Axelle Pintiaux

The immninent dawn of SPRMs in obstetrics and gynecology.

Selective progesterone receptor modulators (SPRMs) have been developed since the late 70s when mifepristone was first described. They act through nuclear progesterone receptors and can have agonist or mixed agonist antagonist actions depending on the cell and tissue. Mifepristone has unique major antagonist properties allowing its use for pregnancy termination. Ulipristal acetate has been marketed in 2009 for emergency contraception and has been recently approved for preoperative myoma treatment. Further perspectives for SPRMs use include long term estrogen free contraception, endometriosis treatment. However long term applications will be possible only after confirmation of endometrial safety.

Hormone therapy and breast cancer risk

Hormone therapy (HT) is the most efficacious intervention for the relief of climacteric symptoms. Controversies surrounding HT have left many women puzzled and afraid. Gynecologists are faced with long-standing beneficial assumptions challenged by an abundance of robust detrimental new data, with little guidance on how to interpret these findings. Prescriptions for HT (and incidence of breast cancers in some areas) have fallen over the last 3 years due to anxiety provoked about breast cancer risk and recurrence. The current ‘clinical climate’ is against HT. Due to a lack of effective alternatives, women suffering from estrogen-deficiency symptoms are still requesting objective information about HT, particularly those at higher risk of breast cancer or those with a past history of breast cancer. In this situation, discussion of the current clinical uncertainty surrounding the use of HT must be undertaken to ensure that women are adequately informed. The objective of this presentation is to provide a framework for understanding breast cancer risk associated with HT. What are the precise molecular mechanisms of estrogen and progestin in the initiation of breast cancer? Does the risk of estrogen-only therapy on breast cancer vary by dose, constituent, route and duration of administration and cessation of use? Does HT, in addition to increasing risk for breast cancer, affect the type of breast cancer (lobular and ductal) diagnosed? Is HT associated with breast cancers that have better prognostic factors? How relevant are the changes in mammographic breast density associated with HT for the evaluation of breast cancer risk? What is the additional global health risk/benefit ratio associated with the selective use of progesterone or progestin that may confer a significant cardiovascular benefit, such as drospirenone? It is currently assumed and tested that new hormones with particular pharmacological profiles may ultimately achieve their therapeutic goal of relieving climacteric symptoms without an associated moderate increased risk of breast cancer.

Effects of oral contraception with ethinylestradiol and drospirenone on oxidative stress in women 18-35 years old.

BACKGROUND Oral contraceptives (OCs) with estrogens and progestins may affect oxidative stress (OS) status. STUDY DESIGN A group of 32 women using oral contraceptives (OCU) containing 0.03 mg ethinylestradiol and 3 mg drospirenone have been compared to a matched control group of 30 noncontraception users (NCU). Blood levels of antioxidants, trace elements and markers of lipid peroxidation were assessed by biochemical methods. A microarray analysis of whole blood mRNA levels of 200 genes involved in OS-dependant pathway was also performed. RESULTS Levels of zinc, vitamin E and antibodies to oxidized low-density lipoproteins (LDLs) were not significantly different between the two groups. On the other hand, significant increases in the mean levels of lipid peroxides (+176%, p<.001), oxidized LDLs (+145%, p<.002), copper (+103%, p<.001), Cu/Zn ratio (+100%, p<.001) and a significant decrease in the mean level of beta-carotene (-41%, p<.01) were observed in the OCU compared to NCU. There was a highly significant positive correlation between the lipid peroxide levels and the copper-to-zinc ratio. From the 200 genes tested by microarray, one coding for HSP70 was significantly up-regulated (log(2) fold change=+ 0.45, p<.02) and one coding for inducible nitric oxide synthase significantly down-regulated (log(2) fold change=-0.24, p<.05) in the OCU compared to the NCU. CONCLUSIONS The recently introduced combination of ethinylestradiol and drospirenone induced the heightening of lipid peroxidation correlated with high levels of copper, a situation that could be associated with increased cardiovascular risk.

Persistence of an Intact Endometrial Matrix and Vessels Structure in Women Exposed to VA-2914, a Selective Progesterone Receptor Modulator

BACKGROUND VA-2914 is a selective progesterone receptor modulator with potential contraceptive activity that induces amenorrhea, whereas progestins cause endometrial spotting and bleeding. This abnormal bleeding due to progestins is a consequence of focal stromal proteolysis by an increase in naked vessel size and density. OBJECTIVE Our objective was to quantify the effects of VA-2914 on endometrial vascularization, fibrillar matrix, and vascular endothelial growth factor (VEGF)-A expression in endometrial biopsies from 41 women before and after 12 wk daily treatment with a placebo, or 2.5, 5, or 10 mg VA-2914. METHODS Collagen fibrillar network was stained by silver impregnation. Vessel area, density, and structure were quantified with a computer-assisted image analysis system after double immunostaining using an anti-von Willebrand factor (endothelial cells) and an anti-alpha smooth muscle actin (vascular smooth muscle cells) marker antibody. VEGF-A mRNAs were quantified by RT-PCR and localized by immunohistochemistry. RESULTS The endometrial vessels, collagen network, and mRNA levels of VEGF-A were identical during the luteal phase at baseline and in VA-2914 treated women. VEGF-A distribution was unchanged. CONCLUSIONS VA-2914 does not alter the endometrial matrix and cells, and does not modify the endometrial vessel morphology as compared with baseline biopsies.

Haemostatic and metabolic impact of estradiol pills and drospirenone-containing ethinylestradiol pills vs. levonorgestrel-containing ethinylestradiol pills: A literature review.

Abstract Objective Since its introduction 50 years ago, the contraceptive pill has continuously evolved to decrease the risk of venous thromboembolism (VTE) associated with its use. An increased risk of VTE still remains, however. Other concerns, such as effects on lipid and carbohydrate metabolism, have also been reported. In this study we compared two reference combined oral contraceptives (COCs) containing ethinylestradiol (EE)/levonorgestrel (LNG) and EE/drospirenone (DRSP) with COCs containing estradiol (E2) (estradiol valerate [E2V]/dienogest [DNG] and E2/nomegestrol acetate [NOMAC]). They were evaluated according to their influence on recognised haemostatic and metabolic markers. Methods A literature search of the MEDLINE/PubMed database was conducted for head-to-head studies. EE/LNG was chosen as the comparator pill. Results The haemostatic impact of E2 pills and EE/LNG has been extensively compared, in contrast to that of EE/DRSP and EE/LNG. Changes in haemostatic and metabolic marker levels between EE/LNG and E2V/DNG were generally not statistically significant. E2/NOMAC showed statistically significantly favourable results on haemostatic markers and had a neutral effect on carbohydrate and lipid metabolism when compared with EE/LNG. Conclusion E2/NOMAC exhibits less haemostatic and metabolic impact than EE/LNG and other COCs, suggesting that it may be a promising candidate to reduce residual VTE risk associated with COC use. Confirmation from a well-powered prospective clinical trial is, however, needed. Chinese Abstract 摘要 目的 自50年前推出以来,口服避孕药不断降低与其使用相关的静脉血栓栓塞(VTE)的风险。但是，增加的静脉血栓栓塞风险仍然存在。其他担忧，如对脂质和碳水化合物代谢的影响也有报道。这项研究中，我们将含炔雌醇（EE）/左炔诺孕酮（LNG）和含炔雌醇/屈螺酮（DRSP）的2个参照复方口服避孕药(COCs)与含雌二醇（E2）（戊酸雌二醇[E2V] /地诺孕素[DNG]和雌二醇/醋酸诺美孕酮[NOMAC]）的复方口服避孕药进行比较。根据它们对已确定的止血和代谢指标的影响来评估。 方法使用MEDLINE/PubMed数据库文献检索进行头对头研究。选择炔雌醇/左炔诺孕酮作为对照组。 结果相比于炔雌醇/屈螺酮和炔雌醇/左炔诺孕酮的止血影响，雌二醇片和炔雌醇/左炔诺孕酮的止血影响被广泛比较。炔雌醇/左炔诺孕酮与戊酸雌二醇/地诺孕素之间的止血和代谢指标的变化则不具统计学意义。与炔雌醇/左炔诺孕酮相比，雌二醇/醋酸诺美孕酮对止血指标具有明显有利的结果，对碳水化合物和脂质代谢则是中性效应。 结论相比于含炔雌醇/左炔诺孕酮口服避孕药及其他口服避孕药，含雌二醇/醋酸诺美孕酮口服避孕药具有更少的止血和代谢影响，这表明它可能是降低与口服避孕药相关的静脉血栓栓塞风险的一种有希望的候选药品。然而，这仍需要良好的前瞻性临床试验来验证。 关键词 复合口服避孕药，雌二醇，炔雌醇，止血指标，脂质和碳水化合物代谢指标，孕激素，静脉血栓栓塞

Gynaecological uses of a new class of steroids: the selective progesterone receptor modulators.

Selective progesterone receptor modulators (SPRM) represent a new class of synthetic steroids, which can interact with the progesterone receptor (PR) and can exert agonist, antagonist or mixed effects on various progesterone target tissues in vivo. This review evaluates the actual and potential usefulness of SPRMs in gynaecology.

Women’s preferences for menstrual bleeding frequency: results of the Inconvenience Due to Women’s Monthly Bleeding (ISY) survey

Abstract Objectives: Our aim was to assess the level of inconvenience associated with monthly bleeding, determine how many women would prefer a bleeding frequency of less than once a month, and what would motivate their choice. Methods: A 15-min quantitative online survey was carried out among 2883 women aged between 18 and 45 years in six European countries (Austria, Belgium, France, Italy, Poland and Spain). Results: Of those surveyed, 1319 women used a combined hormonal contraceptive (CHC group) and 1564 used a non-hormonal contraceptive or no contraceptive (non-HC group). The menstrual period was significantly longer (5 vs. 4.5 days), heavier (16% vs. 8% heavy menstrual flow) and associated with more symptoms (6.1 vs. 5.6) in non-HC users than in CHC users (p < 0.0001). More than half of the women in each group reported pelvic pain, bloating/swelling, mood swings and irritability, but the rate was significantly higher in the non-HC group. Given the choice, 57% of women in both groups said they would opt for longer intervals between periods. Sexuality, social life, work and sporting activities were key factors affecting their decision. Conclusions: The majority of women would prefer to have menstrual periods less than once a month, with a frequency ranging from once every 3 months to no periods at all. This can be explained by the desire to avoid the unpleasant aspects of menstruation and its negative impact on private and professional life.

Toward a new concept of “natural balance” in oral estroprogestin contraception

Abstract The Pill has undergone many changes since its first appearance some 50 years ago. Key developments included the reduction of ethinylestradiol doses and the synthesis of new progestins in order to increase safety, compliance and efficiency. Low-dose combined oral contraceptives (COCs) are currently the preferred option for millions of women. Due to this widespread use, it has been argued that the safety of COCs should be even better, raising the threshold for excellence. Yet in spite of major improvements, there is still an associated risk of venous thromboembolism (VTE). The next step in COCs’ evolution should take total estrogenicity and hepatic estro-androgenic balance into account. The focus on the estrogen component – which has not changed in 50 years – has yielded a new class of natural estrogen pills. Following the introduction of a first quadriphasic pill, a monophasic estradiol pill based on the concept of “natural balance” was subsequently made available. These recent achievements could represent a step forward in the evolution of COCs and pave the way for better safety.

Missed pills: frequency, reasons, consequences and solutions

Abstract Objectives: Oral hormonal contraception is an effective contraceptive method as long as regular daily intake is maintained. However, a daily routine is a constraint for many women and can lead to missed pills, pill discontinuation and/or unintended pregnancy. This article describes the frequency of inconsistent use, the consequences, the risk factors and the possible solutions. Methods: The article comprises a narrative review of the literature. Results: Forgetting one to three pills per cycle is a frequent problem among 15–51% of users, generally adolescents. The reasons for this are age, inability to establish a routine, pill unavailability, side effects, loss of motivation and lack of involvement in the initial decision to use oral contraceptives. The consequences are ‘escape ovulations’ and, possibly, unintended pregnancy. Solutions are either to use a long-acting method or, for women who prefer to take oral contraceptives, use a continuous or long-cycle regimen to reduce the risks of follicular development and thus the likelihood of ovulation and unintended pregnancy. A progestogen with a long half-life can increase ovarian suppression. Conclusions: For women deciding to use oral contraceptives, a shortened or eliminated hormone-free interval and a progestogen with a long half-life may be an option to reduce the negative consequences of missed oral contraceptive pills.