Women have a greater sensitivity to caffeine than men and their bodies may take much longer to detoxify caffeine and recover from its stimulating effects. (Mathias, et al, 1985)

Caffeine directly affects women’s hormonal levels by increasing estrones, or female hormones, while decreasing available testosterone. (Ferrini and Barrett-Connor, 1996)

Oral Contraceptives Compete with Caffeine for Processing time in the Liver

Caffeine is metabolized by the liver, specifically the cytochrome P450 pathways. When caffeine is consumed with other substances (such as pharmaceuticals) also metabolized through this pathway, the rate of clearance of both caffeine and the drugs from the body are significantly reduced. (Labbe, et al, 1999), (Abernethy, et al, 1985), (Patwardhan, et al, 1980), (Rietveld, et al, 1984) Caffeine therefore remains in the body for much longer periods of time, increasing the effect of the morning cup of coffee. Most pharmaceutical drugs utilize this same metabolic pathway, including oral contraceptives and antidepressants. (Carillo and Benitez, 2000)

Genetic Differences and Caffeine Metabolism

We are not all created equal when it comes to our body’s ability to break down caffeine. Newly identified genetic differences reveal that caffeine metabolism is mediated by genetics related to variations of a specific gene. Approximately fifty percent of the population possesses the slow metabolizing allele, or variation of the gene, meaning these people process caffeine in the liver at a much slower rate than those who are identified as fast metabolizers.

In the slow metabolizers, caffeine has the potential to build up in the bloodstream before the liver is able to detoxify it (particularly when people are consuming multiple cups of coffee or other caffeinated drinks). Increased risk of hypertension is correlated with carriers of the slow variation of the gene, known as slow metabolizers. These people also have higher levels of epinephrine (adrenaline) in their urine; caffeine is known to stimulate the release of hormones related to the sympathetic nervous system response, including epinephrine. (Cornelis, et al, 2006), (Palatini, et al, 2009).

Sensitivity to caffeine does not necessarily correlate with whether or not someone is a slow or a fast metabolizer of the chemical. Fast metabolizers can still be sensitive to and get the jitters from drinking coffee.
Differences in caffeine metabolism can also provide an explanation as to why the research results related to the health effects of caffeine can be so divergent, as different people are dramatically differentially sensitive.

References (by alphabetical order)

Abernethy, D.R. and Todd, E.L. 1985. Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives. European Journal of Clinical Pharmacology. 28(4):425-8.

Carrillo, J.A. and Benitez, J. 2000. Clinically siginicant pharmacokinetic interactions between dietary caffeine and medications. Clinical Pharmacokinetics. 39(2):127-53.

Cornelis, M. C., El-Sohemy, A., Kabagambe, E.K., and Campos, H., 2006. Coffee, CYP1A2 Geontype, and Risk of Myocardial Infarction. Journal of the American Medical Association. 295(10):1135-1141.

Ferrini, R.L. and Barrett-Connor, E.. 1996. Caffeine intake and endogenous sex steroid levels in postmenopausal women. The Rancho Bernardo Study. American Journal of Epidemiology. 144(7):642-4.

Labbe, L., Abolfathi, Z., Robitaille, N.M., St-Maurice, F., Gilbert, M. and Turgeon, J. 1999. Stereoselective disposition of the antiarrhythmic agent mexiletine during the concomitant administration of caffeine. Therapeutic Drug Monitor. 21(2):191-9.

Mathias, S., Garland, C., Barrett-Connor, E. and Wingard, D.L. 1985. Coffee, plasma cholesterol, and lipoproteins. A population study in an adult community. American Journal of Epidemiology. 121(6):896-905.

Patantini, P., Ceolotto, G., Ragazzo, R., Dorigatti, Fr., Saladini, F., Papparella, I., Mos, L., Zanata, G., Santonastaso, M. 2009. CYP1A2 genotype modifies the association between coffee intake and the risk of hypertension. Journal of Hypertension. 27(8): 1594-601.

Patwardhan, R.V., Desmond, P.V., Johnson, R.F. and Schenker, S. 1980. Impaired elimination of caffeine by oral contraceptive steroids The Journal of laboratory and clinical medicine. 95(4):603-8.

Rietveld, E.C., Broekman, M.M., Houben, J.J., Eskes, T.K. and van Rossum, J.M. 1984. Rapid onset of an increase in caffeine residence time in young women due to oral contraceptive steroids. European Journal of Clinical Pharmacology. 26(3):371-3.