Oestrogen therapy: Oral versus non-oral administration

As for any other medical treatment, benefits and symptom relief from post-menopausal oestrogen therapy have to be carefully weighed against potential adverse effects and risks. Virtually all oestrogenic compounds may offer effective relief from the vasomotor symptoms provided they are given at sufficient doses. The clinical problem is not to achieve therapeutic efficacy but rather to avoid overdosing and to minimize the risk of adverse events. The differences in pharmacokinetics and metabolic effects between the oral and non-oral oestrogen treatment were explored already 25–30 years ago. However, for many years they were considered of little clinical significance and oral oestrogen treatment was, in general, regarded as devoid of side effects. After the first alarming reports from the large WHI trial this perception was dramatically changed and safety issues of oestrogen therapy were focussed. [1]. Even though there has been a remarkable modification of the original WHO data in later reports where oral oestrogen when started in women near menopause appears both effective and safe, there is still an increased interest in the transdermal alternative [2].

Different impact on liver function

Treatment with exogenous oestrogen is known to affect several aspects of liver function [3]. Changes in the synthesis of liver-derived proteins like angiotensinogen (renin substrate), high and low density lipoproteins, coagulation factors and antithrombin III (AT-III) may influence the risk of hypertension hyperlipidemia and hypercoagulability during the oestrogen treatment (Table I). The mammalian liver contains specific oestrogen receptors [4], but still the liver is quite different from other target organs. The number of binding sites is low and receptor activation is not followed by the induction of progesterone receptor. The effect of sex steroid hormones may principally be mediated in two ways, direct via receptor binding or indirect by modification of the secretion of other hormones as for example growth hormone [5-7].

Table I.  Oestrogen effects on liver metabolism.

Affected function	Possible consequences
Plasma protein synthesis	Increase of transport proteins, hypertension
Blood coagulation	Increase of clotting factors, thromboembolism
Lipid metabolism	Increased HDL fraction, increase of triglycerides, altered risk for ischemic heart disease
Secretory function	Bile secretion, reduced gallbladder disease, cholestasis during pregnancy
Glucose metabolism	Reduced glucose tolerance, diabetes
Enzymatic metabolism	Sex differences, altered drug tolerance
Phagocytic function	Increased phagocytosis, immunological effects

The hepatic impact of oestrogen therapy is markedly influenced by the route of administration [8]. Oral treatment with tablets is simple, cheap, convenient and highly effective but should not be regarded as physiologic therapy. Already in the intestinal wall, about 70% of the oral oestradiol is metabolized to oestrone which has an approximate biological activity of about 1/3 of oestradiol. The intestinal absorption is rapid and yields high concentrations of hormone in the portal circulation to be further converted in the liver. High concentrations are needed before a general therapeutic effect can be achieved. Thus, it is necessary to use higher doses via the oral route than when oestrogens are given parenterally. It is well known that the transdermal administration of 50 μg of oestradiol provides the same therapeutic effect in post-menopausal women as 1–2 mg of oestradiol given orally.

Taken together, the available data imply that many of the effects following oral administration of high doses of oestrogen reflect a pharmacologic rather than a physiologic influence on the liver metabolism. In contrast, when native oestrogen is given parenterally the effects on liver-derived plasma proteins, coagulation factors, lipoproteins, triglycerides and glucose metabolism are very weak or completely abolished [9-11]. The first pass liver effect is avoided and oestrogen is distributed directly to the blood stream. After receptor activation in target organs, hormones are inactivated and excreted. Serum levels are more stable and lower doses are effective. It should be recalled, that the stimulation of liver metabolism can be avoided only by transdermal administration of native oestrogen, e.g. oestradiol. Synthetic compounds as ethinyl oestradiol have a long half life and are resistant towards the enzymatic degradation in target tissues. This means that also after parenteral/transdermal administration and after the first effect in the primary target organs they will in the end, come out with the same degree of liver stimulation as seen from oral treatment.

Possible advantages of the non-oral route

As for the oral contraceptives, there is an increased risk of deep venous thrombosis, which is a well-known, albeit rare, risk from oral oestrogen therapy in post-menopausal women. Accumulating data suggest that this risk may not appear during transdermal oestrogen therapy [12],[13]. Observational data and clinical trials indicate a 2–4-fold increase in the relative risk of thrombosis from oral treatment whereas risk estimates for transdermal therapy did not differ from untreated controls.

After oral administration of oestrogen there is a dose-dependent increase in the production of vitamin K-dependent coagulation factors in the liver. This effect is not seen during transdermal treatment. Likewise, it seems that tablets but not transdermal oestrogen in some individuals may induce APC-resistance [14],[15]. AT-III is an important inhibitor of activated coagulation factors. Following oral administration of oestrogen, the levels of AT-III and also of tissue-factor inhibitor declined whereas the effects from transdermal administration were limited. In contrast to oral oestrogen, transdermal treatment was reported not to increase the risk of thrombosis among women who were carriers of different prothrombotic mutations [16]. Recently, as a consequence of the minimal or even neutral effects on the coagulation it was suggested that women on transdermal oestrogen should not be at any increased risk of stroke [17],[18].

Inflammation seems to have a crucial role in early atherosclerotic development and for risk of myocardial infarction. In contrast to oral treatment, transdermal therapy will not influence markers like C-reactive protein, serum amyloid-A and others [19-21]. Differences between the two treatment principles on endothelial function and arterial vascular tone were also reported [22-24]. Also, transdermal oestrogen administration unlike tablets will not increase triglycerides [25]. Insulin resistance in post-menopausal women was unchanged during transdermal therapy [26]. The North American Menopause Society in a recent policy statement [27] suggests transdermal treatment to be preferable in women with type II diabetes. In a recent large-scale national register study from Denmark a significantly lower risk for myocardial infarction was found with the transdermal route than among women on oral oestrogen therapy [28].

Following oral administration of oestrogen there is an increased synthesis of a large number of oestrogen sensitive plasma proteins in the liver. Many of these proteins are important for binding and biological transport of different hormones, e.g. sex hormone binding globulin, thyroxin binding globulin and cortisol binding globulin. A pharmacologic increase in protein binding could tentatively be adverse and reduce the levels of free testosterone, thyroxin and cortisol. Angiotensinogen (renin substrate) a high-molecular globulin will, like many of the other proteins, increase in a strictly dose-dependent manner following oral oestrogen administration. Angiotensinogen is subject to enzymatic cleavage by renin into vasoactive peptides angiotensin I and II. In parallel, there is an increase in the renin activity and aldosterone secretion. It has been well documented that transdermal administration of natural oestrogens has very little or no effect on any of these liver-derived plasma proteins [9],[29]. Consequently, transdermal therapy could be an advancement for women with hypertension [27].

In summary there is increasing biochemical and clinical data to suggest that differences between oral and transdermal oestrogen therapy are of clinical importance. Reduced stimulation of the liver could imply a reduced risk of side effects. In particular, transdermal oestrogen therapy should be an attractive alternative in women with an increased risk for thrombosis, hypertension, hypertriglyceridemia, gall and liver disease, hypothyreosis and low testosterone levels. It is also interesting to note that no increased risk of breast cancer was found during such treatment in the recent large case–control study from the UK's General Practice Research Database [30].