Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs.

There is an increasing awareness that the exclusion of women from clinical trials may lead to inaccurate application of drug therapy in women. Gender and estrus cycle differences in the pharmacokinetics and pharmacodynamics of drugs in animals have been appreciated for over 60 years, but investigation into these differences in humans has only recently occurred. It is postulated that hormonal fluctuations within the menstrual cycle phase may be a primary cause of documented gender differences in the pharmacokinetics and pharmacodynamics of drugs. Existing data suggest that menstrual cycle variations do occur in renal, cardiovascular, haematological and immune systems. These physiological changes could potentially impact on the pharmacokinetics or pharmacodynamics of drugs by altering properties, such as protein binding or the volume of distribution, and thereby causing significant effects at various times during the menstrual cycle. However, systematic investigations of physiological variability throughout the menstrual cycle are limited. Fluctuations in symptom severity and clinical course coinciding with the menstrual cycle phase have been seen in some diseases. Hormonal fluctuations within the menstrual cycle have been postulated to cause disease exacerbation. They may also worsen disease severity by impacting on the pharmacokinetics or pharmacodynamics of the medication. Menstrual cycle hormonal changes may influence drug absorption, distribution, metabolism or excretion. In vivo data to demonstrate an effect of endogenous estrogen or progesterone on pharmacokinetics are limited and contradictory. Systematic investigations of specific pharmacokinetic and pharmacodynamic changes within the menstrual cycle are lacking. Most published studies have been conducted with small numbers of women and a limited numbers of menstrual cycle phases within 1 menstrual cycle. These design problems have resulted in incomplete data for assessing the effects of the menstrual cycle. To date, there are no demonstrated clinically significant changes that occur in the absorption, distribution or elimination of drugs. With respect to drug metabolism, data are exceedingly sparse and have been collected in a suboptimal fashion. Standardisation of study design and analyses in systematic investigations of the influence of the menstrual cycle on drug pharmacokinetics and pharmacodynamics are needed.