Association of tibolone and fluoride displays a pronounced effect on bone mineral density in postmenopausal osteoporotic women.

A double-blind, placebo-controlled, randomized, prospective two-center study was carried out to assess the effects of tibolone + fluoride versus placebo + fluoride therapy on trabecular and cortical bone in postmenopausal osteoporotic women. Ninety-four subjects (mean age 61.1 years, postmenopausal 13.5 years on average) with low bone mineral density (BMD) at baseline were randomized to 2.5 mg of tibolone (Org OD 14, Livial) plus 26.4 mg of fluoride (Fluocalcic) or placebo plus 26.4 mg of fluoride daily over 2 years; 55 (58.5%) subjects completed the study, the main reason for discontinuation being untoward gastrointestinal effects. BMD at the lumbar spine was measured by both dual photon absorptiometry (DPA) and dual-energy X-ray absorptiometry (DXA), and at the hip by DXA at 6-month intervals. Baseline values (DXA, g/cm2) for tibolone + fluoride and placebo + fluoride groups were 0.733 and 0.744 for the lumbar spine, and 0.761 and 0.788 for the hip. Change from baseline and percentage change from baseline were calculated for the intent-to-treat and completers groups. An analysis of variance (ANOVA) model or Wilcoxon test was used for statistical evaluation. There was a mean increase in BMD at the lumbar spine measured by DPA of 25.3% and 12.3% in tibolone + fluoride and placebo + fluoride groups, respectively (p = 0.01); with DXA, respective changes were 32.6% and 14.0% (p = 0.013). Data on BMD at the hip showed mean increases of 7.9% and 2.6% for the tibolone + fluoride and placebo + fluoride groups, respectively. We conclude that combined tibolone + fluoride treatment induces a highly significant increase in BMD at the lumbar spine without simultaneous loss of the cortical bone allowing for a meaningful reduction of the fluoride dose when given in combination with tibolone.

Double-blind, placebo-controlled study of the effects of tibolone on bone mineral density in postmenopausal osteoporotic women with and without previous fractures.

A 2-year placebo-controlled, randomized, two-center prospective study was carried out to assess the effects of tibolone (Org OD14, Livial) on trabecular and cortical bone mass and bone biochemistry parameters in elderly postmenopausal women with and without previous fractures. In total, 107 subjects, 71 with fractures and 36 without fractures, were randomized to tibolone (n = 64) or placebo (n = 43). Their mean age was 63.1 years. Bone mineral density (BMD) (g/cm2) was assessed at baseline and every 6 months for 2 years by dual-energy X-ray absorptiometry (DXA). Mean baseline values were 0.79 and 0.80 for the lumbar spine in the tibolone and placebo groups, respectively, and for the femoral neck 0.64 in both groups. Serum and urinary bone biochemistry parameters were measured concurrently. An analysis of variance (ANOVA) model including center and group was applied. The completers' group was the primary subset for the analysis; the intention-to-treat (ITT) group was also analyzed. Results are expressed as the percentage change at 24 months and the annual rate of change percentage year. The tibolone group showed an overall mean increase (vs. placebo) in BMD at the lumbar spine of 7.2% (p < 0.001) and for the femoral neck 2.6% (p < 0.001). In subjects with previous fractures increases were 6.0% and 4.0% for the lumbar spine and femoral neck, while in those with no fractures, respective changes were 8.9% and 1.1%. Overall changes in the placebo group were 0.9% and -1.6% for the lumbar spine and femoral neck, respectively. A significant fall in bone biochemistry parameters showed that tibolone inhibits osteoclastic activity. In conclusion we have found that tibolone 2.5 mg induces significant increases of trabecular and cortical bone mass in elderly postmenopausal osteoporotic women with and without previous fractures.

A randomized study of tibolone on bone mineral density in osteoporotic postmenopausal women with previous fractures.

OBJECTIVE: To investigate the effects of tibolone on trabecular and cortical bone mineral density and on indices of calcium metabolism in postmenopausal women with previous fractures. METHODS: In a 2-year, randomized, double-blind, placebo-controlled, bicenter study, 45 women were treated with tibolone and 43 with placebo. All subjects received 800 mg of calcium daily. Trabecular bone mineral density of lumbar spine (L1 to L4) and cortical bone mass at the femoral neck were assessed by dual energy x-ray absorptiometry at baseline and at 6-month intervals. Serum and urinary bone biochemistry variables were also assessed. RESULTS: After 2 years, subjects in the tibolone group gained 6.9% bone mass at lumbar spine and 4.5% at femoral neck, and respective increases from baseline in the placebo group were 2.7% and 1.4%. Tibolone-treated patients gained statistically significantly more bone mass than placebo-treated patients in the spine and femur. Urinary calcium: creatinine and hydroxyproline:creatinine ratios, as well as serum alkaline phosphatase and phosphate levels, were significantly reduced with tibolone compared with placebo. CONCLUSION: Tibolone induced a significant increase in trabecular (lumbar spine) and cortical (femoral neck) bone mass in postmenopausal osteoporotic women compared to placebo, suggesting its potential to treat postmenopausal osteoporosis.

Effects of two doses of tibolone on trabecular and cortical bone loss in early postmenopausal women: a two-year randomized, placebo-controlled study.

The present randomized, double-blind, placebo-controlled, 2-year study is the first to evaluate the effect of 1.25 and 2.5 mg tibolone daily oral administration on trabecular and cortical bone loss in early postmenopausal women. Ninety-four healthy, normal weight, nonsmoking women participated 1-3 years following spontaneous menopause. Twenty-three subjects were randomized to the placebo group, 36 to the 1.25 mg/day tibolone group, and 35 to the 2.5 mg/day tibolone group. Bone density was assessed at 6 month intervals. Spinal trabecular bone density (BD) was measured with quantitative computed tomography. Phalangeal cortical BD was measured by radiographic absorptiometry. The 2-year change vs. baseline in the placebo group for trabecular BD was -6.4% (95% confidence interval -8.1 to -4.7). Cortical BD did not change significantly. At 24 months both tibolone groups showed a statistically significantly higher trabecular [9.4% (6.6-12.2) for the 1.25 mg group and 14.7% (11.8-17.5%) for the 2.5 mg group] and phalangeal BD [4.4% (1.5-7.4) for the 1.25 mg group and 6.8% (3.8-9.8) for the 2.5 mg group] as compared to the placebo group. After 2 years of tibolone in both regimes, trabecular and phalangeal BD was significantly higher as compared to pretreatment values. At 24 months the 2.5 mg group showed a significantly higher trabecular (p < 0.001) but not phalangeal (p = 0.064) BD compared to the 1.25 mg group. Tibolone prevents early postmenopausal bone loss by inducing an increase in trabecular and phalangeal BD.

Org OD 14 and the endometrium.

Long-term therapy with (7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14; tibolone, Livial) has no influence on the endometrium in post-menopausal women. This was concluded from endometrial biopsies taken from 39 post-menopausal women treated with 2.5 mg/day for periods of from 3 months to 5 years 11 months at three centres. These results accord with the data published so far on 129 women who have been treated for up to 2 years. A review of the data relating to a total of 168 patients treated with Org OD 14 is presented. The endometrial pattern observed at the start of therapy showed no change during treatment in 90% of patients. In 15 cases slight proliferation was apparent after treatment, this being a similar pattern to that seen in the initial days of a normal cycle. In a considerable number of patients no tissue could be obtained, indicating an atrophic pattern. The picture following Org OD 14 therapy was the same as that observed in untreated normal post-menopausal women.

Long-term effects of Org OD 14 on lipid metabolism in post-menopausal women.

The effects of 2.5 mg/day 7 alpha, 17 alpha-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14) on lipid metabolism, with particular reference to high-density lipoprotein (HDL)-related variables, were assessed in 14 healthy post-menopausal women after 12 and 36 mth of treatment. There were significant reductions in the following variables after both treatment periods: total phospholipids, total triglycerides, HDL-phospholipids and apolipoprotein A1. No changes were observed in total cholesterol or low-density lipoprotein (LDL) cholesterol over the entire treatment period. A significant but temporary decrease was observed in HDL-cholesterol after 12 mth, with a return to pretreatment values after 36 mth of treatment. The findings of this study clearly show that Org OD 14 has no adverse effects on the atherogenic variables, viz. LDL-cholesterol and triglycerides. Indeed, since the latter were lowered, its action is in fact beneficial. Moreover, its effect on HDL-cholesterol, the anti-atherogenic variable, is only temporary. We concluded from this study that although the composition of HDL changes during Org OD 14 treatment (especially as regards its cholesterol content), there is no evidence that reverse cholesterol transport is impaired.

New steroid for the climacteric syndrome.

Org OD 14 is a new steroid drug taken orally that appears to act weekly but simultaneously on the estrogens, androgens and progestins. The drug eliminates blood FSH and LH in menopausal women without affecting PRL levels. It also proved more effective than a placebo in controlling hot flushes and related disturbances. The patients treated reveal no reduction in bone mineral content. The incidence of side effects was very low and comparable to the findings in the placebo-treated control group: in particular, there were no changes in body weight, hair distribution of blood pressure. Biochemical studies revealed no alteration in live enzymes, bilirubin, CBG, or cortisol. There was a slight reduction in glucose tolerance but long-term studies revealed no change in the glucoproteins. There was a certain drop in HDL-cholesterol with a tendency to normalise even the long-term and a simultaneous decrease in VLDL and triglycerides which should minimise the risk of cardiovascular pathology. No damaging interference with blood clotting was noted. It may be concluded that oral Org OD 14 is effective and safe for the treatment of menopausal patients.

Clinical profile of Org OD 14.

The clinical profile of Org OD 14 ((7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5 (10)-en-20-yn-3-one) is remarkable in that the compound demonstrates simultaneous weak oestrogenic, androgenic and progestational activity after oral administration to animals. It was therefore studied to evaluate its efficacy in the treatment of the climacteric syndrome. Clinical data demonstrating these combined hormonal effects are reviewed in this paper: Administration of 2.5 mg/day Org OD 14 suppressed gonadotrophins in post-menopausal women and inhibited ovulation in fertile women. In post-menopausal women virtually no endometrial proliferation was induced, only occasional, very slight proliferation being seen. Even after 2 yr of therapy no endometrial hyperplasia was observed. A weak stimulatory effect on the vaginal mucosa was apparent. In addition, Org OD 14 prevented post-menopausal bone loss and alleviated vasomotor climacteric symptoms effectively. It also had a beneficial effect on mood and libido. Org OD 14 was well tolerated. The incidence of side effects (changes in body weight, vaginal bleeding) was low and similar to that with placebo treatment. Extensive safety studies of up to 5 yr duration, including liver function tests and metabolic studies, indicated no untoward effects. It was concluded that Org OD 14 is an effective and safe new preparation for the treatment of climacteric patients.

Multicentre study of effects of Org OD 14 on endometrium, vaginal cytology and cervical mucus in post-menopausal and oophorectomized women.

A multicentre study covering 69 post-menopausal or oophorectomized women was performed to determine whether Org OD 14 [7 alpha, 17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) administered orally in a daily dose of 2.5 mg for 90 consecutive days induces endometrial proliferation. The treatment with Org OD 14 was continued in combination with 1 mg/day of lynestrenol from day 91 for 10 days to ascertain whether secretory transformation of the endometrium and subsequent withdrawal bleeding would occur. Endometrial biopsies were obtained before treatment and on day 91. The effects of Org OD 14 on vaginal mucosa and cervical mucus were also evaluated. Org OD 14 did not display any effect on the endometrium in 56 of the study subjects (83.5%). Weak stimulation (initial proliferation) was seen in 11 of the subjects (16.4%) and withdrawal bleeding occurred in only 5 of these after cessation of the combined treatment with lynestrenol. However, moderate 'oestrogenic' effects on vaginal mucosa and cervical mucus were induced in all study subjects.

Applicability of salivary testosterone measurements for the follow-up of therapy of idiopathic hirsutism.

Preliminary data on the applicability of salivary evaluations of testosterone (T), in comparison to plasma evaluations, in monitoring the effects of prednisone treatment in hirsutism are shown by the authors. 7.5 mg daily were administered p.o. to 4 volunteers affected by idiopathic hirsutism and to a fifth case in whom later surgery demonstrated the presence of adrenal virilizing tumour. While in the latter no modification either in plasma or salivary levels of the hormone was shown, in the four cases of idiopathic hirsutism a striking decrease of T levels was observed both in plasma (P less than 0.02) and in saliva (P less than 0.01). The two variations were moreover highly correlated (r = 0.80; P less than 0.001). Data obtained, although from a limited number of cases, seem then to confirm the validity of salivary T determination in this clinical condition, in whom the need of repeated evaluations, if performed on plasma, may become particularly stressful for the patient.

Lack of suppression of increased circulating prolactin by 2-hydroxyestrone.

To study the effect of 2-hydroxyestrone (2-OHE1) on circulating prolactin (PRL) in a hyperprolactinaemic state, seven anovulatory women with hyperprolactinaemia were given a 2-OHE1 infusion at a rate of 80 microgram/h for 3 h following a control infusion. Plasma samples for PRL determination were obtained at 30-minute intervals for 6h. No changes in PRL levels were observed during the 2-OHE1 infusion as compared with the control period. It was concluded under conditions of the present experiment that 2-OHE1 does not suppress circulating PRL in hyperprolactinaemic anovulatory women.

Placebo-controlled cross-over study of effects of Org OD 14 in menopausal women.

A double-blind cross-over study with Org OD 14 and placebo was performed in 82 menopausal patients presenting with hot flushes and associated symptoms. Patients were randomly allocated to Org OD 14 or placebo as first treatment, and switched to placebo or Org OD 14 as second treatment. Each treatment period lasted for 16 weeks; no wash-out period was introduced. Tablets containing 2.5 mg of Org OD 14 or matched placebo tablets were supplied. Data on the following variables were obtained and analysed by the non-parametric randomization test for paired observations: hot flushes, sweating, dizziness, palpitations, fatiguability, headache, sleeplessness, irritability, breathlessness, backache and loss of libido and, in 16 patients, on circulating levels of FSH, LH, PRL, T3, T4, cortisol (F), SHBG, TBG and CBG. Twenty patients (13 placebo, 7 Org OD 14) withdrew, because their symptoms did not improve and one patient withdrew for reasons unrelated to treatment, so that 61 patients completed the study. The data demonstrated a good clinical effect and statistically significant differences in favour of Org OD 14 for hot flushes and a number of associated symptoms. Many patients reported on a general feeling of well being and a mood-elevating effect following Org OD 14. Org OD 14 significantly suppressed FSH and LH levels, while those of PRL remained unchanged. Although there was slight suppression of TBG and T4 which attained statistical significance, there was no influence on the most important parameter, T3. SHBG levels were slightly suppressed, whereas F and CBG levels were unaffected.

A comparative study of clomiphene and epimestrol on plasma progesterone, CBG, TBG and SHBG, and salivary progesterone levels.

The plasma levels of CBG, TBG, SHBG and progesterone, and salivary progesterone levels were measured in eight young ovulatory volunteers. After the control cycle four subjects received 50 mg/day of Clomiphene from days 5 to 9 of the first treatment cycle, and 10 mg/day of Epimestrol from days 5 to 15 of the second treatment cycle. The other four subjects received the treatments in reverse order. Between the two treatments there was one cycle without medication as a "wash-out" period. Plasma and saliva samples were obtained on days +6, +8 and +10 (day of LH peak was denoted by 0), always between 08.00 and 09.00 h. Statistical evaluation was done by means of an analysis of variance (ANOVA), and correlation coefficients were also calculated. Evaluation of data on effects of Clomiphene and Epimestrol on the plasma levels of CBG and salivary progesterone showed that Clomiphene induced a highly significant rise (p less than 0.001) in the CBG levels and decrease (p less than 0.001) in salivary progesterone levels, while no changes were seen following administration of Epimestrol. Both Clomiphene and Epimestrol treatments led towards higher plasma progesterone levels, those following Clomiphene administration being higher. Neither treatment induced significant changes in TBG or SHBG levels. It is concluded that Clomiphene induces significant elevations of CBG and decrease in salivary progesterone, which is thought to reflect the free progesterone fraction and may have significance in relation to a discrepancy between the ovulation and pregnancy rates following Clomiphene therapy.

Ovulation-inhibiting properties of Org OD 14.

Org OD 14 has recently been shown to be an interesting new steroid for the treatment of menopausal women. In view of the importance of treatment of perimenopausal women, in whom ovulation might occur, the aim of the present study was to assess whether or not Org OD 14, administered orally in a daily dose of 2.5 mg for 21 days, inhibits ovulation. Sixteen healthy female volunteers, aged 20-34 years and with established ovulatory cycles, were studied during a control cycle and a treatment cycle. Daily measurements of the plasma levels of FSH, LH, E2, P and PRL were made. Endometrial specimens were obtained from nine of the volunteers between 23rd and 25th day of both cycles. The criteria for an ovulatory cycle were: (1) mid-cycle FSH, LH and E2 peaks; (2) criteria (1) followed by a rise in the P levels of greater than 10 ng/ml; (3) a luteal phase of at least 12 days; (4) biphasic behaviour of E2; and, (5) secretory endometrium on days 23-25 of the cycle. All control cycles were ovulatory. During the treatment the mid-cycle FSH, LH and E2 peaks disappeared, and P levels remained very low. PRL levels showed an occasional moderate rise in some of the volunteers. Endometrial specimens showed a secretory pattern during the control cycle, and different degrees of proliferation during the treatment cycle in all nine volunteers. It was concluded that Org OD 14 inhibited ovulation in all 16 volunteers.

Endocrinological and clinical investigations in post-menopausal women following administration of vaginal cream containing oestriol.

The maturation value (MV), cervical mucus parameters (ferning, Spinnbarkeit), oestrone (E1), oestradiol (E2), oestriol (E3), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyrotropin (TSH), growth hormone (GH), sex hormone binding globulin (SHBG), corticosteroid binding globulin (CBG) and thyroxin-binding globulin (TBG) were determined in 11 post-menopausal women presenting with vaginal atrophy prior to, and following, treatment with Ovestin vaginal cream containing 0.5 mg/day of E3 for 8 wk. In 6 of the patients E3 was measured during frequent plasma sampling on days 1, 21 and 56; in the same patients and on the same days TRH-stimulated PRL, TSH and GH levels were estimated. While the therapy induced a sharp rise in the MV, there was a moderate effect on ferning/Spinnbarkeit. Baseline E3 rose from undetectable levels to a mean value of 86.8 pmol/l at day 21. E3 levels achieved during frequent plasma sampling were higher on day 1 than on days 21 and 56 - a decline of the areas under the response curves being significant (P2-sided = 0.03). There was a slight suppression of FSH and LH. No changes in the circulating levels of E1, E2, SHBG, CBG, TBG, PRL, TSH and GH were seen. TRH-stimulated PRL, TSH and GH levels remained unaffected. Clinical effect was excellent and no untoward effects were reported.

Amplification of LH response to LHRH by dopamine infusion in eugonadal women.

Although the role of biogenic amines in the regulation of gonadotropin release has been studied extensively, the precise role of dopamine (DA) in stimulating LHRH and/or LH release is still controversial. In the present study 6 eugonadal women, aged 20-30, were given an LHRH infusion on day 6 of the menstrual cycle and the pattern and magnitude of LH and FSH responses were estimated. On day 6 of the next cycle, the experiment was repeated and DA was also infused beginning 60 min after the start of the LHRH infusion. Following LHRH infusion plasma LH showed a marked and significant rise with a mean peak increment at 4 h, and with a cumulative response (CR) of 9136 +/- 955 mIU/ml/6h. The pattern of FSH response tended to parallel that of LH; however, mean peak increment at 4 h and a CR of 2640 +/- 169 mIU/ml/6h were markedly lower. Plasma prolactin levels remained unchanged. Addition of DA to LHRH at 60 min evoked a significantly greater mean peak LH increment at 4 h and a CR of 15514 +/- 1836 mIU/ml/6h (p less than 0.001). There were no significant changes in either mean FSH peak at 4 h or in the CR (3257 +/- 309 mIU/ml/6h). As expected, a highly significant (p less than 0.001) decrease in circulating PRL from 12.1 +/- 3.1 to 3.0 +/- 1.5 ng/ml was seen during DA infusion. In conclusion, DA given by iv infusion enhancement LH response to LHRH in eugonadal women under the conditions of the present investigation, supporting a role for a dopaminergic component in the control of LH release in women.

Correlation between incremental changes of oestradiol-17 beta and prolactin during the menstrual cycle by means of multiple plasma sampling.

Incremental changes of circulating oestradiol-17 beta (E2) and prolactin (PRL) at midcycle and in the luteal phase were studied in 7 healthy young women by means of multiple plasma sampling over a longer period of time. The mean E2 and PRL levels were significantly higher at both times of assessment than in the follicular phase (p less than 0.001). Rapid fluctuations of both E2 and PRL levels were observed; amplitude of E2 fluctuations was increased at higher mean E2 plasma levels. Regression analysis showed a significant correlation (r = 0.62; p less than 0.01) between the incremental changes of E2 and PRL levels at midcycle and in the luteal phase. The present data shows that changes in the plasma levels of E2, and perhaps in the amplitude of the fluctuations, play a crucial role in the regulation of PRL secretion and release during the normal menstrual cycle.

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.

The treatment of postmenopausal vaginal atrophy with Ovestin vaginal cream or suppositories: clinical, endocrinological and safety aspects.

Seventy-four postmenopausal women presenting with vaginal atrophy were treated with either Ovestin vaginal cream (Group A, 23 women: 1 mg/day E3; Group B, 30 women: 0.5 mg/day E3) or vaginal suppositories (Group C, 21 women: 0.5 mg/day E3), applied daily for 3 wk (A and B) or 2 wk (C) before retiring. Ten women from A and 10 from B applied a maintenance dose (1 application twice weekly) during wk 4-16. Effects on vaginal cytology, cervical mucus and clinical and colposcopic findings were studied. Endometrial biopsies were done in 16 patients (A) before and after 3 wk of treatment, and, in 8 of the cases, at 16 wk. A routine laboratory screening program was performed before and after 16 wk of treatment in 10 patients (A). Plasma samples for hormone level determinations were obtained in 32 patients. Clinical and colposcopic findings showed a beneficial effect of treatments, confirmed by vaginal smears, and persisting during maintenance therapy. Effect on cervical mucus was slight to moderate. No side effects occurred and tolerance was very good. Endometrium remained atrophic under treatment. Screening program revealed no abnormalities. Treatments induced a sharp rise in plasma E3, followed by a gradual decline. Gonadotropins were slightly suppressed. E1, E2, PRL and SHBG capacity remained unchanged.