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Objective: Levormeloxifene is a selective estrogen receptor modulator (SERM). The development of the drug was discontinued due to intolerable adverse effects. This paper follow-up on the adverse events in a group of 234 women that was followed for 12 months without treatment after 12 months of treatment with levormeloxifene. Methods: Adverse events were recorded at all clinical visits. The double-layer thickness of the uterine endometrium was determined by transvaginal ultrasonography. Endometrial biopsies were obtained by pipelle. The biopsies taken at the entrance to the follow-up phase were taken under hysteroscopy-guidance. Bone mineral density of the total body, lumbar spine (L1–L4), hip and forearm was measured by dual-energy X-ray absorptiometry. Results: The most prominent adverse event was increased endometrial thickness over the pre-defined threshold of 8 mm. No cases of proliferative endometrium were reported. Following withdrawal of treatment the mean endometrial thickness approached baseline levels in a dose dependent manner. Hysteroscopic examinations showed that levormeloxifene was related to increased incidence of edema, vascularization and cysticity. In the levormeloxifene groups, a total of eight women had utero-vaginal prolapse and five women reported urinary incontinence (including worsening of a previously existing condition). Bone density in the spine and hip approached baseline levels during the 12 months of follow-up without treatment. Conclusion: Endometrial thickening, seen in association with the use of some SERM's, may lead to harmful adverse effects more than 12 months after treatment is initiated. Levormeloxifene prevents the postmenopausal bone loss, but the lowest effective dose is unknown.

Progestogen treatment is associated with a number of subjective symptoms. In the present study, 148 healthy post-menopausal women suffering from mild climacteric symptoms were randomly allocated to 12 weeks of treatment with (a) 2 mg oestradiol valerate combined with cyproterone acetate, medroxyprogesterone acetate or levonorgestrel; (b) 1.5 mg 17 beta-oestradiol combined with desogestrel; or (c) placebo. Climacteric symptoms, Kupperman index scores and potential adverse progestogen effects were recorded before treatment and three times per month during therapy. All the hormone regimens had a rapid effect, reducing the severity of climacteric symptoms to about 30% of the baseline values (P less than 0.001) within one month. Hot flushes were reduced in severity and/or frequency by 76 100% within 3 months (P less than 0.001). The regimens which included hydroxyprogesterone derivatives produced a transient increase in breast tenderness. Other recorded potential adverse progestogen effects showed no significant changes during the study. We concluded that the addition of progestogens (whether 19-nortestosterone or hydroxyprogesterone derivatives) does not produce significant side effects during combined hormone replacement therapy.

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 17 beta-oestradiol with 1 mg norethisterone acetate [E2 + NETA]; 2 mg oestradiol valerate with 75 micrograms levonorgestrel [E2V + LNG]; 2 mg oestradiol valerate with 10 mg medroxyprogesterone acetate [E2V + MPA]; or 1.5 mg 17 beta-oestradiol with 150 micrograms 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 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.

The secretory endometrial protein PP14 was measured in serum from 49 healthy, early post-menopausal women receiving continuous combined oestradiol valerate/cyproterone acetate (2 mg E2V + 1 mg CPA daily) or placebo over a period of 2 years. In the hormone group, serum PP14 increased from 2.1 micrograms/l to a maximum of 8.1 micrograms/l after 1 month of treatment, then fell after 3 months to 3.8 micrograms/l and remained at that level for the rest of the 2-year period. After the first month, the occurrence of uterine bleeding was associated with significantly increased serum PP14 levels. Bleeding was not correlated with the serum concentration of 17 beta-oestradiol (E2) or CPA, or the CPA/E2 ratio. Serum PP14 was significantly dependent on the serum concentration of E2, but not on that of CPA. The present data confirm that serum PP14 levels reflect the secretory phase of the endometrium and that bleeding during continuous combined hormone replacement therapy is probably caused by a sub-optimal hormonal balance.

The two most important risk factors for maintaining skeletal health are the bone mass obtained at skeletal maturity (peak bone mass) and the subsequent bone loss. Those women with a low peak bone mass and a rapid bone loss are thus at increased risk of developing osteoporosis in the future, and should be identified. This may be accomplished by determination of the bone mass combined with an estimate of the rate of the postmenopausal bone loss. The bone mass can be accurately assessed in the forearm by single photon absorptiometry. The postmenopausal bone loss can be estimated by three or four biochemical markers of bone turnover. The women at highest risk of developing osteoporosis should be offered preventive therapy, e.g., hormonal replacement therapy (HRT). HRT arrests the bone loss not only in early, but also in elderly postmenopausal women. The effect lasts as long as the therapy is continued. Several epidemiological studies have demonstrated tht HRT decreases the number of osteoporotic fractures.

In view of the increasing use of oestrogen-progestogen therapy in post-menopausal women the availability of possible biochemical marker of endometrial response to progestogen would be highly desirable. Placental protein 14 (PP14) has recently been shown to be excreted from the endometrium during the secretory phase of the menstrual cycle. In the present study we examined the concentration of serum PP14 (S-PP14) in 15 pre-menopausal women during the menstrual cycle and in 30 early post-menopausal women receiving three different doses of 17 beta-oestradiol (E2), cyclically combined with norethisterone acetate (NETA). S-PP14 levels peaked on day 1 following the onset of menstrual bleeding and on day 7 during NETA administration. It was possible to estimate the area under the S-PP14 curve reliably from one or two blood samples taken at optimal times. In the post-menopausal women, S-PP14 varied in a highly significant dose-dependent manner, i.e., the higher the E2 dose (in relation to the fixed NETA dose) the higher the S-PP14 response was found to be. We suggest that S-PP14 measurements might reflect the quantitative development of the endometrium in the secretory phase in both pre-menopausal and post-menopausal women.

In order to clarify the effect of smoking on androgen status in the early post-menopause we examined 267 women aged 45-54 years, of whom 146 (55%) were smokers. The cigarette smokers had a significantly higher serum concentration of androstenedione (P less than 0.001) and a raised serum concentration of luteinizing hormone (P = 0.06) in comparison with the non-smokers. The number of cigarettes consumed was apparently immaterial. The concentrations of oestrone, oestradiol and follicle-stimulating hormone were similar in the two groups. This study lends support to the hypothesis that the observed decreased risk of endometrial and breast cancer associated with cigarette smoking may be mediated by androgenic protection.

We assessed the effects of a continuous oral combination of estradiol and norethisterone acetate, nandrolone decanoate, or salmon calcitonin on the vitamin D endocrine system. One hundred and nineteen postmenopausal women, aged 55-75 years, with at least one osteoporotic fracture, were randomly allocated to one year of treatment with estradiol and norethisterone acetate, nandrolone decanoate, or calcitonin, all drugs with a beneficial effect on bone. All three trials were double-blind and placebo-controlled; 104 women (87%) completed the study. We measured the total serum concentration of 1,25-dihydroxyvitamin D (1,25(OH)2D) and vitamin D-binding protein, and estimated the free 1,25(OH)2D index and the "24-hydroxylase activity" initially, and at 6 and 12 months. Furthermore, the 24-h urinary excretions of calcium, phosphate, and adenosine 3'-5'-cyclic monophosphate were assessed initially and at 12 months. The serum concentration of vitamin D-binding protein and 1,25(OH)2D increased transiently during estradiol and norethisterone acetate treatment and vitamin D-binding protein decreased transiently during nandrolone decanoate treatment. None of the other parameters were significantly affected by any of the three treatments. The risk of type II errors was below 10 per cent for all vitamin D measurements. We conclude that the vitamin D metabolites are unlikely to be of major importance for the mechanism by which these drugs exert their positive skeletal effects.

The suggestion that norethisterone acetate (NETA) stimulates bone formation prompted us to investigate calcium and bone metabolism in post-menopausal women treated with a continuous combination of oestrogen and NETA. The study included 49 healthy post-menopausal women. After an initial examination the women were randomly allocated to 2 yr of treatment with either hormones or placebo; 43 women completed the study. Within the first year of treatment the hormone group showed a slight, but significant, increase in bone mineral content in the forearms (single photon absorptiometry) and in the total skeleton (dual photon absorptiometry). After this initial increase the bone mass remained constant throughout the trial. Bone mineral density of the spine (dual photon absorptiometry) showed a significant increase of more than 5% in the hormone group. There were significant decreases of 4-7% in bone mass in the placebo group over 2 yr. Biochemical estimates of bone turnover (plasma bone Gla protein, serum alkaline phosphatase, fasting urinary calcium and fasting urinary hydroxyproline) fell significantly in the hormone group, but remained unchanged in the placebo group. We conclude that continuous administration of NETA in combination with oestrogen provides effective prophylaxis against post-menopausal bone loss, although it does not produce a persistent positive calcium balance in early post-menopausal women.

This study investigated the effects of nandrolone decanoate (ND) therapy (50 mg i.m. every 3 or 4 wk) on bone mass and soft tissue body composition in post-menopausal women. Twenty-two (22) women were followed up over a period of 30 mth, during which they received ND therapy for 12–24 mth and were treatment-free for the other 6–18 mth. While they were receiving treatment forearm bone mineral content (BMC) and lean body mass (LBM) increased, whereas fat mass (FM) decreased. After withdrawal of ND therapy the BMC, LBM and FM values all tended to return to pretreatment levels. Serum high-density-lipoprotein cholesterol showed a non-significant decrease, while serum lowdensity-lipoprotein cholesterol and serum total cholesterol remained unchanged during therapy. It was concluded that ND therapy can achieve an increase in BMC in post-menopausal women, but this is maintained only for as long as therapy is continued.

The effect of combined oestrogen/progestogen and calcium therapy on vitamin D metabolites was studied in a double-blind, controlled clinical study over a period of 12 mth. Seventeen healthy post-menopausal women were randomly allocated for treatment with either oestrogen/progestogen or placebo. All the participants received a daily calcium supplement of 0.5 g throughout the study. The oestrogen-treated group showed the well-known changes in calcium metabolic variables, i.e. decreases in serum phosphate (P less than 0.001), serum alkaline phosphatase (P less than 0.001) and 24-h urinary calcium excretion rate (P less than 0.01). However, the serum calcium and serum 1,25-dihydroxycholecalciferol concentrations were unchanged. In the placebo group all the measured values remained virtually unchanged throughout the study. The findings indicate that calcium seems to potentiate the bone-preserving effect of oestrogen treatment in early post-menopausal women by keeping the serum calcium level unchanged and thus maintaining an unchanged vitamin D metabolism.

One hundred and ten (110) healthy early post-menopausal women with mild subjective vasomotor symptoms (mean Kupperman index score 11) participated in a long-term, double-blind, placebo-controlled therapeutic trial. The effects of 2 hormone regimens were evaluated. Group I received percutaneous oestrogen therapy for 2 yr, opposed by oral micronized progesterone (200 mg) during the second year, while Group II received oral 17 beta-oestradiol valerate together with cyproterone acetate (CPA). The serum oestrogen concentrations differed markedly in the 2 treatment groups. In Group I the serum/oestrone/oestradiol ratio was 1 (comparable to the pre-menopausal value), but in group II the ratio was greater than 5. Despite the difference in the serum oestradiol and oestrone concentrations, the mean symptom scores were rapidly and similarly reduced in both treatment groups (P less than 0.001). They remained low throughout the study and were not significantly different from pre-menopausal values.

Serum lipids and lipoproteins were studied in 86 healthy post-menopausal women at 3-monthly intervals throughout 2 yr of treatment with cyclic oestradiol valerate plus cyproterone acetate (E2V + CPA), continuous 17 beta-oestradiol plus norethisterone acetate (E2 + NETA), or placebo. Withdrawal effects were also investigated. Serum oestrogen levels were similar following the 2 hormone regimens. Serum total and low-density-lipoprotein (LDL) cholesterol were significantly reduced by 5-8% during cyclic E2V + CPA therapy and by 15-20% during continuous E2 + NETA treatment. The concentrations remained significantly reduced throughout the 2 yr of treatment. Virtually no changes were observed in the placebo group. High-density-lipoprotein (HDL) cholesterol concentrations were significantly reduced in relation to pretreatment values during the first year of continuous E2 + NETA therapy, but were not significantly different from the levels in the cyclic E2V + CPA or the placebo groups. Serum triglyceride levels remained almost constant in all the groups. Withdrawal of hormone therapy resulted in steep increases in total and LDL-cholesterol, the levels returning to pretreatment values. A similar increase in HDL-cholesterol was observed in the E2 + NETA group, following withdrawal. Vaginal bleeding episodes were experienced by all the women receiving the E2V + CPA regimen and they occurred regularly in 63% of the women. Fifty-two (52) percent of the women receiving E2 + NETA did not bleed at all. The results of the present study suggest that the continuous addition of NETA may enhance the oestrogen-induced changes in total and LDL-cholesterol, whereas only minor changes in the oestrogen-induced effects on these variables are produced by the cyclic addition of CPA. However, in the case of HDL-cholesterol, the antagonistic effect of CPA seems to be moderate in comparison with that of NETA.

Thirty-nine osteoporotic (prior spine or Colles' fracture) but otherwise healthy postmenopausal women were allocated to receive blindly either 50 mg nandrolone decanoate (ND) intramuscularly or placebo injections every 3 weeks for 1 year. Thirty-six women (92%) completed the study. ND treatment resulted in an increase in non-osseous lean weight and a corresponding decrease in fat mass (measured by dual photon absorptiometry). A 20% increase in the 24-hour urinary creatinine excretion indicated that the increase in non-osseous lean weight was caused mainly by an increase in muscle mass. With regard to serum lipids and lipoproteins, ND treatment slightly decreased high density lipoprotein (HDL) cholesterol without significantly affecting total cholesterol, low density lipoprotein (LDL) cholesterol or triglycerides. In conclusion, treatment with ND changes the soft tissue composition in osteoporotic postmenopausal women towards a leaner and more muscular body.

Bone loss was determined in 178 women in the early postmenopausal period by photon absorptiometry measurement of forearm bone mineral content (BMC) every 3 months for 2 years. With a sequential cut-off technique, the results of a single determination of body fat mass, urinary calcium and hydroxyproline, and serum alkaline phosphatase, carried out at the first examination, correctly identified 79% of "fast bone losers" (bone loss greater than 3% annually) and 78% of "slow bone losers". With this simple approach the majority of women at highest risk of osteoporotic fractures in later life can be identified in the early postmenopausal period and started on prophylactic hormone replacement therapy.