutic options are limited. Many patients present with advanced stages of disease, and palliative chemotherapy remains the only treatment option. Prognostic markers to assess the outcome of chemotherapeutic treatment in CCA are limited. We therefore evaluated bone mineral density (BMD) as a prognostic tool in patients with advanced CCA. Patients and Methods: We included 75 patients with advanced CCA that were treated at our academic tumor center. Prior to treatment, bone mineral density was analyzed at the first lumbar vertebra using routine CT scans in the venous phase and the local PACS (IntelliSpace PACS, Philips, Amsterdam, The Netherlands). Results: BMD was not significantly different between male and female patients but decreased with age. Patients with BMD above 167 HU have a significantly improved overall survival (474 days vs. 254 days; log-rank X²(1) = 6.090; p = 0.014). The prognostic value of BMD was confirmed using univariate (HR 2.313 (95%CI: 1.170–4.575); p = 0.016) and multivariate (HR 4.143 (95%CI: 1.197–14.343); p = 0.025) Cox regression analyses. Subgroup analysis revealed that the prognostic value of BMD was only present in female patients and not in male patients, suggesting sex-specific differences. Conclusions: Our data suggest that BMD is a valuable, easily accessible, and independent prognostic marker for overall survival in patients with advanced CCA. Furthermore, subgroup analysis showed the sex specificity of this marker, which demonstrated relevance only in female patients. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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15 pages, 11065 KiB

Open AccessArticle

Stem Cell Growth and Differentiation in Organ Culture: New Insights for Uterine Fibroid Treatment

by Ana Salas, Silvia Beltrán-Flores, Carmen Évora, Ricardo Reyes, Francisco Montes de Oca, Araceli Delgado and Teresa A. Almeida

Biomedicines 2022, 10(7), 1542; https://doi.org/10.3390/biomedicines10071542 - 29 Jun 2022

Cited by 4 | Viewed by 2644

Abstract

Organ culture allows for the understanding of normal and tumor cell biology, and tissues generally remain viable for 5–7 days. Strikingly, we determined that myometrial and MED12 mutant leiomyoma cells repopulated cell-depleted tissue slices after 20 days of culture. Using immunofluorescence and quantitative [...] Read more.

Organ culture allows for the understanding of normal and tumor cell biology, and tissues generally remain viable for 5–7 days. Strikingly, we determined that myometrial and MED12 mutant leiomyoma cells repopulated cell-depleted tissue slices after 20 days of culture. Using immunofluorescence and quantitative PCR of stem cell and undifferentiated cell markers, we observed clusters of CD49b⁺ cells in tumor slices. CD49b⁺ cells, however, were sparsely detected in the myometrial slices. Almost all LM cells strongly expressed Ki67, while only a few myometrial cells were stained for this proliferation marker. The CD73 marker was expressed only in tumor cells, whereas the mesenchymal stem cell receptor KIT was detected only in normal cells. HMGA2 and CD24 showed broader expression patterns and higher signal intensity in leiomyoma than in myometrial cells. In this study, we propose that activating CD49b⁺ stem cells in myometrium leads to asymmetrical division, giving rise to transit-amplifying KIT⁺ cells that differentiate to smooth muscle cells. On the contrary, activated leiomyoma CD49b⁺ cells symmetrically divide to form clusters of stem cells that divide and differentiate to smooth muscle cells without losing proliferation ability. In conclusion, normal and mutant stem cells can proliferate and differentiate in long-term organ culture, constituting a helpful platform for novel therapeutic discovery. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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13 pages, 1663 KiB

Open AccessArticle

Different Effects of Valproic Acid on SLC12A2, SLC12A5 and SLC5A8 Gene Expression in Pediatric Glioblastoma Cells as an Approach to Personalised Therapy

by Eligija Damanskienė, Ingrida Balnytė, Angelija Valančiūtė, Marta Marija Alonso and Donatas Stakišaitis

Biomedicines 2022, 10(5), 968; https://doi.org/10.3390/biomedicines10050968 - 22 Apr 2022

Cited by 6 | Viewed by 2341

Abstract

Valproic acid (VPA) is a histone deacetylase inhibitor with sex-specific immunomodulatory and anticancer effects. This study aimed to investigate the effect of 0.5 and 0.75 mM VPA on NKCC1 (SLC12A2), KCC2 (SLC12A5) and SLC5A8 (SLC5A8) co-transporter gene [...] Read more.

Valproic acid (VPA) is a histone deacetylase inhibitor with sex-specific immunomodulatory and anticancer effects. This study aimed to investigate the effect of 0.5 and 0.75 mM VPA on NKCC1 (SLC12A2), KCC2 (SLC12A5) and SLC5A8 (SLC5A8) co-transporter gene expressions in pediatric PBT24 (boy’s) and SF8628 (girl’s) glioblastoma cells. The SLC12A2, SLC12A5 and SLC5A8 RNA expressions were determined by the RT-PCR method. The SLC12A2 and SLC5A8 expressions did not differ between the PBT24 and SF8628 controls. The SLC12A5 expression in the PBT24 control was significantly higher than in the SF8628 control. VPA treatment significantly increased the expression of SLC12A2 in PBT24 but did not affect SF8628 cells. VPA increased the SLC12A5 expression in PBT24 and SF8628 cells. The SLC12A5 expression of the PBT24-treated cells was significantly higher than in corresponding SF8628 groups. Both VPA doses increased the SLC5A8 expression in PBT24 and SF8628 cells, but the expression was significantly higher in the PBT24-treated, compared to the respective SF8628 groups. The SLC5A8 expression in PBT24-treated cells was 10-fold higher than in SF8628 cells. The distinct effects of VPA on the expression of SLC12A2, SLC12A5 and SLC5A8 in PBT24 and SF8628 glioblastoma cells suggest differences in tumor cell biology that may be gender-related. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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12 pages, 1045 KiB

Open AccessArticle

Epigenetic Effects of Gender-Affirming Hormone Treatment: A Pilot Study of the ESR2 Promoter’s Methylation in AFAB People

by Francesco Pallotti, Giulia Senofonte, Fani Konstantinidou, Silvia Di Chiano, Fabiana Faja, Flavio Rizzo, Francesco Cargnelutti, Csilla Krausz, Donatella Paoli, Andrea Lenzi, Liborio Stuppia, Valentina Gatta and Francesco Lombardo

Biomedicines 2022, 10(2), 459; https://doi.org/10.3390/biomedicines10020459 - 16 Feb 2022

Cited by 5 | Viewed by 2932

Abstract

Virilization of gender-incongruent subjects to whom were assigned the female gender at birth (AFAB) is achieved through testosterone administration. Inter-individual differences in the timing and acquisition of phenotypic characteristics, even if the same hormone preparations and regimens are used, are frequently observed. Polymorphisms [...] Read more.

Virilization of gender-incongruent subjects to whom were assigned the female gender at birth (AFAB) is achieved through testosterone administration. Inter-individual differences in the timing and acquisition of phenotypic characteristics, even if the same hormone preparations and regimens are used, are frequently observed. Polymorphisms of sex hormone receptors and methylation of their gene promoters, as well of several imprinted genes as H19, may underlie the differential response to treatment. Thus, the aim of this study was to examine the possible relationship between the CpG methylation profile of the estrogen receptor 2 gene (ESR2) and H19 promoters and their influence on phenotype modifications in a cohort of AFAB people at baseline (T0) and after 6 mo (T6) and 12 mo (T12) of testosterone therapy (testosterone enanthate, 250 mg i.m. every 28 d). A total of 13 AFAB subjects (mean age 29.3 ± 12.6) were recruited. The percentage of methylation of the ESR2 promoter significantly increased at T6 (adj. p = 0.001) and T12 (adj. p = 0.05), while no difference was detected for H19 (p = 0.237). Methylation levels were not associated with androgen receptor (AR)/estrogen receptor beta (ERβ) polymorphisms nor hormone levels at baseline and after six months of treatment. On the other hand, total testosterone level and patient age resulted in being significantly associated with ESR2 methylation after twelve months of treatment. Finally, the difference in ESR2 promoter methylation between T6 and baseline was significantly associated with the number of CA repeats of the ERβ receptor, adjusted vs. all considered variables (R² = 0.62, adj. R² = 0.35). No associations were found with CAG repeats of the AR, age, and estradiol and testosterone levels. Despite the small sample size, we can hypothesize that treatment with exogenous testosterone can modify the ESR2 methylation pattern. Our data also indicated that epigenetic changes may be regulated, suggesting that the modulation of estrogen signaling is relevant shortly after the beginning of the treatment up to T6, with no further significant modification at T12. Furthermore, estrogen receptor methylation appears to be associated with the age of the subjects and exogenous testosterone administration, representing a marker of androgenic treatment. Nonetheless, it will be necessary to increase the number of subjects to evaluate how epigenetic regulation might play a relevant role in the modulation of phenotypical changes after testosterone treatment. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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11 pages, 1682 KiB

Open AccessCommunication

Tempol Preserves Endothelial Progenitor Cells in Male Mice with Ambient Fine Particulate Matter Exposure

by Xuanyou Liu, Aimin Wang, Zhiheng Chen, Yuqi Cui, Hong Hao, Timothy L. Domeier, Qinghua Sun and Zhenguo Liu

Biomedicines 2022, 10(2), 327; https://doi.org/10.3390/biomedicines10020327 - 29 Jan 2022

Cited by 7 | Viewed by 3313

Abstract

Ambient fine particulate matter (PM) exposure associates with an increased risk of cardiovascular diseases (CVDs). Major sex differences between males and females exist in epidemiology, pathophysiology, and outcome of CVDs. Endothelial progenitor cells (EPCs) play a vital role in the development and progression [...] Read more.

Ambient fine particulate matter (PM) exposure associates with an increased risk of cardiovascular diseases (CVDs). Major sex differences between males and females exist in epidemiology, pathophysiology, and outcome of CVDs. Endothelial progenitor cells (EPCs) play a vital role in the development and progression of CVDs. PM exposure-induced reduction of EPCs is observed in male, not female, mice with increased reactive oxygen species (ROS) production and oxidative stress. The lung is considered an important source of ROS in mice with PM exposure. The aim of the present study was to investigate the sex differences in pulmonary superoxide dismutase (SOD) expression and ROS production, and to test the effect of SOD mimic Tempol on the populations of EPCs in mice with PM exposure. Both male and female C57BL/6 mice (8–10 weeks) were exposed to intranasal PM or vehicle for 6 weeks. Flow cytometry analysis demonstrated that PM exposure significantly decreased the levels of EPCs (CD34⁺/CD133⁺) in both blood and bone marrow with increased ROS production in males, but not in females. ELISA analysis showed higher levels of serum IL-6 and IL-1βin males than in females. Pulmonary expression of the antioxidant enzyme SOD1 was significantly decreased in males after PM exposure, but not in females. Administration of the SOD mimic Tempol in male mice with PM exposure attenuated the production of ROS and inflammatory cytokines, and preserved EPC levels. These data indicated that PM exposure-induced reduction of EPC population in male mice may be due to decreased expression of pulmonary SOD1 in male mice. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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Review

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14 pages, 290 KiB

Open AccessReview

Fertility Preservation and Reproductive Potential in Transgender and Gender Fluid Population

by Ji Young Choi and Tae Jin Kim

Biomedicines 2022, 10(9), 2279; https://doi.org/10.3390/biomedicines10092279 - 14 Sep 2022

Cited by 11 | Viewed by 2713

Abstract

The gender diverse and transgender community is a minor patient group that is encountered with increasing frequency in the clinical setting, attributed to the improved awareness and access to medical facilities. Partial impairment to permanent elimination of fertility potential and outcomes depending on [...] Read more.

The gender diverse and transgender community is a minor patient group that is encountered with increasing frequency in the clinical setting, attributed to the improved awareness and access to medical facilities. Partial impairment to permanent elimination of fertility potential and outcomes depending on the treatment modality usually is a result of gender-affirming therapy, which includes both hormone therapy and surgical intervention. Although seldom conducted in the clinical field, transgender patients should be counseled on their fertility preservation options prior to medical and surgical gender transition. There is relatively limited data and clinical information regarding fertility preservation for transgender individuals. Current treatment regimens are based on protocols from fertility preservation after oncological treatments. Major barriers for the transgender population exist due to the lack of information provided and clinical narrative that is not familiar to the physician or health care provider, although there are various options for fertility preservation. A deeper understanding of this clinical agenda and the mandatory processes will ultimately result in a much more comprehensive and specific care for transgender individuals who are in great need for fertility counseling or treatment options that concern fertility preservation. In this review, current clinical approaches will be summarized and fertility preservation options along with ongoing and future clinical trials in fertility preservation for transgender individuals will be thoroughly reviewed. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

23 pages, 488 KiB

Open AccessReview

SARS-CoV-2 Infection, Sex-Related Differences, and a Possible Personalized Treatment Approach with Valproic Acid: A Review

by Donatas Stakišaitis, Linas Kapočius, Angelija Valančiūtė, Ingrida Balnytė, Tomas Tamošuitis, Arūnas Vaitkevičius, Kęstutis Sužiedėlis, Daiva Urbonienė, Vacis Tatarūnas, Evelina Kilimaitė, Dovydas Gečys and Vaiva Lesauskaitė

Biomedicines 2022, 10(5), 962; https://doi.org/10.3390/biomedicines10050962 - 21 Apr 2022

Cited by 9 | Viewed by 3104

Abstract

Sex differences identified in the COVID-19 pandemic are necessary to study. It is essential to investigate the efficacy of the drugs in clinical trials for the treatment of COVID-19, and to analyse the sex-related beneficial and adverse effects. The histone deacetylase inhibitor valproic [...] Read more.

Sex differences identified in the COVID-19 pandemic are necessary to study. It is essential to investigate the efficacy of the drugs in clinical trials for the treatment of COVID-19, and to analyse the sex-related beneficial and adverse effects. The histone deacetylase inhibitor valproic acid (VPA) is a potential drug that could be adapted to prevent the progression and complications of SARS-CoV-2 infection. VPA has a history of research in the treatment of various viral infections. This article reviews the preclinical data, showing that the pharmacological impact of VPA may apply to COVID-19 pathogenetic mechanisms. VPA inhibits SARS-CoV-2 virus entry, suppresses the pro-inflammatory immune cell and cytokine response to infection, and reduces inflammatory tissue and organ damage by mechanisms that may appear to be sex-related. The antithrombotic, antiplatelet, anti-inflammatory, immunomodulatory, glucose- and testosterone-lowering in blood serum effects of VPA suggest that the drug could be promising for therapy of COVID-19. Sex-related differences in the efficacy of VPA treatment may be significant in developing a personalised treatment strategy for COVID-19. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

13 pages, 548 KiB

Open AccessReview

Sex, Allergic Diseases and Omalizumab

by Maria Maddalena Sirufo, Francesca De Pietro, Lia Ginaldi and Massimo De Martinis

Biomedicines 2022, 10(2), 328; https://doi.org/10.3390/biomedicines10020328 - 29 Jan 2022

Cited by 3 | Viewed by 3936

Abstract

Gender differences are increasingly emerging in every area of medicine including drug therapy; however, specific gender-targeted studies are infrequent. Sex is a fundamental variable, which cannot be neglected. When optimizing therapies, gender pharmacology must always be considered in order to improve the effectiveness [...] Read more.

Gender differences are increasingly emerging in every area of medicine including drug therapy; however, specific gender-targeted studies are infrequent. Sex is a fundamental variable, which cannot be neglected. When optimizing therapies, gender pharmacology must always be considered in order to improve the effectiveness and safety of the use of drugs. Knowledge of gender differences promotes appropriate use of therapies and greater health protection for both genders. Further development of gender research would make it possible to report on differences in the assimilation and response of the female organism as compared to the male, in order to identify potential risks and benefits that can be found between genders. Furthermore, a better understanding of sex/gender-related influences, with regard to pharmacological activity, would allow the development of personalized “tailor-made” medicines. Here, we summarize the state of knowledge on the role of sex in several allergic diseases and their treatment with omalizumab, the first biologic drug authorized for use in the field of allergology. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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