Background
Withthe onset of menopause, sex hormones drop to a fraction of premenopausal values. This decrease in hormones affects many processes involved in drug absorption, metabolism, and excretion. Estrogens reduce gastric acid production [1], which can affect drug uptake. Estrogens affect plasma protein levels, changing the unbound fraction of drugs and act on p-glycoprotein (P-gP), an important efflux transporter in the gut, liver, kidneys, and brain [1]. Estrogens affect the activity of several cytochrome P450 (CYP) enzymes, most pronounced for CYP1A2, where metabolic activity can be reduced by some 50% [1]. This CYP enzyme is important for the clearance of some 3% of commonly used drugs. Concentrations of drugs metabolized by CYP1A2 may drop significantly at menopause, due to higher enzyme activity, reducing bioavailability and efficacy. CYP3A4 is induced by estrogens [1], and its activity decreases at menopause, which may lead to more side effects and even toxicity. CYP3A4 is responsible for the oxidation of over 50% of all drugs currently on the market and determines the elimination of a wide range of therapeutics. Phase II drug metabolism by uridine diphosphate glucuronosyltransferase (UGT) is also expected to change at menopause, as UGT activity depends on estrogens as well [1]. UGT also metabolizes many prescription drugs. Declining estrogens at menopause is expected to reduce elimination by UGT, causing higher drug concentrations and presumably more side effects. These hormone-dependent mechanisms involved in drug metabolism can work in opposite directions, with little net effect, but can also strengthen each other, in which case net effects on drug concentrations can be large [2].
Findings
Literature search identified only very few studies investigating the effects of menopause on pharmacokinetics of different drugs. We here provide some examples to showcase potential effects of menopause.
Clearance of alfentanil (a short-acting anesthetic) metabolized largely by CYP3A4, was studied in 21 women and found to be more than double as high at premenopausal age compared to menopausal age, with no such effect in age-matched men [3]. Clearance of tirilazad, a neuroprotective steroid, metabolized by CYP3A4, was one third higher in 10 premenopausal women compared to 10 menopausal women [4]. The same study showed a similar difference in the clearance of midazolam (a short acting tranquilizer), which is considered a marker of CYP3A4 activity [4]. Zijp et al. [5] analyzed the effect of menopausal status on metabolism of tacrolimus, an immunosuppressant metabolized by CYP3A4 in 818 patients. Metabolism in women of premenopausal age was 43% higher than in women of menopausal age, while there was a non-significantly (12%) higher metabolism in men of comparable age groups.
Castberg et al. [6] analyzed age and sex effects in 7626 users of quetiapine, an antipsychotic, metabolized by CYP3A4. They found a sex-by-age interaction and showed that male and female serum concentrations are similar until age 50, after which women develop significantly higher values than men, inducing a 33% sex difference.
Rosuvastatin, a competitive hydroxymethylglutaryl-coenzyme A inhibitor, partly metabolized by CYP2C9, was studied in 40 women [7]. Three hours after administration of a single dose of 40 mg, more than fourfold higher plasma levels were found in premenopausal women, compared to menopausal women.
Olanzapine, an antipsychotic drug metabolized by CYP1A2, was studied in 248 patients, finding a sex-by-age interaction, with higher blood levels in young women and lower blood levels in older women [8]. While the dose-corrected concentration (C:D ratio) of olanzapine increased with age in men, it decreased in women; an effect that may be attributable to menopause. Finally, a study including over 3000 men and women using lamotrigine (an anti-epileptic drug metabolized by UGT) demonstrated a significant drop in clearance in women aged 51–55 [9], but not in male peers, again suggesting interaction between menopausal status and pharmacokinetics.
Discussion
These examples suggest that exposure to different drugs can either increase or decrease at menopause and that changes can be clinically relevant. We found several different examples in which CYP3A4 substrates reached significantly higher levels at menopause. As metabolism by CYP3A4 is a relevant factor for over 50% of drugs, a change in pharmacokinetics and drug exposure after menopause may be rather common. In contrast, we found an example of a CYP1A2 substrate, where blood levels decreased at menopause, to be expected given the inhibiting effects of estrogens on this enzyme. While such changes are often attributed to increasing age, our findings suggest that menopausal status itself may contribute independently to altered drug metabolism. Although drug dosage is frequently adjusted when patients age, this is often assumed to reflect chronological aging with less attention given to the physiological changes associated with menopause. Distinguishing age-related effects from those driven by the hormonal transition of menopause is challenging but clinically important for accurate dosing and better drug safety in women. Current prescribing guidelines do not account for menopausal status, which may contribute to a lack of awareness among clinicians when managing medication use in women of menopausal age.
Our search alerted us to the paucity in studies investigating potential effects of menopause. Yet, the possibility that menopause can be an important factor in drug availability is relevant for doctors of all medical disciplines. We therefore plead for more research into this subject. Investigating potential effects of menopausal status on pharmacokinetics is doable and feasible. Menopausal status should be determined during consultation as part of clinical routine and also as part of observational studies and randomized controlled trials to allow cross-sectional comparisons. In longitudinal cohort studies, premenopausal and menopausal drug concentrations should be examined to prospectively investigate menopausal effects. As such investigations take time, a rough estimate of the menopausal effect can already be obtained retrospectively by using data sets in large existing cohorts. Information on menopausal status can be estimated by comparing men and women of specific age groups; differentiation can be made between effects of aging (present in both sexes) or menopause (exclusively present in women). Mean menopausal age is 51 for Europe and 49 for the USA [10]. Although interindividual variation is high, age can provide a rough approximation of menopausal status in larger samples.
We here advocate a medicine-wide effort to evaluate the influence of menopause, as this information is important to optimize pharmacotherapy for women. Such an effort is excellent value-for-money, as it can improve efficacy and prevent side effects in a large group of consumers.
Conclusions
We provided theoretical reasons to expect relevant changes in pharmacokinetics at menopause for many drugs. This expectation was supported by anecdotal evidence from literature. However, research into the menopausal effect on the safety and efficacy of drugs is very scarce and needs to be extended urgently, as for most drugs it is currently unclear if a dose adjustment at menopause is needed.
Acknowledgements
We would like to thank Dr. Shiral Gangadin and M.Sc Eline L. Bosch for their thoughtful comments. We would like to thank M.Sc. A.J. Boer for her help in preparing this manuscript.
Abbreviations
- C:D ratio
Dose-corrected concentration
- CYP
Cytochrome P450
- CYP1A2
Cytochrome P450 family 1 subfamily A member 2
- CYP3A4
Cytochrome P450 family 3 subfamily A member 4
- CYP2C9
Cytochrome P450 family 2 subfamily C member 9
- P-gP
P-glycoprotein
- UGT
Uridine diphosphate glucuronosyltransferase
Authors’ contributions
IECS wrote the first version of the manuscript. BAB improved the text and provided data on clozapine. TZ improved the text and provided data on tacrolimus. MM improved the text and provided expertise regarding the menopausal transition. DT improved the text and provided expertise regarding pharmacokinetics.
Funding
Not applicable.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
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Data Availability Statement
No datasets were generated or analysed during the current study.