Estradiol

What is estradiol?

Estradiol is one of the major naturally occurring estrogens in women, and the most potent. Like the other steroid hormones, it is a derivative of cholesterol (R).

It has been shown to play many roles in the human body, including sexual reproduction and the menstrual cycle, appetite and eating behaviour, fat metabolism, auditory and visual processing, the development of breast cancer and osteoarthritis, the prevention of heart disease and neuroprotection during cerebral ischaemia and in multiple sclerosis (R).

The common bean Phaseolus vulgaris also produces estradiol endogenously (R).

Is estradiol stable?

A formulation containing 1% estradiol in liposomes was found to have very poor chemical stability, with >60% of the estradiol degraded after only 2 weeks of storage at room temperature. Microbial contamination was also observed. When the liposomes were coated with various polymers, both the chemical and the microbial stability of the formulation were improved. Polycarbophil was the best polymer, leading to 87% of the estradiol being preserved even after 2 months of storage (R).

Formulations containing 1% estradiol in addition to 2% estriol, 1% estrone, 20% progesterone and 5% testosterone have been demonstrated to remain stable when incorporated in 3 different cream bases and refrigerated or stored at room temperature for 6 months (R).

Does estradiol get absorbed?

The topical delivery of estradiol is very well-studied, as it is one of the options for hormone replacement therapy to relieve the symptoms of menopause (R).

There are 2 penetration pathways to the dermis for topical estradiol - through the stratum corneum and epidermis, or through the hair follicles (R). Being lipophilic, estradiol permeates the skin more readily than cosmeceuticals that are hydrophilic, such as the polyphenols. One study found that several penetration enhancers were not very effective in promoting the skin absorption of estradiol, presumably because estradiol is already relatively non-polar (R). Nevertheless, to further improve uptake, many transdermal delivery systems for estradiol have been developed (R), including gels, patches, sprays, microemulsions and nanoparticles (R, R).

A gel containing estradiol showed an uptake of 41.7% of the applied dose in reconstructed human skin while 42.9% of the applied dose of estradiol in a transdermal patch successfully penetrated pig skin (R). In another study, 2 gel formulations containing 0.1% and 0.06% estradiol showed a penetration of 17% to 18% of the applied dose (R). A comparison between a gel and a patch revealed that the extent of absorption varied widely for both formulations (R).

A topical spray containing a penetration enhancer significantly enhanced the transdermal delivery of estradiol by aiding its partition into the stratum corneum (R, R, R). Liposomes have been demonstrated to improve delivery over aqueous solutions as well, with experimental data suggesting that lipid vesicles increase drug partitioning into the skin (R), and that liposome components in solution also have an additive effect (R). Furthermore, derformable liposomes are superior to traditional liposomes in improving skin delivery (R, R, R).

A microemulsion formulation of estradiol was found to increase its flux dramatically by 200 too 700-fold, due to a 1500-fold improvement in the solubilization of estradiol, but also decreased its permeability coefficients by 5-18 times (R). Topical micellar nanoparticle estradiol emulsions have also been validated for transdermal delivery of estradiol (R).

What happens after estradiol is absorbed?

A significant proportion of the estradiol that penetrates the skin is metabolised. In a study on reconstructed human skin, the proportion was found to be 42.6%. The dominating metabolite was estrone, which accounted for 36.3% of the metabolites (R).

Percutaneous doses of estradiol has also been found to elicit a slow but significant increase in serum estrogen (R, R) to levels typical of the early follicular phase in premenopausal women (R). The serum concentration of estradiol depends on the dose (R), and serum estradiol and estrone levels also remain nearly constant through their use (R, R, R).

Continuous administration of transdermal estradiol over 3 weeks did not result in any accumulation of estradiol or its conjugates (R).