Papers by Flavia Franconi
Italian journal of anatomy and embryology, 2016
Endothelial dysfunction has been defined as an “integrated risk factor”, and several gender diffe... more Endothelial dysfunction has been defined as an “integrated risk factor”, and several gender difference have been reported in endothelial function. Several evidences suggest that endothelial progenitor cells (EPCs) are an important endogenous system that maintains integrity and vascular homeostasis. Their function is regulated by estrogens and estrogen receptors (ERs), but the effect of estrogenic compounds such as bisphenol A (BPA) and (R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (THC) on human EPCs is unknown. BPA is used in plastic industry and BPA exposure is associated to abnormalities such as obesity, diabetes, disorders of the reproductive and immune systems, to endothelial dysfunction, and oxidative stress. This endocrine disruptor binds to ERα and ERβ with higher affinity for ERβ. THC is a specific agonist of ERα with a stronger ERβ antagonist activity. Therefore, the present work aimed to analyze if BPA and THC influence in a sex-specific manner the migration of...
The Biochemist, 2017
It is important to remember that gender health and illness should not to be conflated with women&... more It is important to remember that gender health and illness should not to be conflated with women's health and illness. Turshen1 reports that numerous studies with ‘gender’ in the title use the word gender as a synonym for ‘women’ and as a result, men's gender-specific needs are missed. In addition, in reporting demographic characteristics of the study participants, some clinical trialists use the term ‘gender’ and some ‘sex’ to indicate men and women and this may create confusion. It can be difficult to separate the two concepts, because there are continuous and constant interactions and relationships between sex and gender3. In other words, sex and gender work together. However, little attention is paid to the fact that gender is a sex modifier. It is relevant to have in mind that both sex and gender affect health and illness4.
Current pharmaceutical design, Jan 30, 2017
Among individuals with Type 2 diabetes (T2DM), cardiovascular disease (CVD) is the leading cause ... more Among individuals with Type 2 diabetes (T2DM), cardiovascular disease (CVD) is the leading cause of morbidity and mortality. Sex and gender differences (SGDs) in the cardiovascular consequences of T2DM are relevant suggesting the need for a more aggressive CVD preventive strategy in diabetic women as they lose the so-called "female advantage" in terms of CVD risk comparing with the nondiabetic population. Multiple factors may explain the disproportion in CVD risk among women with diabetes comparing with diabetic men or non-diabetic women. Both genetic and hormonal factors only partially explain SGDs in CVD risk in diabetes. However, women likely reach diagnosis later and in worse conditions, they undergo both diagnostic and therapeutic supports in lower percentage and, finally, they are not able to obtain therapeutic goals recommended by guidelines. Concerning the cardiovascular system, diabetes amplifies the extent of damage at both micro- and macrovascular level differen...
Italian journal of anatomy and embryology, 2013
Italian journal of anatomy and embryology, 2014
International Journal of Medical Sciences, 2016
Background: Gender medicine requires a global analysis of an individual's life. Menopause and age... more Background: Gender medicine requires a global analysis of an individual's life. Menopause and ageing induce variations of some cardiometabolic parameters, but, it is unknown if this occurs in a sex-specific manner. Here, some markers of oxidative stress, systemic inflammation, and endothelial dysfunction are analysed in men younger and older than 45 years and in pre-and postmenopausal women. Methods: Serum and plasma sample were assayed for TNF-α and IL-6, malondialdehyde and protein carbonyls and for methylated arginines using ELISA kits, colorimetric methods and capillary electrophoresis. Results: Before body weight correction, men overall had higher creatinine, red blood cells and haemoglobin and lower triglycerides than women. Men younger than 45 years had lower levels of TNF-α and malondialdehyde and higher levels of arginine than age-matched women, while postmenopausal women had higher IL-6 concentrations than men, and higher total cholesterol, triglycerides, creatinine and IL-6 levels than younger women. Men younger than 45 years had lower total cholesterol and malondialdehyde than older men. After correction, some differences remained, others were amplified, others disappeared and some new differences emerged. Moreover, some parameters showed a correlation with age, and some of them correlated with each other as functions of ageing and ageing/menopausal status. Conclusions: Ageing/menopausal status increased many more cardiovascular risk factors in women than ageing in men, confirming that postmenopausal women had increased vascular vulnerability and indicating the need of early cardiovascular prevention in women. Sex-gender differences are also influenced by body weight, indicating as a matter of debate whether body weight should be seen as a true confounder or as part of the causal pathway.
Biology of Sex Differences, 2014
Background: Human umbilical endothelial cells (HUVECs) are widely used to study the endothelial p... more Background: Human umbilical endothelial cells (HUVECs) are widely used to study the endothelial physiology and pathology that might be involved in sex and gender differences detected at the cardiovascular level. This study evaluated whether HUVECs are sexually dimorphic in their morphological, proliferative and migratory properties and in the gene and protein expression of oestrogen and androgen receptors and nitric oxide synthase 3 (NOS3). Moreover, because autophagy is influenced by sex, its degree was analysed in male and female HUVECs (MHUVECs and FHUVECs). Methods: Umbilical cords from healthy, normal weight male and female neonates born to healthy non-obese and non-smoking women were studied. HUVEC morphology was analysed by electron microscopy, and their function was investigated by proliferation, viability, wound healing and chemotaxis assays. Gene and protein expression for oestrogen and androgen receptors and for NOS3 were evaluated by real-time PCR and Western blotting, respectively, and the expression of the primary molecules involved in autophagy regulation [protein kinase B (Akt), mammalian target of rapamycin (mTOR), beclin-1 and microtubule-associated protein 1 light chain 3 (LC3)] were detected by Western blotting. Results: Cell proliferation, migration NOS3 mRNA and protein expression were significantly higher in FHUVECs than in MHUVECs. Conversely, beclin-1 and the LC3-II/LC3-I ratio were higher in MHUVECs than in FHUVECs, indicating that male cells are more autophagic than female cells. The expression of oestrogen and androgen receptor genes and proteins, the protein expression of Akt and mTOR and cellular size and shape were not influenced by sex. Body weights of male and female neonates were not significantly different, but the weight of male babies positively correlated with the weight of the mother, suggesting that the mother's weight may exert a different influence on male and female babies. Conclusions: The results indicate that sex differences exist in prenatal life and are parameter-specific, suggesting that HUVECs of both sexes should be used as an in vitro model to increase the quality and the translational value of research. The sex differences observed in HUVECs could be relevant in explaining the diseases of adulthood because endothelial dysfunction has a crucial role in the pathogenesis of cardiovascular diseases, diabetes mellitus, neurodegeneration and immune disease.
Neurological Sciences, 2014
Migraine is three times as common in females as in males, and attacks may be more severe and diff... more Migraine is three times as common in females as in males, and attacks may be more severe and difficult to treat in women. However, no study specifically addressed possible gender differences in response to antimigraine therapy. The objective of this study was to review the efficacy of frovatriptan vs. other triptans, in the acute treatment of migraine in subgroups of subjects classified according to gender (men vs. women) through a pooled analysis of three individual randomized Italian studies. 414 patients suffering from migraine with or without aura were randomized to frovatriptan 2.5 mg or rizatriptan 10 mg (study 1), frovatriptan 2.5 mg or zolmitriptan 2.5 mg (study 2), frovatriptan 2.5 mg or almotriptan 12.5 mg (study 3). All studies had a multicenter, randomized, double-blind, crossover design. After treating 1-3 episodes of migraine in no more than 3 months with the first treatment, patients switched to the other treatment for the next 3 months. In this analysis, traditional migraine endpoints were compared between the 66 men and 280 women of the intent-to-treat population. At baseline, long-term and debilitating migraine attacks were more frequently reported by women than men. During the observation period, the proportion of pain-free attacks at 2 h did not significantly differ between frovatriptan and the comparators in either men (32 vs. 38 %, p = NS) or women (30 vs. 33 %, p = NS). Pain relief was also similar between treatments for both genders (men: 56 % frovatriptan vs. 57 % comparators; women: 55 vs. 57 %; p = NS for both). The rate of relapse was significantly lower with frovatriptan than with the comparators in men (24 h: 10 vs. 30 %; 48 h: 21 vs. 39 %; p \ 0.05) as well as in women (24 h: 14 vs. 23 %; 48 h: 28 vs. 40 %; p \ 0.05). The rate of adverse drug reactions was significantly larger with comparators, irrespectively of gender. Although migraine presents in a more severe form in women, frovatriptan seems to retain its good efficacy and favorable sustained antimigraine effect regardless of the gender.
PloS one, 2014
the SMILE studies proved the prognostic benefit of zofenopril vs. placebo or other ACE-inhibitors... more the SMILE studies proved the prognostic benefit of zofenopril vs. placebo or other ACE-inhibitors (ACEIs) in post-acute myocardial infarction (AMI). In this retrospective pooled analysis of these studies we assessed whether the zofenopril effect is influenced by gender. the four double-blind, randomized, parallel-group SMILE studies, compared the efficacy and safety of 6-48 week treatment with zofenopril 60 mg/day with that of placebo, lisinopril 10 mg/day or ramipril 10 mg/day in 3630 AMI patients. This pooled analysis compared treatment efficacy (1-year combined occurrence of death or hospitalization for CV causes) in 2733 men and 897 women. women were older than men, had a higher prevalence of diabetes and of other major CV risk factors. The risk of a major CV event was significantly larger for women (23% vs. 17% men, p<0.001). Between-gender risk difference was more marked for people living in Southern (+54%) than in Northern Europe (+12%). In both genders zofenopril similarl...
British Journal of Pharmacology, 2014
Pharmacological response depends on multiple factors and one of them is sex-gender. Data on the s... more Pharmacological response depends on multiple factors and one of them is sex-gender. Data on the specific effects of sex-gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex-gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex-gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex-gender-based approach with the aim of tailoring therapies to an individual's needs and concerns.
Clinical Dermatology, 2014
PSYCHAE was a multicenter observational study conducted in 2004-2005, which included 1580 psoriat... more PSYCHAE was a multicenter observational study conducted in 2004-2005, which included 1580 psoriatic patients. We performed a post-hoc analysis to explore gender differences and the gender-specific therapeutic approaches adopted by Italian dermatologists. Type, severity and duration of psoriasis, presence of psoriatic arthritis, General Health Questionnaire score, Brief COPE questionnaire, Brief Symptom Inventory indexes and prescribed therapies were compared between genders. 786 patients were evaluable for the analysis, 477 (61%) males. Highly significant differences were found in frequency of alcohol consumption and of smokers, which were higher in men, and in GHQ-12 and all BSI scores, which were all significantly worse in women at baseline. Other significant differences were familiarity for psoriasis or arthritis (higher in women), and severity of psoriasis (higher in men). Topical pharmacological therapy was the most prescribed treatment in both genders and no significant differences were observed in prescribed therapies, except for phototherapy (37% of males vs 29% of females; p=0.0121). With the major limitation of referring to a cohort studied in 2004-2005, when biologicals were not used yet for psoriasis, this analysis shows that, at that time, Italian dermatologists seemed to have the same approach in treating male and female patients with psoriasis, although females should have deserved more attention to their higher psychological distress.
The Scientific World Journal, 2015
Background. The early detection of wearing-off in Parkinson disease (DEEP) observational study de... more Background. The early detection of wearing-off in Parkinson disease (DEEP) observational study demonstrated that women with Parkinson’s disease (PD) carry an increased risk (80.1%) for wearing-off (WO). This post hoc analysis of DEEP study evaluates gender differences on WO and associated phenomena.Methods. Patients on dopaminergic treatment for ≥1 year were included in this multicenter observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as the use of the 19-item wearing-off questionnaire (WOQ-19); WO was defined for scores ≥2. Post hoc analyses were conducted to investigate gender difference for demographic and clinical features with respect to WO.Results. Of 617 patients enrolled, 236 were women and 381 were men. Prevalence of WO was higher among women, according to both neurologists’ judgment (61.9% versus 53.8%,P=0.045) and the WOQ-19 analysis (72.5% versus 64.0%,P=0.034). In patients with WO (WOQ-19), women experience...
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, 2007
Abstract: This review summarizes the important issue of gender difference in drug response as reg... more Abstract: This review summarizes the important issue of gender difference in drug response as regards the therapeutic aspect of drugs utilized for diabetes mellitus and related disorders. Although, gender differences have been individuated both in experimental and ...
Journal of Clinical Medicine
The aim of this study was to evaluate the risk of death after hospitalizations for diabetic foot ... more The aim of this study was to evaluate the risk of death after hospitalizations for diabetic foot (DF) complications, comparing two different cohorts of people with or without a prior history of DF hospitalizations across the years 2011 to 2018 in Tuscany, Italy. The DF complications were categorized by administrative source datasets such as: amputations (both major and minor), gangrene, ulcers, infections, Charcot and revascularizations. A further aim was to present the trend over time of the first ever incidents of diabetic foot hospitalizations in Tuscany. The eight-year-mortality rate was higher in the cohort with prior hospitalizations (n = 6633; 59%) compared with the cohort with first incident DF hospitalizations (n = 5028; 44%). Amputations (especially major ones) and ulcers had the worst effect on survival in people without basal history of DF hospitalizations and respectively in those with a history of prior DF hospitalizations. In both cohorts, revascularization procedures...
Biomolecules, 2021
Individual response to drugs is highly variable and largely influenced by genetic variants and ge... more Individual response to drugs is highly variable and largely influenced by genetic variants and gene-expression profiles. In addition, it has been shown that response to drugs is strongly sex-dependent, both in terms of efficacy and toxicity. To expand current knowledge on sex differences in the expression of genes relevant for drug response, we generated a catalogue of differentially expressed human transcripts encoded by 289 genes in 41 human tissues from 838 adult individuals of the Genotype-Tissue Expression project (GTEx, v8 release) and focused our analysis on relevant transcripts implicated in drug response. We detected significant sex-differentiated expression of 99 transcripts encoded by 59 genes in the tissues most relevant for human pharmacology (liver, lung, kidney, small intestine terminal ileum, skin not sun-exposed, and whole blood). Among them, as expected, we confirmed significant differences in the expression of transcripts encoded by the cytochromes in the liver, C...
Journal of Clinical Medicine, 2021
There is an urgent need to optimize pharmacology therapy with a consideration of high interindivi... more There is an urgent need to optimize pharmacology therapy with a consideration of high interindividual variability and economic costs. A sex–gender approach (which considers men, women, and people of diverse gender identities) and the assessment of differences in sex and gender promote global health, avoiding systematic errors that generate results with low validity. Care for people should consider the single individual and his or her past and present life experiences, as well as his or her relationship with care providers. Therefore, intersectoral and interdisciplinary studies are urgently required. It is desirable to create teams made up of men and women to meet the needs of both. Finally, it is also necessary to build an alliance among regulatory and ethic authorities, statistics, informatics, the healthcare system and providers, researchers, the pharmaceutical and diagnostic industries, decision makers, and patients to overcome the gender gap in medicine and to take real care of ...
Life, 2021
Biological differences between sexes should be considered in all stages of research, as sexual di... more Biological differences between sexes should be considered in all stages of research, as sexual dimorphism starts in utero leading to sex-specific fetal programming. In numerous biomedical fields, there is still a lack of stratification by sex despite primary cultured cells retaining memory of the sex and of the donor. The sex of donors in biological research must be known because variations in cells and cellular components can be used as endpoints, biomarkers and/or targets of pharmacological studies. This selective review focuses on the current findings regarding sex differences observed in the umbilical cord, a widely used source of research samples, both in the blood and in the circulating cells, as well as in the different cellular models obtainable from it. Moreover, an overview on sex differences in fetal programming is reported. As it emerges that the sex variable is still often forgotten in experimental models, we suggest that it should be mandatory to adopt sex-oriented res...
Metabolites, 2021
Prematurity is the leading cause of neonatal deaths and high economic costs; it depends on numero... more Prematurity is the leading cause of neonatal deaths and high economic costs; it depends on numerous biological and social factors, and is highly prevalent in males. Several factors can affect the metabolome of premature infants. Accordingly, the aim of the present study was to analyze the role played by gestational age (GA), parenteral nutrition (PN), and caffeine treatment in sex-related differences of blood metabolome of premature neonates through a MS/MS-based targeted metabolomic approach for the detection of amino acids and acylcarnitines in dried blood spots. GA affected the blood metabolome of premature neonates: male and female very premature infants (VPI) diverged in amino acids but not in acylcarnitines, whereas the opposite was observed in moderate or late preterm infants (MLPI). Moreover, an important reduction of metabolites was observed in female VPI fed with PN, suggesting that PN might not satisfy an infant’s nutritional needs. Caffeine showed the highest significant...
Pharmacoepidemiology and drug safety, Jan 28, 2018
To investigate whether the hospitalization rate for bacterial infections was modified by statin t... more To investigate whether the hospitalization rate for bacterial infections was modified by statin therapy in a population retrospectively followed up, over years 2011 to 2015. By using administrative databases, the 5-year hospitalization rate due to bacterial infections in population living in Tuscany, Italy exposed to statin therapy (n = 52,049) was stratified by 5 prescribed daily doses classes (0%-20%, 20%-50%, 50%-80%, 80%-100%, ≥100% of DDD) and subsequently compared with that of a population of untreated individuals (n = 3 300 ,675), matched through a propensity score accounting for all available covariates potentially able to modulate risk of infections such as age, gender, previous hospitalizations for infections, cardiovascular events, previous co-morbidities, diabetes, as well as general practitioners' proactive behaviour of care delivery according to current guidelines. Unmatched individuals of each treatment-class had significantly more hospitalizations than controls, ...
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Papers by Flavia Franconi