Overview of sex and gender differences in drug treatment

Sex and gender

Sex refers to biological sex. Sex differences refer to differences that are perceived to be dependent on the biological sex. Sex-related genetic differences and presence of sex hormones can influence pharmacological parameters. In adulthood, male hormone levels vary little compared to female sex hormone levels, which vary during menstrual cycle as well as pre- and postmenopausal.

Gender is a concept that primarily describes an individual’s social gender and the ideas, beliefs and actions that shape it. Gender differences refer to differences originated from societal and social factors linked to gender.

 

About gender medicine

Gender medicine is a research field that integrates a sex and gender perspective in medicine where biological as well as social sex differences matter. Analyses of what disease and health means from a sex and gender perspective is a very important area for optimizing prescription of and treatment with drugs to men and women.

In the current quest for individualized treatment (“personalized medicine”), it is important to also understand what the X and Y chromosome means for genotype and phenotype; that is, at the cellular level, organ level, for disease mechanisms and expression of disease, for the pathophysiology, and the socio-psychological.

 

Disease prevalence in men and women

It is now well-known that the incidence of some diseases differs between men and women even if one disregards the diseases related to our reproductive systems.

Some diseases occur to same extent in both sexes but there are still always aspects of how pregnancy, menopause and oral contraceptives or estrogen affect drug efficacy and drug use.

We also know that heredity, risk factors, disease mechanisms, treatment response and prognosis often differ between men and women.

Some examples of diseases that are more common in women are osteoporosis, many lung diseases, inflammatory diseases (SLE, rheumatoid arthritis, multiple sclerosis, thyroid disease), gallstones, certain brain tumors, irritable bowel syndrome, eating disorders, depression, migraine, fibromyalgia, Raynaud’s disease, whip-lash, leakage and prolapse of the mitral valve, Takotsubos disease, paroxysmal atrial tachycardia, spasm and dissection of the coronary arteries and myocardial infarction without coronary artery stenosis.

Examples of diseases that are more common in men are myocardial infarction with coronary artery stenosis, infections, diabetes, esophageal cancer, colon cancer, peptic ulcer disease, schizophrenia, autism, ADHD, alcoholism, obesity, and psoriasis.

The same disease may also differ mechanistically and cause different symptoms (myocardial infarction, heart failure), and manifestations of disease (Lyme disease) in men and women.

 

Pharmacology and sex differences

Different pharmacokinetic concepts describe what happens to a drug in the body, how it is absorbed, how it is metabolized and excreted. Pharmacodynamic concepts describe what the drug does to the body and how it takes effects. We have collected and briefly explained some pharmacokinetic and pharmacodynamic concepts where sex differences can be important.

 

Which pharmacokinetic parameters are influenced by patient’s sex?

Bioavailability (F): The fraction of an administered dose that reaches the systemic circulation unchanged. The most common causes of low bioavailability are incomplete absorption and so called first-pass metabolism in the gut wall and liver. Women generally have longer transit time [1, 2]  which in turn can affect the absorption and bioavailability of drugs. There are several transport proteins, including P-glycoprotein (Pgp), which is the transport protein that has been studied most with consideration to sex differences. Pgp is a membrane protein that transports drugs. Pgp reduces absorption and increases renal clearance of certain substances. The amount of the transport protein (Pgp) is expected to be lower in women, which theoretically should provide increased bioavailability in women for the drugs that are Pgp substrates (e.g. digoxin) [3].

Distribution volume (Vd): A factor that relates the amount of drug in the body to the concentration in plasma. Plasma concentration measures unbounded drug. The drug can also be bound to plasma proteins (albumin or alpha-1-acid glycoprotein) or in different tissues. Women generally have more body fat than men while men have a greater amount of total body water, two factors that influence the distribution volume. This means that women generally have higher distribution volume for lipophilic drugs (e.g. diazepam) while men have a higher distribution volume for hydrophilic drugs. This means that women excrete lipophilic drugs more slowly than men. Conversely, women excrete hydrophilic drugs faster than men. During pregnancy, the distribution volume can change significantly for certain drugs, which may require dose adjustment [4]. For example, higher doses of antiepileptic drugs such as lamotrigine and levetiracetam are needed and more frequent monitoring of plasma concentrations is required during pregnancy [4].

Metabolism:  The activity of CYP3A4 is generally higher in women than in men [5-8]. During pregnancy, the activity of some drug-metabolizing enzymes is increased (CYP3A4, CYP2D6, CYP2C9 and UGT) while the activity of CYP2C19, CYP1A2 and NAT2 are decreased [4]. Many CYP3A4 substrates are also Pgp substrates, and this has been proposed as a cause to described contradictory sex differences in CYP3A4 activity [8].

Glomerular Filtration Rate (GFR): In general, the renal function is estimated with formulas based on the plasma concentration of creatinine or cystatin C. Formulas that only contain cystatin C generally provides good accuracy. The creatinine-based formulas (e.g. Cockroft-Gault, MDRD and CKD-EPI) must contain information on patient’s sex, age, and sometimes even measures as weight, height and ethnicity in order to give equivalent accuracy. After correction for age and weight, estimated GFR in women will be on average 10% less than in men.

Creatinine is formed in the muscles, while cystatin C is a small protein that is formed in almost all cells of the body. Creatinine is excreted by glomerular filtration, tubular secretion (which itself can be affected by certain drugs) and extra-renally in the colon. The excretion depends on muscle mass, diet, age, and patient’s sex (men generally have more muscle mass than women).

Clearance (CL): Women generally have lower renal clearance than men, because women GFR is lower (about 10%) [5-8]. There is also some evidence that women have less transport proteins such as Pgp, which also could contribute [8]. Theoretically, this could mean that women receive a higher exposure to drugs and thus an increased risk of adverse effects.

 

Which pharmacodynamic parameters are influenced by patient’s sex?

Pharmacodynamics describes what influences the drug’s mechanism of action, relationship between dose and pharmacological effect and between dose and adverse effects.

Mechanisms of action for different substances are usually similar between men and women. Differences in receptor density, binding and affinity can occur at different ages in men and women respectively [8]. There are examples of the relationship concentration-effect/adverse effect can differ between the sexes. For example, reduced mortality has been seen with enalapril treatment in men but not women with severe heart failure [9]. Hormonal interactions may also be important for sex differences in pharmacodynamics. These sex differences vary over time because sex hormone levels vary partly in the menstrual cycle and over time throughout life.

Adverse effects: Definition of an adverse effect according to WHO: any harmful or unwanted effect (adverse effect) of a drug that occurs at doses normally given for therapeutic, preventive or diagnostic purposes [10]. The regulatory terminology [11] used in the English-language literature regarding drug side effects is “adverse drug reactions” (ADRs), which means all undesirable effects of drugs when treated with normal doses and normal use. “Adverse drug events” (ADEs) is a broader concept, which in addition to ADRs also includes over- and under-dosing, treatment interruption. In addition, the definition for ADR requires that there must be a causal relationship between the drug and the symptom that occurred.

These are usually divided into two groups. Type A adverse effects are predictable based on the drug’s mechanism of action and dose/concentration dependence. This type is the most common and accounts for approximately 80% of all adverse effects. Type B adverse effects are usually unpredictable and neither related to the drug’s mechanism of action nor clearly dose-dependent.

In general, women report more adverse effects than men, and the reason for this is controversial. One reason that women report more type A- adverse effects may be that women weigh less, have lower GFR and renal excretion, which results in a higher concentration if the same dosage is used.

The most common type B- adverse effects is drug-induced rash, which occurs more often in women than in men. Stronger immuno-reactivity in women and the influence of sex hormones on autoimmunity has been proposed as an explanation for this. Women are also more likely to have prolonged QT syndrome and thus ventricular tachycardia of the type Torsade de Pointes (often a fatal cardiac dysrhythmia) than men. One reason for this is probably that women generally have longer QT interval than men. It has been proposed that male sex hormones leads to shorter QT interval, which would be protective [12-15]. Drug-induced liver disease is the most common adverse effect leading to drug withdrawal, and this event is also generally more common in women.

 

References

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