Low thrombin generation in postmenopausal women using estetrol.

OBJECTIVE: Estetrol (E4) represents a novel estrogen of interest to relieve vasomotor symptoms. E4 activates the nuclear estrogen receptor α (ERα) but antagonizes the estradiol ERα-dependent membrane-initiated steroid signaling pathway. The distinct pharmacological properties of E4 could explain its low impact on hemostasis. This study aimed to assess the effect of E4 on coagulation in postmenopausal women, using the thrombin generation assay (TGA). METHODS: Data were collected from a multicenter, randomized, placebo-controlled, dose-finding study in postmenopausal women (NCT02834312). Oral E4 (2.5 mg, n = 42; 5 mg, n = 29; 10 mg, n = 34; or 15 mg, n = 32) or placebo (n = 31) was administered daily for 12 weeks. Thrombograms and TGA parameters were extracted for each subject at baseline and after 12 weeks of treatment. RESULTS: After 12 weeks of treatment, all treatment groups showed a mean thrombogram (±95% confidence interval [CI] of the mean) within the reference ranges, that is, the 2.5th-97.5th percentile of all baseline thrombograms (n = 168), as well as for TGA parameters. CONCLUSIONS: The intake of E4 15 mg for 12 weeks led to significant but not clinically relevant changes compared to baseline as the mean values (±95% CI of the mean) remained within reference ranges, demonstrating a neutral profile of this estrogen on hemostasis.

Impact of estetrol (E4) on hemostasis, metabolism and bone turnover in postmenopausal women.

OBJECTIVE: This study aimed to determine the effects of estetrol (E4) on hemostasis, lipids, carbohydrate metabolism and bone turnover in postmenopausal women. METHODS: This study was a multicenter, randomized, double-blind placebo-controlled phase 2 trial. Participants (n = 180, age 43-64 years) received E4 2.5 mg, 5 mg, 10 mg and 15 mg or placebo once daily for 12 weeks. Changes from baseline at week 12 were evaluated versus placebo for hemostasis parameters, sex hormone binding globulin (SHBG), lipids, carbohydrate metabolism and bone markers. RESULTS: Changes for hemostasis parameters were minimal with a small increase only in the normalized activated protein C sensitivity ratio in the E4 15 mg group versus placebo. SHBG increased in the E4 5 mg, 10 mg and 15 mg groups versus placebo. High-density lipoprotein cholesterol increased in all E4 groups; changes were not consistent for other lipids. Significant decreases versus placebo were seen for insulin resistance (E4 10 mg group), hemoglobin A1c (E4 15 mg group) and type 1 collagen C-terminal telopeptide (E4 10 mg and 15 mg groups). Small decreases in osteocalcin in the E4 5 mg, 10 mg and 15 mg groups were significant versus the increase observed in placebo. CONCLUSION: E4 had limited impact on hemostasis and potentially beneficial effects on lipids, carbohydrate metabolism and bone turnover.

[«I am not pregnant !¼ About denial of pregnancy ]. / «Je ne suis pas enceinte !¼ A propos du déni de grossesse .

The term «denial of pregnancy¼, although used in current medical practice since 1970, does not yet have a universal definition. The literature allows to define it as «the non-recognition of a pregnancy beyond the first trimester, which can last until delivery and cover it¼. The changes related to pregnancy are biologically reduced or incorrectly perceived or even ignored. Although often wrongly considered as a rare phenomenon, the literature describes it as having a prevalence of 2 to 3 cases per 1.000 viable deliveries. This case report associated with a short review of the literature aims to optimise the clinician awareness, leading to the diagnosis as well as the potential perinatal consequences linked to this phenomenon.

Le terme de «déni de grossesse¼, bien qu'utilisé dans la pratique médicale courante depuis 1970, n'a, à ce jour, pas encore de définition universelle. La littérature permet de le définir comme la «non-reconnaissance d'une grossesse au-delà du premier trimestre, qui peut se prolonger jusqu'à l'accouchement et recouvrir ce dernier¼. Les changements liés à la grossesse sont biologiquement réduits et incorrectement perçus par la femme, ce qui fait passer son évolution sous silence. Bien que souvent considéré à tort comme un phénomène rare, la littérature le décrit, cependant, avec une prévalence de 2 à 3 cas pour 1.000 accouchements viables. Le cas clinique rapporté ici, accompagné d'une revue succincte de la littérature, vise à conscientiser les cliniciens quant aux circonstances de diagnostic d'un déni de grossesse et la morbi-mortalité périnatale qui y est, potentiellement, associée.

Exploring the interest in and the usage of the internet among patients eligible for osteoporosis screening.

The aim of this study was to evaluate the interest in the Internet and its usage for health-related issues among people eligible for osteoporosis screening. Self-administered questionnaires have been distributed to subjects who were screened for osteoporosis and to menopausal women. 177 patients have responded to the survey (64.5 ± 10.1 years, 88.1% of women). There are 78.5% of Internet users. Among them, 67.2% said searching information about their health and 74.5% said using the Internet for this purpose. All respondents attributed an average score, out of 10, of 5.7 ± 2.3 regarding the reliability of information that they could find on the Internet. The use of the Internet differs significantly depending on age: those who use the Internet are younger (62.1 ± 8.91 years) than those who do not use it (73.3 ± 9.42 years). The socioeconomic status also has an impact on the Internet use: Internet users have a higher education, are more professionally active and have a higher net monthly household income compared to the group of non-users. Even if age and socioeconomic status appear to be determining factors in the use of the Internet for the search of health information in patients eligible for osteoporosis screening, almost 75% of the study population use the Internet for this purpose. Action to promote health through an Internet platform must therefore take these parameters into account.

[The use of intrauterine device in nulliparous over 18 years: a Belgian consensus]. / La contraception intra-utérine chez la nultlipare de plus de 18 ans: vers un consensus belge.

Under the presidency of prof. H. Depypere (UZ Ghent) and Prof. P. Simon (ULB Erasme) a Belgian panel of thirteen experts (gynecologists, representatives of universities and scientific associations for gynecology-obstetrics) reached a consensus on the use of intrauterine systems, both copper IUDs as hormone IUDs, in nultiparous women.

[Zoely, a combined oral contraceptive, monophasic pill containing estradiol and nomegestrol acetate]. / La médicament du mois. Zoely, une association monophasique d'estradiol et d'acétate de nomégestrol.

A new combined oral contraceptive called Zoely has just been marketed in Belgium. It contains nomegestrol acetate, a progestin known for its high contraceptive reliability based on its antigonadotropic power and long half-life. This progestin is associated with estradiol and Zoely is devoid of ethinyl estradiol, which is the usual component of the majority of combined oral contraceptives and is primarily responsible for thrombotic side effects of the pill. The compositon and type of regimen of this new oral contraceptive contribute to its efficacy and excellent clinical tolerance.

[Breast cancer in Belgium: why are we the first in Europe?]. / Le cancer du sein en Belgique: pourquoi sommes-nous les premiers en Europe?

Breast cancer incidence in Belgium is on the top of European countries, with 9.697 new cases in 2008 and 106/100.000 women/year. The explanation of this high incidence in our country is probably the accumulation of risk factors (many of them are linked to lifestyle), and the impact of screening and registration of cases. The relative impact of each of theses factors is less clear because we don't have powerful statistical studies. Belgium is slightly above the European mean for breast cancer mortality, with 19,4/100.000 women/year and an all stages 15-year survival of 75%. Breast cancers are responsible for around 3% of all-cause mortality in Belgian women. This article discusses the causes of this high Belgian incidence and of current decrease of incidence in western countries, and reviews known and less known risk factors of breast cancers, with a special focus on menopause hormonal treatments.

[Medication of the month. Femoston Low (0.5 mg estradiol plus 2.5 mg dydrogesterone) for menopausal hormonal replacement therapy]. / Le médicament du mois. Femoston Low (0,5 mg d'estradiol plus 2,5 mg de dydrogestérone) comme traitement hormonal de substitution a la ménopause.

Femoston Low is a hormone replacement therapy that combines low dosages of steroids, i.e. 0.5 mg of estradiol and 2.5 mg of dydrogesterone. This oral preparation should be taken continuously to treat climacteric symptoms in menopausal women. Femoston Low is in agreement with the recent recommendations for menopausal hormone replacement therapy, which give the preference to low dosage therapy whenever possible. The goals are to potentially minimize the risk of breast cancer, the danger of venous or arterial thrombosis and the glucose and lipid metabolic disturbances. Nevertheless, the preparation should efficaciously oppose to endometrial hyperplasia and yield a high degree of amenorrhea.

[Medication of the month. A new combined oral contraceptive containing estradiol valerate and dienogest (Qlaira)]. / Le médicament du mois. Nouvelle contraception orale combinée au valérate d'estradiol et au diénogest (Qlaira).

In combined oral contraception (OC), a drastic reduction of both ethinylestradiol and androgenic progestins mostly derived from 19 NOR testosterone, allowed to moderately reduce the adverse impact of classical combined pills on metabolism and circulation (both arterial and venous). However, the marked hepatic action of ethinylestradiol, even in small dosages, lessens the expected risk reduction. For the first time, an OC has been developed, which contains estradiol valerate (with reduced hepatic action because of lack of a 17alpha ethinyl group) with dienogest, a 19 NOR testosterone-derived nonandrogenic progestin, which powerfully inhibits endometrial proliferation. Thanks to a dynamic modulation of estrogen and progestin doses (26 active days + 2 placebo days), an adequate contraceptive effectiveness, a good cycle control and drug tolerance are achieved, similar to those obtained with a classical low-dose OC. Recent data indicate that this new combination reduces the usually observed metabolic impact. An adequate cycle control (with 20% amenorrhea) is achieved for the first time with estradiol valerate + progestin,, in opposition with prior catastrophic results with other formulations containing 17beta-estradiol. A second combination containing estradiol + nomegestrol acetate (monophasic, 24 active days + 4 placebo days) is under study and seems also to yield promising results. Of course, in-depth study of metabolic and vascular effects of these new combinations is mandatory - and ongoing.

[Ulipristal acetate: an emergency contraception extended to 5 days using a progesterone receptor modulator (Ellaone)]. / Le médicament du mois. Ulipristal acétate: une contraception d'urgence étendue à 5 jours par progesterone receptor modulator (Ellaone).

Emergency contraception is a second chance for prevention of pregnancy after unprotected intercourse. Hormonal emergency contraception with levonorgestrel 1.5 mg, only provides an effective contraception from 0 to 72 hours after intercourse with decreasing effectiveness as time elapses. It was accordingly mandatory to develop an alternative approach with a stable contraceptive efficacy and good tolerance for 5 days, knowing additionally that the estimated lifespan of sperm in the female genital tract is about 5 days. In comparative studies bearing on more than 3000 young women, the progesterone receptor modulator (PRM) ulipristal acetate, a progesterone antagonist (taken in a single dose of 30 mg), or levonorgestrel (1.5 mg) were administered. Results indicated that the PRM was as effective as levonorgestrel, or even more, kept a stable efficacy for 120 hours after an unprotected intercourse, and was well tolerated. This establishes ulipristal acetate as the new standard for hormonal emergency contraception.

[Prevention of coronary heart disease by early postmenopausal hormone therapy: new supporting data]. / Prévention des troubles coronaires par le traitement hormonal précoce à la ménopause: une idée qui s'impose à nouveau.

The important controversy concerning the potential beneficial, neutral or unfavourable effect of estrogens or estrogen plus progestin on the risk of coronary heart disease in postmenopausal women is beginning to settle down. Reanalysis of large observational and randomized trials according to age and years since menopause and recent additional studies allow to positively state that postmenopausal hormone therapy - and particularly estrogens alone - is safe and effective. For instance, in the Women's Health Initiative study, provided hormone therapy is initiated within 10 years since menopause, a reduction of the risk of coronary heart disease by 12 to 52% according to the use of estrogen plus progestin or estrogen alone, respectively, is observed versus placebo use. Global mortality is also reduced by 30% with both hormone therapies. This favourable effect is not observed when treatment is initiated in older postmenopausal women. These important and reassuring data should encourage regulatory authorities to reassess clinical recommendations in that prospect.

[Female sexual dysfunction and postmenopausal androgen therapy]. / Dysfonction sexuelle féminine et androgénothérapie a la ménopause.

Female sexual dysfunction is essentially multifactorial and its therapeutic management is accordingly diversified. However, after natural menopause or, even more, surgical menopause, age, climacteric syndrome, progressive loss of endogenous androgens, all facilitate the occurrence of the Hypoactive Sexual Desire Disorder (HSDD), defined by loss of libido and sexual responsiveness leading to sexually related personal distress. In that prospect, administration of varied medications with androgenic properties has been tried in addition to postmenopausal hormone therapy. Type, dosages, routes of administration of androgens are adapted toward minimizing side effects inasmuch as long-term safety of androgens is not yet clearly established. Recent randomized controlled studies appear very promising in terms of efficacy and safety, at least when androgen therapy is limited to 6-12 months in case of HSDD.

[Therapeutic progress in gynecology: functional approaches]. / Actualités thérapeutiques en gynécologie: approches fonctionnelles.

Over the last ten years, progress in evidence-based medicine coupled with technological breakthroughs and introduction of new drugs have deeply changed the management of our patients. In the field of hormone therapy, lower dosages of estrogens and new progestins have increased tolerance and non-contraceptive benefits of oral contraceptives, while lower-doses, new progestins, new routes of administration have optimized the benefit/risk balance for the treatment of menopause. About 500,000 cycles of IVF are performed worldwide each year, optimizing male and female fertility, with less multiple pregnancies, and use of new recombinant gonadotropin, LHRH agonists/antagonists, new ovarian tissue cryopreservation techniques, etc...

[Therapeutic progress in gynecology: organic diseases]. / Actualités thérapeutiques en gynécologie: pathologies organiques.

Over the last ten years, progress in evidence-based medicine coupled with technological and surgical breakthroughs have deeply changed the management of our patients. Uterine bleeding is the first cause of gynaecological consultation and the intrauterine progestin delivery system as well as new hysteroscopic procedures have optimized the therapeutic approach to this problem. Introduction of magnetic resonance imaging and interventional procedures have improved breast disease diagnosis and management; likewise sentinel node localization, introduction of aromatase and growth factors inhibitors, new radiotherapy procedures and pharmacogenomics, have helped to ameliorate breast cancer treatment. Pelvic surgery has been switching more and more towards laparoscopic procedures not only in the field of benign lesions (eg endometriosis), of surgery of prolapse and incontinence with new prosthetic materials, but also for an improved management of gynaecological cancers.

[Can we sort out from the jumble about oral contraceptives and skin cancers?]. / Peut-on sortir de l'embrouillamini relatif aux contraceptifs oraux et aux cancers cutanés?

Skin contains various hormonal receptors, particularly those for estrogens, progesterone and androgens. Steroid hormones of oral contraceptives affect the skin, in particular the control of the cell cycle, DNA replication, apoptosis and other cellular functions. Some estrogen-responsive pathways have the potential to promote tumor development. The question of whether oral contraceptives increase the risk for the development of skin cancer, particularly melanoma, remains an area of concern. There is some evidence that steroid hormones present in oral contraceptives do not significantly increase the risk of developing skin cancer when estrogen exposure is not excessive.

Effect of different contraceptive methods on the oxidative stress status in women aged 40 48 years from the ELAN study in the province of Liege, Belgium.

BACKGROUND: Oxidative stress is associated with the development of several disorders including cardiovascular disease and cancer. Among conditions known to influence oxidative stress, the use of oral contraception (OC) in women has been a matter of ongoing discussion. METHODS: A total of 897 eligible and healthy volunteers were recruited from among the patients of 50 general practitioners participating in the ELAN study (Etude Liégeoise sur les ANtioxydants). A subsample consisting of 209 women aged 40-48 years was studied for a comprehensive oxidative stress status (OSS), including the analysis of antioxidants, trace elements and three markers of oxidative damage to lipids. Among 209 subsample, 49 (23%) were OC users (OCU), 119 (57%) non-contraception users (NCU) and 41 (20%) were intrauterine (hormonal and copper) devices users (IUD). RESULTS: After adjustment for smoking, systolic and diastolic blood pressure and BMI (or waist circumference), a marked and significant increase in lipid peroxides was observed among OCU women when compared with NCU and IUD users. A cut-off value of 660 microM in lipid peroxides allowed the discrimination of OCU from the two other groups. In contrast, no difference was observed in the plasma concentration of both oxidized low-density lipoprotein (LDL) and their related antibodies. The increased level in lipid peroxides was strongly related to higher concentrations of copper (r < 0.84; P < 0.0001, cut-off value 1.2 mg/l). When compared with NCU and IUD users, plasma antioxidant defences were significantly altered in OCU women as shown by lower levels of beta-carotene (decrease of 39%; P < 0.01) and gamma-tocopherol (decrease by 22%; P < 0.01). In contrast, higher concentrations of selenium (increased by 11.8%; P < 0.01) were observed in OCU women. Blood concentrations of vitamin C, alpha-tocopherol and zinc were unaffected by OC use. CONCLUSIONS: The intake of OC significantly increases the lipid peroxidation in women aged 40-48 years. This may represent a potential cardiovascular risk factor for these women.

Skin climacteric aging and hormone replacement therapy.

A gender perspective is indispensable for a full understanding of aging. Menopause is a turning point in women's lives. In addition to the effects of chronological aging, sunlight exposure, and other environmental and endogenous stimuli, the climacteric appears to exert some dramatic consequences on skin biology and aspect. The epidermis may become xerotic and exhibit altered functions. The dermis thins out and its elasticity decreases in concert with the decline in bone mass. The skin microcirculation is impaired. These aspects are some of the better worked-out changes of the climacteric, which in turn seem to be stabilized or in part reversible with hormone replacement therapy (HRT). The HRT effect on menopause consequences on hair growth and sebum production is less impressive. This review summarizes some important impacts of the climacteric on skin, and highlights the benefits of HRT that may influence cosmetic dermatology.

[Management of Chlamydia tracomatis pelvic infection]. / Prise en charge d'une infection pelvienne a Chlamydia trachomatis.

The infection by Chlamydia trachomatis is a serious infection that affects the male and female tractus, and that induces complications such as infertility and extrauterine pregnancy. The antibiotic treatment needed must necessarily reach the intracellular milieu to be efficient enough to eradicate the infection.

[The skin and menopause]. / La peau et le temps de la ménopause.

The estrogen deficit occurring at menopause manifests itself under various modalities in the diverse organs and their functions. Skin does not escape this global involutive process. In addition to the effects of chronological ageing, sunlight exposure and other environmental and endogenous stimuli, the climacteric appears to exert some dramatic consequences on skin biology and aspect. The epidermis, its adnexae and the dermis are altered by this process. The epidermis may become xerotic and exhibits altered functions. The dermis thins out and its elasticity decreases in concert with the decline in bone mass. The skin microcirculation is impaired. These aspects are some of the better-worked out skin climacteric changes of which in turn seem to be stabilized or in part reversible with hormone replacement therapy (HRT).