31 July 2017: 

Pharmacogenomics is the study of how genes affect a person's response to drugs. This relatively new field combines pharmacology and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person's genetic make-up [1]. Many drugs that are currently available are 'one size fits all', but they don't work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side-effects. Pharmacogenomics aims to develop rational means to optimize drug therapy, with respect to the patient's genotype, and to ensure maximum efficacy with minimal adverse effects.

Personalized management of menopausal symptoms and other menopause-related disorders should be based, among other variables, on pharmacogenomics. One main example is hormone therapy (HT), as nicely discussed in the Editorial by Moyer and colleagues [2]. Typically, dosing is targeted toward symptom relief, but there is significant variability in the doses required for symptom relief among women. In addition, if therapy is needed not only for symptoms but also for prevention of chronic diseases of old age, such as osteoporosis or cardiovascular diseases, then the effective doses might be different. Pharmacogenomic approaches may help identify women with different estrogen-dose requirements based on identification of genetic variants in enzymes involved in hormone/drug metabolism and impacting hormone/drug targets. The Kronos study provided data on the impact of genetic variations on the development of atherosclerosis in healthy, recently menopausal women receiving HT [3].

There were three study arms: placebo, estradiol patch (50 µg/day) and conjugated equine estrogen (0.45 mg/day), the latter two in combination with progesterone (200 mg/day) for the first 12 days of the month. Mean carotid intima-media thickness (CIMT) increased over the 4 years' duration of the study, independent of treatment. Twenty single nucleotide polymorphisms (SNPs) with the smallest p values of longitudinal association with changes in CIMT at 4 years of treatment were detected. There were no statistically significant signals for any particular SNP with a pharmacogenomic effect; however, SNPs in the innate immunity pathway did have an overall effect. Also, the effects of SNPs on the 4-year change in CIMT varied by treatments. Interestingly, there was little evidence for any SNP by treatment interaction effect in regard to the amount of coronary artery calcium.

Although progress has been made in understanding the influence of genetic variation on estrogen efficacy and metabolism through candidate gene studies, due to the complexity of both the estrogen pharmacodynamic and pharmacokinetic pathways, and the many additional variables reviewed here that may be of importance, large studies will be required to develop genetically based algorithms for estrogen administration/dosing. Furthermore, it will likely be important to consider other medications and environmental factors if such algorithms are to be developed in the future. Advances in research regarding the pharmacogenetics and pharmacogenomics of estrogen metabolism may allow for more personalized use of HT for management of menopausal symptoms. However, for the vision for the use of genomics to enhance personalized HT to become a reality, additional resources will be required to perform the necessary research further to develop these promising research findings into information that is clinically actionable.

Gene expression, gene profiling, pharmacogenomics and epigenetics are all part of the next-generation medicine, which will enable an accurate, individual approach to pharmacological therapies, and will help in choosing the best approach carrying maximal efficacy and least odds for severe adverse outcomes. Sporadic articles have already pointed at the need to employ these genetic tests in the future in various fields of women's health medicine, such as female sexual disorder [4], osteoporosis [5] and pregnancy [6]. The gender differences in this respect need to be elucidated as well [7].

Amos Pines

Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. What is pharmacogenomics?
   https://ghr.nlm.nih.gov/primer/genomicresearch/pharmacogenomics
2. Moyer AM, Miller VM, Faubion SS. Could personalized management of menopause based on genomics become a reality? Pharmacogenomics 2016;17:659-62
   http://www.ncbi.nlm.nih.gov/pubmed/27142773
3. Miller VM, Jenkins GD, Biernacka JM et al. Pharmacogenomics of estrogens on changes in carotid artery intima-medial thickness and coronary arterial calcification: Kronos Early Estrogen Prevention Study. Physiol Genomics 2016;48:33-41
   http://www.ncbi.nlm.nih.gov/pubmed/26508701
4. Nappi RE, Domoney C. Pharmacogenomics and sexuality: a vision. Climacteric 2013;16(Suppl 1):25-30
   http://www.ncbi.nlm.nih.gov/pubmed/23848488
5. Riancho JA, Hernandez JL. Pharmacogenomics of osteoporosis: a pathway approach. Pharmacogenomics 2012;13:815-29
   http://www.ncbi.nlm.nih.gov/pubmed/22594513
6. Hellden A, Madadi P. Pregnancy and pharmacogenomics in the context of drug metabolism and response. Pharmacogenomics 2013;14:1779-91
   http://www.ncbi.nlm.nih.gov/pubmed/24192125
7. Franconi F, Campesi I. Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women. Br J Pharmacol 2014;171:580-94
   http://www.ncbi.nlm.nih.gov/pubmed/23981051