Essential for good compliance with hormone replacement therapy (hormone replacement therapy) is the appropriate choice of estrogen and progestin, their dosage and the form of administration. An individual approach to the choice of drug is the first condition of successful long-term therapy. Treatment has to be efficacious, with a minimum of adverse side-effects. Ineffectual treatment with adverse side-effects often results in withdrawal within the first month of therapy. This may engender distrust or fear, and, as a consequence, permanent refusal of such treatment. Not only is the appropriate choice of drug, dose and form of administration necessary, but also full information on possible adverse side-effects, which for the most part disappear within the first 3 months of treatment.

Types Of Estrogens, Dosage And Administration

The main circulating estrogen in the premenopause is 17β-estradiol, produced in the ovarian granulosa cells by conversion from testosterone. Another circulating estrogen is estrone, produced during the conversion of estradiol and by peripheral conversion from androstenedione in fatty tissue. In the postmenopause, estrone produced by peripheral conversion from androstendione is the main circulating estrogen. Estradiol and estrone are the most frequent components of hormone replacement therapy preparations.

Natural and synthetic estrogens may be used in hormone replacement therapy. Natural estrogens include 17β-estradiol, estradiol valerate and estriol, which are human hormones, and conjugated vegetal and equine estrogens (conjugated equine estrogen). The basic component of conjugated equine estrogen is estrone sulfate, and preparations also contain non-human estrogens, for example equilin and equilinin. These bind to estrogen receptors and have a long half-life. Synthetic estrogens are still used in some oral hormone replacement therapy preparations, primarily ethinylestradiol. They are more efficacious than natural estrogens, as may be seen in their effects on liver function and fibrinolytic and coagulation factors, as well as an increased risk of hypertension and thromboembolism especially in users of hormonal contraceptives. Estrogen is most frequently administered orally. Alternative formulations are transdermal (patch), percutaneous (gel), subcutaneous (implants), intranasal (spray) and vaginal (tablets, cream and rings). Oral administration has a two-fold specific effect not seen with any of the other methods. First, conversion to estrone occurs in the intestinal mucosa. This results in a change of the premenopausal condition where the estradiol/ estrone ratio is in favor of estradiol. Conversion of estradiol to estrone does not depend on the type of oral estrogen. The other specific effect of oral estrogens is the so-called ‘first-pass’ effect in the liver. Absorbed estrogen enters the liver via the portal vein, and is then metabolized 35-95% into the inactive estrone-3-glucuronide. This means that oral estrogen doses must be substantially higher than non-oral doses to obtain similar therapeutic plasma levels.

Estrogens vary in their dose equivalence and their effect on target tissues. Oral micronized estradiol 1 mg is equivalent to conjugated equine estrogen 0.625 mg, piperazine estrone sulfate 0.625 mg, esterified estrogens 0.75 mg and ethinylestradiol 0.005-0.015 mg. Today, the trend is to minimize estrogen doses. Findings on the efficacy and safety of and tolerance towards lower estrogen doses in hormone replacement therapy are key to the compliance problem. Recent studies suggest that lower estrogen doses may provide benefits similar to those with the currently used standard doses, while at the same time reducing the incidence of side-effects. For example, doses of 1 mg estradiol and 0.3 mg conjugated equine estrogen relieve acute symptoms of the climacteric syndrome, have a bone-sparing effect, relieve vaginal atrophy and result in minimal side-effects.

Special Features Of Transdermal And Percutaneous Administration

Transdermal patches have been used in Europe since 1985. The results of the first four Estraderm ® studies by Whitehead and coworkers and Place and colleagues were presented at the 4th International Congress on the Menopause in Orlando, Florida. Findings from both single-center and multicenter studies soon revealed that the transdermal system was more efficacious and better tolerated than conjugated estrogens, and did not affect liver proteins.

Transdermal administration has improved during the past decade, and is being used more and more. A satellite symposium of the XIV FIGO Congress discussed hormone replacement therapy methods and alternatives to oral administration. Nachtigall had evaluated both the advantages and the disadvantages of oral and transdermal hormone replacement therapy delivery, and suggested that the benefit of transdermal systems was that they secure the therapeutic effect with lower doses and uniform estradiol release. Owing to ‘direct estrogen infusion’ with no effect on liver protein production, transdermal delivery is suitable for women presenting with certain health conditions.

It was reported at the 8th International Congress on the Menopause in Sydney in 1996 that, of all types of hormone replacement therapy application, transdermal systems are used most frequently with oral administration coming next, while vaginal methods (rings delivering estradiol) are used less often and implants are rare. However, the situation in the Czech Republic is different. Oral administration is used most often and transdermal patches represent a third of the total amount of prescribed hormone replacement therapy, although their application is increasing. Vaginal hormone replacement therapy administration is quite unsatisfactory; so far, vaginal rings delivering estradiol have not been approved for clinical use in the above country.

Basically, all kinds of administration, with the exception of oral and vaginal estriol, have a very similar effect; there are, of course, some differences owing to the individuality of patients and the symptoms for which hormone replacement therapy is indicated.

Some particular traits may be seen in transdermal and percutaneous administration not seen with oral drugs, and they may be beneficial under specific conditions. Such advantages result from the following properties:

  1. (1) Hormones bypass the gastrointestinal tract;
  2. (2) Hormones are absorbed directly from the skin into the blood circulation and diffused to target organs before passing through the liver, i.e. there is no ‘first-pass’ effect;
  3. (3) In the case of oral estradiol administration as much as 70% of the hormone is converted into estrone and thus the efficacy is lower. The estradiol/estrone ratio in transdermal application is approximately 1, i.e. the natural premenopausal balance. Transdermal therapy therefore has an optimum pharmacokinetic profile, and estradiol blood levels reach their peak faster and are more stable;
  4. (4) Triacylglycerol levels in the lipid profile do not rise;
  5. (5) The positive effect on bone density may be quicker with transdermal delivery than after oral administration;
  6. (6) There are fewer adverse side-effects.

The indication area is basically the same for transdermal and percutaneous hormone replacement therapy as for hormone replacement therapy generally. However, transdermal hormone replacement therapy can be prescribed in the presence of some pathological conditions that do not allow oral therapy, or when such therapy is less effective than transdermal patches. These conditions include:

  1. (1) After thrombophlebitis or deep vein thrombosis;
  2. (2) Liver disease with abnormal liver function;
  3. (3) More serious osteoporosis with a higher risk of fractures;
  4. (4) Dyslipidemia with higher triacylglycerols;
  5. (5) Gastrointestinal and gall-bladder problems;
  6. (6) Other side-effects of oral hormone replacement therapy.

In clinical practice, transdermal patches and percutaneous gel (Oestrogel ® and Estreva ®) reduce the incidence of hot flushes and eliminate all signs of estrogen deficiency, and thus improve the quality of life of women. They raise neither blood pressure nor blood sedimentation rate factors (fibrinogen and antithrombin III). They reduce plasma levels of total cholesterol and of low-density lipoprotein (low-density lipoprotein) cholesterol. This effect seems to be associated with a rise of serum estradiol concentration and increased activity of low-density lipoprotein receptors. A cross-study involving gel, transdermal patches and oral estradiol carried out to compare the pharmacokinetic indicators of various kinds of estradiol (E2) administration revealed that Oestrogel, Estreva and Estraderm resulted in stable E2 and estrone (E1) concentrations, while the E2/E1 ratio was similar to that in women with an active menstrual cycle. Percutaneous Oestrogel (1.5 mg dosage) resulted in least individual variability. Oral Estrace ® exhibited better biological availability, but conspicuous changes of level with time and a non-physiological E1 level. As far as E2 biological availability in transdermal preparations using a matrix patch is concerned, a statistically significant increase in E2 serum levels after a week of application was found with both Dermestril 50 ® and Climara ® at a 1% significance level for both drugs. E2 levels remained stable with both preparations over a period of 4 weeks, and the nature of changes was very similar. Both medicaments had a very good clinical effect. The Kupperman index improved with Dermestril from an average of 20 points to 4.6 after 4 weeks’ administration, and the result was similar with Climara. In a study of 186 women, von Hoist and Salbach evaluated the efficacy of and tolerance towards a 7-day transdermal E2 patch versus placebo in women after hysterectomy with postmenopausal complaints. They assessed the Kupperman index, a score of urogenital complaints and adverse dermal side-effects of the patch in three treatment cycles. Compared with placebo, the patch was well tolerated, and genuinely attenuated mild and severe vasomotor symptoms in women after hysterectomy; the onset of this effect was rapid and it persisted for 7 days. Although our group used a different 7-day E2 patch (in the above-mentioned study the patch used was Fem7 ®), our results are similar. The effects of transdermal and percutaneous forms of estradiol and the nature of changes in hormone levels are known from the literature; the situation is somewhat different with vaginal and intranasal estradiol.

When E2 biological availability was assessed after daily Oestrogel or Estreva application, a statistically significant increase in serum E2 levels was found already after 1 week, and the nature of the rise was very similar to that found with Climara transdermal application. Thus, Oestrogel represents a valuable first-choice drug in hormone replacement therapy indications. It provides fast biological availability and stable E2 levels.

Estreva is a new gel preparation containing an estradiol dose of 0.1% (the daily dose of gel, 1.5 g, provides the recommended daily dose of E2, 1.5 mg), administered with three squeezes of the pump dispenser. It contains glycol derivatives that completely dissolve E2 in a hydro-alcohol medium and allow a lower ethanol content in the gel base. The nature of E2 levels seen in our patients is indicative of a persisting statistically significant rise in E2 serum levels already within the first week of administration. Pharmacokinetic data, followed during the first 24 h after administration of the same daily dose of 1.5 mg of E2 in the gel, presented a smooth rise of E2 and E1 to a maximum within 12 h after administration; the authors found no statistically significant differences in E2 and E1 values with the reference gel. The values of serum E2 seen in our study with the administration of an identical dose were significantly higher, and corresponded to the values Scott and colleagues found after the administration of a daily dose of 3 mg. The biological availability of E2 with a daily dose of 3 mg of E2 was greater than with the reference gel. With this dose, the maximum serum levels are reached very quickly, within 2-4 h after administration. Our results obtained 12 h after administration of the gel presented significantly higher E2 levels, yet essentially their nature corresponds to the maximum found 12 h after administration by other authors. In these cases we found significantly higher serum E2 values after a daily dose of 1.5 mg of E2, but the relatively small set of patients does not allow a reliable comment. Oral estrogen therapy is the priority for patients presenting problems with skin tolerance of the patch adhesive and/or adverse side-effects.

Characteristics Of Intranasal Administration

The intranasal form of estradiol, Octodiol ® (Aerodiol ®), is a new delivery form that works on the principle of the pulsed nature of changes in E2 levels. Our results confirm a significant reduction of the Kupperman index with a daily E2 dose of 300 mg. Studd and colleagues found this to be the optimum dose for 80% of women. A significant decrease in the Kupperman index sets in after 4 weeks, with a maximum decrease reached after 12 weeks of treatment. The intensity and number of hot flushes decreases similarly to those found with oral E2 in a daily dose of 2 mg. Also, the effect is similar to that of transdermal E2 in a daily dose of 50 µg. Compared with placebo, the Kupperman index decreases after 1 week of intranasal therapy, and after 3 weeks this decrease is statistically significant. The effect is long-lasting, as shown by the study of Gompel and associates. After 12 weeks there was a statistically significant decrease of the Kupperman index at a level of p<0.001.1 n accordan with data from the literature, our results show that the treatment has a minimum of adverse side-effects. Mattsson and colleagues and Lopes and co-workers found that use of Octodiol results in a smaller occurrence of mastalgia than that with oral or transdermal hormone replacement therapy. In women with a preserved uterus Octodiol presents fewer cases of irregular bleeding than with oral or transdermal E2. Octodiol gives stable absorption and high biological availability, i.e even small doses may be administered. Our results confirm a persisting biological ratio of E1/E2. Studd and colleagues found that Octodiol does not produce changes in mucociliary clearance or mucus viscosity of the nasal mucosa. Local symptoms are responsible for less than 3.5% of withdrawals from treatment, as against 5-8% with transdermal therapy. The compliance with Octodiol in long-term treatment is very good. After 1 year it is still taken by 85% of women. In our study, we found a relatively high fluctuation of E2 levels with a statistically significant rise only after 1 week of treatment, which could, theoretically, indicate a lower absorption of the drug than with other parenteral forms. However, it must be taken into consideration that our values were measured 12 h after nasal administration of the drug. None the less, the mean E2 values throughout the period of the study were within the range of premenopausal values or transdermal hormone replacement therapy values. They indicated a possible effect after 24 h.

Plasma Lipoproteins And Selective Hormone Replacement Therapy In Clinical Practice

Dyslipidemia participates in the onset of cardiovascular disease, or, expressed more clearly, in the development of coronary ischemia, in one-third of patients. It is important, therefore, to examine lipids as a certain risk indicator both before hormone replacement and during hormone replacement therapy. Long-term monitoring of lipid metabolism indicators is required; this is sometimes rather difficult owing to the great variability of input parameters and individual differences in hormone replacement therapy effect. Lipid evaluation must be carried out in every study in a way that would eliminate as much as possible any distortion, both positive and negative.

In a continuous study we investigated lipid profiles with various hormone replacement therapy methods. This was a short-term study; we studied a few sets of patients treated with conjugated estrogens (Presomen ® 0.625 mg and Oestrofeminal ® 0.6 mg) with and without medroxyprogesterone acetate (medroxyprogesterone acetate) (daily dose 5 mg) and with 17β-estradiol using a transdermal system (Estraderm ® 50 and 25) with and without medroxyprogesterone acetate for a period of 1-2 years. The goal of the study was to evaluate the effect of different hormone replacement therapy methods on plasma lipoprotein levels in postmenopausal women, and to determine the best possible form of hormone replacement therapy delivery to dyslipidemic patients. The following values were determined before hormone replacement therapy and at specific intervals in a total of 98 women treated with hormone replacement therapy: plasma lipid levels including total cholesterol, high-density lipoprotein (high-density lipoprotein) cholesterol, low-density lipoprotein cholesterol, triacylglycerol and low-density lipoprotein/high-density lipoprotein ratio, and hormone levels including luteinizing hormone (luteinizing hormone), follicle stimulating hormone (follicle stimulating hormone) E2, Eb prolactin and, in some cases, thyroid stimulating hormone, tri-iodothyronine, thyroxine and parathormone. Statistical analysis of differences in all monitored values was carried out using both paired and unpaired /-tests. Attention was paid to determination of differences in the following values before and during treatment between groups on estrogen monotherapy and in combination with medroxyprogesterone acetate; and between groups on oral therapy with conjugated estrogens (Presomen ®, Oestrofeminal ®) at a daily dose of 0.625 mg and transdermal administration (Estraderm ® TTS 50 and/or TTS 25)

Patients were divided into nine groups in the following way:

(1) Patients treated with transdermal estradiol:

(a) Estraderm ® 50 and normolipidemia;

(b) Estraderm ® 50 and dyslipidemia;

(c) Estraderm ® 50+medroxyprogesterone acetate and normolipidemia;

(d) Estraderm ® 50+medroxyprogesterone acetate and dyslipidemi

(e) Estraderm ® 25+medroxyprogesterone acetate an d dyslipidemi

(2) Patients treated with conjugated estrogens

(a) Presomen ® 0.625 mg in monotherapy;

(b) Presomen ® 0.625 mg+medroxyprogesterone acetate;

(c) Oestrofeminal ® 0.625 mg in monotherapy;

(d) Oestrofeminal ® 0.625 mg+medroxyprogesterone acetate.

Average age and time elapsed since natural or artificial menopause were comparable in all groups. Patients on estrogen monotherapy had undergone a hysterectomy; those with the medroxyprogesterone acetate combination had an intact uterus. The groups were identical; all followed patients were examined before starting hormone replacement therapy and then after 6, 12, 18 and sometimes even 24 months. This suggests that the results obtained may be considered relatively accurate. An interesting finding is that with Estraderm ® there was deterioration of the studied parameters of lipid metabolism in cases of normolipidemia, but we should be careful in evaluating such results as the values remained within physiological limits. Patients after hysterectomy and with dyslipidemia treated with Estraderm ® 50 presented significantly increased E2 levels only after 18 months and a favorable effect on all lipid metabolism indicators, but these were not statistically significant. Statistically significant lower high-density lipoprotein cholesterol levels at a 1% level of significance were found in the group on combined therapy with Estraderm ® 50+medroxyprogesterone acetate and dyslipidemia after 1 year of treatment. Estraderm ® TTS 25+medroxyprogesterone acetate (daily dose 2.5 mg) was prescribed to perimenopausal women without any conspicuous estrogen deficiency. No statistically significant results were found in women with normolipidemia. With regard to oral conjugated estrogens, women after hysterectomy were on therapy with Presomen ® alone (daily dose of 0.625 mg). Lower low-density lipoprotein cholesterol levels and low-density lipoprotein/high-density lipoprotein ratio were found in women with dyslipidemia after 1 year of treatment, but this was not statistically significant. Results were even better after 18 months’ therapy. The total picture of lipid metabolism was favorable.

After 24 months of therapy, the E2 level increased, which was significant at a 5% level. After therapy with Oestrofeminal ® alone (daily dosage o f 0.6 25 mg) in dyslipid em ia, no s cant differences in levels were found after 12 months of treatment and no differences were found in women with dyslipidemia treated with Presomen ® 0.625 mg+medroxyprogesterone acetate 5 mg. Of course, we were interested in the relationship between lipid levels in patients treated with transdermal estradiol and in those on oral conjugated estrogens. Statistical comparison in both groups was performed of both initial values and those measured during therapy. After 12 months of hormone replacement therapy, statistically significantly lower values were found in the Oestrofeminal ® group (1% significance) as well as significantly lower low-density lipoprotein cholesterol concentration and low-density lipoprotein/high-density lipoprotein ratio (1 % significance). On the basis of the above, we believe that the effect of conjugated estrogens is more favorable.

Interpretation of the relationship between hormone replacement therapy and plasma lipoproteins is not easy, as we noted at the end of our study; it requires the assessment of identical groups comparable in the following basic parameters: menopause both natural and induced, duration of menopause, initial E2 and follicle stimulating hormone levels, strict differentiation between normolipidemia and dyslipidemia, and stable type of hormone replacement therapy with or without progestogens. It is sometimes difficult to secure stability of an hormone replacement therapy method as a number of patients change hormone replacement therapy depending on their compliance, or in the case of side-effects. To determine the effect of hormone replacement therapy on lipoproteins in the case of normolipidemia may be questionable: ‘adverse changes’ remain within the standard range. hormone replacement therapy has a positive effect on plasma lipoproteins in cases of dyslipidemia. Conjugated estrogens have a greater effect on plasma lipoproteins. Oestrofeminal ® reduces cholesterol and low-density lipoprotein cholesterol more significantly than Estraderm ®. medroxyprogesterone acetate does not significantly affect the favorable influence of conjugated estrogens, but it can reduce the favorable effect of Estraderm ® on high-density lipoprotein cholesterol. The results have revealed that it is always necessary to adopt a selective approach to hormone replacement, depending on whether the woman has undergone a hysterectomy and whether the woman is normolipidemic or dyslipidemic.

Vaginal Estrogen Therapy

Vaginal estrogens may be used as tablets, globules, suppositories, cream, rings or pessaries. The following estrogens are used for vaginal administration in the Czech Republic: estradiol (Vagifem ® tablets) and estriol (Ortho-Gynest ® suppositories and cream, Ovestin ® suppositories and cream). Vaginal absorption depends on several factors, i.e. thickness of the vaginal wall, its vascular supply and blood return, occurrence of inflammatory changes and pathological microbes. A little greater absorption may be seen in an atrophic vaginal wall. With a thicker wall and the reappearance of glandula, estrogen systemic absorption reduces markedly. Vaginal administration is thus less suitable for treatment of vasomotor problems and for the prevention of osteoporosis and cardiovascular disease, but it is good for treating urogenital problems.

Estrogens have a specific effect of stimulation on urogenital tissues, i.e. the vagina, cervix, urethra and trigone of the bladder. The result is regeneration of the vaginal epithelium and proliferation of the urethral epithelium with rapid improvement of urogenital problems caused by atrophy, such as vaginal dryness, soreness, itching and burning, dyspareunia and problems with urination defined as the urethral syndrome. There is neither endometrium proliferation nor vaginal bleeding with vaginal hormone replacement therapy, especially when estriol is used, so there is no need for progesterone administration to women with an intact uterus. In the case of vulvar skin atrophy, a possible factor predisposing to dystrophic changes, vaginal estrogen cream may be indicated. Pruritus, tingle, paresthesia and tendency to inflammatory changes of the skin are first signs, which should indicate hormone replacement therapy.

Postmenopausal vulvovaginitis therapy should be performed in three areas:

  1. (1) Alleviation of complaints and cure of acute inflammation: non-specific antiinflammatory and antimicrobial therapy;
  2. (2) Targeted antimicrobial therapy based on results of tissue cultures and microbial sensitivity: both local and general therapy using chemotherapy and antibiotics;
  3. (3) Long-term estrogen therapy to eliminate or relieve symptoms of atrophy of the vulvar skin and epithelium: local, general therapy or their combination depending on the patient’s condition.

After local estrogen therapy, symptoms of vaginal atrophy improve in a few days; with vulvar atrophy improvement is seen usually after 2-3 weeks.

Strategies for treatment of the urethral syndrome depend on the severity of symptoms. Local and vaginal estriol (cream, suppositories, globules) is recommended for treating mild initial complaints. At the beginning of therapy it is administered daily, and then every other day after alleviation. Moderate symptoms of mucosal atrophy should be treated using a combination of general and local estrogen therapy (vaginal estradiol or total estradiol with local estriol). In severe complaints caused by mucosal atrophy, any infection should be cured first and then long-term administration of combined hormone replacement therapy, total oral treatment or transdermal therapy with vaginal estrogens is indicated.

Although vaginal E2 has proved efficacious in the urogenital area, its possible systemic effect has not been taken into consideration in some studies. Obviously, this is affected by the condition of the vaginal mucosa, its absorption capacity, secondary infection and so on. As early as 1984, Martin and colleagues published a study in which they established, already within 1 h after administration of a vaginal tablet containing 0.5 mg of micronized estradiol, a 5.3-fold rise in E2 serum levels and a 1.5-fold rise of E1 levels. They also determined a corresponding significant decrease in luteinizing hormone and follicle stimulating hormone levels. According to their results, vaginal absorption of micronized E2 into the systemic circulation was rapid and efficacious. Moreover, patients readily accepted and tolerated well the vaginal path of administration. In this respect, our results tally with this earlier study. According to the literature, in women with a preserved uterus, vaginal administration twice weekly did not result in endometrial hyperstimulation. After 1 year of treatment endometrial proliferation was found in only 6% of cases, and after 2 years atrophy of the endometrium was found in 100% of cases.

Biological Availability Of Estradiol With Different Hormone Replacement Therapy Methods

The basic precondition of biological availability of E2 in the various methods of hormone replacement therapy administration is to achieve premenopausal and well-balanced E2 blood levels in both short- and long-term profiles and a favorable ratio of E2 and El levels. This problem was investigated in our case studies. We found that with vaginal E2 application a statistically significant rise in E2 blood levels appeared as early as 2 weeks after the beginning of therapy and persisted, with a marked improvement of the Kupperman index, for 4 weeks (short-term profile). On the basis of this observation, we prepared a study comparing the effects of different methods of hormone replacement therapy application on the biological availability of E2 in a group of 80 postmenopausal women. The goals of our study were the following:

  1. (1) To assess the effect of E2 administration on gonadotropin serum levels of luteinizing hormone, follicle stimulating hormone, E1 and E2;
  2. (2) To evaluate the biological availability of E2 with transdermal, percutaneous, intranasal and vaginal hormone replacement therapy as related to the nature of changes in serum levels;
  3. (3) To assess possible advantages and disadvantages of different hormone replacement therapy methods and their potential mutual substitutability.

The group was divided according to hormone replacement therapy methods into the following subgroups:

  1. (1) Transdermal E2 (Climara ®);
  2. (2) Percutaneous E2 (Oestrogel ® and Estreva ®);
  3. (3) Intranasal E2 (Octodiol ®);
  4. (4) Vaginal E2 (Vagifem ®)

The studied parameters, i.e. serum luteinizing hormone, follicle stimulating hormone, E1 and E2, were analyzed statistically using the non-parametric Wilcoxon method for the paired /-test and the Mann-Whitney method for the unpaired /-test. Simultaneously the Kupperman index was also studied. The following results were obtained in a short-term 4-week hormone replacement therapy profile:

  1. (1) A statistically significant rise in E2 levels with all therapeutic methods (transdermal, percutaneous, intranasal and vaginal): with transdermal, percutaneous and intranasal administration after 1 week and with vaginal therapy after 2 weeks;
  2. (2) A statistically significant rise in E1 levels wit percutaneous (Oestrogel ®) and intranasal administration after 1 week, and a statistically significant drop in luteinizing hormone and follicle stimulating hormone levels with both transdermal and percutaneous applications after 1 week;
  3. (3) A conspicuous drop in the Kupperman index with all four methods of administration.

We drew the following conclusions from the above results

  1. (1) All four hormone replacement therapy methods induced a rapid rise in E2 levels up to almost double values (to the premenopausal level), after 1 week with transdermal, percutaneous and intranasal administration, and in 2 weeks with vaginal therapy;
  2. (2) E2 levels were well-balanced in all four therapeutical methods without any risk of hyperstimulation of the target organs;
  3. (3) E1 levels did not change with transdermal and vaginal administration but they rose nearly three-fold with percutaneous therapy; the final E2/E1 ratio was, however, normal in a 12-month profile;
  4. (4) All four hormone replacement therapy methods had a good clinical effect on climacteric symptoms;
  5. (5) Theoretically, depending on E2 availability, all four methods can be equally efficient and mutually substitutable.

Our experience suggests that examination of E1 and E2 blood levels is useful. It is especially important in the postmenopausal period, as it provides information on the current E2 level, which is the basic precondition of biological availability, and on the efficacy of the selected therapeutical method. Hormone level determination may be decisive for the choice of an hormone replacement therapy method from the viewpoint of individual selective hormone replacement therapy.

Conclusions

Parenteral forms of administration ensure a rapid onset of action and attenuation of complaints within 1-2 weeks of treatment. Their advantage is that they achieve steady serum levels of E2, similar to premenopausal levels. They bypass the gastrointestinal tract and the liver and thus present fewer adverse side-effects, especially gastrointestinal; they are a smaller burden for the liver and for the venous system; and in the lipid spectrum they do not raise triglycerides. We prefer them in patients pre senting with hepatic disorders, after thromboembolic events and in hypertriglyceridemia. The investigated parenteral hormone replacement therapy forms presented, over a 4-week study period, a rapid and significant reduction of acute symptoms of the climacteric. It was most pronounced with transdermal estrogen administration. Equally interesting is the vaginal administration of E2 in relation to its systemic effect. In addition to the treatment of urovaginal symptoms of an organic estrogen deficiency syndrome, we are justified in expecting with this therapy also a favorable impact on vasomotor symptoms of the climacteric. This is, in a way, indicated by the profile of peripheral E2 levels with this treatment. A rise of E2 levels was statistically significant, although less pronounced and slower than with other forms. All other hormone replacement therapy forms presented a similar statistically significant rise of E2 levels and a drop of follicle stimulating hormone levels. Lower E2 levels with Octodiol ®, compared with transdermal and percutaneous hormone replacement therapy, correspond to the pulsed nature of the drug, with E2 levels reaching their maximum soon after administration; we found such values, however, 12 h after administration, i.e. long after the pulse peak. A statistically significant rise of E1 could be seen with percutaneous gels and an unfavorable E1/E2 ratio, especially with Oestrogel ®. A similar rise of E1 with intranasal administration was, however, accompanied by an adequate rise of E2, so that the E1/E2 ratio remained within normal limits. With all the evaluated hormone replacement therapy types we saw good efficacy, tolerance and no adverse side-effects.

With Octodiol ®, patients appreciate the speed and ease of administration, discrete form and rapid onset of effect. With regard to compliance at the beginning of treatment, all the investigated types of hormone replacement therapy seem appropriate, and it will be solely up to the patient which form she prefers for comfort. Parenteral forms of estrogen therapy applied percutaneously, intranasally or vaginally seem to be effective in relieving acute vasomotor and subacute urogenital symptoms of estrogen deficiency, and are mutually interchangeable when side-effects appear. In addition, percutaneous and intranasal estrogen application forms allow individual low-dose treatment with the use of minimal efficacious doses.

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