Use of progestogens and the risk of intracranial meningioma: national case-control study.

OBJECTIVE: To assess the risk of intracranial meningioma associated with the use of selected progestogens. DESIGN: National case-control study. SETTING: French National Health Data System (ie, Système National des Données de Santé). PARTICIPANTS: Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls). MAIN OUTCOME MEASURES: Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association. RESULTS: Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) v 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) v 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) v 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) v 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) v 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) v 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use. CONCLUSIONS: Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.

Progesterone, Inflammatory Cytokine (TNF-α), and Oxidative Stress (H2O2) Regulate Progesterone Receptor Membrane Component 1 Expression in Fetal Membrane Cells.

Progesterone receptor membrane component 1 (PGRMC1) is an important novel mediator of progesterone (P4) function in fetal membrane cells. We demonstrated previously that PGRMC1 is differentially expressed in fetal membranes among pregnancy subjects and diminished in preterm premature rupture of membrane subjects. In the current study, we aim to elucidate whether PGRMC1 expression is regulated by P4, tumor necrosis factor α (TNF-α), and H2O2 in fetal membrane cells. Primary cultured membrane cells were serum starved for 24 hours followed by treatments of P4, 17 hydroxyprogesterone caproate, and medroxyprogesterone 17 acetate (MPA) at 10(-7) mol/L with ethanol as vehicle control; TNF-α at 10, 20, and 50 ng/mL with phosphate-buffered saline (PBS) as control; and H2O2 at 10 and 100 µmol/L with culture media as control for 24, 48, and 72 hours. The messenger RNA (mRNA) and protein expression of PGRMC1 was quantified using polymerase chain reaction and Western blotting, respectively. We found that PGRMC1 protein expression was regulated by MPA, TNF-α, and H2O2 in a dose-dependent manner. This regulation is also specific to the type of cell (amnion, chorion, or decidua). The upregulation of PGRMC1 by MPA might be mediated through glucocorticoid receptor (GR) demonstrated using amnion and chorion cells model with GR knockdown by specific small interfering RNA transfection. The mRNA expression of PGRMC1 was decreased by H2O2 (100 µmol/L) treatment in amnion cells, which might ultimately result in downregulation of PGRMC1 protein as our data demonstrated. None of other treatments changed PGRMC1 mRNA level in these cells. We conclude that these stimuli act as regulatory factors of PGRMC1 in a cell-specific manner.

Crystallographic and spectroscopic study on a known orally active progestin.

6,17α-Dimethyl-4,6-pregnadiene-3,20-dione (medrogestone, 2) is for a long time known steroid endowed with progestational activity. In order to study its crystallographic and NMR spectroscopic properties with the aim to fill the literature gap, we prepared medrogestone following a traditional procedure. A careful NMR study allowed the complete assignment of the (1)H and (13)C NMR signals not only of medrogestone but also of its synthetic intermediates. The structural and stereochemical characterizations of medrogestone together with its precursor 17α-methyl-3-ethoxy-pregna-3,5-dien-20-one were described by means of X-ray analysis, allowing a deepened conformational investigation.

Dydrogesterone and other progestins in benign breast disease: an overview.

Progestogens appear to have a dual effect on the cell cycle in breast cells and breast cancer cells. There is initially stimulation of mitotic activity. However, continuous application leads to cell apoptosis. This depends on type, dose and length of progestogen application in relation to estrogen action. In benign breast disease the use of progestogens results not only in reduction of mastodynia, but also a reduction in breast gland size and disappearance of nodularity proven by clinical examination and follow-up including breast ultrasound.

Effects of hormone replacement therapy on the main fatty acids of serum and phospholipids of postmenopausal women.

BACKGROUND: The anti-atherosclerotic effects of hormone replacement therapy (HRT) in postmenopausal women are partly mediated by improvement of the lipid and lipoprotein profiles. The present study aimed to investigate the effects of HRT on the main fatty acids of serum and phospholipids in postmenopausal women. PATIENTS AND METHODS: Serum samples of two groups of postmenopausal women, receiving either single oestrogen or in combination with progestogens, were analysed before and after a 6- month treatment period. RESULTS: Of the main serum fatty acids, there was a significant reduction in palmitic (p < 0.05) and arachidonic acids (p < 0.001), followed by an increase in oleic (p < 0.05) and linoleic acids (p < 0.05) in postmenopausal women receiving HRT compared to single oestrogen. The main fatty acids in phospholipids showed a similar pattern in those women. CONCLUSION: The above results demonstrate the beneficial effects of HRT in reducing the risk of cardiovascular disease through modification of the fatty acid profiles of postmenopausal women.

Age-related cognitive decline in the menopause: effects of hormone replacement therapy on cognitive event-related potentials.

OBJECTIVE: Although epidemiological and clinical studies suggest that hormone replacement therapy (HRT) may protect against cognitive disorders and neurodegenerative diseases, the relation between estrogen and cognition in postmenopausal women remains controversial. METHODS: In a double-blind placebo-controlled, parallel group design study the effects of HRT with the estrogen-progestogen combination Presomen 1.25 compositum((R)) (1.25mg equine conjugated estrogens administered for 21 days plus the progestogen 5mg medrogeston given for 11 days) on event-related potentials (ERPs) in postmenopausal patients with age-related cognitive decline (DSM-IV code 780.9, ICD-10 code R 41.8) were investigated. After a pre-drug comparison with age-matched normal postmenopausal controls, 48 psychotropic drug-free patients aged 60 +/- 6 years were randomized to receive either placebo or verum for 4 months. ERPs were recorded before as well as on the 91-92 days of the study, which thus fell into the estrogen phase of the treatment during the fourth cycle. RESULTS: At baseline, patients showed a lengthening of P300 latency and an attenuation of P300 amplitudes as compared with normal controls. After HRT with Presomen, a significant shortening of P300 latency as compared with placebo was observed. CONCLUSIONS: The baseline P300 differences suggest that in the patient group the aging process was advanced, while after HRT with Presomen a significant improvement and normalization of information processing as indexed by P300 was observed.

Influence of different HRT regimens on mammographic density.

OBJECTIVES: A prospective, randomized, open-label study was conducted to evaluate effects on mammographic density in postmenopausal and late perimenopausal women receiving continuous combined or sequential combined hormone replacement therapy (HRT). METHODS: The subjects were randomized to treatment with low-dose continuous combined HRT containing 1 mg 17beta-estradiol plus 0.5 mg norethisterone acetate (Activelle) or a sequential combined HRT regimen consisting of 0.625 mg conjugated equine estrogens for 28 days plus 5 mg medrogestone for 14 days (Presomen). Mammograms were obtained at baseline and after 9 cycles (each 28 days) of treatment. RESULTS: The majority of women (approximately two-thirds in each treatment group) had no changes in mammographic breast density between baseline and the final study visit. There were no marked differences between treatment groups. Approximately 20% of women in both groups had a slight increase in mammographic density. Only 10-14% of women in both groups had a pronounced increase in mammographic density. The analyses of the degree of change showed no remarkable differences between treatments. CONCLUSION: These results indicate that the increase in mammographic density with a low-dose continuous combined HRT regimen is no greater than that with a sequential combined HRT regimen. The type of progestogen does not have an impact on the extent of mammographic density changes.

Bleeding patterns in peri and postmenopausal women taking a continuous combined regimen of estradiol with norethisterone acetate or a conventional sequential regimen of conjugated equine estrogens with medrogestone.

OBJECTIVES: The aim of this study was to compare the incidence of women presenting irregular bleeding episodes following 9 months of treatment with a low dose continuous combined hormone replacement therapy consisting of estradiol (E(2)) and norethisterone acetate (NETA) versus a sequential hormone replacement therapy consisting of conjugated equine estrogens (CEE) and medrogestone (MG). Secondary aims were to establish the relationship between menopausal age and the occurrence of irregular bleeding for both therapies and to assess the efficacy of both therapies in alleviating menopausal symptoms. METHODS: This was a stratified and randomised, open label study conducted with late peri and postmenopausal women at 35 sites in Austria and Germany. A total of 446 women were randomly allocated into two cohorts based on time since last bleeding and then stratified to either a low dose continuous combined therapy consisting of 1 mg E(2) and 0.5 mg NETA for 28 days or a sequential therapy consisting of 0.625 mg CEE for 28 days and 5 mg MG for the final 14 days. Bleeding and menopausal complaints were continuously assessed. Treatments were administered for 9 lunar months. RESULTS: The incidence rate of women presenting irregular bleeding episodes including spotting during cycle 9 was 12.2% with 1mgE(2)/0.5mgNETA and 25.8% with 0.625mgCEE/5mgMG (P = 0.0014). In the group of postmenopausal women (time since last bleeding > or = 12 months) the incidence of irregular bleeding during cycle 9 was 11.0% for 1mgE(2)/0.5mgNETA and 25.0% for 0.625mgCEE/5mgMG). In the group of late perimenopausal women (time since last bleeding 6-11 months) the incidence of irregular bleeding was similar for both treatments at cycle 3, but markedly less in patients with 1mgE(2)/0.5mgNETA at cycle 6 and 9, being significantly different compared to patients with 0.625mgCEE/5mgMG at cycle 6 (P < 0.05). The cumulative rate of amenorrhea (no bleeding or spotting) achieved with 1mgE(2)/0.5mgNETA was 89% for the postmenopausal women and 83.7% for the late perimenopausal women. Both treatments relieved menopausal complaints equally effective. CONCLUSIONS: Regarding the occurrence of irregular bleeding, the low dose continuous combined therapy was superior to the sequential therapy (0.625mgCEE/5mgMG). The low dose continuous combined E(2)/NETA regimen is also suitable for late perimenopausal women since more than 80% of the women had no bleeding or spotting after 9 months of treatment.

[Tibolone]. / La tibolone.

INDIRECT MECHANISM OF ACTION: Tibolone (OD 14) is the precursor of its active principles that are its metabolites: 3 alpha and 3 beta hydroxylated derivatives. In vivo, the latter behave like estrogens. Certain tissues (liver, endometrium) may metabolize the 3 beta ol derivative into the delta 4 isomer with progestagenic and androgenic activity. The metabolism of the product in other tissues such as the breast and brain is unknown. ACTIVITY: At the dose of 2.5 mg/day, the product expresses an estrogen activity equivalent to that observed with classical doses of estrogens in the brain, genito-urinary tract, vascular endothelium and bone. In the brain and muscle, it also has a slightly androgenic effect and in the breast an antiestrogenic effect. ON METABOLIC LEVEL: The product acts like a minor androgen (lowering triglycerides and HDL cholesterol without interfering in the cholesterol cell flow) and it stimulates fibrinolysis. ON CLINICAL LEVEL: Tibolone treats the symptoms of estrogen privation and protects against bone loss, without inducing bleeding or mastodynia. There is a lack of large epidemiological studies on prevention of fracture risks, cardiovascular effects and breast. Tolerance in the population studied was excellent (healthy population). However, tolerance remains to be assessed in particular sub-groups (populations at risk of certains pathologies).

Effect of tibolone compared with sequential hormone replacement therapy on carbohydrate metabolism in postmenopausal women.

OBJECTIVE: To investigate the effects of tibolone on carbohydrate metabolism, and to compare these effects with those of a sequential regimen of conjugated equine estrogens and medrogestone. METHODS: This was an open-label, multicentre, comparative study. Seventy-two postmenopausal women were randomized to receive either tibolone 2.5 mg/day or conjugated equine estrogens 0.6 mg plus sequential medrogestone 5 mg (CEE/M) for six 28-day cycles. Carbohydrate metabolism was evaluated at baseline and after three and six cycles of treatment by an oral glucose tolerance test (OGTT). A blood sample was taken at 30, 60, 90 and 120 mm after glucose 75 mg dosing for determination of plasma glucose, insulin and connecting peptide (C-peptide) levels. RESULTS: The changes from baseline of glucose, insulin and C-peptide area-under-the-curve (AUC) values were not statistically significant after 3 and 6 months of tibolone or CEE/M treatment. There was a small transitory decrease in HbA(1C) after three cycles of treatment with tibolone. CONCLUSION: The effects of tibolone and CEE/M on carbohydrate metabolism were considered to have no clinical significance.

Risk of calcium oxalate nephrolithiasis in postmenopausal women supplemented with calcium or combined calcium and estrogen.

BACKGROUND: Recent studies showed that postmenopausal women lost less bone mass when supplemented with calcium or estrogen therapy. However, the safety of the treatments in terms of the risk of calcium oxalate stone formation is unknown. We therefore conducted this study to determine the alteration in calcium oxalate supersaturation after calcium supplement or after combined calcium and estrogen therapy in postmenopausal osteoporotic women. METHODS: Fifty-six postmenopausal women were enrolled in this study. All subjects were more than 10 years postmenopausal with vertebral or femoral osteoporosis by bone mineral density criteria. They were randomly allocated to receive either 625 mg of calcium carbonate (250 mg of elemental calcium) at the end of a meal three times a day (group A, n=26) or calcium carbonate in the same manner plus 0.625 mg/day of conjugated equine estrogen and 5 mg medrogestone acetate from day 1-12 each month (group B, n=30). The age (mean +/- S.E.M.) was 66.3 +/- 1.2 and 65.1 +/- 1.1 years, weight 54.1 +/- 1.2 and 55.3 +/- 2.1 kg, in group A and group B, respectively. Urine specimens (24-h) were collected at baseline and 3 months after treatment for the determination of calcium oxalate saturation by using Tiselius's index (AP(CaOx)) and calcium/citrate ratio. RESULTS: After 3 months of treatment, there was no significant alteration from baseline for urinary excretion of calcium, citrate and oxalate. Urinary phosphate excretion was significantly reduced (6.3 +/- 0.7 vs. 5.1 +/- 0.7 mmol/day for group A and 8.2 +/- 0.9 vs. 5.8 +/- 0.7 mmol/day for group B, P<0.05), whereas net alkaline absorption was significantly elevated (10.1 +/- 3.6 vs. 20.1 +/- 4.4 meq/day for group A and 4.8 +/- 3.2 vs. 19.9 +/- 3.6 meq/day for group B, P<0.05). Calcium/citrate ratio and AP(CaOx) determined at baseline were not different from the corresponding values after treatment in both groups; calcium/citrate: 10.1 +/- 3.1 vs. 10.1 +/- 2.5 for group A and 9.3 +/- 1.8 vs. 11.9 +/- 2.5 for group B and AP(CaOx): 1.1 +/- 0.1 vs. 1.3 +/- 0.2 for group A and 1.2 +/- 0.2 vs. 1.1 +/- 0.1 for group B. There were eight and nine patients with high AP(CaOx), or >2, at baseline and after treatment, respectively. CONCLUSIONS: Calcium supplement with a meal or combined calcium supplement and estrogen therapy is not associated with a significant increased risk of calcium oxalate stone formation in the majority of postmenopausal osteoporotic patients. Determination of urinary saturation for calcium oxalate after calcium and estrogen supplements, especially at the initial phase of treatment, may be helpful in the avoidance of nephrolithiasis.

Effects of estrogen/medrogestone therapy on the apoprotein B-containing lipoproteins in postmenopausal women with type 2 diabetes mellitus under satisfactory and non-satisfactory glycemic control.

BACKGROUND: Information is lacking on the effects of hormone replacement therapy in women with diabetes, especially during moderate chronic hyperglycemia. OBJECTIVES: To study the effects of HRT on the lipid profile and the low density lipoprotein subclass distribution in women with type 2 diabetes under satisfactory and non-satisfactory glycemic control. METHODS: Fifty-four postmenopausal women after a 6 week run-in diet were randomized to receive either placebo (HbA1c < 8%, n = 13; HbA1c > 8%, n = 17) or HRT (HbA1c < 8%, n = 11; HbA1c > 8%, n = 13) for 12 weeks. HRT consisted of cyclical conjugated estrogens 0.625 mg/day plus medrogestone 5 mg/day. At the beginning and at the end of each treatment period the LDL subclass distribution was estimated by density gradient ultracentrifugation. RESULTS: At the baseline and during the study, the HbA1c level was significantly higher in hyperglycemic patients than in the near-normoglycemic controls (baseline 10.2 +/- 2.9 vs. 6.5 +/- 0.7%, P < 0.01). They showed a trend for higher total and LDL cholesterol, triglycerides and lower high density lipoprotein-cholesterol compared to near-normoglycemic controls, as well as significantly higher triglyceride concentrations in very low density lipoprotein, intermediate density lipoprotein and LDL-1 particles and cholesterol content in LDL-1 and -2 particles. HRT decreased LDL-cholesterol in both groups. In the normoglycemic patients a small increase in HbA1c was observed (6.5 +/- 0.7 vs. 7.4 +/- 1%, P = 0.04). In all cases, HRT did not modify the proportion of LDL represented by denser LDLs. CONCLUSIONS: HRT did not modify the LDL subclass distribution, even in the presence of moderate chronic hyperglycemia in women with type 2 diabetes.

Cyclic progestin therapy for the management of mastopathy and mastodynia.

The management of benign diseases of the breast aims to halt the progression of fibrocystic transformation and to eliminate the symptoms of pain and breast tenderness. Progestins can be used for this purpose. In a controlled, randomized, double-blind, parallel-group study we treated 31 women with mastopathy/mastodynia with the progestins medrogestone (10 mg/day) or dydrogesterone (10 mg/day) from day 14 to day 25 for six cycles. Before, during and at the end of therapy the following parameters were evaluated: subjective symptoms (pain, tenderness, impairment of daily activities), palpatory findings, sonographic diagnosis and sex hormone profiles. Cyclic administration of the low-dose progestins medrogestone and dydrogesterone proved to be an effective and safe treatment of mastodynia and mastopathy. The objective parameters palpatory findings and sonographic imaging of breast nodules and cysts improved in more than 50% of patients. Improvement was particularly marked in women with low progesterone levels in the second half of the cycle. After six treatment cycles, 75% of the patients treated with dydrogesterone and 86% of the patients treated with medrogestone were completely pain-free.

Monitoring bone effect of transdermal hormone replacement therapy by ultrasound investigation at the phalanx: a four-year follow-up study.

OBJECTIVE: A controlled 4-year follow-up study was conducted on a population composed of 112 healthy early postmenopausal women to evaluate the ability of ultrasound technology in detecting the effects of hormone replacement therapy (HRT) on bone. At the end of the study, 47 untreated and 25 treated women had been evaluated. Cyclic sequential estrogen/progestogen therapy, 50 microg/day of transdermal 17beta-estradiol (Rotta Research Laboratorium) plus 5 mg/day of medrogestone (Wyeth-Ayerst) was used. DESIGN: Ultrasound transmission through the distal metaphysis of hand phalanxes was measured by DBM Sonic. Beside amplitude-dependent speed of sound (AD-SoS), three new parameters could be calculated: pure speed of sound (pSOS), bone transmission time (BTT), and ultrasound bone profile index (UBPI). Ultrasound measurements were taken at baseline and after 1, 2, and 4 years. RESULTS: Among untreated women a significant decrease of all ultrasound parameters was observed at follow-up measurements. In the HRT-treated group we observed a significant increase of AD-SoS, pSoS, and BTT. We qualified as "responders" women in the treated group for whom AD-SoS, pSoS, and BTT increased by more than 2.77 times the coefficient of variation of the measurement, i.e., 95% variability. Women in the treated group were identified as responders at 4 years of follow-up by AD-SoS (56%), pSOS (56%), and BTT (60%). Ultrasound bone profile index declined in both groups, although to a lower extent among HRT-treated subjects. CONCLUSIONS: The 4-year data confirm the results obtained at 1 and 2 years of follow-up. This study demonstrates that bone tissue investigation by ultrasound at the phalanx can be used to monitor the effect of HRT, and thus it should be considered a potential technology for the management of menopause by gynecologists.

[Parameters of lipid metabolism in postmenopausal women on oral or transdermal hormone replacement with or without progesterone]. / Lipidstoffwechselparameter postmenopausaler Frauen unter oraler und transdermaler Hormonsubstitution mit oder ohne Gestagenzusatz vom Progesterontyp.

OBJECTIVE: Aim of the study was to show different influences of transdermal and oral hormone replacement therapies (conjugated and micronized estrogens) with or without varying dosages of C21-progestogens on serum lipids and lipoproteins. MATERIAL AND METHODS: We report on serum triglycerides, cholesterol, HDL-, LDL-cholesterol, apolipoprotein A 1 and B levels of 80 postmenopausal women, who received hormone replacement therapies for more than one year. RESULTS: All patients showed increasing (non-significant) serum HDL/LDL-cholesterol-ratios. Transdermal estrogen monotherapy also influenced the lipid parameters in a positive way. Apolipoprotein B, cholesterol and LDL-Cholesterol decreased, apolipoprotein A 1 increased. Transdermal replacement therapy combined with C21-progestagens and all oral therapies resulted in HDL-cholesterol increases. Positive changes in lipid parameters were most remarkably in women receiving oral therapies. The addition of 42 mg medrogestone/cycle caused a more significant decrease of cholesterol serum levels than higher dosages of medrogestone did. During subsequent treatment cycles, serum triglycerides showed increasing levels within the reference limits in women receiving conjugated estrogens and medrogeston. CONCLUSIONS: Transdermal and oral hormone replacement therapies with and without C21-progestogens are ideal for hormone replacement therapy in postmenopausal women with normal or minor pathological lipid parameters. The lowest possible medrogestone dose necessary for endometrium protection should be used.

Prevention of postmenopausal bone loss by low and conventional doses of calcitriol or conjugated equine estrogen.

OBJECTIVES: Estrogen deficiency is the most common cause of postmenopausal osteoporosis and estrogen replacement is well known to retard postmenopausal bone loss. Calcium supplement alone is generally considered to be insufficient for the prevention of bone loss associated with estrogen deficiency while the role of calcitriol is unclear. In the present study we examined the efficacy different doses of estrogen or calcitriol in the prevention of postmenopausal bone loss in Thais. METHODS: The subjects consisted of 146 Thai women no more than 6 years postmenopausal. The subjects were randomly allocated to receive 750 mg supplemental calcium alone, calcium and conjugated equine estrogen (CEE) at 0.3 or 0.625 mg, calcium and calcitriol at 0.25 or 0.5 microg daily. Those receiving CEE also took 5 mg medrogestone for 12 days each month. BMD at L2-4 and femoral neck were measured at baseline 1 year and 2 years after treatments. Data were expressed as mean +/- S.E. RESULTS: Subjects on supplemental calcium alone had approximately 2.5% decreases in L2-4 (P < 0.05) and femoral BMD (P < 0.01) at 2 years. CEE (0.3 mg) resulted in 3.20 +/- 1.2% increase in vertebral BMD (P < 0.05) while no significant change in BMD was demonstrated at the femoral neck. Likewise, 0.625 mg of CEE induced 5.4 +/- 1.4% increase in vertebral BMD at 2 years (P < 0.001) without change in the femoral BMD. In regard to calcitriol, no significant change in vertebral or femoral BMD was demonstrated with either 0.25 or 0.5 microg calcitriol. CONCLUSION: We concluded that calcitriol is effective in the prevention of early postmenopausal bone loss in Thais. It represents an option for the prevention of osteoporosis in postmenopausal women who are contraindicated for estrogen replacement.

[Effect of combined conjugated estrogen-medrogestone replacement therapy on lipid profiles, climacteric symptoms and the endometrium]. / Effets sur les lipides, les symptômes climatériques et l'endomètre d'une association d'estrogènes conjugués et de médrogestone dans le traitement hormonal substitutif.

OBJECTIVE: To assess the effects of continuous administration of conjugated estrogen combined with sequential administration of medrogestone on lipid profiles, climateric symptoms and endometrial tolerance. METHODS: This multicenter open study was conducted for one year to assess the effects of a hormone replacement therapy (HRT) regimen using Premarin (0.625 mg/day 28d/28) combined with medrogestone 5mg for 12 days (d17-d28 of each 28-day cycle) on lipid profiles, climateric symptoms and cycle control in 228 post menopausal women with an intact uterus. The subjects were recruited in 23 centers in 7 countries in Europe and Asia. Serum lipid/lipoprotein levels were determined at baseline and at cycles 3, 6, 13; endometrium biopsies were performed at screening then at cycle 13. Climateric symptoms and bleeding patterns were recorded by the patients from daily diaries cards collected at baseline and at visits during cycle 3, 6, 9, and 13. RESULTS: By cycle 3, the conjugated estrogen-medrogestone combination induced significant modifications of the lipid profile which were judged favorable. These modifications were maintained throughout treatment. All the baseline values were within normal limits. Mean variations compared with baseline values (expressed in mmol/l) after cycles 3, 6, and 13 were -0.46, -0.54, and -0.46 for total cholesterol (p<0.05), + 0.053, + 0.057, and + 0.078 for HDL-cholesterol (p<0.05) and -0.556, -0. 542, and -0.493 for LDL-cholesterol (p<0.001) respectively. VLDL-cholesterol levels were unchanged. Triglycerides increased significantly though moderately: + 0.12, + 0.15, and + 0.15 mmol/l at cycles 3, 6, and 13 respectively. Endometrial biopsies obtained at cycle 13 (n=195) did not reveal any endometrial hyperplasia. Withdrowal bleeding was predictable for a 6 to 7.4 day interval. The incidence of irregular bleeding varied from 7 to 33% and decreased progressively over the 13-cycle treatment. The incidence of amenorrhea increased from 14 to 52% over the 12 months studied. Finally, at each cycle, menopausal symptoms (mean number of hot flushes/day and Küpperman score) were significantly improved compared with the baseline. As expected, modifications were more pronounced after cycle 1, but improvements were maintained throughout the study. CONCLUSION: Continuous administration of Premarin in combination with sequential administration of medrogestone was found to be an effective treatment for menopausal symptoms. It was associated with favorable modifications of the lipid profile and was safe for the endometrium.

A randomized trial of oral contraceptive and hormone replacement therapy on bone mineral density and coronary heart disease risk factors in postmenopausal women.

OBJECTIVE: To identify the effects of oral contraceptive (OC) and hormone replacement therapy (HRT) on bone mineral density and coronary heart disease risk factors in postmenopausal women. METHODS: Eighty healthy postmenopausal women were randomly assigned to a cyclic regimen of OC containing 30 microg of ethinyl estradiol and 150 microg of desogestrel or HRT containing 0.625 mg of conjugated equine estrogens 21 days per cycle and 5 mg of medrogestone 10 days per cycle for 12 months. Bone mineral density of lumbar spine and hip, biochemical markers of bone turnover, lipid-lipoprotein profiles, coagulation profiles, fasting plasma glucose, and blood pressure were evaluated. RESULTS: Both regimens caused significant increase in bone mineral density of lumbar spine, trochanter, intertrochanteric region, total hip, and Ward triangle. Only OC therapy was associated with a significant increase in femoral neck bone mineral density (mean score +/- standard error 2.5% +/- 0.7%, P < .01). Biochemical markers of bone turnover, total cholesterol, and low-density lipoprotein cholesterol decreased significantly in both groups. Posttreatment levels of those bone markers and lipid-lipoprotein were significantly lower after OC therapy than HRT. Fasting plasma glucose and systolic blood pressure decreased significantly in both groups; however, only the OC group showed a significant decrease in diastolic blood pressure. CONCLUSION: Both OC and HRT increased bone mineral density of lumbar spine and hip, but OC suppressed bone turnover more than HRT. Both methods favorably affected lipid-lipoprotein metabolism, fasting plasma glucose, and blood pressure during the 12 months of treatment.

Control of sulfatase and sulfotransferase activities by medrogestone in the hormone-dependent MCF-7 and T-47D human breast cancer cell lines.

In the present study, we explored the effect of the progestin medrogestone on the sulfatase and sulfotransferase activities in the hormone-dependent MCF-7 and T-47D human breast cancer cell lines. After 24 h incubation at 37 degrees C of physiological concentrations of estrone sulfate ([3H]-E1S: 5x10(-9) mol/l), it was observed that this estrogen was converted in a great proportion to E2 in both cell lines. Medrogestone significantly inhibits this transformation, at all the concentrations tested (5x10(-8) to 5x10(-5) mol/l), in both cell lines. The IC50 values were 1.93 micromol/l and 0.21 micromol/l in MCF-7 and T-47D cells, respectively. In another series of studies, after 24 h incubation at 37 degrees C of physiological concentrations of estrone ([3H]-E1: 5x10(-9) mol/l), the sulfotransferase activity was detectable in both cell lines. Estrogen sulfates (ES) are found exclusively in the culture medium, which suggests that as soon as they are formed they are excreted into the medium. Medrogestone has a biphasic effect on sulfotransferase activity in both cell lines. At low doses: 5x10(-8) and 5x10(-7) mol/l, this compound stimulates the enzyme by +73.5 and 52.7%, respectively, in MCF-7, and by 84.5 and 62.6% in T-47D cells. At high concentrations: 5x10(-6) and 5x10(-5) mol/l, medrogestone has no effect on MCF-7 cells, but inhibits the sulfotransferase activity in T-47D cells by -31.4% at 5x10(-5) mol/l. In conclusion, the inhibitory effect provoked by medrogestone on the enzyme involved in the biosynthesis of E2 (sulfatase pathway) in estrogen-dependent breast cancer, as well as the stimulatory effect on the formation of the inactive ES, support a probable anti-proliferative effect of this progestin in breast tissue. Clinical applications of these findings can open new therapeutic possibilities for this disease.

Add-back medrogestone does not prevent bone loss in premenopausal women treated with goserelin.

To investigate the effect of medrogestone on bone mineral density (BMD) and bone turnover under conditions of estrogen withdrawal, premenopausal women with endometriosis were treated with goserelin (Zoladex), combined with either placebo (group A, n = 12) or 10 mg medrogestone (Prothil, group B, n = 11) for six months, and followed for an additional six months. Lumbar spine BMD was measured at 0 and 6 month. Markers of bone turnover were serum bone alkaline phosphatase (sBAP) and osteocalcin (sOC) by ELISA, and urinary total pyridinoline (uPYD) and deoxypyridinoline crosslinks (uDPD) by HPLC. Patients in both groups had a similar and significant decrease in BMD after 6 months (4%, p < 0.01). The time course of changes in bone turnover, in contrast, was different in both groups. In group A, crosslink excretion increased from one month onwards, while no changes were seen in group B. In group A, sBAP levels rose during treatment, while in group B, this rise was delayed until treatment was terminated. Additionally, group B showed an initial suppression of sBAP and sOC. In both groups, sOC increased after treatment was discontinued. Medrogestone at 10 mg/d does not prevent lumbar bone loss in premenopausal women under estrogen deprivation. In the medrogestone add back group, the changes in bone turnover are compatible with low turnover bone loss,as ooposed to a state of high turnover seen in the unopposed goserelin group. This effect may be due to glucocorticoid receptor mediated actions of medrogestone on bone.