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Highlights: [•] We evaluated a database on patients with birth defects prenatally exposed to Duogynon. [•] Birth defects were compared to data from a population based birth register. [•] Proportional reporting ratio revealed an OR of 37 for bladder exstrophy among exposed. [•] A reporting bias of consumer ADR reports may explain our finding. [•] The present study highlights the difficulties of evaluating consumer reports which may be influenced by public media. [ABSTRACT FROM AUTHOR]

Whether hormonal contraceptives increase HIV-1 acquisition, transmission and disease progression are critical questions. Clinical research has been hampered by a lack of understanding that different progestins used in contraception exhibit differential off-target effects via steroid receptors other than the progesterone receptor. Of particular, relevance is the relative effects of medroxyprogesterone acetate ( MPA) and norethisterone enanthate ( NET- EN), widely used as injectable contraceptives in sub-Saharan Africa. While most high-quality clinical studies find no increased risk for HIV-1 acquisition with oral contraception or injectable NET- EN, most do find an increase with MPA, particularly in young women. Furthermore, mounting evidence from animal, ex vivo and biochemical studies are consistent with MPA acting to increase HIV-1 acquisition and pathogenesis, via mechanisms involving glucocorticoid-like effects on gene expression, in particular genes involved in immune function. We report that MPA, unlike NET and progesterone, represses inflammatory genes in human PBMCs in a dose-dependent manner, via the glucocorticoid receptor ( GR), at concentrations within the physiologically relevant range. These and published results collectively suggest that the differential GR activity of MPA versus NET may be a mechanism whereby MPA, unlike NET or progesterone, differentially modulates HIV-1 acquisition and pathogenesis in target cells where the GR is the predominant steroid receptor expressed. [ABSTRACT FROM AUTHOR]

Epilepsy and the medications used in its treatment are known to affect the menstrual cycle, aspects of contraception, and bone health in women. Adolescence is an important time to review the diagnosis of both epilepsy and the epilepsy syndrome because of the implications and decisions, which should be made regarding antiepileptic drug (AED) treatment. In girls, once they are on AED therapy, seizure free, and driving, it becomes difficult to change therapy because of the risk of breakthrough seizures and the fact that the new AED may not be as effective as the first. So a treatment choice made in adolescence is often life-long. Therefore, women need to be started on an AED that currently appears to be the most suitable for their seizure type, has a low teratogenic risk, and hopefully does not interact with contraception. There are no contraindications to the use of non-hormonal methods of contraception in women with epilepsy. Nonenzyme-inducing AEDs (valproate, benzodiazepines, ethosuximide, levetiracetam, tiagabine, and zonisamide) do not show any interactions with the combined oral contraceptive. There are interactions between the combined oral contraceptive and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [dosages >200 mg/day], oxcarbazepine, eslicarbazepine and perampanel [dosages >12 mg/day]) and lamotrigine. Women taking enzyme inducing AEDs should be encouraged to use a method of contraception that is unaffected by their epilepsy medication. Interactions between AEDs and other hormonal therapies are less well studied. Studies have suggested that women with epilepsy are at increased risk of fractures, osteoporosis, and osteomalacia. No studies have been undertaken looking at preventative therapies for these comorbidities. This article will concentrate on current contraceptive treatment options in patients taking AEDs. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effects of steady-state concentrations of the selective S1P receptor modulator ponesimod on the pharmacokinetics (PK) of a single dose of a combined oral contraceptive, containing 1 mg norethisterone (NET) and 35 μg ethinyl estradiol (EE) and to investigate the effects on heart rate at different ponesimod doses within an up-titration regimen prior to co-administration of the contraceptive. Methods: Twenty-two healthy women (age: 29-60 years) received twice a single oral dose of the combined oral contraceptive, alone or in combination with multiple doses of 40 mg ponesimod attained by an up-titration regimen. Heart rate (HR) effects were assessed on the first day of each up-titration level. PK parameters of NET and EE were determined by non-compartmental analysis. Results: Geometric mean ratios (ponesimod and contraceptive / contraceptive alone) of C and AUC of NET were 0.87 (90 % CI: 0.80, 0.94) and 0.84 (90 % CI: 0.76, 0.93), respectively. Geometric mean ratios of C and AUC of EE were 0.94 (90 % CI: 0.86, 1.03) and 0.95 (90 % CI: 0.89, 1.01), respectively. The maximum mean HR reduction after the first dose of 10 mg ponesimod was 12.4 bpm (SD ± 6.2) at 2.5 h post-dose. On Day 4 (first dose of 20 mg) and Day 7 (first dose of 40 mg) the maximum mean HR reduction was 4.3 bpm (SD ± 5.7) and 1.4 (SD ± 6.4), respectively, at 2.5 h post-dose compared to baseline. Conclusion: No clinically relevant PK interactions between ponesimod and the combined oral contraceptive were observed, therefore, efficacy of hormonal contraceptives is not expected to be affected by concomitant administration of ponesimod. The up-titration regimen showed that HR reductions are diminished upon repeated ponesimod administration. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To compare the efficacy of norethisterone acetate (NETA; group N) or letrozole combined with NETA (group L) in treating endometriotic ovarian cysts. Study design: This patient-preference study included 20 patients in group N and 20 patients in group L. The primary aim of the study was to compare the volume of the endometriomas during and after treatment. The secondary outcome was the evaluation of the changes in pain symptoms during and after treatment. Results: After six months of treatment, the volume of the endometriomas significantly decreased compared with baseline in both study groups; it was smaller in group L than in group N (p =0.026). The rate of satisfied patients at six months of treatment was similar between the study groups (p =0.451). No significant difference was reported between the two study groups in the amelioration of pain symptoms and in the incidence of adverse events. Conclusions: Letrozole combined with NETA is more efficacious than NETA alone in reducing the volume of endometriotic cysts but in none of the 40 patients included in the study did the endometriomas disappear. The efficacy of aromatase inhibitors, however, should be balanced with the need to administer long-term treatment. [Copyright &y& Elsevier]

Abstract: The interaction characteristics between norethisterone (NET) and bovine serum albumin (BSA) were studied by fluorescence spectroscopy combined with UV–vis spectrophotometric techniques under simulative physiological conditions. The influence of Cd(II) and/or Se(IV) ions on the interaction between NET and BSA was also investigated. The fluorescence quenching rate constants and binding constants for BSA–NET system were determined at different temperatures. The mechanism of BSA fluorescence quenched by NET was discussed according to the Stern–Volmer equation. The results of thermodynamic parameters, ΔG, ΔS and ΔH, indicated that van der Waals interaction and hydrogen bonding played a major role for NET–BSA association. The results of competitive experiments demonstrated that the primary binding site of NET within subdomain IIA of BSA, and the second binding site within subdomain IIIA. The distance between BSA and NET is estimated to be 3.65nm based on the Förster resonance energy transfer theory. The conformational change of BSA was observed in the existence of NET, Cd(II) or/and Se(IV) ions by synchronous fluorescence and three-dimensional fluorescence spectra. [Copyright &y& Elsevier]

Abstract: Objectives: Low-dose estrogen–progestin (LEP) agents are often used for relieving endometriosis-associated chronic pelvic pain, but a direct effect of LEP on endometriotic lesions remains to be demonstrated. The objective of this study is to investigate the antiproliferative and apoptotic effects of the synthetic progestin norethisterone (NET) against human endometriotic stromal cells (ESCs). Study design: Ovarian endometrioma specimens were obtained at laparoscopy from 19 patients with endometriosis, and ESCs were isolated. The antiproliferative effect of compounds against cultured ESCs was evaluated by measuring the inhibition of [3H]thymidine incorporation. The ability of compounds to induce apoptosis in the cultured cells was evaluated by the measurement of caspase 3/7 activity and by nuclear staining. The cytotoxicity of compounds was evaluated by measuring the leakage of lactate dehydrogenase (LDH) into the supernatant of the cell culture. Results: NET and progesterone (P4) at concentrations of greater than 10nM significantly inhibited [3H]thymidine incorporation in a dose-dependent manner. Co-treatment with 17β-estradiol at 0.1ng/mL did not affect the inhibition of [3H]thymidine incorporation by NET. At concentrations greater than 100nM, NET significantly increased caspase 3/7 activity and the numbers of apoptotic cells, whereas P4 did not. Treatment of ESCs for 24h with NET or P4 at concentrations of up to 1000nM did not cause LDH leakage. Conclusions: NET inhibits the proliferation of ESCs and induces their apoptosis. These results suggest a possible direct effect of NET on endometriotic lesions in patients with endometriosis. [Copyright &y& Elsevier]

Background: Biotransformation by using microbial and plant cell cultures has been applied effectively for the production of fine chemicals on large scale. Inspired by the wealth of literature available on the biotransformation of steroids, we decided to investigate the biotransformation of ethynodiol diacetate (1) by using plant andmicrobial cultures. Results: The biotransformation of ethynodiol diacetate (1) with Cunninghamella elegans and plant cell suspension cultures of Ocimum basilicum and Azadirachta indica is being reported here for the first time. Biotransformation of 1 with Cunninghamella elegans yielded three new hydroxylated compounds, characterized as17?-ethynylestr-4-en-3β, 17β-diacetoxy-6β-ol (2), 17β-ethynylestr-4-en-3β,17β-diacetoxy-6β-ol (3), and17β-ethynylestr-4-en-3β, 17β-diacetoxy-10β-ol (4) and a known metabolite, 17?-ethynyl-17?-acetoxyestr-4-en-3-one (5). The biotransformation of 1 with Ocimum basilicum included hydrolysis of the ester group, oxidation of alcohol into ketone, and rearrangement of the hydroxyl group. Thus four major known metabolites were characterized as 17β-ethynyl-17β-acetoxyestr-4-en-3-one (5), 17β-ethynyl-17β-hydroxyestr-4-en-3-one (6), 17β-ethynyl-3 β-hydroxy-17β-acetoxyestr-4-ene (7) and 17β-ethynyl-5β,17β-dihydroxyestr-3-ene (8). Biotransformation of 1 with Azadirachta indica culture yielded compounds 5 and 6. Spectroscopic data of compound 8 is being reported for the first time. Structure of compound 6 was unambiguously deduced through single-crystal x-ray diffraction studies. Conclusion: Biotransformation of an oral contraceptive, ethynodiol diacetate (1), by using microbial and plant cell cultures provides an efficient route to the synthesis of a library of new steroids with potential contraceptive properties. These methods can be employed in the production of such compounds with high stereoselectivity. [ABSTRACT FROM AUTHOR]

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The principle of male hormonal contraception is based on the suppression of LH and FSH and the replacement of testosterone to maintain androgenicity. The goal can best be achieved by testosterone alone or by testosterone in combination with a gestagen. The five clinical trials using pregnancy rates as end points and the one trial performed by the pharmaceutical industry are reviewed here. An ongoing large multicenter trial launched by WHO and the US CONRAD Programme will decide about the future of male hormonal contraception. [ABSTRACT FROM AUTHOR]

Abstract: Research has established the principle of hormonal male contraception based on suppression of gonadotropins and spermatogenesis. All hormonal male contraceptives use testosterone, but only in East Asian men can testosterone alone suppress spermatogenesis to a level compatible with contraceptive protection. In Caucasians, additional agents are required of which progestins are favored. Clinical trials concentrate on testosterone combined with norethisterone, desogestrel, etonogestrel or depot-medroxyprogesterone acetate. The first randomized, placebo-controlled clinical trial performed by the pharmaceutical industry demonstrated the effectiveness of a combination of testosterone undecanoate and etonogestrel in suppressing spermatogenesis in volunteers. [ABSTRACT FROM AUTHOR]

Abstract: Norethisterone is one kind of widely used anabolic steroid hormones which can help to promote livestock growth and sometime has been illegally used for livestock breeding. The residues of norethisterone in animal food will harm people''s health, therefore, it has been banned to use for the growth promotion purposes in livestock. In this study, amino-group functionalized mesoporous silica nanoparticles (MSN) were prepared and used to immobilize Au nanoparticles, which was further utilized for the adsorption of horseradish peroxidase (HRP) and the secondary antibody (Ab2). The resulting nanoparticles, Au-MSN-HRP-Ab2 were used as labels for immunosensors to detect norethisterone antigen. A sandwich-type protocol was used to prepare the immunosensor with the primary antibody (Ab1) immobilized onto thionine (TH) and graphene sheet (GS) modified glassy carbon electrode surface. The sensitivity of the sandwich-type immunosensor using Au-MSN-HRP-Ab2 as labels for norethisterone antigen detection was much higher than that using either Au-MSN-Ab2 or MSN-HRP-Ab2 as labels. Within norethisterone concentration range (0.01–10ng/mL), a linear calibration plot (Y =0.55671+8.27101X, r =0.9993) was obtained with a detection limit of 3.58pg/mL under optimal conditions. The proposed immunosensor shows good reproducibility, selectivity, and acceptable stability. This new type of labels for immunosensors may provide many potential applications for the detection of growth hormone in animal derived food. [Copyright &y& Elsevier]

Objectives To evaluate the effect on breast density of two low-dose hormone therapy regimens identical in their estrogen component but different in the progestin. Methods A total of 81 non-hysterectomized postmenopausal women were allocated either to 17β-estradiol 1 mg and norethisterone acetate 0.5 mg (E2/NETA, n = 43) or to 17β-estradiol 1 mg and drospirenone 2 mg (E2/DRSP, n = 38). Treatment was continuous and lasted 12 months. The main outcomes were the changes in breast density according to the Wolfe classification between baseline and 12-month mammograms. Results Involution of the fibroglandular tissue was not seen in either of the treatment groups. Under E2/NETA, breast density increased in seven women (16.3%). In contrast, only three women (7.9%) exhibited a density increase under E2/DRSP. Conclusions Although hormone therapy appears to suspend breast involution, it does not increase breast density in the majority of treated women. Progestins differing in pharmacological properties may have a variable impact on breast density. [ABSTRACT FROM AUTHOR]

High-performance liquid chromatography coupled with tandem mass spectrometry has been used for sensitive and specific quantitative analysis of norethisterone (NE) in human serum. NE and the internal standard fentanil were isolated by solid-phase extraction. Chromatographic separation was achieved on a 4.6 mm × 50 mm, 5-μm particle, C18 column. The mobile phase was 70:30 ( v/ v) methanol–0.5% aqueous formic acid. NE and the internal standard were detected by multiple-reaction monitoring of precursor/product ion combinations at m/ z 299.4/231.2 and 377.1/188.1, respectively; an atmospheric-pressure-photoionization source was used in positive-ion mode. Linearity was established in the concentration range 0.2–49.24 ng mL−1 and the lowest limit of quantification was 0.2 ng mL−1. Recovery of NE ranged from 92.54 to 102.74% and relative standard deviations were <15%. The method was used for a pharmacokinetic study of NE in healthy postmenopausal Chinese female volunteers. [ABSTRACT FROM AUTHOR]

Abstract: The detection of 19 norandrosterone (19-NA) in a competitor''s urine sample is taken as prima facie evidence of administration of nandrolone or other 19-norsteroid but a potential problem is that administration of norethisterone, a progestogen used for menstrual disorders and for hormonal contraception, also results in the excretion of 19-NA that can exceed the laboratory reporting threshold of 2ng/mL. The contribution of norethisterone to urinary 19-NA with and without 19-norandrostenedione, a known norethisterone tablet impurity, requires evaluation. Preparations containing, either <2ng or 1μg 19-norandrostenedione impurity per 5mg of norethisterone, administered to female volunteers (n =10) in doses comparable to those used for menstrual disorders (5mg three times daily for 10 days), resulted in maximal 19-NA concentrations of 51 and 63ng/mL, respectively. The maximal concentration of 19-NA, 2h post-administration of a single 1μg dose of 19-norandrostenedione, was 2.4ng/mL. These results prove unequivocally that norethisterone is metabolized to 19-NA and that there is only a minor contribution from the impurity 19-norandrostenedione. Administration to women (n =30) of a single contraceptive tablet containing norethisterone (1mg) with one of the highest proportions of the impurity 19-norandrostenedione (∼0.5μg, 0.05%, w/w) resulted in a urinary 19-NA concentration of 9.1ng/mL, with a maximum concentration ratio of 19-NA to the norethisterone metabolite 3α,5β-tetrahydronorethisterone of 0.36. We provide data that should remove the need for time-consuming follow-up investigations to consider whether doping with 19-norandrogens has occurred. [Copyright &y& Elsevier]

Abstract: The finding of measurable amounts of 19-norandrostenedione in norethisterone tablets prompted us to develop an assay to quantify this steroid. 19-Norandrostenedione is an anabolic steroid whose use in sport is prohibited by the World Anti-Doping Agency (WADA). The assay was developed using isotope dilution and liquid chromatography–tandem mass spectrometry (LC–MS/MS) for the quantification of 19-norandrostenedione in norethisterone formulations, with [3,4-13C2]-19-norandrostenedione as the internal standard. The results showed amounts up to 1.01±0.01μg (mean±S.E.M.) per tablet in those containing 5mg of norethisterone or norethisterone acetate (0.02%, w/w) and up to 0.5±0.01μg (mean±S.E.M.) per tablet (0.05%, w/w) in oral contraceptive tablets containing 0.35–1.5mg of norethisterone or norethisterone acetate. No tablet tested exceeded the British Pharmacopoeia limit of 0.1% for this impurity. [Copyright &y& Elsevier]

Abstract: 19-Norandrosterone (19-NA) is the principal urinary metabolite of the anabolic steroid nandrolone and its prohormones. The administration of these 19-nor androgens is prohibited in sport by the World Anti-Doping Agency (WADA) but, even so, adverse findings for 19-NA continue to be commonly reported. Little is known about the urinary concentrations of 19-NA that can occur in women who are not using anabolic steroids, including those using oral contraceptives containing the 19-nor progestogen norethisterone. In 2004, WADA lowered the reporting threshold for 19-NA for females from 5 to 2ng/mL. The lack of any substantial data on 19-NA excretion in women prompted this large-scale investigation. In this investigation, single untimed urines collected from 1202 female volunteers, 38 of whom were taking norethisterone containing contraceptives, were analysed for 19-NA. None of the women was a competitive athlete and pregnancy had been excluded by a urinary test for human chorionic gonadotropin (hCG). Only one sample exceeded the 19-NA reporting threshold having a concentration of 4.1ng/mL. This sample was from a user of a norethisterone-containing contraceptive. [Copyright &y& Elsevier]

Objective To assess whether use of tranexamic acid is associated with an increased risk of venous thromboembolism (VTE). Design Nested case–control study. Setting Database study using the General Practice Research Database for the years 1992–1998. Population Women aged 15–49 years with a diagnosis of menorrhagia. Methods Multivariate conditional logistic regression was used to estimate the risk for VTE associated with different drug treatments for menorrhagia, adjusting for confounders. Main outcome measures Adjusted odds ratios with 95% CI. Results A total of 134 cases of VTE and 552 matched controls were identified. Recent use of tranexamic acid was scarce, yielding an adjusted odds ratio for VTE of 3.20 (95% CI 0.65–15.78). The use of mefenamic acid (ORadj 5.54 [95% CI 2.13–14.40]) or norethisterone (ORadj 2.41 [95% CI 1.00–5.78]) was associated with an increased risk of VTE, as was a recent—in relation to menorrhagia—diagnosis of anaemia or a haemoglobin value <11.5 g/dl (ORadj 2.23 [95% CI 1.02–4.86]). Conclusions We found that tranexamic acid was associated with an increased risk of VTE, although the risk estimate did not reach statistical significance. Increased risks of VTE associated with other treatments for menorrhagia were observed. The increased risk of VTE observed with a diagnosis of anaemia—a proxy for more severe menorrhagia—suggests that menorrhagia could be a prothrombotic condition. The observed association between VTE, tranexamic acid and other treatments for menorrhagia may thus partly be explained by confounding by indication. The possibility that menorrhagia is itself a risk factor for VTE merits further investigation. [ABSTRACT FROM AUTHOR]

Abstract: Background: The contraceptive effect of the progestogen norethisterone (NET) and its main metabolites 5α-NET and 3β,5α-NET has been demonstrated in several species, and most studies have focused on the effects of these compounds in the uterus. We previously reported that 5α-NET inhibits the progesterone (P4)-induced acrosome reaction in pig and mouse spermatozoa and induces severe morphological damage in two-cell fertilized mouse oocytes. Study Design: The main goal of this study was to analyze the possible role of P4 receptor (PR) in the effects of NET and 5α-NET on the oocyte fertilization process. Different steroid treatments were used with or without cumulus-enclosed oocytes. Results: It was demonstrated that NET increases the percentage of fertilized oocytes in the same manner as P4 does, while 5α-NET reduces the percentage of fertilized oocytes. This effect was not reversed by P4 in the same concentrations. Conclusion: A possible molecular mechanism for the effects of 5α-NET may be through a PR localized in the oocyte plasma membrane. [Copyright &y& Elsevier]

Objective: To evaluate the efficacy of a low-dose oral contraceptive pill (OCP) for patients with dysmenorrhea associated with endometriosis. Design: A double-blind, randomized, placebo-controlled trial. Settings: Clinical trial sites in Japan. Patient(s): One hundred patients with dysmenorrhea associated with endometriosis. Most enrolled patients had radiologic evidence of endometriosis rather than surgical diagnosis. Intervention(s): Patients were randomly assigned to receive either monophasic OCP (ethinylestradiol plus norethisterone) or placebo. Participants used their usual pain medications as needed during the trial. Main Outcome Measure(s): After four cyclic treatments, we used a zero- to three-point verbal rating scale and a visual analogue scale to measure the severity of disability because of dysmenorrhea in daily life, and the patients'' use of analgesics. Result(s): Total dysmenorrhea scores assessed by the verbal rating scale were significantly decreased at the end of treatment in both groups. From the first cycle through the end of treatment, dysmenorrhea in the OCP group was significantly milder than in the placebo group. Nonmenstrual pelvic pain was present at baseline in 24.5% (12 of 49) of the OCP group and 34.0% (16 of 47) of the placebo group. The volume of endometrioma (larger than 3 cm in diameter) was significantly decreased in the OCP group, but not in the placebo group. No serious adverse events related to using OCPs occurred. Conclusion(s): The present study clearly demonstrated for the first time that OCPs could be used to effectively and safely treat pain associated with endometriosis. [Copyright &y& Elsevier]

Abstract: Objectives: To evaluate the lipid profile, insulin resistance and vasomotricity, and the interaction between these factors, in postmenopausal women receiving hormone therapy. Methods: A prospective, randomized, double-blind study was carried out in which 77 postmenopausal women received one of the three treatment regimens: (A) 2mg oral micronized estradiol (E2) (n =25); (B) 2mg oral E2 +1mg oral norethisterone acetate (NETA) (n =28); or C) placebo (n =24), daily for 6 months. Evaluations were carried out at baseline and at the end of treatment on lipid and lipoprotein profiles, homeostasis model assessment of insulin resistance (HOMA-IR) and pulsatility index (PI) of the internal carotid artery by Doppler ultrasonography. Results: Mean increases of 15.6% and 2.4% and a reduction of 6.4% in high-density lipoprotein (HDL) levels were found for the E2, E2 +NETA and placebo groups, respectively. Reductions of 9.5% and 3.7% and an increase of 12.1% in low-density lipoprotein (LDL), and reductions of 20.0% and 3.8% and an increase of 28.8% in the LDL:HDL ratio were found for the E2, E2 +NETA and placebo groups, respectively (p <0.001 in all cases). Insulin levels and HOMA-IR decreased 12.8% and 12.3% in the E2 group and increased 12.9% and 16.0% in the E2 +NETA group (p <0.05), respectively. Carotid PI following treatment was 1.18±0.23, 1.38±0.20 and 1.41±0.21 for the E2, E2 +NETA and placebo groups, respectively (p =0.0006). Conclusions: Oral estrogen therapy led to an improvement in lipid profile, insulin resistance and carotid blood flow, which was cancelled when NETA was associated. [Copyright &y& Elsevier]

Objective To study the influence of smoking on uterine bleeding patterns during continuous and interrupted oral hormone therapy (HT). Methods Using a post-hoc strategy, we included five oral HT groups from three studies. The therapies consisted of continuous estrogen (estradiol, estradiol valerate or piperazine estrone sulfate) in combination with continuous progestogen (cyproterone acetate, gestodene or norethisterone acetate) or in combination with interrupted progestogen (norethisterone) given on days 4-6, 10-12, 16-18, 22-24 and 28-30. A total of 145 healthy postmenopausal women (54 smokers and 91 non-smokers), who had been followed for 2 years, were included in the analyses. Uterine bleeding data were collected from bleeding calendars. Results In general, smoking women experienced significantly less days with uterine bleeding per cycle than non-smoking women during continuous and interrupted HT (0.53 ± 0.1 vs. 1.6 ± 0.1; p < 0.001). Smoking women were also more likely than non-smoking women to be amenorrheic during these therapies (48.2% vs. 29.7%; p < 0.05). Finally, more smoking than non-smoking women attained amenorrhea during HT (94.4% vs. 76.9%p < 0.01). Conclusions In healthy postmenopausal women, smoking may reduce uterine bleeding during interrupted and continuous HT regimens containing a broad selection of estrogens and progestogens. Further study with appropriate stratification for smoking status is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The objective of this study was to develop a simple, sensitive, stable and validated HPLC method for the determination of mifepristone levels in human plasma. Methods: Solid-phase extraction cartridges were used to extract plasma samples. Separation was carried out on a C18 column maintained at 20°C with acetonitrile–water (80:20, v/v) as mobile phase at a flow rate of 0.6 mL/min. Norethisterone was employed as the internal standard. Dual wavelength mode was used, with mifepristone monitored at UV 302 nm and norethisterone at 240 nm. Results: The calibration curve was linear in the concentration range of 5–10000 ng/mL, with linear correlation coefficient r being 0.9999. The limit of detection for the assay was 3 ng/mL. The inter-day accuracy ranged from 92.4% to 98.4% and precision 3.6% to 11.4%. The intra-day accuracy ranged from 92.1% to 100.6% and precision 4.7% to 12.2%. The absolute recovery was 91.7–100.1%. Plasma samples were stable for at least 1 month if stored at −20°C. This validated HPLC method was successfully applied to pharmacokinetic study of mifepristone in human plasma samples collected from volunteers after oral administration of 10 mg mifepristone. Conclusion: The simple, accurate and stable method allows the sensitive determination of mifepristone in human plasma at the nanogram level. It could be applied to assess the plasma level of mifepristone in women up to 5 days after oral administration of 10 mg mifepristone. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate the safety and endometrial protection of low-dose transdermal estradiol (E2)/norethisterone acetate (NETA) patches (Estalis 25/125) in terms of post-treatment incidence of endometrial hyperplasia/cancer after 1 year of treatment in postmenopausal women with intact uteri. Methods: Patients were randomized to receive either transdermal E2/NETA (delivering daily doses of E2 25μg and NETA 125μg; applied every 3–4 days) or oral E2/NETA (E2 1mg and NETA 0.5mg; given daily) in this open-label study. The primary variable was the incidence of endometrial hyperplasia/cancer based on endometrial biopsies; secondary variables included vaginal bleeding/spotting patterns, patch adhesion, safety and tolerability. Results: Six hundred and seventy-seven patients were randomized (507 in the transdermal group and 169 in the oral group; one did not receive study drug) and >80% completed the study. There were no cases of endometrial hyperplasia or cancer in either group and the upper limit of the one-sided 95% confidence interval in the transdermal group was 0.85%. Over time, both treatments were associated with a decreasing frequency of spotting/bleeding days. The overall incidence of adverse events (AEs) was comparable in both groups, and the majority was mild-to-moderate in intensity. Breast tenderness was the most frequently reported AE (transdermal 19.9% versus oral 28.4%). AEs related to the gastrointestinal system were more frequent with oral E2/NETA, and episodes of spotting and bleeding were more frequent with transdermal E2/NETA. Local skin tolerability of the transdermal matrix system was good. Conclusions: Transdermal E2/NETA (25 and 125μg) provided adequate endometrial protection in postmenopausal women when evaluated according to CPMP/CHMP criteria, achieved a high rate of amenorrhea, and was well tolerated. [Copyright &y& Elsevier]

Abstract: The electrochemical behavior of norethisterone at the mercury electrode was studied in the universal buffer of various pH values using dc-polarography, cyclic voltammetry and controlled-potential electrolysis. Norethisterone was reduced at the mercury electrode via the consumption of two electrons corresponding to reduction of the 3-keto-delta-4-group in the A-ring of the molecule. The pK a value (8.7) of norethisterone was determined from the polarographic and spectrophotometric measurements. A fully validated, simple, sensitive, precise and inexpensive square-wave adsorptive cathodic stripping (SWAdCS) voltammetry procedure was described for trace quantification of bulk norethisterone. The stripping voltammetry peak current of norethisterone in a universal buffer of pH 5 following its accumulation onto the hanging mercury drop electrode (HMDE) at −0.6V (versus Ag/AgCl/KCls) for 130s showed a linear response with the concentration over the range 5×10−9 to 3×10−7 M norethisterone. Detection and quantitation limits of 1.5×10−9 and 5×10−9 M bulk norethisterone, respectively, were achieved. The proposed procedure was successfully applied for the assay of norethisterone in Steronate tablets without interference from excipients. [Copyright &y& Elsevier]

Objectives: To establish whether transdermal continuous hormone replacement therapy (HRT) with estrogen/progestogen provides adequate long-term endometrial protection in postmenopausal women over a period of 96 weeks.Methods: This multicenter, randomized, open-label, parallel-group study evaluated the endometrial effects and overall safety and tolerability of a transdermal matrix patch delivering estradiol (E2) 50 microg/day and norethisterone acetate (NETA) 140 microg/day (Estalis; patches applied twice weekly without intermediate breaks) and a once-daily oral comparator (Kliogest; one tablet containing E2 2 mg/NETA 1 mg) in postmenopausal women. A total of 406 women with an intact uterus, aged 44-69 years, were randomized in the 48-week core phase of the study, and 239 continued into the 48-week extension phase. Subjects were randomized in the ratio 3 : 1 to transdermal or oral E2/NETA treatment.Results: No cases of endometrial hyperplasia or endometrial cancer were reported with either treatment during the core or extension phase. Both treatments were generally well tolerated, with most adverse events (>90%) being mild to moderate, although minor differences in the tolerability profile were observed between treatments.Conclusions: Continuous combined transdermal HRT with E2/NETA shows no evidence of an increased endometrial hyperplasia or endometrial cancer risk over a 96-week period. [ABSTRACT FROM AUTHOR]

Objective: To compare the effects of continuous combined 17β-estradiol (E2) plus norethisterone (acetate) [NET(A)] therapy by either intranasal or oral administration on the lipid profile in postmenopausal women. Design: Randomized, double-blind, multicenter trial. Setting: Gynecologic outpatient department. Patient(s): Two-hundred thirty-three healthy postmenopausal women. Intervention(s): Women received continuous combined hormone therapy, either intranasal E2/NET (175 μg/275 μg) as a spray (n = 117) or oral E2/NETA (1 mg/0.5 mg) as a capsule (n = 116), for 1 year. Main Outcome Measure(s): Fasting plasma concentrations of lipids and (apo)lipoproteins; and atherogenic indices at baseline and after 12, 24, and 52 weeks of treatment. Result(s): We found a significant (P<.001) decrease from baseline in both treatment groups in total, low-density lipoprotein- (LDL), high-density lipoprotein- (HDL), and HDL2-cholesterol, in triglycerides, apolipoprotein B (apoB), and lipoprotein(a). Levels of HDL3-cholesterol and apolipoprotein A1 (apoA1) were transiently decreased in the intranasal group. In the oral group, compared with the intranasal group, the decrease was larger for ratio total and LDL-cholesterol and lipoprotein(a) and smaller for triglycerides and apoA1. In the oral group, the ratios total/HDL cholesterol and LDL/HDL cholesterol were lowered, and the ratio apoB/LDL was increased, more than in the intranasal group. Conclusion(s): Both intranasal and oral E2/NET(A) therapy improved the lipid profile of healthy postmenopausal women, with some effects being more pronounced after oral administration. [Copyright &y& Elsevier]

Objective: Bosentan has been shown in vitro and in vivo to induce the cytochrome P450 enzymes CYP2C9 and CYP3-A4. The present study was conducted to investigate the effect of bosentan on the pharmacokinetics of a combined oral contraceptive. Subjects and methods: In a randomized, 2-way cross over study, 20 healthy fe male subjects received Treatments A and B. Treatment A consisted of a single dose of Ortho-Novum containing 1 mg norethisterone (norethindrone) and 35 mg ethinyl estradiol. Treatment B consisted of bosentan, 125 mg b.i.d. for 7 days plus concomitant norethisterone and ethinyl estradiol on Day 7. Plasma concentrations of norethisterone and ethinyl estradiol were measured on days of oral contraceptive administration. Results: In the absence of bosentan, the pharmacokinetics of norethisterone and ethinyl estradiol were characterized by C max and AUC0-∞ values (95% CI) of 9.8 (8.1, 11.9) ng/ml and 72.9 (57.0, 93.1) ng × h/ml, and 53.0 (47.0, 59.9) pg/ml and 758 (655, 878) pg × h/ml, respectively. Concomitant bosentan did not affect the Cmax but significantly decreased the AUC of norethisterone and ethinyl estradiol by 13.7% (-23.5, -2.6) and 31.0% (-40.5, -20.2), respectively. The maximum decrease in AUC of norethisterone and ethinyl estradiol in an individual subject was 56% and 66%, respectively. Conclusions: Bosentan decreases the AUC of norethisterone and ethinyl estradiol in healthy female subjects. In patients treated with bosentan, reduced efficacy of hormonal contraceptives should be considered. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Recent trials have suggested an adverse early effect on cardiovascular risk of hormone therapy (HT) in postmenopausal women, an effect which could be due to an increase in arterial thrombosis via platelet activation. We examined the effect of HT on platelet surface expression of P-selectin, a marker of platelet activation, and plasma levels of soluble P-selectin, also believed to be a marker of platelet activation, and compared these effects with pravastatin, a drug proven to reduce cardiovascular events and reported to decrease both platelet and soluble P-selectin. Methods: Surface expression of platelet P-selectin, soluble P-selectin and fasting lipids were measured at baseline and 6 months in a randomized, double-blind study of postmenopausal hypercholesterolemic women comparing low-dose combined HT (1mg estradiol+0.5mg norethisterone acetate; n =26) with pravastatin (n =24). Results: After adjusting for baseline levels, HT and pravastatin produced similar reductions in soluble P-selectin (p <0.0001 for both). The percentage of platelets expressing P-selectin was also reduced by pravastatin (p =0.025), but there was a trend to an increase in platelet P-selectin expression with HT (p =0.13), and a significant difference between pravastatin and HT in the changes in platelet P-selectin (p <0.002). No relationship was evident between changes in soluble or platelet P-selectin and changes in lipids with either treatment. Conclusions: In postmenopausal hypercholesterolemic women, both pravastatin and HT reduced soluble P-selectin levels, but only pravastatin reduced P-selectin expression on the surface of platelets. An implication of these findings is that the reduction in soluble P-selectin by HT may occur by a non-platelet related mechanism. [Copyright &y& Elsevier]

Abstract: The synthetic progestins, medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-EN or NET-A), are widely used as female contraceptive agents and in hormone replacement therapy (HRT). Competitive binding revealed that MPA displays a higher relative binding affinity than NET-A and progesterone (prog) for the human GR (Kd of 4.2nM for dexamethasone (dex) and Ki''s of 10.8, 270 and 215nM for MPA, NET-A and prog, respectively). Furthermore, MPA displays much greater glucocorticoid (GC) transactivation agonist potency than NET-A or prog (EC50s of 1.1, 7.2, >1000 and 280nM for dex, MPA, NET-A and prog, respectively) and much greater GC agonist potency for transrepression than NET-A or prog (EC50s of 0.21, 2.7, >100 and 26nM for dex, MPA, NET-A and prog, respectively). In addition, MPA induces phosphorylation of the GR at Ser 211 to a much greater extent than NET-A or prog and protects the GR from partial trypsin digestion in vitro to a much greater extent than NET-A or prog at saturating concentrations. Together these results suggest that the differences in biological activity of the progestins are not merely due to differences in their affinity for the GR but also due to the induction of different conformational changes in the liganded-GR. MPA and NET-A therefore display very different GC-like properties compared to each other and to prog, and are likely to exhibit different side effects via the GR. [Copyright &y& Elsevier]

Objective . To compare the efficacy of two sequential 17β-estradiol (17β-E2)/trimegestone (TMG) combinations with the sequential estradiol valerate (E2V)/norethisterone (NET) regimen in relieving climacteric symptoms. Study design . This was a double-blind, randomized, multicenter study conducted among 1218 Caucasian (99%) postmenopausal women with an intact uterus in seven European countries and Israel, over 13 cycles (each of 28 days). Study duration was extended further for 13 cycles, with 531 women receiving treatment for up to 26 cycles. Treatments consisted of 1&ThickSpace;mg 17β-E2 on days 1–14 and 1&ThickSpace;mg 17β-E2/0.125&ThickSpace;mg TMG or 0.25&ThickSpace;mg TMG on days 15–28, and 1&ThickSpace;mg E2V on days 1–16 and 1&ThickSpace;mg E2V/1&ThickSpace;mg NET on days 17–28. Results . Rapid and significant reductions in the mean daily number and severity of hot flushes and in the mean daily number of nocturnal sweats were established in most women with 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG and E2V/NET. These treatments also induced a significant improvement in the quality-of-life assessments. Conclusion . The 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG regimen provides rapid and effective relief of menopausal symptoms, with a reduction in the number of hot flushes ‘at least as good as’ that of the E2V/NET comparator. [ABSTRACT FROM AUTHOR]

Objective . To compare the bleeding profiles and endometrial protection of two sequential regimens of 17β-estradiol (17β-E2) and trimegestone (TMG) with a sequential estradiol valerate (E2V)/norethisterone (NET) regimen. Study design . This was a randomized, double-blind, multicenter study conducted in eight countries in healthy, postmenopausal women with an intact uterus. A total of 1218 women were enrolled into the initial 1-year study (13 cycles), and subsequently 531 of these received treatment for a further year (26 cycles). Treatment regimens were 1&ThickSpace;mg 17β-E2 on days 1–14 and 1&ThickSpace;mg 17β-E2/0.125&ThickSpace;mg TMG or 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG on days 15–28, and 1&ThickSpace;mg E2V on days 1–16 and 1&ThickSpace;mg E2V/1&ThickSpace;mg NET on days 17–28. Results . Mean percentage of women reporting onset of withdrawal bleeding episodes during the week following discontinuation of progestogen was higher in the 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG group than in the other two treatments, showing a more efficient progestogen effect on the endometrium and good predictability of bleeding onset with this treatment. The mean numbers and average lengths of bleeding episodes were similar in the three treatment groups. Overall, the bleeding profile was more favorable with 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG than with the lower-dose TMG preparation. Both of the TMG regimens demonstrated a good protective effect on endometrial proliferation, with the 0.25&ThickSpace;mg TMG dose showing a lower incidence of proliferative endometrium. Conclusion . The 1&ThickSpace;mg 17β-E2/0.25&ThickSpace;mg TMG regimen showed an adequate protection of the endometrium, with an overall favorable bleeding profile. [ABSTRACT FROM AUTHOR]

Background: Fatal venous thromboembolism (VTE) is a rare complication of combined oral contraceptive (COC) treatment. This study aims to determine incidences of fatal VTE in relation to the type of COC and the percentage of cases reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). A further aim is to compare the characteristics of reported and not reported cases.Methods: This retrospective study is a separate analysis using data from a larger study that included women aged 15-44 years between 1990 and 1999 with VTE coded as the underlying or contributory cause of death in the Swedish Cause of Death Register. COC use within 2 months of the date of symptom onset or death was identified in 28 cases. Sales data were obtained from the National Corporation of Swedish Pharmacies. Reported cases were identified in the SADRAC database.Results: After excluding two cases where the type of COC was unknown, the crude incidences of fatal VTE were 5.1 (95% CI 2.3, 9.6), 8.6 (95% CI 4.3, 15.4) and 9.1 (95% CI 3.3, 19.8) cases per million women per year for levonorgestrel-, desogestrel- and norethisterone-containing COCs, respectively. Age-adjusted incidences were approximately twice as high for desogestrel- and norethisterone-containing COCs compared with levonorgestrel-containing COCs, although differences were not statistically significant. Thirty-six percent of cases were reported. Reporting was positively associated with information in medical records relevant to the VTE diagnosis that the patient was a COC user and was significantly higher in northern Sweden.Conclusion: Results from this study support a higher incidence of fatal VTE with desogestrel-containing COCs than with levonorgestrel-containing COCs. [ABSTRACT FROM AUTHOR]

FERNANDES, E.O.,et al.: Hormone Replacement Therapy Does Not Affect the 24-hour Heart Rate Variability in Postmenopausal Women: Results of a Randomized, Placebo-controlled Trial with Two Regimens. Postmenopausal women are at greater risk of coronary heart disease. The results of previous studies of the effects of hormone replacement therapy (HRT) on cardiac autonomic modulation in postmenopausal women have been contradictory. This study examined whether continuous treatment for 3 months with estradiol alone (ERT) or with estradiol plus norethisterone (HRT), increases 24-hour heart rate variability (HRV) in postmenopausal women. In this double-blind, placebo-controlled trial, 40 healthy postmenopausal women, 46–63 years of age, were randomly assigned to (1) continuous 2 mg of estradiol plus 1 mg of norethisterone acetate daily (HRT, n= 13), or (2) 2 mg of estradiol daily (ERT, n= 14), or (3) placebo (n= 13). Before and after 3 months of therapy, blood estradiol concentrations were measured and 24-hour electrocardiograms recorded for evaluation of 24-hour time-domain indices of HRV, and indices derived from the three-dimensional return map. Both hormone replacement regimens significantly increased blood estradiol concentrations, while no change occurred in the placebo group. In the three treatment groups, multiple 24-hour time-domain indices of HRV and indices derived from the three-dimensional return map remained unchanged. In healthy postmenopausal women, HRT with estradiol or estradiol and norethisterone for 3 months did not modify cardiac autonomic activity evaluated by 24-hour indices of HRV. These findings are consistent with a lack of protective cardiovascular effect of HRT described in recent large randomized trials.(PACE 2005; 28:S172–S177) [ABSTRACT FROM AUTHOR]

Drug therapy may become difficult when a significant amount of the small intestine is resected, as happens in patients with a short small bowel. Drug absorption from the gastrointestinal tract is altered in these patients; however, this effect is variable in patients and differs with each drug. Literature regarding clinical outcomes of normal or alternative administration routes in patients with a short small bowel is limited. We explored what is written about the normal absorption of commonly used drugs and what difference the resection of different but substantial parts of the small intestine makes. Changes in the gastrointestinal tract after resection of >50% of the small intestine causes malabsorption of macronutrients and micronutrients, and may alter the drug absorption process. The metabolic activity of the abundantly present intestinal lactobacilli can also affect the enteral drug absorption in patients with short small bowel as this results in the production of lactic acid, gaseous CO(2), ethanol and an increased bile acid deconjugation. Accelerated intestinal luminal transit time causes a reduction in absorption of certain antimicrobial agents, digoxin, hydrochlorothiazide, ciclosporin, cimetidine, mesalazine (5-aminosalicylic acid), oral contraceptives and levothyroxine. Gastric hypersecretion and lack of sufficient contact time with the intestinal mucosa in patients with short small bowel leads to insufficient absorption of drugs such as omeprazole. Successful treatment with warfarin, tricyclic antidepressants, metronidazole, fluconazole, procainamide, sotalol and pindolol are reported in several studies. Many different factors cause this variability in drug absorption in such patients. Monitoring the serum drug concentration in these patients may ease dealing with the management problems. [ABSTRACT FROM AUTHOR]

Objective: Two randomized comparative multicenter studies were conducted to establish the endometrial safety and tolerability of a triphasic sequential hormone replacement estradiol valerate/medroxyprogesterone acetate (E2V/MPA) therapy regimen.Methods: Study 1 was a randomized, double-blind, clinical phase III study in 399 postmenopausal women, following parallel-group design with two groups. The duration of study treatment was 12 or 13 cycles of 28 days. A double-dummy technique was used to ensure blinding in the study. The investigational drugs were E2V/MPA triphasic and E2V/MPA biphasic (Diviseq and Divina, respectively; Orion Pharma). In study 2, a total of 341 subjects were randomly allocated by computer into two parallel groups receiving either E2V/MPA or estradiol/norethisterone acetate triphasic (E2/NETA, Trisequens; Novo Nordisk A/S) for 12-13 cycles. The study was an open, clinical phase III trial with a randomized, parallel-group design. Endometrial biopsies combined with transvaginal ultrasound were undertaken before and at the end of treatment during the progestogen phase. Bleeding patterns and symptom control were assessed throughout both studies.Results: E2V/MPA triphasic was found to have similar endometrial effects and bleeding patterns to those with E2V/MPA biphasic and E2/NETA triphasic. Climacteric symptoms were relieved as quickly and effectively as with the two comparator treatments. No adverse drug reactions specific to E2V/MPA triphasic were observed. At the end of the study, the proportions of secretory samples were 67.1% for the combined E2V/MPA triphasic groups, 65.6% for the E2V/MPA biphasic group and 71.6% for the E2/NETA triphasic group. One case of hyperplasia occurred in the E2V/MPA triphasic group. Thus the incidence of hyperplasia for the combined groups was 0.33%.Conclusions: The triphasic E2V/MPA regimen was well tolerated and produced endometrial effects similar to those of the two comparators. Extending estrogen during the so-called treatment-free week with a lower dose of estradiol was effective in controlling vasomotor symptoms. [ABSTRACT FROM AUTHOR]

: ObjectiveTo compare the modifications on basal and post-methionine homocysteine (Hcy) levels induced by transdermal vs. oral continuous combined hormone therapy (HT).: DesignProspective randomized study.: SettingOutpatient service at university hospital.: Patient(s)Twenty-four healthy postmenopausal women.: Intervention(s)Six-month administration of transdermal (50 μg/d of E2 and 140–170 μg/d of norethisterone [NET] acetate; n = 12) or oral (2 mg of E2 and 1 mg of NET acetate; n = 12) HT.: Main outcome measure(s)Fasting levels of Hcy, cysteine (Cys), folate, and vitamin B12. Post-methionine Hcy concentrations.: Result(s)During HT, a slight decrease of fasting Hcy (8.9 [6.7; 15.2] μmol/L vs. 8.3 [4.9; 12.0] μmol/L) and fasting Hcy/Cys, a possible index of Hcy trans-sulfuration (0.061 [0.039; 0.107] μmol/L vs. 0.048 [0.032; 0.093] μmol/L) was observed. Modifications were similar in the transdermal and oral group. Net decreases of Hcy and Hcy/Cys observed during HT were related linearly to pretreatment values (r = 0.821 and r = 0.775, respectively), and were significant for Hcy above, but not below, 9 μmol/L. Transdermal (33.5 [27.5; 75.9] μmol/L vs. 28.4 [17.4; 48.9] μmol/L) or oral HT (36.1 [17.7; 74.8] μmol/L vs. 29.9 [17.5; 50.3] μmol/L), decreased, similarly, post-methionine Hcy levels.: Conclusion(s)Similarly to oral, transdermal HT reduces post-methionine Hcy and fasting Hcy when it is elevated. [Copyright &y& Elsevier]

Objectives: To determine if the vascularisation of the endometrium is dependent on the administered progestin during sequential hormone replacement therapy. Methods: Nine women received percutaneous estradiol-17β, 1.5 mg/day from days 1 to 24 combined with 200 mg/day micronised progesterone from days 11 to 24 of the treatment cycle. Fifteen women received percutaneous estradiol, 1.5 mg/day from days 1 to 24, combined with 10 mg/day chlormadinone acetate from days 11 to 24. Eleven women received percutaneous estradiol, 50 μg/day from days 1 to 28 combined with percutaneous norethisterone acetate, 0.3mg/day form days 14 to 28. Twelve women received intranasal estradiol, 300 μg/day from days 1 to 25 combined with 0.5 mg of promegestone from days 11 to 24. Eleven spontaneous cycling women had an endometrial biopsy during luteal phase and served as controls. Endometrial biopsies were processed routinely between days 18 and 24 and sections were immunostained using anti-CD34 antibody to identify vascular endothelial cells, which were treated with an automatic image analysis system. Results: mean (±S.D.) vascular density for controls was 147±41.5 vessels/mm2, with mean vessel area of 143±60.9 μm2. In chlormadinone users endometrial microvascular density and mean vessel area did not differ from the control group (150.2±58.6 and 152.9±70.5). The other three progestins generated a significant increase of mean vessel density, 179.6±51.6 with micronised progesterone, 178.5±67.6 with norethisterone and 179.6±48.4 with promegestone. The mean vessel area was lower in the latter three groups, respectively, 108.4±39.0, 97.5±46.5 and 141.6±66.7 μm2, promegestone leading to non significant difference with control. Conclusion: regarding vascularisation, chlormadinone and control group gave similar patterns. Promegestone was associated with an increase of the number of vessels, as did micronised progesterone or norethisterone; the mean vascular area was the smallest in the norethisterone group. [Copyright &y& Elsevier]