Effective bleeding control and symptom relief by lower dose regimens of continuous combined hormone replacement therapy: A randomized comparative dose-ranging study

Objectives: We compared two different continuous combined hormone replacement therapy (HRT) regimens of estradiol valerate (E₂V) and medroxyprogesterone acetate (MPA) with a combination of micronized estradiol (E₂) and norethisterone acetate (NETA) to determine bleeding pattern, control of climacteric symptoms, lipid profile, endometrial and general safety in a 1-year multicenter study. Methods: 440 postmenopausal women were randomized to three treatment groups to receive: 1 mg E₂V+2.5 mg MPA; 1 mg E₂V+5 mg MPA; or 2 mg of E₂+1 mg NETA. After the first 6 months, the E₂V dose was increased to 2 mg in both E₂V/MPA groups. Information on bleeding was recorded on diaries by the women and intensity of climacteric symptoms was assessed using VAS scales. Physical and laboratory examinations, endometrial biopsy and vaginal ultrasonography were performed at baseline and follow-up visits. Results: Significantly fewer bleeding days were experienced in the first 3 months by women taking E₂V/MPA compared with women taking E₂/NETA. When the dose of E₂V was increased in the E₂V/MPA groups, an increase in maximum bleeding intensity was observed in the group receiving 2.5 mg of MPA, but not in the group taking 5 mg of MPA. All dose combinations effectively relieved climacteric symptoms and beneficial effects on the lipid profile were seen after 6 months in all groups. Tolerability and endometrial safety were good and no cases of hyperplasia were observed. More women discontinued treatment prematurely in the E₂/NETA group compared with either of the E₂V/MPA groups. The overall continuation rates ranged from 70 to 86%. Conclusions: These results confirm that lower dose combinations of continuous combined HRT are usually sufficient to control symptoms or avoid breakthrough bleeding. However, if higher E₂V dose is needed for symptom control, it should be combined with the higher dose of progestin (5 mg) to avoid bleeding disturbances. Flexible treatment regimens should be available for individualized HRT.     

Profiles of plasma estrogens, progesterone and their metabolites after oral or vaginal administration of estradiol or progesterone

Doses of 100 mg of micronized progesterone (P) and of 0.5 mg of micronized estradiol (E₂) were administered vaginally and orally, respectively, in the early follicular phase of the menstrual cycle in six premenopausal women. In the second cycle, the same doses were administered in the same subjects, orally for P and vaginally for E₂. Serial blood samples were collected and the following steroids were assayed by highly reliable techniques: P, E₂, estrone (E₁), deoxycorticosterone (DOC), 5- and 5β-pregnanolone and the sulfates of E_l, E₂, and DOC. Circulating P and E₂ levels were higher after vaginal than after oral administration, while those of E₁ were similar after either route. Metabolites of P (DOC, DOCS and pregnanolone) were higher after oral administration. Concerning estrogen sulfates, E₁S concentrations were similar whichever the route, while those of E₂S were lower after oral than after vaginal administration. This study has confirmed that metabolism of ingested P and E₂ occurs mainly in the intestine. Moreover, P was predominantly metabolized to 5-reduced derivatives, whatever the route of administration. In view of the metabolic pathways which are operative and of the peripheral plasma levels which were found, the vaginal route appears to be more adequate than the oral one for hormone replacement therapy.     

The effects of continuous combined transdermal oestrogen-progestogen treatment on bleeding patterns and the endometrium in postmenopausal women

Fifty postmenopausal women requiring hormone replacement therapy for the treatment of climacteric symptoms were recruited in six centers. All patients received a new combined norethisterone acetate (NETA)/oestradiol (E₂)-TTS, (Estragest TTS, Ciba-Geigy Ltd), delivering 0.25 mg NETA and 50 μg E₂ per day, continuously for 12 calendar months. Bleeding occurred in 38 (76%) of the 50 patients at any time during the 1 year treatment. The percentage of patients without bleeding increased gradually each month, from 24% in the second month to a relatively stable level of 80% in month 7 and thereafter. Twenty-seven patients (54%) did not complete the whole trial period; 15 of which discontinued the treatment within the first few months due to irregular bleeding. In patients who remained in the trial, a clear decrease in the frequency and intensity of the bleeding was observed with time. Bleeding was mostly light or consisted of spotting only. None of the post-trial biopsies showed proliferation or hyperplasia of the endometrium. The treatment resulted in a substantial decrease of climacteric symptoms (Kupperman index) within 4 months and was well tolerated. It was concluded that the continuous NETA/E₂-TTS treatment is an effective and safe alternative for the treatment of climacteric symptoms in selected patients.     

The vaginal absorption of oestrogens in post-menopausal women

Serum E₁, E₂ and E₃ concentrations and E₂/E₁ ratio were measured after vaginal application of conjugated oestrogens, micronized 17β-oestradiol and oestriol. 2.4 mg of conjugated oestrogens caused a prompt elevation in the serum E₁ concentration; the E₂ level changed only slightly. After vaginal application of 2 mg micronized 17β-oestradiol the main serum oestrogen is E₂ and the conversion of E₂ to E₁, as in oral administration, does not occur. A significant elevation in the serum E₃ concentration was noted 2 h after the vaginal application of 0.5 mg oestriol. The E₂/E₁ ratio changed little after the application of conjugated oestrogens but increased considerably after the vaginal administration of 2 mg micronized 17β-oestradiol.     

Bleeding pattern and climacteric symptoms during different sequential combined HRT regimens in current use

Four sequential combined oestrogen and progestogen regimens were compared in terms of bleeding pattern and relief of climacteric symptoms. Treatment was with either 2 mg 17β-oestradiol with I mg norethisterone acetate [E₂ + NEta]; 2 mg oestradiol valerate with 75 μg levonorgestrel [E₂V + Lng]; 2 mg oestradiol valerate with 10 mg medroxyprogesterone acetate [E₂V + Mpa]; or 1.5 mg 17β-oestradiol with 150 βg desogestrel [E₂ + DG]. A placebo-controlled study lasting 12–24 months was completed by 143 healthy early postmenopausal women. Bleeding lengths were not substantially different; in all regimens the majority of women were bleeding for 3–6 days. Bleeding onset showed differences when related to the 11th day of progestogen addition; in the regimen with E₂V + LNG, 21% of the women were bleeding before the 11th day of progestogen addition 26% on, and 53% after that day. In the regimen with E₂V + MPA, 56% of the women were bleeding before the 11th day, 28% on, and 17% after that day, whereas in the regimen with E₂ + DG, 15% of the women were bleeding before the 11th day, 5% on, and 80% after that day. All regimens reduced climacteric symptoms to the same extent. Breast tenderness occurred in all the regimens, except in the E₂ + DG. Conclusively, the differences between the responses to treatment were not conspicuous. However, our data indicate that one regimen (E₂ + DG) resulted in optimal bleeding control, optimal effect on climacteric symptoms, and no production of breast tenderness.     

Sleep in menopause: differential effects of two forms of hormone replacement therapy

OBJECTIVES: The aim of the present study was to evaluate differences between two regimens of estrogen/progestogen replacement therapy on nocturnal sleep in postmenopausal women. METHODS: Twenty-one (21) postmenopausal women were studied. They were randomized into two treatment groups: (1) estrogen (Premarin 0.625 mg) and medroxyprogesterone acetate (Provera 5 mg) (n = 11) or (2) estrogen (Premarin 0.625 mg) and oral micronized progesterone (Prometrium 200 mg) (n = 10). Postmenopausal women were recorded for two consecutive nights in the sleep laboratory at baseline and again after 6 months of treatment in a randomized trial. The women also had to fill out evening and morning sleep and vigilance questionnaires for 7 days before baseline recordings and for 23 days before month 6 recordings. RESULTS: Sleep efficiency was found to be significantly improved in the micronized progesterone group. It increased by 8% (p = 0.014) with no such increase observed in the medroxyprogesterone acetate group. Time spent awake after sleep onset was also significantly improved in the micronized progesterone group but not in the medroxyprogesterone acetate group. On the other hand, menopausal symptoms and subjective measures of sleep (questionnaires) improved in both groups after treatment. CONCLUSION: This study suggests that medroxyprogesterone acetate and micronized progesterone are both effective for treating menopausal symptoms but that the latter might better improve the quality of sleep in postmenopausal women taking estrogen.     

Endometrial morphology after 12 months of vaginal oestriol therapy in post-menopausal women

The endometrial effect of long-term vaginal oestriol (E₃) therapy for urogenital atrophy was assessed in 23 post-menopausal women. Hysteroscopic and histological examinations were performed in each patient to assess endometrial atrophy before treatment and after 6 and 12 months of therapy (0.5 mg vaginal E₃ for 21 days, then 0.5 mg twice weekly). The primary atrophie picture was confirmed at the end of the 6th month in all but one of the patients. In one case, the histology showed an abnormal stromal reaction with no epithelial alterations. Treatment was continued and after the 12th month complete atrophy was confirmed both hysteroscopicaliy and histologically in all patients. Efficacy as regards vaginal and urogenital complaints was good. Our results demonstrate that in women with endometrial atrophy effective and well-tolerated treatment with vaginal E₃ can be safely continued for up to 12 months.     

Can climacteric women self-adjust therapeutic estrogen doses using symptoms as markers ?

Objectives: To investigate if disappearance of climacteric symptoms during hormone replacement therapy (HRT) also means good therapeutic level of serum estradiol. The study group comprised of 32 postmenopausal women who had frequent climacteric symptoms. Methods: The women increased the daily treatment doses of percutaneous estradiol every 2 weeks until they felt comfortable with it. Each woman continued at that treatment dose for up to 3 months. Blood samples for estradiol assay were drawn at baseline, every time before the estradiol dosage was increased and at the end of the study. Climacteric symptoms were scored according to the Kupperman menopausal index. Results: Despite the relief of climacteric symptoms, serum estradiol concentration was at a menopausal level (<50 pg/ml) in 22% of the women. In all, 45% of the subjects showed serum estradiol remaining under 60 pg/ml, 29% of the women showed levels of 60–100 pg/ml and 26% showed serum estradiol concentration more than 100 pg/ml. Conclusions: The disappearence of climacteric symptoms during HRT does not quarantee that estrogen levels are sufficiently high for obtaining long term benefits of HRT.     

Serum levels of oestrogens, progesterone, follicle-stimulating hormone and sex-hormone-binding globulin during simultaneous vaginal administration of 17β-oestradiol and progesterone in the pre- and post-menopause

Serum concentrations of 17β-oestradiol (E₂), unconjugated oestrone (E₁), total oestrone (tE₁), progesterone (P), follicle-stimulating hormone (FSH) and sex-hormone-binding globulin (SHBG) were measured before and after daily intravaginal administration of 250 μg micronized E₂ and 10 mg micronized P for 14 days to 12 post-menopausal and for 1 day only (during cycle days 5–8) to 11 pre-menopausal women. In the post-menopausal women the levels of all steroids increased to maximum values on day 1, 8–10 h after administration and fell thereafter. In the pre-menopausal women the steroid concentrations rose slowly to a plateau level 10–15 h after administration. Significantly higher absorption of E₂ and E₁ (area under the curve increments) was noted in the post-menopausal than in the pre-menopausal women.

In the post-menopausal women the steroid levels measured on days 7 and 14 corresponded to those observed in the very early or late luteal phase. Area under the curve increments were usually smaller on days 7 and 14 than on day 1 and the absorption kinetics altered to a ‘pre-menopausal’ pattern. FSH levels were significantly reduced as from 12 h after administration on day 1 and onwards. A slight (10%) but significant increase in SHBG levels was noted on day 14. It was concluded that the combined E₂ and P treatment used in this investigation brings about a physiological response with only minimal side effects on the liver as judged from changes in SHBG concentrations.     

Comparative metabolic study of percutaneous versus oral micronized 17β-oestradiol in replacement therapy

The aim of this study was to compare the metabolic effects of two presentations of 17β-oestradiol (E₂) which are of recognized effectiveness in the prevention of post-menopausal bone loss, one being administered via the oral and the other via the percutaneous route. During this prospective, randomized study, 32 patients were treated for 2 mth with either 2 mg/day of oral micronized E₂ (n = 16) or 3–5 mg/day of percutaneous E₂ (n = 16). Both regimens proved efficacious, since significant increases in oestrone (E₁) and E₂ concentrations ranging up to mid-follicular values were observed.

In the percutaneous-treatment group we noted a significant decrease in triglycerides (TG), without any significant changes in high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C). In the oral-treatment group, we saw no significant increase in HDL-C, although significant increases were observed in body weight, TG, plasma renin substrate (PRS) and sexhormone-binding globulin (SHBG) as well as significant decreases in antithrombin III (AT III) activity and antigen. All of these metabolic variations led us to the conclusion that oral E₂ at the dose established as effective in preventing post-menopausal osteoporosis may, even when micronized, alter certain metabolic and haemostatic parameters in a population characterized by increases in cardiovascular risk factors and morbidity. Oral oestrogen replacement therapy should therefore continue to be used only in carefully selected patients and be strictly followed up by systematic checks on a series of metabolic criteria.     

A group-comparative study of effects of Ovestin cream versus premarin cream in post-menopausal women with vaginal atrophy

Fourteen post-menopausal women with vaginal atrophy applied, intravaginally, Ovestin® cream (0.5 mg oestradiol/day; 7 patients) or Premarin® cream (1.25 mg conjugated oestrogens/day; 7 patients) for 3 wk. Effects on plasma E₁, E₂, E3, FSH, LH, PRL, TRH-stimulated PRL release, SHBG, and on maturation value (MV), ferning (F) and spinnbarkeit (S) were studied. Endometrial biopsies at pre-treatment and at 2 wk were obtained from 2 patients from each group.

Premarin induced a significant and progressive rise in E₁ and E₂ levels and in SHBG, whereas Ovestin induced no changes. Both creams increased E₃ slightly and suppressed FSH and LH, Premarin suppression of FSH and LH being significantly greater. No significant changes in PRL or TRH-stimulated PRL release occurred with either cream. A similar, marked rise in the MV occurred, but the effect of Premarin on F and S was significantly greater. Endometrium remained atrophic in the 2 Ovestin-treated patients, but moderate proliferation occurred in the 2 Premarin-treated patients. The data showed Ovestin cream to be superior to Premarin cream because of the absence of undesirable effects on E₁ and E₂ levels and the subsequent changes in SHBG and endometrium.     

Plasma androstenedione and oestrone levels in the climacteric syndrome

Plasma androstenedione (A) and oestrone (E₁) levels were measured by radioimmunoassay in a group of 78 healthy women who had undergone a natural menopause. Of this total, 23 were symptomless (Group 1), 39 presented with a moderate climacteric syndrome (Group 2) and 16 had a severe climacteric syndrome (Group 3). The average body weight was found to be significantly higher in Groups 2 (P < 0.01) and 3 (P < 0.05), than in Group 1, but the age distribution and number of years since the menopause were similar in all three groups. Nevertheless, significantly lower levels of A (0.75± 0.06 ng/ml, P < 0.01, in Group 2; 0.24 ± 0.05 ng/ml, P < 0.001, in Group 3) and E₁ (20.80 ± 2.18 pg/ml, P < 0.05, in Group 2; 12.22 ± 1.65 pg/ml, P < 0.001, in Group 3) were observed in the women with climacteric symptoms than in those with no symptoms (A = 1.08 ± 0.08 ng/ml, E₁ = 27.73 ± 2.22 pg/ml in Group 1).

Since, after the menopause, the concentrations of A and E₁ in the plasma represent the most important source of oestrogens, these results suggest that climacteric symptoms are related to oestrogen deficiency which is secondary to low A production.     

Comparative controlled trial of a novel oral estrogen therapy, estradiol acetate, for relief of menopause symptoms

OBJECTIVE: To compare the efficacy and tolerability of a new oral estradiol prodrug, estradiol acetate, with micronized estradiol or conjugated equine estrogens for alleviation of postmenopausal vasomotor and urogenital symptoms. DESIGN: A total of 249 postmenopausal women experiencing seven or more moderate or severe vasomotor symptoms daily for 1 week or 60 or more symptoms in 1 week were randomized to 0.9 mg of estradiol acetate (n = 79), 1 mg of micronized estradiol (n = 85), or 0.625 mg of conjugated equine estrogens therapy (n = 85). Efficacy endpoints were the change in frequency and severity of vasomotor symptoms from baseline to week 12, participant-assessed urogenital symptoms, and investigator-assessed signs of vaginal atrophy. Efficacy results were considered equivalent if estradiol acetate was at least 80% as effective as estradiol and conjugated estrogens. RESULTS: At week 12, frequency of vasomotor symptoms decreased comparably in all groups, and at weeks 4 and 12, the decrease in frequency of symptoms was statistically equivalent for estradiol acetate and conjugated estrogens. Severity of vasomotor symptoms also improved comparably for all groups, with least squares mean decreases of 1.05 for estradiol acetate, 1.34 for estradiol, and 1.17 for conjugated estrogens at week 12. Urogenital symptoms and vaginal signs showed similar improvement in all groups. Overall, the majority of adverse events were mild or moderate and consistent with estrogen therapy. CONCLUSION: Estradiol acetate 0.9 mg was comparable to 1 mg of estradiol and 0.625 mg of conjugated equine estrogens in reducing the number and severity of vasomotor and urogenital symptoms in postmenopausal women. Oral estradiol acetate was well tolerated.     

Hormone levels in healthy post-menopausal women and in women with post-menopausal bleeding with or without endometrial carcinoma

FSH, oestrone (E₁), 17β-oestradiol (E₂) and androstenedione (A) were determined in 250 healthy pre- and post-menopausal women, with ages ranging from 40 to 78 yr. These hormone levels were not found to have changed significantly in women of this stable, post-menopausal phase after the age of 54. The results found in this group of women (n = 107), who now range between the ages of 55 and 78, were compared with results from two groups of women who were found to have gynaecological disorders. The first group consisted of 45 women with post-menopausal bleeding without endometrial carcinoma. The second group consisted of 38 women with post-menopausal bleeding and endometrial carcinoma.

FSH was determined by double-antibody radioimmunoassay. E_l, E₂ and A were fractionated chromatographically after extraction with ether and determined radioimmunologically. The data were analysed using the Kruskal—Wallis test and the Wilcoxon test.

When comparing the measurement of hormone levels in the healthy group of women with that of women with post-menopausal bleeding without endometrial carcinoma, no differences were found. However, in the group of women with post-menopausal bleeding and endometrial carcinoma, lower levels of FSH and E₂ and increases in the E₁/E₂ ratio were found; both changes were statistically significant. The slight increase in E₁ and A found in these women was not significant. Any changes which occur in the hormone levels of women with endometrial carcinoma may indicate a correlation between hormones and the onset of endometrial carcinoma.     

Comparison of the long-term effects of oral estriol with the effects of conjugated estrogen on serum lipid profile in early menopausal women

Objective: We investigated the long-term effects of oral estriol (E₃) on serum levels of total cholesterol (t-Cho), high-density lipoprotein cholesterol (HDL-Cho), low-density lipoprotein cholesterol (LDL-Cho), and triglycerides in early menopausal women. Methods: We studied 67 healthy early menopausal women who were treated for 48 months with 2.0 mg of E₃ plus 2.5 mg of medroxyprogesterone acetate daily (E₃ group, n=21), 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate daily (CE group, n=19), or 1.0 μg of 1-hydroxyvitamin D₃ daily or 1.8 g of calcium lactate containing 250 mg of elemental calcium daily (control group, n=27). The serum levels of t-Cho, HDL-Cho, LDL-Cho, and triglycerides were evaluated at baseline and every 6 months. Results: After 48 months of treatment, the t-Cho decreased significantly by 4.3±2.1% (mean±SE) from baseline in the E₃ group, did not change in the CE group (−1.9±2.1%), and significantly increased (5.4±3.4%) in the control group. The HDL-Cho significantly increased in the CE group (10.7±2.4%), but not in the E₃ group (3.8±3.3%) or in the control group (−3.6±3.0%). The LDL-Cho significantly decreased in the CE group (−11.4±4.0%), did not change in the E₃ group (−5.2±3.6%), and significantly increased in the control group (11.8±6.3%). The triglyceride level decreased significantly in the E₃ group (−6.7±4.9%), whereas it significantly increased in the CE group (17.6±11.4%), and did not change in the control group (6.1±6.4%). Conclusions: Oral E₃ prevented a postmenopausal rise in the t-Cho. Oral estriol did not induce the hypertriglyceridemia that was seen after treatment with conjugated estrogen. Oral E₃ may be a useful alternative therapy in women with hypertriglyceridemia and in women who are reluctant to continue conventional hormone replacement therapy because of uterine bleeding.     

Progestogen deficiency and endometrial cancer risk

There is a close relationship between the amount of estogen and progesterone secreted by the ovary from puberty to menopause and the development of hyperplastic endometrium of all types and finally endometrial cancer. The endogenous endocrine pattern reflects progesterone deficiency (corpus luteum deficiency). Such deficiency can also develop when treatment with exogenous estrogen and progestogen is done and a deficiency of the progestogen in comparison to the used estrogen is induced in pre- and postmenopausal women. This risk is particular accentuated in the climacteric female when the endocrine milieu was unfavorable in the years before (menstrual cycle disorders, PCOS, obesity, no full-term pregnancy, no breast feeding, etc.).However, there are the additional factors, which modify the biological end result: “Progestogen deficiency”. One main factor is the level of SHBG determined by the amount of free, biologically active estradiol. A low level of SHBG is for instance induced by high body weight. Therefore, the amount of overweight correlates with increased risk of endometrial hyperplasia and finally endometrial cancer. In addition, increasing body weight negatively affects proper ovarian function leading to corpus luteum deficiency and this in addition increases the risk of endometrial cancer. The classical risk increase for endometrial cancer is associated with oligomenorrhea or polymenorrhea combined with corpus luteum deficiency or anovulation. Therefore, women with PCOS are at increased risk for endometrial cancer in the pre- and postmenopausal years. Examples from the therapeutic point of view have been the risk increase found with biphasic estrogen high-dosed oral contraceptives with a long estrogen phase and a short progestogen phase. In climacteric females estrogen-only treatment results in a predictable increase in endometrial cancer risk. Therefore, it is mandatory to use estrogen/progestogen combinations. The lowest risk is achieved when a continuous estrogen/progestogen regimen is used. In addition, the lowest dose of estrogens for the individual woman should be chosen.     

What role of estrogens in ovarian stimulation

Estrogens and progesterone represent the key ovarian hormones produced by the developing ovulatory follicle. Serum concentrations start to rise from the mid-follicular phase onwards, coinciding with the development of the dominant follicle. Androgens are converted into estrogens by aromatase activity of the granulosa cells and secreted into the follicular fluid compartment. Their significance for oocyte maturation and fertilizing potential remains unknown.

Paradoxically, serum estrogen levels are within the normal range in the majority of patients presenting with cycle abnormalities due to ovarian dysfunction. Similarly, the distribution of estradiol (E₂) and follicle-stimulating hormone (FSH) levels within the normal range is comparable between normo-ovulatory controls and normogonadotropic anovulatory women. Moreover, E₂ levels are only moderately correlated with luteïnizing hormone (LH), testosterone (T), androstenedione (A), sex hormone binding globulin (SHBG), the free androgen index (FAI) and finally ovarian volume as measured by ultrasound. No correlations could be found between E₂ and age, body weight and cycle history and FSH. Androgen concentrations and cycle history – but not E₂ – were the most prominent predictors of ovarian response tot the conventional ovulation induction.

Anti-estrogenic compounds like clomiphene citrate and tamoxifen have remained the first-line treatment of choice for anovulation. Certainly, CC and to a lesser extent tamoxifen have demonstrated to exhibit undesired anti-estrogenic properties at the uterine level however. However, large follow-up studies demonstrate cumulative ovulation rates around 75%, and the overall pregnancy rates of around 50%.

Aromatase inhibitors, another way to interfere with estrogen feedback, represent a feasible option. This claim should, however, be substantiated by further sufficiently powered, controlled studies, and the possibility of embryo toxicity remains a major concern.

In retrospect, CC and tamoxifen represent the first generation of selective estrogen receptor modulators (SERMs), and many new compounds have recently been introduced into the clinic or are currently under investigation. The major focuses of these compounds are bone density, the cardiovascular system and breast cancer. No studies have been reported in the area of ovarian stimulation.     

Endometrium and plasma hormone profile in the peri-menopause and post-menopause

Endometrial histology and plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17β-oestradiol (E₂), oestrone (E₁) and progesterone (P) were studied in 483 women over a period of 13 yr (6 yr before and 7 yr after the start of definitive amenorrhoea, defined as the last menstrual bleeding). The patterns for these parameters were established on the basis of the results of 1227 gonadotrophin and steroid determinations and 721 endometrial biopsies.

Three periods were identified. During the first, from year −6 to year−3, gonadotrophin levels increased gradually, while those of E₂ remained normal, with peaks in some cases. Mean plasma P levels were within the normal range until year −3, but they then decreased progressively. Endometrial histology was similar to that observed during reproductive life.

In the second period, from year −3 to year +1, there was a concomitant rise in gonadotrophins as the E₂ and P levels decreased. However, at the start of definitive amenorrhoea, the mean E₂ and P levels fluctuated between 60 and 100 pg/ml and between 2 and 3 ng/ml, respectively. The endometrium reflected this decrease in E₂ and P production. It was not atrophic but proliferative when definitive amenorrhoea commenced.

During the last period, from year +1 to year +7, gonadotrophins reached a plateau at high levels, while those of E₂ continued to fall, reaching very low values at year +4, after which they reached a plateau. P levels were at the detection limit of the technique.

The correlations between all plasma steroid levels and endometrial histology demonstrated discrepancies in 30% of cases: prliferative or hyperplastic endometria were seen at E₂ levels of under 60 mg/ml, atrophic endometric at E₂ levels of over 60 pg/ml and secretory endometria at very low P levels.     

Benefits and risks of different hormonal replacement therapies in post-menopausal women

A total of 113 women who presented with climacteric symptoms participated in the study. They were randomly allocated to seven groups of 10–27 subjects, who received for 6 mth the following therapies, respectively: (1) conjugated oestrogens (CE) 0.625 mg/day for 21 days + norethisterone (NET) 5 mg/day from day 12 to day 21; (2) CE + cyproterone acetate (CPA) 12.5 mg/day from day 1 to day 10; (3) oestradiol valerate (EV) 2 mg/day for 21 days + NET; (4) EV + CPA; (5) oestriol (E₃) 2–4 mg/day; (6) tibolone (ORG OD14) 2.5 mg/day; and (7) placebo, one tablet/day.

Hot flushes decreased significantly over the treatment period in all seven groups. However, E₃ was less effective at the dose used than CE, EV or ORG OD 14. At the end of the 6 month treatment period histological examination revealed no changes in endometrial morphology in any of the patients treated. Indeed, the addition of a progestogen even induced regression of endometrial hyperplasia in 8 cases.

No significant variation in the plasma levels of tryglycerides, total cholesterol, high-density lipoprotein (HDL) or low-density lipoprotein (LDL) was observed after the second and sixth months of treatment with E₃ or ORG OD 14. After 6 months, treatment with CE/EV + CPA produced a significant increase in HDL, while treatment with CE/EV + NET brought about a reduction in total cholesterol and HDL and an increase in LDL.     

Plasma concentrations of unconjugated and conjugated estrogens and gonadotrophins following application of various estrogen preparations after oophorectomy and in the menopause.

In 55 patients after oophorectomy and 20 women after natural menopause an oral estrogen replacement therapy was performed with estrone-sulfate, estradiol 17-valerate, estriol-succinate, a combination of micronized estradiol and estriol (Estrifam, Trisequens), and natural conjugated estrogens. In 4 patients a 3 mg estradiol per 5 g ointment substance was applied on the abdominal skin. The interindividual variations of estrogen increments during therapy were considerably high. Oral intake of 2 mg estriol-succinate daily was followed by a 500% increase of total (conjugated + unconjugated) estriol. Concentrations of unconjugated estrogens were not altered by this dosage. Following oral application of the other above mentioned preparations, prominent rises--especially of unconjugated estrogens in plasma--were noted. The concentration peaks occurred within 3--6 h after application. Unconjugated estradiol-17 beta in plasma was comparable with values of the follicular phase of a normal menstrual cycle, unconjugated estrone, however, was nonphysiologically high. Consequently, the E1/E2 ratio was greater than one whereas it is normally below one. 12 h after oral estrogen application, plasma estrogens dropped to almost initial values, so that a second medication seems to be necessary in order to guarantee an adequate supplementation over the course of the day. The hormone values determined in this study did not show significant differences between patients after a natural menopause and after oophorectomy. There was a positive correlation between rising estrogen levels and suppressed gonadotrophins during replacement therapy. The occurrence of climacteric symptoms did not exclusively depend on low estrogen and high gonadotrophin levels. Good tolerance of estrogen therapy with significantly elevated estrogen concentrations in plasma can be obtained transcutaneously in the form of estrogen ointments. Such therapy might simulate the physiological estrogen pattern even better than oral application does because of delayed and diluted steroid flow to the liver.