Endometrial and menstrual response to subcutaneous oestradiol and testosterone implants and continuous oral progestogen therapy in post-menopausal women

A regimen of subcutaneous implants of oestradiol and testosterone in combination with continuous oral norethisterone (0.35mg to 5mg daily) was used to treat 71 non-hysterectomised post-menopausal women for up to 30 mth in an attempt to avoid the withdrawal periods associated with conventional cyclical therapy, while at the same time protecting the endometrium from oestrogenic overstimulation. Amenorrhoea, defined as no vaginal bleeding for at least 3 mth, occurred immediately in 5.4–55.6% of women, the percentage depending on the daily dose of the progestogen. In those women who bled, the dose of norethisterone was adjusted at 3-mth intervals. Despite this protocol, only 51.0% of the patients were amenorrhonic after 6 mth, and 63.2% after 1 yr. Although eight women did develop amenorrhoea for 12–27 mth, there was a high drop-out rate by the others, mainly because of unacceptable irregular bleeding. Irrespective of the bleeding pattern, endometrial biopsies 6 mth after treatment revealed endometrial atrophy. It is concluded that this form of therapy is inferior to oral continuous combined hormone replacement where amenorrhoea can almost invariably be achieved.     

Serum oestrone,oestradiol and oestriol concentrations in castrated women during intramuscular oestradiolvalerate and oestradiolbenzoate-oestradiolphenylpropionate therapy

Serum oestrone, oestradiol and oestriol concentrations were studied during intramuscular Primogyn Depot® (10 mg of oestradiolvalerate) and Dimenformon prolongatum® (2.5 mg of oestradiol-benzoate + 10 mg of oestradiolphenylpropionate) treatments. The serum oestrone concentrations were markedly elevated in both therapeutic groups 24 h after the injection. After the Primogyn Depot injection the serum oestrone concentration 10 days after the injection was still significantly higher than the pretreatment level. The serum oestradiol concentrations of both groups were markedly elevated 24 h after the injections and were significantly higher than the pretreatment concentration 10 days later. The oestriol values were low during both treatments.     

Metabolic clearance rate of oestrone sulphate in post-menopausal women

The feasibility of using constant infusions of unlabelled oestrone sulphate (E₁S) for the purposes of calculating its metabolic clearance rate (MCR_E1S) and its conversion ratios to oestrone (E₁) and oestradiol (E₂) in post-menopausal women was exploited in this study.

The results obtained by the infusion of unlabelled E₁S were similar to those obtained by the infusion of labelled steroid.

The MCR_E1S values seen in our group of post-menopausal women fell within the range previously reported for fertile women.

The contribution of E₁S to circulating E₁ averaged 18% (range 14–24%), indicating that the E₁S-E₁ equilibrium should be taken into account during studies on oestrogen balance in post-menopausal women.     

The effects of oestrogen therapy on the sex life of post-menopausal women

The literature concerning sexual behaviour around the time of the menopause is reviewed. Mentioned is a decline in sexual activity and satisfaction in women which is attributed to the changes in the women themselves, and not merely a reaction to the decline in the sexual capacity of their husbands.

Forty women were treated during 1 yr with oestrogens. The eventual effect of this treatment on sexual activity and satisfaction was investigated and compared with a group who had undergone partial treatment only. The results show that in the completely treated Group A, symptoms such as hot flushes and depression diminished, and the pain of sexual relations was relieved. As a consequence of this improvement, coital activity and satisfaction were more gratifying. The partially treated Group B showed a clear decline in sexual activity and in sexual satisfaction.     

Serum concentrations of oestrone,oestradiol and oestriol during various oestrogen treatments

Serum oestradiol/oestrone ratios were measured during various oestrogen treatments in castrated women. Oral oestriol succinate therapy (8 mg/day) caused little change in the pre-treatment oestradiol/oestrone ratio. During oestradiol valerianate therapy (2 mg/day) serum total oestrogens and the E₂/E₁ ratio were considerably increased. One day after the injection of 10 mg of oestradiol valerianate and 2.5 mg of oestradiol benzoate + 10 mg of oestradiol phenylpropionate the E₂/E₁ ratio was similar to the ratio in the middle of the normal ovulatory cycle. The change in serum oestriol was rather small after oral doses of 8 mg of oestriol succinate 15, 30 and 120 min after the application.     

Haemodynamic and hormonal effects of short-term oestradiol treatment in postmenopausal women

Haemodynamic changes during a 3-wk treatment with oestradiol valerianate (2 mg/day orally) were studied in 12 postmenopausal women by isotope ¹¹³In^m radiocardiography.

Systolic blood pressure measured in the supine position decreased during oestradiol treatment by 3% (P < 0.05) and the diastolic blood pressure decreased by 4% (P < 0.01). The heart rate decreased by 15% (P < 0.001).

Blood volume increased during oestrogen treatment by 5% (P < 0.05) whereas cardiac output decreased by 9% (P < 0.05). Stroke volume increased by 13% (P < 0.001) due to concomitant decrease in heart rate.

Changes in plasma oestrone and oestradiol concentrations during oestradiol valerianate substitution showed a positive correlation with the changes of blood volume.     

Effect of natural oestrogen/gestagen therapy on uric acid metabolism in post-menopausal women

Uric acid metabolism was studied in groups of early post-menopausal women before and during long-term administration of natural oestrogen/gestagen (n = 21), bendroflumethiazide (n = 19) or placebo (n = 34). Serum uric acid rose definitely, by 13.0% during thiazide, and decreased slightly, by 4.9%, during hormone treatment. The latter deviation did not differ significantly from that of -2.9% seen in the placebo group. The urinary excretion rates of uric acid observed during thiazide and hormone treatment did not differ significantly from that of the placebo group.It is concluded, that within the present design of study, which readily permits detection of the well-known hyperuricaemic action of thiazide, oestrogen/gestagen hardly affects uric acid metabolism.     

Serum oestrone, oestradiol and oestriol levels in ovariectomized women receiving a high dose of oestradiol valerate

Fourteen recently ovariectomized women received 4 mg of oestradiol valerate therapy daily for 6 mth. Serum oestrogens were measured by radioimmunoassay at monthly intervals. The results of therapy produced a 25-fold increase in serum oestrone (E₁) concentration. Circulating oestradiol (E₂) increased 5-to 6-fold. No accumulation of oestrogens was observed as a consequence of treatment. Serum concentration of oestriol (E₃) showed no elevation. One month after the completion of therapy the E₁ and E₂ concentrations had returned to pre-treatment levels. Although therapy of high-dose oestradiol valerate was well-tolerated, it is not recommended because of the non-physiological high serum concentrations of oestrone and high serum level of oestradiol.     

Serum oestrone, oestradiol and oestriol concentrations during oral oestradiol valerate and oestriol succinate therapy in ovariectomized women

Serum oestrone, oestradiol and oestriol concentrations were investigated during oral treatment with oestradiol valerate and oestriol succinate in ovariectomized women. The dosages used were 1 mg oestradiol valerate in the morning and 2 mg oestriol succinate in the evening of the first day and 2 mg oestradiol valerate in the morning of the second day of treatment. The other group of patients received the same therapy in reverse order. The variations in the serum oestrone and oestradiol concentrations with a daily dose of 1 or 2 mg of oestradiol valerate were considerable. 2 mg oestriol succinate caused a fairly small elevation of serum oestriol concentration. In both treatment groups the quotient E₃/(E₂ + E₁) was similar to that found at the 6–7th day and in the middle of the normal menstrual cycle, the quotient E₁/(E₂ + E₃) was somewhat higher than during normal cycle.     

Endogenous factors affecting bone mineral content in post-menopausal women

Eighty-eight healthy post-menopausal women were divided into two groups, one of 35 subjects who had undergone menopause up to 9 years previously and the second of 53 subjects who were 10 or more years post-menopausal. In each individual we related the bone mineral content (BMC), measured by single photon absorptiometry in the distal forearm, to anthropometric variables and urinary oestrogen excretion. There was a positive association between BMC and both urinary oestrogen excretion and anthropometric variables, but this was statistically significant only in the older women. As expected, BMC in the distal forearm decreased with advancing age, the fall being greatest in the first 9 years after the menopause. We concluded that although a single measurement of urinary oestrogen and anthropometric variables does not provide enough information to predict an individual's BMC, the values obtained may prove of use, along with a single BMC determination, in helping to predict the rate of bone loss.     

Comparative metabolism of oestrone sulphate after oral and intravenous administration in post-menopausal women

Oestrone sulphate (E1S) is currently used in hormone replacement therapy in post-menopausal women. While isotope studies have demonstrated that E1S is metabolised in a similar way after administration by either the oral or intravenous route, pharmacokinetic studies point to its efficient extraction and metabolism by the liver. E1S was accordingly administered orally and intravenously at pharmacological dosages in a group of post-menopausal women and its conversion to oestrone (E1) and oestradiol (E2) was determined. We were able to demonstrate that E1S may cross the splanchnic area unaltered, since its conversion to E1 and E2 was similar after administration by each of the routes investigated.     

Pharmacokinetic and pharmacological features of oestradiol valerate

Natural oestrogenic hormones are the appropriate substances for the therapy of climacteric complaints. After oral or parenteral administration, oestradiol valerate, the synthesis compound contained in various commercially available preparations, is completely converted into the natural substances 17β-oestradiol and valeric acid. The 17β-oestradiol produced on cleavage of the ester behaves in the organism like the endogenous steroid hormone. Oestradiol valerate and 17β-oestradiol are virtually dose-equivalent. No differences in the spectrum of action of the oestrogen and its ester have been found either in animal experiments or man. The pharmacokinetic behaviour and the biotransformation of the 17β-oestradiol originating from oestradiol valerate are no different from those of natural 17β-oestradiol. Differences of practical significance exist in respect of the quantitative effect of oestradiol valerate following oral and intramuscular administration, whereas 4 mg oestradiol valerate administered intramuscularly is therapeutically sufficient for a period of 2–4 wk (depot effect). As much as 2 mg daily over 3 wk must be administered via the oral route to achieve the same effect. This difference is due to the greatly diverging pharmacokinetic behaviour of oestradiol valerate depending on which of the two modes of administration is employed.     

Bioavailability of oestradiol and oestriol administered orally to oophorectomized women

A bioavailability study was performed on ten oophorectomized women in a randomized cross-over design. The absorption of tablets containing 2 mg of micronized oestradiol and 1 mg of micronized oestriol (Estrofem®) was compared to the absorption of the same micronized hormones administered in an aqueous suspension. Serum concentration values of oestradiol, oestriol and oestrone were measured by radioimmunoassay. The data obtained were analyzed both by univariate and multivariate analyses, and neither the serum concentrations at the various sample times, the maximum concentrations, the times for the maximum concentrations, nor the areas under the serum concentration curves disclosed any significant differences between the tablet and suspension administrations at the 5% level. The serum concentration values achieved by giving 2 mg of oestradiol and 1 mg of oestriol were of the same magnitude or higher than those of the normal menstrual cycle.     

The association of serum oestradiol level, age, and education with cognitive performance in peri- and late postmenopausal women

Objectives

To evaluate whether healthy women show cognitive changes after menopause and whether the possible changes are oestrogen-, age- or education-dependent.

Methods

Forty-eight women, 21 perimenopausal (aged 43–51 years) and 27 late postmenopausal (aged 59–71 years), participated in the study. Verbal and visuomotor functions, visuoconstructive skills, visual and verbal episodic memory as well as attention were evaluated.

Results

Perimenopausal women performed better than postmenopausal women. Serum oestradiol (E₂) level was included in the model in perimenopausal women only given the lack of endogenous oestrogen in postmenopausal women who were also not using hormone therapy (HT). In perimenopausal women, lower E₂ was associated with better visual episodic memory (p < .05), and older age was related to poorer verbal episodic memory (p < .05). In postmenopausal women, more education was associated with better performance in verbal and visuomotor functions, attention as well as verbal episodic memory (p < .05), older age was related to poorer performance in the visuoconstructive test and visual episodic memory (p < .05).

Conclusions

Perimenopausal women had better cognitive performance compared to late postmenopausal women. In perimenopausal women the effect of E₂ was minor. In both groups, age modified cognitive performance, but more so in postmenopausal women. Education did not have any effect on cognitive performance in perimenopausal women, whereas in postmenopausal women education exceeded age as a source of variation. Thus the relevance of education for better cognition was accentuated after menopause.     

Effect of orally administered oestrogens on gonadotrophin levels in post-menopausal women

The gonadotrophin-suppressing effect of 4 peroral oestrogen regimens (A: 2.5 mg piperazine oestrone sulphate; B: 1.25 mg piperazine oestrone sulphate + 5.0 mg oestriol; C: 2.0 mg oestradiol valerate; D: 10.0 mg oestriol; all administered daily) was studied in 7 post-menopausal women, in the absence, and then in the presence of daily oral doses of 250 micrograms of levonorgestrel. A randomized, complete cross-over design was used, and from each volunteer 80 blood samples were drawn during a period of 252 days for the assay of immunoreactive follicle stimulating hormone (FSH), luteinizing hormone (LH) and bioactive LH levels. All 4 formulations significantly diminished pretreatment gonadotrophin levels. Combination with levonorgestrel enhanced the suppressive effects. Subsequent placebo administration for a week restored gonadotrophin levels to those found previously during oestrogen administration, but not to pretreatment levels. Regimen D exhibited the relatively weakest and regimens A and B the strongest suppression, both in the absence and in the presence of levonorgestrel. Treatment with all oestrogen formulations decreased, and the addition of levonorgestrel increased the ratio of bioactive (B) to immunoreactive (I) LH. Seven days of placebo administration abolished the effect of levonorgestrel, but not that of the various oestrogens on the B/I ratios.     

Dry eye in post-menopausal women using hormone replacement therapy

PURPOSE: To evaluate the effect of hormone replacement therapy (HRT) on dry eye in post-menopausal women. METHODS: Forty post-menopausal women with dry eye (20 patients, group 1) and without dry eye (20 patients, group 2), and planning to receive HRT (estrogen plus progesterone), were recruited as the study groups. Forty age-matched untreated women were enrolled as controls (group 3 with dry eye, 5 patients; group 4 without dry eye, 35 patients). Patients having at least one of the symptoms (dryness, itching, photophobia, foreign body sensation, and tearing) together with two of the tests with positive results for dry eye (tear film break-up time (BUT), fluorescein staining of the cornea, analysis of the meibomian gland, and Schirmer I test) in both eyes were considered dry eye positive. Hormonal assay for follicle stimulating hormone, luteinizing hormone, estradiol, and free testosterone was performed. Dry eye statuses in the groups were evaluated statistically. RESULTS: Four patients with incomplete follow-up data were excluded. HRT use increased estradiol levels in the groups. Mean ages of patients (50.2+/-4.8 and 50.7+/-3.9 years, and 50.0+/-4.6 and 53.0+/-3.9 years) were similar (p=0.67). Duration of menopause in groups 1 and 2 (3.2+/-2.2 and 1.4+/-1.2 years; p=0.01), and in groups 3 and 4 (3.0+/-1.6 and 1.7+/-1.3 years; p=0.014) were different. At the third month examinations, all of the patients in group 1, and 11 patients (61.1%) in group 2 had dry eye (p=0.003). CONCLUSION: Duration of menopause and use of HRT may increase the incidence of dry eye in post-menopausal woman.     

Effect of orally administered oestrogens on circulating oestrogen profiles in post-menopausal women

The effect of 4 peroral oestrogen regimens without and with levonorgestrel (LNG) supplementation (250 micrograms/day) was studied in 7 post-menopausal women. The regimens were: A: 2.5 mg piperazine oestrone sulphate/day; B: 1.25 mg piperazine oestrone sulphate + 5.0 mg oestriol/day; C: 2.0 mg oestradiol valerate/day and D: 10.0 mg oestriol/day. A randomized complete cross-over design was employed and systemic blood levels of progesterone (P), oestrone (E1), oestradiol (E2), oestriol (E3), oestrone sulphate (E1S), oestradiol sulphate (E2S) and oestriol sulphate (E3S) were analyzed. All subjects were consistently post-menopausal, as indicated by low P, E2, E1S and E3S and high FSH and LH levels. The pretreatment and post-treatment levels of E2 and E2S as well as those of E3 and E3S were invariably below detection limit (60 pmol/l and 220 pmol/l, respectively). Treatment with regimens A, B and C resulted in consistently detectable levels of E2, E2S and E3S, but not of E3, and in grossly elevated E1 and E1S levels. Treatment with regimen D gave rise to very high E3S levels. The oestrogen profiles produced by regimens A and C were almost identical, with the exception of higher E1 and lower E3S levels following the administration of regimen A. Combination with LNG did not modify the levels of unconjugated oestrogens, but in certain cases it seemed to diminish those of oestrogen sulphates. A comparison with the results of a preceding study (Aedo A-R et al., Effect of orally administered oestrogens on gonadotrophins levels in post-menopausal women. Maturitas 1989; 11:) reveals that the gonadotrophin-suppressing effect of all 4 regimens still persisted in the post-treatment period at a time when the levels of all oestrogens analyzed returned to those of the pretreatment period.     

Plasma oestrone,oestradiol and androstenedione levels in post-menopausal women: Relation to body weight and height

To study the relation between body weight and height and the plasma sex-hormone levels we measured the plasma levels of oestrone (E₁), oestradiol (E₂) and androstenedione (A) in a group of healthy post-menopausal women with a wide range of body weight.The sex hormones were measured by radioimmunoassay with highly specific antisera after purification of the plasma extract by column chromatography.Our findings show that there is significant positive correlation between the E₁ level and body weight as well as A level and, to a lesser extent, between the E₁ level and Quetelet index. For E₂ there is no correlation with these parameters. There is also a very slight correlation between A level, body weight and Quetelet index.Calculation of the partial correlation coefficient shows that E₁ correlates to the same degree with body weight and A level, whereas the A level does not correlate with body weight at a fixed value for the E₁ level. We conclude that variation in the E₁ level depends to the same degree on the variation in body weight as well as the variation in A level.     

Apolipoprotein A1 levels in oophorectomized women treated with Org OD 14, oestradiol valerate and a placebo

Org OD 14 is a synthetic steroid which in animal bioassays displays oestrogenic as well as very weak androgenic-anabolic properties. Earlier studies have shown that it alleviates oestrogen-deficiency symptoms and retards osteoporosis. OD 14 can be administered continuously with little effect on the endometrium.

The aim of this study was to evaluate the effect of OD 14 on apolipoprotein A1 (Apo-A1), the major protein constituent of the high-density lipoprotein (HDL) fraction, as compared with that of oestradiol valerate (E₂V) and a placebo.

Twenty-two women, who had been oophorectomized when undergoing surgical treatment for stage IB or IIA cervical carcinoma, were given OD 14 2.5 mg/day, a placebo, and E₂V 2 mg/day for a period of 6 wk in each case using a double-blind, cross-over method. Serum Apo-A1 was determined by electro-immunoassay after each treatment period.

There was a marked decrease in Apo-A1 after OD 14 as compared with the levels seen after the placebo and E₂V. This decrease is interpreted as evidence of a strong androgenic influence by OD 14. In epidemiological studies low levels of Apo-A1 have been associated with a higher incidence of atherosclerosis and cardiovascular disease.

Long-term treatment with OD 14 might therefore be hazardous in this respect.     

Pharmacokinetics and pharmacodynamic effects of vaginal oestradiol administration from silastic rings in post-menopausal women

Silastic rings releasing approximately 200 μg of 17β -oestradiol per day were inserted into the vaginas of 4 post-menopausal women for one to three 21-day periods. Plasma concentrations of oestrone and oestradiol were analysed by radioimmunoassay. The effect of circulating oestrogens on FSH, LH and sex-hormone binding globulin (SHBG) levels as well as on the endometrium was studied. During the first 24 h of treatment the plasma oestradiol levels were higher than the oestrone levels. But during the following days of the 21-day periods, the levels of the two oestrogens were almost equal, varying between about 100 and 200 pg/ml plasma, a pattern similar to that seen in fertile women. The release of oestradiol from the ring gave stable plasma oestrogen levels. The FSH and LH levels were clearly depressed while the SHBG levels did not change. Characteristics of oestrogen influence were found in endometrial biopsies. The rings were well accepted and could be inserted and removed easily by the women. Absorption of oestradiol from the vagina is good and more complete than after oral administration allowing lower doses to be used for treatment.