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.

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.

Effect of epimestrol on gonadotropin and prolactin plasma levels and response to luteinizing hormone-releasing hormone/thyrotropin-releasing hormone in secondary amenorrhea and oligomenorrhea.

The effects of epimestrol (5 mg every 6 hours for 5 days) on basal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (Prl), estradiol, progesterone, and dehydroepiandrosterone sulfate, and on the response to LH-releasing hormone (LH-RH) and thyrotropin-releasing hormone (TRH) stimulation, were studied in 18 cases of secondary amenorrhea and oligomenorrhea of hypothalamic-pituitary origin, in three cases of anorexia nervosa, in two cases of long-lasting progestin-induced amenorrhea, and in one case of precocious menopause. The results in the first 18 patients indicate that epimestrol treatment induces a significant increase in LH and Prl levels after 24 hours, while the FSH increase becomes significant only after 4 days of therapy. Twelve hours after discontinuation of treatment, all three hormone levels decreased significantly to values similar to the basal levels, while the pituitary response to LH-RH indicated a much more marked LH secretion than before treatment. A second test, performed 36 hours after the last drug administration, again showed a significantly higher LH response than that found under basal conditions. No significant variations were observed in the FSH response to LH-RH, nor in the Prl response to TRH. These data suggest that epimestrol interferes at the level of the centers responsible for Prl and gonadotropin secretion in the manner of a weak estrogen.

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.

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.

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.

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.

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.

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.

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.

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.

Effects of testosterone undecanoate administration on LH and FSH response during the standard LH-RH test in healthy male volunteers.

The effects of orally administered testosterone undecanoate (TU) on the pituitary responsiveness to the intravenous injection of 100 microgram of synthetic LH-RH were studied in 10 young healthy male subjects. They were given TU in a daily dose of 160 mg for 14 days. The LH-RH Test was performed before the medication, on day 14, and on the 7th day of the post-treatment phase. Pituitary responsiveness remained normal throughout the whole study. A somewhat lower response for LH was observed in the post-treatment phase, most probably attributable to the increased baseline plasma testosterone levels.

Effects of oral testosterone undecanoate in hypogonadal male patients.

Effects on plasma T, DHT, A, FSH, LH and PRL concentrations and the pituitary responsiveness to the LHRH/TRH stimulation, as well as on libido and sexual, mental and physical activities were studied in ten hypogonadal male patients undergoing therapy with oral testosterone undecanoate (TU) for 9 weeks. The daily dose of TU needed for satisfactory clinical effect was 120 mg (6 cases) and 240 mg (4 cases). There was a significant rise in circulation androgen concentrations in all patients. Mean plasma T, DHT and A increased at 9 weeks from 1.20, 0.12 and 0.36 ng/ml to 4.34 (P less than 0.0004), 0.39 (P less than 0.0004) and 1.24 ng/ml (P less than 0.005), respectively. In hypergonadotrophic patients (N = 6) plasma FSH and LH fell progressively (P less than 0.05), while in hypogonadotrophic patients (N = 4) a marked rise in plasma FSH (P less than 0.05) was found, while LH tended to rise as well. Base-line plasma PRL remained unchanged. In three out of four patients with poor PRL response to TRH, normal responses were established after TU therapy. Increase in libido and sexual activity was reported by nine patients. An increase in mental and physical activity was found in seven and two patients, respectively. Tolerance was excellent. It was concluded that oral TU is an effective form of substitution therapy in male hypogonadal patients.

Circulating prolactin and its response to TRH following administration of testosterone undecanoate in normal men.

To investigate the effect of orally administered testosterone undercanoate (TU) on circulating prolactin (PRL) and PRL response to TRH stimulation, 8 eugonadal male volunteers, aged 19--30, presenting with normal plasma levels of FSH, LH, testosterone (T), estradiol (E2) and PRL, were given 120 mg/day of TU for 6 days. Plasma PRL levels were measured daily during the pre-treatment phase (3 days), treatment phase (6 days) and post-treatment phase (3 days) by radioimmunoassay. The TRH Test (200 micrograms iv) was done on the 3rd day of the pretreatment phase and on the treatment phase. No significant changes in circulating PRL levels or in PRL response to TRH stimulation were observed. Plasma T and E2 levels showed a slight, but not significant tendency to increase, while gonadotropin levels remained unchanged.

Effects of orally administered oestradiol decanoate on plasma oestradiol, oestrone and gonadotrophin levels, vaginal cytology, cervical mucus and endometrium in ovariectomized women.

Six ovariectomized women with the uterus left in situ were given a daily oral dose of 0.5 mg of oestradiol decaneoate in oil for 14 days. After a single dose of oestradiol decanoate mean plasma oestradiol rose from 26.8 pg/ml to 66.8 pg/ml within 30 min. There was a further rise to 100-110 pg/ml (P less than 0.001) remaining at the same level over a 24 h period. On repeated daily administration of oestradiol decanoate this rise continued reaching the mean value of 187.1 pg/ml (P less than 0.001) at 2 weeks, while plasma oestrone remained at the same level (147.1 pg/ml) as it was at 24 h. The ratio of plasma oestrone:oestradiol was less than 1 at 2 weeks. Plasma FSH and LH fell progressively during the medication. Changes of the Maturation Index, cervical mucus Ferning and Spinnbarkeit demonstrated the strong 'peripheral' activity of this dose of oestradiol decanoate. All endometrial specimens showed late proliferative changes at 2 weeks. It was concluded that the favourable properties of oestradiol decanoate offer new possibilities for a more physiological oestrogen supplementation therapy.

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.

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.

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.