The First World Congress On: Controversies in Obstetrics - Get Now DOC by HC120917201712


									 The First World Congress On: Controversies in Obstetrics, Gynecology & Infertility
                          Prague, Czech Republic - 1999

                     Selecting the Oestrogen for Treatment

J. Studd and A. Vashisht

Dept. of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London,
United Kingdom

The aim of hormone replacement therapy is to essentially compensate for the
oestrogen-deficient postmenopausal state with all its adverse associated sequelae. In
theory, one would want to achieve constant levels of hormone, providing maximal
symptom relief at the minimal blood level. This would further serve to maintain
satisfaction and compliance as high as possible. There is as yet no ideal preparation,
suitable for all women, that functions as womens’ panacea.

There are three ‘natural’ oestrogens most commonly used for HRT: conjugated
equine oestrogens, oestradiol valerate and17b-oestradiol. The former two are given
orally, the latter may be given orally, transdermally, or subcutaneously. Oestrogen
replacement therapy was originally introduced in the oral form. Since then patches,
implants, gels and nasal spray preparations have been used.

Oral preparations have the advantage of being cheap, convenient, with a range of
different types. They can be combined with a cyclical or continuous progestogen
should there be a need to protect the endometrium. The oral oestrogen is converted
to oestrone(less potent) by the gut and liver, reversing the normal premenopausal
2:1 ratio of 17b-oestradiol to oestrone. A relatively large bolus of oestrogen is
introduced to the systemic circulation, with levels peaking after 4-8 hours. By 24
hours the levels are back to baseline.1 With problems of reduced bioavailability and
variable absorption, the plasma levels of oestradiol may be insufficient to achieve
osteo-protection, or relief of climacteric symptoms.

Oral preparations are subject to the hepatic first-pass metabolism effect. As a result
of this, the production of coagulation factors and renin substrate is increased. For
this reason, this route of administration should be avoided in any woman with an
increased thrombotic potential. However, the production of lipid apoproteins is
similarly increased, which will conversely have a cardioprotective role. The net result
is raised HDL and triglyceride levels, with a fall in LDL.2

Non-oral preparations avoid many of the pitfalls of oral oestrogen delivery. There is
no hepatic first-pass effect, and the physiological ratio of oestradiol to oestrone are
maintained. Furthermore, there is a better physiological pharmacokinetic distribution
of oestradiol.

The first transdermal patches consisted of oestradiol in an alcohol reservoir. The
most common problem associated with these were skin reactions, ranging from
minor skin irritation to blistering and ulceration. Newer preparations have attempted
to minimize these by mixing oestradiol in a glue matrix. Additionally with matrix
patches, the absence of alcohol alters the pharmacokinetic properties, giving a more
constant level of serum oestradiol. The patches are applied to the lower half of the
body and changed every 3-4 days.

Oestrogen gel is rubbed into the skin of the upper arm or inner thigh on a daily
basis. It offers flexibility in terms of dosage administration, but similarly patients
may unwittingly under or over self-medicate. A few patients may develop skin
irritation, or find the procedure messy.

Subcutaneous implants offer 6-monthly administration. Furthermore, at the time of
administration, it is possible to simultaneously add a testosterone implant should the
woman be complaining of menopause-related loss of libido, or lowered energy.
Despite the twice annual inconvenience of a minor surgical procedure, the infrequent
administration enhances compliance. As yet unpublished data from our unit has
shown long-term compliance rates in hysterectomised women as 90%. Day-to-day
levels of plasma oestradiol are remarkably constant. With implant therapy, it is
possible to elevate the oestradiol levels to the higher premenopausal physiological
range. This provides women with the maximal potential to reverse bone loss, and
may even have an anabolic effect on bone.3

It is important to remember with implant therapy that due to the prolonged duration
of action of the oestradiol, it is necessary in non-hysterectomised women to protect
the endometrium for up to two years after the last implant with a progestogen.
Additionally, there is the occasional occurrence of tachyphylaxis when
supraphysiological levels of oestradiol are achieved. In order to prevent this, it is
recommended that a woman should maintain a consistent duration in-between the
implants, and if she is symptomatic of ‘oestrogen-withdrawal’ towards the end of the
implant, that she should top-up her oestradiol levels with a gel or patch.

Most recently, an intranasal 17-oestradiol spray has been introduced. It has the
benefits of avoiding first-pass metabolism and provides lower inter- and intra-
individual variability in terms of serum oestradiol concentrations. Early findings
suggest it is well tolerated.4

The chosen preparation is obviously dependent on patient preference, patient type
and on presenting symptoms. In the younger patient, for example with a premature
menopause, it will be ideal to chose a higher physiological dose of oestradiol to
achieve symptom relief and to afford maximal osteoprotection. The older patient
may tolerate these doses less well, complaining of side effects such as breast
tenderness. The return of menses may well also be unwelcome. Local vaginal
application of oestriol is extremely effective in providing relief from vaginal
symptoms associated with postmenopausal atrophic changes, with minimal systemic
absorption. The lower oestradiol levels achieved by tablets or low-dose patches may
relieve vasomotor symptoms, vaginal dryness and insomnia. Higher doses achievable
by implants or high-dose patches may be necessary to combat low bone mass,
cyclical headache, irritability and depression.

The use of hormone replacement therapy is increasing in the Western world. As more
and more information is found regarding its benefits, and as women strive for a
fitter,longer and healthier life, so its popularity rises. There are an increasing variety
of preparations on the market, giving physicians and women alike the flexibility to
choose a preparation most suitable for them.

1. Kuhl H. Pharmacokinetics of oestrogens and progestogens. Maturitas

2. Lobo RA, Speroff L. International consensus conference on postmenopausal
hormone therapy and the cardiovascular system. Fertil Steril 1994;61:592-595

3. Khastgir G, Studd J, Holland N, Alaghband-Zadeh J, Fox S, Chow J.
Histomorphometric evidence of an anabolic effect of oestrogen on bone in older
postmenopausal women. Br. J Obs Gynae 1998;105(Suppl):5

4. Studd J, Pornel B, Marton I, Bringer J, Varin C, Tsouderos Y, Christiansen C.,
Efficacy and acceptability of intranasal 17 beta-oestradiol for menopausal symptoms:
randomised dose-response study. Lancet 1999;353:1574-8

To top