ReviewGender differences in drug responses
Introduction
Although numerous gender differences (GDs) have been described in humans, so far most clinical research has been carried out considering the male can fulfil the function of the true representative of the human species. This in spite of the increasing evidence pointing out physiological and pathological differences between the sexes, beyond those related to the reproduction [1]. As women differ from men in gene expression and regulation, in the susceptibility to, and risk for many medical conditions and in the response to numerous drugs [1], [2], [3], [4], [5], [6], [7], [8], GDs in drug response may explain, at least in part, the inter-individual variations occurring in therapeutic response and toxicity, especially considering that female sex has been shown to be a risk factor for the development of adverse drug reactions (ADRs) [2].
Given the complexity of gender pharmacology, the scant availability of adequate animal models and human studies, specific GDs are quite difficult to be evidenced [3]. Nonetheless, current results indicate that GDs in pharmacological response are more widespread than believed before and involve pharmacodynamics and pharmacokinetics, being the pharmacokinetic one of the most investigated [2], [3], [4], [6], [7], [8].
The role of pharmacokinetics versus pharmacodynamics is not completely appreciated yet and only a few contributions have evaluated the impact of genetics, hormonal variations and their relative interactions. Indeed, GDs in drug response are not only a matter of differences between genders, but also they necessarily involve critical periods of both sexes. Only a few studies have been dedicated to evaluate how the biological rhythms influence drug responses [9] and even more limited researches have investigated whether and how they influence drug-to-drug, drug-to-herb and drug-to-food interactions and whether this occurs in a gender-dependent manner. Additionally, fertile female population has to be divided in two subpopulations depending on the use of oestrogen–progestin association, because of the huge hormonal influence on endocrine and metabolic pathways [10]. Oral contraception can modify the metabolism and the concentrations of co-administered medications, which, in turn, can affect the hormone activity [11].
The purpose of the present manuscript is to highlight a few specific examples in some areas, in which GDs may be important, considering beyond its aim to provide an extensive and detailed overview of GDs in pharmacokinetics, pharmacodynamics and pharmacogenetics. Moreover, this article gives a quick snapshot view of GDs in drug response as a basis for considering when GDs start, how they influence placebo response and therapy appropriateness.
Section snippets
Have gender pharmacological differences an early onset?
Although GDs in growth and susceptibility to diseases are generally believed to start at puberty, they have been evidenced since foetal and neonatal life [1]. Actually, GDs seem to initiate in uterus. Indeed, Y chromosome is known to accelerate the growth and increase glucose metabolism [12]. At birth, growth curve and heart rate are different in males and females [13], while sexual dimorphism in fat patterning starts at 5–7 years of age [14] and a difference in body composition could influence
Is the placebo effect a gender-related phenomenon?
Since the pioneer work of Beecher [23], it has become evident that whenever a supposedly inert treatment or inert preparation is used, a certain number of patients exhibit some benefit from such “placebo” (from Latin “I shall please”) treatment. Placebo-controlled trials show that the supposedly inert treatment can even produce harmful side effects or frankly toxic effects, the so-called “nocebo” (from Latin “I shall harm”) effect [24]. The question of whether women and men respond differently
Pharmacokinetics
Gender-related variations in pharmacokinetics have been frequently considered as potential relevant determinant for the clinical effectiveness of therapeutic agents.
Differences in the four major determinants of pharmacokinetic variability – bioavailability, distribution, metabolism and elimination – are theorized to stem from variations between the sexes in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, CYP activity, drug transporter function and
Is gender difference a risk factor for ADR?
It has been estimated that ADRs occur approximately in 3–5% of subjects taking a drug [230] but the gender's importance as a risk factor remains a matter of debate. A recent study, which reviewed 10 years (1986–1996) of ADR in a Canadian institution, reported that more than 70% of the 2367 patients assessed were females [2]. Several reports have revealed that women are more exposed to ADRs than men [230], [231], [232], [233], [234] and this is in line with the evidence that 8 of 10 drugs, which
Conclusions
From the previous examples it is apparent that differences in the pharmacokinetics, pharmacodynamics and side effects of medications are gender-dependent and might correspond to different effect profiles of drugs. The effect of gender on drug response has begun to be investigated only recently for most drugs, and even more recently, the effect of specific dosages and routes of administration have begun to be explored. Despite the fact that, in the last years, more women have been enrolled in
Acknowledgments
We regret that strict space limitation necessitated frequent citation of review and prevented the referencing of many original studies and recent work. This review was supported by GIO.I.A Foundation onlus, Pisa-Italy.
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