Differences in drug use between men and women: an Italian cross sectional study

Drugs are the most important treatment option for most diseases and, the majority of medical consultations result in a prescription [1]. Women and men receive different drug prescriptions and differ in therapeutic response to pharmacological therapy [2‐5]. This disparity between men and women is most apparent in the population ranging from 45 to 64 years of age; an age when women’s health issues primarily revolve around chronic conditions [5].

In order to discuss the differences between men and women as regards drug prescription, it is necessary to distinguish between sex and gender. Sex differences are based on biological factors (reproductive function, concentrations of sex hormones, expression of genes on X and Y chromosomes and their effects and the higher percentage of body fat in women). By contrast, gender is associated with behavior, lifestyle and life experience. Both sex and gender may be considered as a factor in the prescription of drugs, yet, while it is evident that sex differences should be considered when prescribing medicines, it is unclear as to what gender differences should be considered by the prescribing physician.

It is known that women are more likely to use several classes of medications including antidepressants and anti-anxiety and pain medications, while men use more cardiovascular medications than do women [6]. In addition, sex differences in drug use have been demonstrated in several therapeutic areas [7‐11]. However, there is a lack of overviews regarding both sex and gender differences concerning the use of drugs in an entire population. We have assumed, therefore, that a study of drug use based on information obtained from administrative databases [12‐14] represents a suitable tool for the evaluation of use of drugs by women and men.

The volume of drugs belonging to the 31 pharmacological group included in this study and dispensed in Italy in 2012 was 19 billion DDD, corresponding to 888.4 DDD/1000 inhabitants daily. The analysis of the prevalence of drug prescription stratified by age group showed that antibiotics such as penicillins (ATC: J01C 28.1‰), drugs for obstructive airway diseases (ATC: R03B 13.5‰) and antihistamines for systemic use (ATC: R06A 12.3‰) were the most common drugs used by children and adolescents for both men and women. Antibiotics remained the most used pharmacological group in prevalent cases until 59 years old (25.6‰) followed by non-steroidal anti-inflammatory drugs (ATC: M01A 16.0‰). Prescription of gastrointestinal and cardiovascular drugs increased starting from 60 years old.

In all age groups, women had a higher prescription prevalence for most pharmacological groups except for drugs used in benign prostatic hypertrophy, anti-gout preparations and drugs used to treat cardiovascular disease (including anti-lipemic agents, beta- blockers and related medicines and angiotensin – converting enzyme inhibitors). Drugs affecting bone structure and mineralization (31.7‰ women vs 2.0‰ men), calcium (24.3‰ women vs 2.8‰ men) and thyroid preparations (64.8‰ women vs 12.0‰ men) had a higher prevalence of use in women than men as did iron preparations (10.1‰ women vs 3.8‰ men), vitamin B12 and folic acid (7.0‰ women vs 3.7‰ men) and antidepressants (68.0‰ women vs 29.5‰ men). On the contrary, drugs used in benign prostatic hypertrophy (61.9‰ men), anti-gout (11.5‰ women vs 20.9‰ men) and Angiotensin-converting enzyme inhibitors (ACE inhibitors) (58.6‰ women vs 70.2‰ men) were more used for men than for women (Table 1) Additional file 1.

The crude differences between men and women for the 31 therapeutic categories in the study, expressed in terms of prevalence, were statistically significant. Overall, after age adjustment, differences remained. The large differences in drugs used for bone disease such as osteoporosis diminished after age adjustment, even though they were still more common in women. The pharmacological groups with the largest relative differences, and more commonly dispensed to women, were drugs affecting bone structure and mineralization (RR 15.9), calcium (RR 8.6), thyroid preparations (RR 5.4), iron preparations (RR 2.6), antidepressants (RR 2.3) and anti-anemic preparations (RR 2.0) (Fig. 2).

To the best of our knowledge, this is the first study exploring gender difference in drug use and carried out on the entire Italian population. Our findings showed substantial differences between men and women in terms of prevalence of drug prescriptions. The volume of drugs belonging to the pharmacological groups in the study which were dispensed in Italy in 2012 was 19 billion DDD corresponding to 888.4 DDD/1000 inhabitants daily. Antibiotics and anti-asthmatics were the most used drugs in Italian children and adolescents for both males and females. These results were consistent with another national drug use study in which antibiotics were widely prescribed in pediatric outpatients with both quantitative and qualitative marked territorial differences [18].

Our results highlighted that some differences between males and females, stratified by pharmacological groups, are expected. In all age groups, women had a higher prescription prevalence for most pharmacological groups. More particularly, approximately 5% of women received at least one prescription for calcium and drugs for bone structure and this value was higher than that for men (0.4%). It comes as no surprise since the use of antiosteoporosis drugs is a mainly a female issue worldwide [19, 20]. Apart from the greater risk older women run of developing osteoporosis owing to the more extensive loss of bone mineral density [21, 22], the crucial impact of gender may also reflect the greater likelihood of women to obtain a relative drug or supplement with or without prescription.

Another relevant result of our study regarded thyroid preparations. Italian women used these drugs more than men, and the reason is probably to be found in the epidemiological development of thyroid disease [23, 24]. Hoffman F et al. [24] showed that, in Germany, thyroid diseases affect women almost 5 times more frequently than men.

In 2012, Italian women took more antidepressants then men (9.7% women vs 4.5% men). Major depression affects both sexes, but more women than men are likely to be diagnosed with depression in any given year [3, 25]. The prevalence of depression is estimated to be 11.2% in the Italian population, with women using more drugs than men (women 7.8% men vs 3.6%). Women are twice as likely to use antidepressant drugs compared to men.

In addition, such as other international studies, Italian women were undertreated as regards cardiovascular drugs (including antilipidemicemic agents, beta- blockers and related medication and angiotensin – converting enzyme inhibitors). ACE inhibitors primarily used for the treatment of heart failure and hypertension, were more commonly used in Italian men. In this context, in 1991 Bernardine Healy called attention to the discriminatory behavior of cardiologists towards women with under-diagnosed and under-treated ischaemic heart disease (IHD) in a publication in the New England Journal of Medicine entitled “Yentl syndrome” [26]. This disparity between men and women regarding healthcare management appeared to depend largely upon multiple factors related to the patient, to consequences of the disease and to the physician’s assessment of patient risk. Over time, the term ‘Yentl Syndrome’ has come to be used in medicine to define the possibility that diagnostic and therapeutic strategies are not offered in a similar manner to both men and women (or that women are discriminated against). In 2011, Merz CN [27] suggested that the Yentl syndrome is alive and well 10 years later [28, 29]. With regard to this, two new studies demonstrating the medical under-treatment of women, including lower rates of aspirin and ACE inhibitor use in stable women compared to men and lower rates of ACE inhibitor, b-blocker, and statin medication in women with acute coronary syndrome compared to men became available.

It was clear that women in Italy used more drugs then men, and this result is consistent with other drug use statistics. According to data published by the National Agency for Medicines, Italian women have more contact with the healthcare system which may provide them with an opportunity for detecting disease and receiving prescriptions. Women have a higher life expectancy at birth than men (79.4 years men vs. 84.5 years women), suffer from chronic degenerative diseases associated with aging more than men (35.3% men vs 40.0% women), benefit more from the health services and, in the age group between 15 and 64 years in Italy, show a level of drug exposure 8% higher than that of men. Moreover, the fact that most of the preclinical and clinical studies are conducted on male animals and men (gender blindness) and then the results of these studies are then shifted onto women gives rise to most cases of inappropriate therapy. In literature, several papers have highlighted that belonging to one gender rather than to the other represents a risk factor as regards the development of adverse drug reactions (ADR). In fact, female patients have a 1.5 to 1.7 fold greater risk of developing an ADR compared to male patients [30]. In Italy, the data of the National Network of Pharmacovigilance show a greater number (59% in 2011) of spontaneous reports of adverse drug reactions (ADR) in women in all age groups starting from the second year of life. ADRs in women are more numerous and even more serious than in men and lead to a higher number of hospital admissions (about 60% of hospitalizations for ADR regard women) [31]. In contrast with this evidence, a typical antipsychotic prescribed with dementia, psychosis or attention-deficit hyperactivity disorder (ADHD) shows a greater risk of provoking ADRs in male patients than in women [32].

The main strength of this study is the coverage of all dispensed prescription drugs reimbursed by the National Health Service to the entire Italian population. Another strength is the data source of the study which provides a more accurate picture of actual drug use stratified by gender.

The most important limitation of this study is the lack of clinical information on patients in order to assess the reason behind the observed differences. It is important to emphasise that gender differences may only be hypothesised from these data. Moreover, data on out of pocket drugs were excluded. We only had information on the third level ATC, but, in reality, this is not a severe limit since we can identify the pharmacological group by means of the ATC III.

Despite the limitations detailed above, the results of this study made it possible to formulate some thoughts of interest to public health. They represent a starting point for informing health care workers of the importance of gender differences in order for them to provide the best possible health care. In this context, behavourial and preventive interventions would be necessary to reduce the gender disparity. Moreover, the doctor-pharmacist-patient relationship should be characterized by dialogue as an opportunity for education management therapies.

In this large study, we found substantial differences in drug use between men and women in Italy. The findings may subsequently be used to plan future studies to address differences suggesting inequity in treatment approaches.

Some drug use differences may be explained by variations prevalence and severity of disease, pathophysiology or by other biological differences (due to sex differences). However, it is also evident that other differences need further investigation in order to explain the apparent lack of a rational medical explanation for some findings. A greater awareness of the influence of gender in health and disease is needed to ensure rational drug use in both men and women. Moreover, due to conflicting outcomes between gender differences and ADRs, new surveys in the active pharmacovigilance field should be carried out in order to improve our knowledge of the safety profile of drug use in the treatment of male or female patients.