The obtention of stable plasma estradiol values in the proliferative range, makes predictable the correction of estrogen deficiency and the efficacy of the treatment at the target level. The relief of hot flushes and night sweats occurs rapidly, within the first days of treatment and the vaginal dryness is reversed. Psychologic symptoms and particularly depressive mood, can be reversed, provided the levels of plasma E2 remain comprised between 50 and 150 pg/mL.
As far as the endometrium is concerned, that percutaneous E2 induced an increase in nuclear estradiol receptor (REN) and in soluble progesterone receptor (RPC) within the proliferative phase range, demonstrating the efficacy of this therapy on this target organ. Thus, progestin therapy should be added on a sequential basis, to avoid endometrial hyperplasia, like with any other, active estrogenic therapy.
Finally, the activity of percutaneous estradiol at the breast level has not been assessed by in vitro measurements. However, the appearance of breast tenderness and mastodynia which have been correlated to high estradiol levels in premenopausal women have been observed in some postmenopausal women treated with percutaneous estradiol. In these cases, E2 plasma levels reached high values >150 pg/mL. Therefore, the percutaneous administration of estradiol is efficient on most of the target organs; however its efficacy in preventing osteoporosis remains to be demonstrated and is at the moment under investigation. Preliminary results are encouraging.
Pharmacokinetics: The ability of the skin to absorb steroids has been recognized since the beginning of this century and has been extensively studied. The use of appropriate vehicles allows the penetration of the solute through the stratum corneum which plays the principal "barrier function" of the epidermis.
Different processes occur in sequence: First, absorption of the molecules within the stratum corneum; second, retention in the stratum corneum (reservoir effect); third, diffusion through epidermis and papillary dermis until they reach the capillary plexus and are transferred to the circulating blood. Each step of these different events is essential and individual variations of any step can influence the rate of absorption.
Among the substances that should well penetrate the stratum corneum, steroids penetrate quite readily from an appropriately polar vehicle which can affect solute permeation.
The reservoir function of human skin for steroids is localized in the stratum corneum, as demonstrated by Vickers.
This role of reservoir of the stratum corneum induces a sustained release, extended to >24 hrs, of the steroid percutaneously applied.
Estradiol, when applied to human skin in an alcoholic solution, rapidly penetrates the stratum corneum within the 10 min following application. Then diffusion of the steroid through epidermis and dermis according to the pathway described occurs with a delay of several hours. The rate of absorption depends upon the dose topically applied, and about 10% of the total dose passes through the cutaneous barrier, is transferred to the vascular system and eliminated in the urine over the following 72 hrs.
In women, application of a single dose of 3 mg of 17β-estradiol in a hydroalcoholic solvent leads to a plasma E2 increase within the 12 hrs following administration. The levels obtained are extremely variable from one individual to another.
However, after 3 daily repeated applications, the mean plasma concentrations of E2 become stable and reach levels of 110±24 pg/mL within the follicular phase range. No peak increments are observed and this is mainly due to the "reservoir effect" of the skin, which allows a progressive and constant diffusion of the steroid.
The E2/E1 ratio observed after percutaneous application of estradiol gel remains around 1, close to the physiologic values observed during the follicular phase of a normal cycle.
In addition, the levels of E2 around 100 pg/mL are able to relieve postmenopausal symptoms and to prevent hypoestrogenic consequences. The plasma levels of FSH and LH, exhibit a significant decrease, even if, like with other estrogenic therapy, the gonadotropins do not decrease to premenopausal levels. However, it is known that a decrease in plasma gonadotropins is not necessary to obtain a relief of postmenopausal symptoms.