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Pharmacokinetics of Estrogens and Hormone Replacement Therapy
Author: J.M. Kaufman
 Abstract:

Various estrogen preparations can be used in hormone replacement therapy for peri- and postmenopausal women. Different progestagens can be combined with these estrogens and different methods of administration, different dosages and administration schemes can be used. The pharmacokinetics can vary greatly in the same treatment according to the individual, and there are also significant individual differences in sensitivity to the hormonal effects. 

The doctor's task to adapt a replacement therapy to the needs of his patients is therefore not simple. This necessitates a pragmatic policy, supported by some knowledge of several principles of the pharmacology of hormone replacement. This article will briefly review the pharmacokinetics of estrogens with special attention to the various methods of administration. [Eur Menopause J 4(1):14-22, 1997. © 1997 PMSI Bugamor B.V.] 

• Online Resources
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• Introduction

17b-estradiol production is drastically reduced after the menopause with serum levels usually lower than 30 pg/ml, whilst the estrone level remains at a relatively higher level, generally above 40 pg/ml. The circulating estrogens after the menopause originate mainly from aromatisation of adrenal gland androgens, mainly androstenedione to estrone, which can itself be further converted to 17b-estradiol. This aromatization occurs principally in the fat tissue so that the circulating estrogen concentrations are relatively higher with obese postmenopausal women.

......the estrogen dose needed to effectively prevent or treat the consequences of postmenopausal estrogen deficiency may vary according to the considered aspect of the "postmenopausal syndrome". As an example, in many women vasomotor symptoms are treated satisfactorily which a lower estrogen dose than the average dose believed to be required for effective prevention of postmenopausal bone loss. 
• Determinants of Estrogen Effects

Indeed, the estrogen receptor, in combination with different estrogenic compounds, regulates more than one DNA response element, which allows for the possibility that estrogenic compounds can have differential effects in different estrogen-responsive tissues, through activation of specific pathways. 
• The Bio-Transformation of Estrogens
• Central Role of the LiverThere is an important "first passage phenomenon" with extensive metabolic change in the intestinal wall and the liver with oral administration of estrogens before the molecule reaches the general circulation; in some cases virtually no unaltered substance will reach the circulation....... In addition to the first passage phenomenon, which is important for the bio-transformation and the metabolic effects of orally administered estrogens, the liver is also involved in the bio-transformation of estrogens after they have already reached the circulation....................
• The Protein-Binding of Estrogen
• Natural and Synthetic Estrogens

Various estrogen preparations are available for therapy. These can be classified into "natural estrogens" and synthetic estrogens. Among the natural estrogens are 17b-estradiol, estrone, estriol and estrogen conjugates such as estrone sulphate; also available is a series of esterified forms of estradiol such as estradiol valerate, estradiol cypionate, estradiol phenyl propionate and estradiol benzoate. A special position is occupied by a mixture of conjugated estrogens, excreted in the urine of pregnant mares. This mixture has a complex composition with at least nine different estrogens, including estrone sulphate and a series of estrogens which is admittedly natural but which does not occur in humans, e.g. equiline sulphate and 17a-dihydroequiline sulphate. 

.....Natural estrogens are usually recommended for hormone replacement therapy, whereas ethinyl estradiol is the classical estrogen component of oral contraceptives..... 

• Therapy With Estradiol and Estradiol Esters

Oral administration
Using "micronised" preparations, estradiol is readily taken up with maximum concentrations usually attained between two to six hours. 
Transdermal administration
In practice two forms of parenteral administration of estradiol through the intact skin are used, i.e. with an estradiol-containing hydro-alcoholic gel or by using a transdermal therapeutic system with controlled release of estradiol, the patch or plaster. In a first generation of patches, an alcoholic estradiol solution is held in a reservoir and is separated from the skin by a rate controlling membrane. In a more recently developed type of patches, estradiol is directly dissolved or dispersed into the adhesive matrix of the patch, the rate of release being controlled by the specific formulation of the matrix. 

The estrogen penetrates the stratum corneum within several minutes of the estrogen-containing gel being applied to the skin, where most of it is stored, and then diffuses out during the subsequent hours to the capillary plexus in the dermis so as to reach the general circulation. 
Other methods of administration
Fairly constant serum levels are attained over several months with subcutaneous implantation of a rod or pellet of crystalline estradiol. Variability of serum levels over prolonged periods of time may be smaller than with the transdermal delivery systems. There are nevertheless significant variations in the total time during which adequate levels are maintained. This method of administration leaves little room for individual dose adaptations. 

• Therapy With Other Estrogens

Estriol
Estriol is a weak estrogen which cannot be converted to estradiol. It is almost completely conjugated in the intestine to glucoronides and sulphates after oral intake; only 1-2% estriol reaches the circulation. Enterohepatic circulation can contribute significantly to the estriol levels, with food ingestion resulting in a secondary rise of estriol levels. It may therefore be advisable that estriol is taken in the evening in order to avoid endometrial proliferation during unopposed treatment. It is noteworthy that unexpectedly high systemic concentrations can be attained with vaginal applications (creams, ovules). 
Equine estrogen conjugates
The complex composition of the clinically used mixture of sulphated estrogens separated from horse urine makes it extremely difficult to study the kinetics and there is an almost complete absence of data for various components of this estrogen mixture. 
• Differences Between Oral and Transdermal Administration 

It has been argued, but not confirmed, that the favourable effects of estrogen therapy on lipid metabolism (lowering of the total cholesterol and increasing the HDL cholesterol) can be more limited with transdermal administration than with oral administration. There have been no current studies which allow the proposal that either of the administration methods offers clinically tangible clinical advantages. It must be remembered here that the choice of the progestagen which is associated with the estrogen treatment can also have important metabolic consequences. 
• Conclusions

The pharmacokinetics of estrogens is marked by a large interindividual variability. The determination of the plasma concentrations is, however, of little use for monitoring of the treatment in individuals. Indeed, for a same treatment plasma estrogen levels may vary greatly in function of time in a single individual. 

For the choice of treatment in individuals, this general context forces a pragmatic policy in which a scrupulous clinical evaluation remains of crucial importance. The prescribing doctor should allow himself to acquire sufficient clinical experience with a limited number of treatment regimens, but the clinical findings, the wishes of the patient and her own evaluation of the clinical results should always remain decisive elements when choosing or adjusting a treatment. 
References


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There are two main groups of progestogen, progesterone and its  analogues (dydrogesterone, hydroxyprogesterone, and  medroxyprogesterone) and testosterone analogues (norethisterone and norgestrel). The newer progestogens (desogestrel, norgestimate, and gestodene) are all derivatives of norgestrel; levonorgestrel is the active isomer of norgestrel and has twice its potency. Progesterone and its analogues are less androgenic than the testosterone derivatives and neither progesterone nor dydrogesterone causes virilisation. Other synthetic derivatives are variably metabolised into testosterone and oestrogen; thus side-effects vary with the preparation and the dose.

Abstract:

The inclusion of progesterone or a progestogen in hormone replacement therapy (HRT) inhibits endometrial proliferation and minimizes the risk of endometrial hyperplasia and subsequently endometrial carcinoma caused by unopposed exogenous estrogens. Progestogens are therefore an essential part of HRT for women with an intact uterus. Beside the effect on the estrogen-primed endometrium, progesterone has many other properties. Its name is derived from its progestational activity: the maintenance of pregnancy. Progestogens are steroids with many properties in common with progesterone, though not always all. Some progestogens are even lacking progestational activity. This makes a proper definition of progestogens difficult. The best fitting definition of a progestogen seems to be: steroids which induce secretory changes in endometrium after priming with estrogens. There are substantial differences between the currently available progestogens both in chemical structure and in pharmacological profile. It is important to consider these differences when HRT is prescribed. [Eur Menopause J 3(4):266-271, 1996. © 1966 PMSI Bugamor B.V.] 

Contents

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• Classification

Progesterone is the only natural progestogen with a clear biological function. The other progestogens which are used clinically are all synthetic. Synthetic progestogens have always been classified according to their structure. This differentiates between progestogens derived from progesterone (C21-progestogens) and the derivatives of testosterone (C19-progestogens). This classification has no bearing on the activity of the progestogens, only on the structure.
• Potency of the Various Progestogens 

Whatever applies to the progestogen potency of the various progestogens also applies to the androgen and estrogen potency of these substances. All progestogens derived from testosterone also possess some androgenic activity. But also some C21-progestogens, such as medroxyprogesterone acetate and chlormadinone acetate bind to the androgen receptor, albeit to a much lesser extent. Progesterone, dydrogesterone, cyptoterone acetate and promegestone have no androgenic activity at all. Norethisterone and its derivatives bind also to the estrogen receptor and therefore have an intrinsic estrogenic activity. 
• Selectivity
• Bio-Availability

Unfortunately, little is known about the pharmacokinetics of most progestogens. The scarce information is mainly from short-term, acute experiments. There is no information about absorption, maximum blood levels or half-life over longer periods. These large differences in biological availability do mean however that the standard dosages are too high for some women, with resulting side-effects, and too low for other women with the risk of insufficient effect on the endometrium (figure 1). 
• Metabolic Effects

Regarding the dose, the problem of the interindividual variation in bio-availability becomes problematic. This 10-fold variation, mainly due to variable absorption, hampers a correct uniform dose suitable for everyone. The usually advised dose is based on research, aimed for complete inhibition of mitotic activity in virtually 100% of tested persons. Following this advice, a large number of women will therefore receive too high a dose and virtually nobody will receive too low a dose. 

Medroxyprogesterone acetate (MPA) has been investigated extensively in this context. This progestogen gives variable and inconsistent results on the endometrium, even with a dose of 10 mg. Nevertheless an extensive research programme involving 270 women showed no hyperplasia after a year with a sequential dose of 10 mg of MPA, and in less than 1% with 5 mg MPA. 

A definite answer about the duration and dose on the basis of the bleeding pattern can only be obtained in a prospective study specially designed for this purpose. 

The bleeding pattern with continuous combined HRT is not influenced by the choice of the progestogen. With all progestogens the same pattern of spotting and/or bleeding has been reported. 

Most of the C19-progestogens, when used in the commonly recommended doses for HRT, have an unfavourable effect on lipoproteins. Although a large body of literature is devoted to these effects, the clinical significance is as yet not clear. 

For continuous combined HRT (ccHRT), the use of C21-progestogens or micronised progesterone is preferred on theoretical grounds, given the pronounced changes in lipoproteins with both levonorgestrel and norethisterone. MPA exhibits an unfavourable effect on HDL when continuously administrated in the recommended dose of 2,5 mg. 

• Clinical Relevance of the Differences

The only difference between the various progestogens with clinical significance is the androgenicity of many of them. Micronised progesterone, medrogestone, promegestone, dydrogesterone and cyproterone acetate are free of any androgenic activity. Of the C19- progestogens, the newer ones (gestodene and desogestrel) have a much more favourable selectivity (progestogen/androgen ratio) than the other derivatives of norethisterone. Theoretically, one should prefer them over to norethisterone or norgestrel. But for these progestogens virtually no data exist for use in HRT. 
• Conclusion
• Tables

References