Geneviève Plu-Bureau

Long-Term Outcome of Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Aims: Conflicting results exist regarding bone mineral density (BMD), metabolism and reproductive function of adult patients with congenital adrenal hyperplasia (CAH). We evaluated the long-term outcome and the impact of chronic glucocorticoid replacement in these patients. Methods: Physical characteristics, serum hormone concentrations, BMD and metabolism were studied in 45 consecutive CAH adult patients. Results: Among the 36 women, only 14 (39%) had regular menses. Among the 27 women with classical CAH, the mean number of surgical reconstructions of virilized genitalia was 2.1 ± 0.2. Twenty of them (74%) were sexually active. Three men presented with testicular adrenal rest tumors. Twenty-five patients (55%) had decreased BMD at the femoral neck and/or at the lumbar spine. BMI was correlated with the BMD T-score at the femoral neck (p < 0.001) and at the lumbar spine (p < 0.01). Hydrocortisone dose was negatively correlated with the BMD T-score at the femoral neck (p = 0.04). Subjects with osteopenia had a significantly lower BMI and received higher hydrocortisone dose than those with normal BMD. Overweight was found in 21 patients (47%). There was a significantly positive correlation between HOMA and BMI (p < 0.001), and between HOMA and 17-OHP levels (p = 0.016). Conclusions: Adult patients with CAH treated with long-term glucocorticoids are at risk for decreased BMD, increased BMI, and disturbed reproductive function.

The Neurotensin Receptor-1 Pathway Contributes to Human Ductal Breast Cancer Progression

Background The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion. Methods and Results we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients. Conclusion these data support the activation of neurotensinergic deleterious pathways in breast cancer progression.

Catamenial pneumothorax and endometriosis-related pneumothorax: clinical features and risk factors

BACKGROUND Catamenial pneumothorax and thoracic endometriosis (TE) are still under diagnosed. The purpose of this study is to increase the diagnostic accuracy for these conditions in patients with spontaneous pneumothorax and to identify their risk factors. METHODS We conducted a retrospective study on all consecutive women of reproductive age referred to our Centre for surgical treatment of spontaneous pneumothorax between July 2000 and January 2009. RESULTS The study population comprised 156 premenopausal women of whom 49 (31.4%) had catamenial and/or TE-related pneumothorax. Over a quarter of these 49 patients had a previous history of recurrent thoracic or scapular catamenial pain. They experienced their first pneumothorax episode at an older age (mean ± SD) (34.0 years ± 6.7) than women with idiopathic pneumothorax (28.7 ± 6.1 years, P < 0.001). Pelvic endometriosis was found in 51% of women with catamenial and/or TE-related pneumothorax. After adjustment for confounding factors by multiple logistic regression analysis, the results show that, infertility [odd ratio (OR) = 4.21, 95% confidence interval (CI) = 1.28-13.88] and a history of pelvic surgery with a uterine procedure and/or uterine scraping (OR = 2.85, 95% CI = 1.12-7.26) were the strongest predictors of catamenial and/or TE-related pneumothorax. CONCLUSIONS Infertility and uterine procedures are significantly associated with catamenial and/or TE-related pneumothorax. Scapular or thoracic pain during menses often precedes the occurrence of pneumothorax and is highly specific for the diagnosis of TE. Our results suggest that in women with pelvic endometriosis, these symptoms should be systematically investigated for an earlier diagnosis of TE.

MECHANISMS IN ENDOCRINOLOGY: Epidemiology of hormonal contraceptives-related venous thromboembolism

For many years, it has been well documented that combined hormonal contraceptives increase the risk of venous thromboembolism (VTE). The third-generation pill use (desogestrel or gestodene (GSD)) is associated with an increased VTE risk as compared with second-generation (levonorgestrel) pill use. Other progestins such as drospirenone or cyproterone acetate combined with ethinyl-estradiol (EE) have been investigated. Most studies have reported a significant increased VTE risk among users of these combined oral contraceptives (COCs) when compared with users of second-generation pills. Non-oral combined hormonal contraception, such as the transdermal patch and the vaginal ring, is also available. Current data support that these routes of administration are more thrombogenic than second-generation pills. These results are consistent with the biological evidence of coagulation activation. Overall, the estrogenic potency of each hormonal contraceptive depending on both EE doses and progestin molecule explains the level of thrombotic risk. Some studies have shown a similar increased VTE risk among users of COCs containing norgestimate (NGM) as compared with users of second-generation pill. However, for this combination, biological data, based on quantitative assessment of sex hormone-binding globulin or haemostasis parameters, are not in agreement with these epidemiological results. Similarly, the VTE risk associated with low doses of EE and GSD is not biologically plausible. In conclusion, newer generation formulations of hormonal contraceptives as well as non-oral hormonal contraceptives seem to be more thrombogenic than second-generation hormonal contraceptives. Further studies are needed to conclude on the combinations containing NGM or low doses of EE associated with GSD.

Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology.

Hormonal contraceptive methods are widely used in France, including not only oral estrogen-progestin combinations but also non-oral estrogen-progestin delivery methods (patches, vaginal rings), as well as oral forms, implants and intra-uterine devices that deliver only a progestin. Hormonal contraception has only a modest impact on lipid and carbohydrate metabolism, but estrogen-progestin contraceptives have been linked to a variety of vascular risks. Overall, the risk of venous thrombosis is multiplied by a factor of about 4, depending on age, the compounds used, and other risk factors (including biological thrombophilia and a personal history of thrombosis), whereas the risk of arterial events is only increased in women with risk factors. Available data suggest there is no excess risk with progestin-based contraceptives, but far fewer studies have been conducted. At the initiative of the French Society of Endocrinology, an expert group met in 2010 in order to reach a consensus on the use of hormonal contraceptive methods in women with vascular or metabolic risk factors, based on available data and international guidelines published by WHO in 2009 and subsequently adapted to the United States context. The following text, intentionally limited to hormonal contraception, is intended to serve as a guide when prescribing in specific clinical situations, such as a family or personal history of arterial or venous thromboembolism, or the existence of cardiovascular risk factors (hypertension, smoking, diabetes, dyslipidemia, obesity).

Contraception hormonale et risque thromboembolique veineux : quand demander une étude de l'hémostase ? Et laquelle ?

One of the deleterious effects of the combined oral contraceptives is venous thromboembolism (VTE) and it is the most frequent. VTE is potentially serious because it is sometimes responsible for fatal pulmonary embolism. Because of the large use of hormonal contraception among healthy women and often for long durations, it is fundamental to target the prescriptions and detect women at high risk of VTE. It has been demonstrated that some congenital or acquired coagulation anomalies are associated with an increase of thromboembolic risk. In addition, combined oral contraceptives modify some parameters of the hemostasis, whatever the route of administration. In order to optimize the benefit-risk balance of oral contraception, the search for a biological thrombophilia is essential in some clinical situations such as in young women with a history of venous thromboembolic event or with a family history of thrombosis at a relatively young age. A thorough questioning must be performed. On the other hand, this biological research is not systematically recommended before any prescription of hormonal contraception in patients having neither previous personal nor family history of venous thrombosis.

Postpartum practice: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF)

OBJECTIVE To make evidence-based recommendations for the postpartum management of women and their newborns, regardless of the mode of delivery. MATERIAL AND METHODS Systematic review of articles from the PubMed database and the Cochrane Library and of recommendations from the French and foreign societies or colleges of obstetricians. RESULTS Because breast-feeding is associated with reductions in neonatal, infantile, and childhood morbidity (lower frequency of cardiovascular, infectious, and atopic diseases and infantile obesity) (LE2) and improved cognitive development in children (LE2), exclusive and extended breastfeeding is recommended (grade B) for at least 4-6 months (professional consensus). Pharmacological treatments for inhibition of lactation should not be given routinely to women who do not wish to breastfeed (professional consensus). Because of potentially serious adverse effects, bromocriptine is contraindicated in inhibiting lactation (professional consensus). For women aware of the risks of pharmacological treatments to inhibit lactation but choose to take them, lisuride and cabergoline are the preferred drugs (professional consensus). Regardless of the mode of delivery, only women with bleeding or symptoms of anemia should be tested for it (professional consensus). Immediate postoperative monitoring after cesarean delivery should be performed in the postanesthesia care unit (PACU). An analgesic multimodal protocol for analgesia, preferring oral administration, should be developed by the medical team and be available for all staff (professional consensus) (grade B). Thromboprophylaxis with compression stockings should begin the morning of all cesarean deliveries and maintained for at least 7 postoperative days (professional consensus) with or without the addition of LMWH, depending on the presence and severity (major or minor) of additional risk factors. It is recommended that women be informed of the dangers of closely spaced pregnancies (LE3), that effective contraception begin no later than 21 days post partum for women who do not want such a pregnancy (grade B), and that it be prescribed at the maternity ward (professional consensus). In view of the postpartum risk of venous thromboembolism, use of combination hormonal contraception is not recommended before six weeks post partum (grade B). Pelvic floor rehabilitation in asymptomatic women to prevent urinary or anal incontinence in the medium or long term is not recommended (professional consensus). Rehabilitation using pelvic floor muscle contraction exercises is recommended to treat persistent urinary incontinence at 3 months post partum (grade A), regardless of the type of incontinence. Postpartum pelvic floor rehabilitation is recommended to treat anal incontinence (grade C), but not to treat or prevent prolapse (grade C) or dyspareunia (grade C). The months following the birth are a period of transition and of psychological changes for all parents (LE2) and are still more difficult for those with psychosocial risk factors (LE2). Situations of evident psychological difficulties can have a significant effect on the childs psychological and emotional development (LE3). Among these difficulties, postpartum depression is most common, but the risk of all mental disorders is generally higher in the perinatal period (LE3). CONCLUSION The postpartum period presents clinicians with a unique and privileged opportunity to address the physical, psychological, social, and somatic health of women and babies.

Should women suffering from migraine with aura be screened for biological thrombophilia?: Results from a cross-sectional French study

INTRODUCTION Migraine, particularly migraine with aura (MA), is associated with a higher risk for ischemic stroke (IS). A procoagulant state may predispose to IS. Whether inherited biological thrombophilia are associated with migraine risk remains controversial. OBJECTIVE To assess the risk of migraine without or with aura related to inherited biological thrombophilia adjusted for the main potential confounders. MATERIAL AND METHODS A cross-sectional study was conducted in 1456 French women aged 18 to 56years, referred for biological coagulation check-up because of personal or familial venous thrombosis history. Between April 2007 and December 2008, all women answered a self-administered questionnaire to determine whether they had headache. RESULTS There were 294 (20%) migrainous sufferers (including 71 [5%] with MA), 975 (67%) non migrainous women and 187 (13%) non migrainous headache women. Inherited thrombophilia were detected in 576 (40%) women, including 389 (40%) non migrainous women, 90 (40%) migraine without aura (MWA), 33 (46%) MA women and 64 (34%) non migrainous headache women. Factor V Leiden (FVL) i.e. F5rs6025 or Factor II G20210A (FIIL) i.e. F2rs1799963 mutation was detected in 296 (30%) non migrainous women and in 100 (34%) migrainous women of which 27 had MA. There was a significant association between MA and FVL or FIIL mutations (adjusted OR=1.76 [95% CI 1.02-3.06] p=0.04) whereas this association in MWA and in non migrainous headache women was not significant. There was no significant association between migraine and other biological thrombophilia. CONCLUSION FVL or FIIL mutations were more likely among patients suffering from MA. Whether biological thrombophilia screening should be systematically performed in women suffering from MA remains to be determined.

[Post-partum: Guidelines for clinical practice--Short text].

OBJECTIVE To determine the post-partum management of women and their newborn whatever the mode of delivery. MATERIAL AND METHODS The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. RESULTS Because breastfeeding is associated with a decrease in neonatal morbidity (lower frequency of cardiovascular diseases, infectious, atopic or infantile obesity) (EL2) and an improvement in the cognitive development of children (EL2), exclusive and extended breastfeeding is recommended (grade B) between 4 to 6 months (Professional consensus). In order to increase the rate of breastfeeding initiation and its duration, it is recommended that health professionals work closely with mothers in their project (grade A) and to promote breastfeeding on demand (grade B). There is no scientific evidence to recommend non-pharmacological measures of inhibition of lactation (Professional consensus). Pharmacological treatments for inhibition of lactation should not be given routinely to women who do not wish to breastfeed (Professional consensus). Because of potentially serious adverse effects, bromocriptin is contraindicated in inhibiting lactation (Professional consensus). For women aware of the risks of pharmacological treatment of inhibition of lactation, lisuride and cabergolin are the preferred drugs (Professional consensus). Whatever the mode of delivery, numeration blood count is not systematically recommended in a general population (Professional consensus). Anemia must be sought only in women with bleeding or symptoms of anemia (Professional consensus). The only treatment of post-dural puncture headache is the blood patch (EL2), it must not be carried out before 48 h (Professional consensus). Women vaccination status and their family is to be assessed in the early post-partum (Professional consensus). Immediate postoperative monitoring after caesarean delivery should be performed in the recovery room, but in exceptional circumstances, it may be performed in the delivery unit provided safety rules are maintained and regulatory authorities are informed (Professional consensus). An analgesic multimodal protocol developed by the medical team should be available and oral way should be favored (Professional consensus) (grade B). For every cesarean delivery, thromboprophylaxis with elastic stockings applied on the morning of the surgery and kept for at least 7 postoperative days is recommended (Professional consensus) with or without the addition of LMWH according to the presence or not of additional risk factors, and depending on the risk factor (major, minor). Early postoperative rehabilitation is encouraged (Professional consensus). Postpartum visit should be planned 6 to 8 weeks after delivery and can be performed by an obstetrician, a gynecologist, a general practitioner or a midwife, after normal pregnancy and delivery (Professional consensus). Starting effective contraception later 21 days after delivery in women who do not want closely spaced pregnancy is recommended (grade B), and to prescribe it at the maternity (Professional consensus). According to the postpartum risk of venous thromboembolism, the combined hormonal contraceptive use before six postpartum weeks is not recommended (grade B). Rehabilitation in asymptomatic women in order to prevent urinary or anal incontinence in medium or long-term is not recommended (Expert consensus). Pelvic-floor rehabilitation using pelvic-floor muscle contraction exercises is recommended to treat persistent urinary incontinence at 3 months postpartum (grade A), regardless of the type of incontinence. Postpartum pelvic-floor rehabilitation is recommended to treat anal incontinence (grade C). Postpartum pelvic-floor rehabilitation is not recommended to treat or prevent prolapse (grade C) or dyspareunia (grade C). The optimal time for maternity discharge for low risk newborn depends more on the organisation of the post-discharge follow up (Professional consensus). The months following the birth are a transitional period, and psychological alterations concern all parents (EL2). It is more difficult in case of psychosocial risk factors (EL2). In situations of proven psychological difficulties, the impact on the psycho-emotional development of children can be important (EL3). Among these difficulties, postpartum depression is the most common situation. However, the risk is generally higher in the perinatal period for all mental disorders (EL3). CONCLUSION Postpartum is, for clinicians, a unique and privileged opportunity to address the physical, psychological, social and somatic health of their patients.

Thrombose et assistance médicale à la procréation (AMP)

Assisted reproductive techniques (ART) concern procedures designed to increase fertility of couples: artificial insemination, in vitro fertilization (IVF), either classical or after intracytoplasmic sperm injection (ICSI), transfer of frozen embryos, or gamete intrafallopian transfer. Their use has greatly increased these last years. They may be associated with severe ovarian hyperstimulation syndrome and one possible major complication is venous or arterial thrombosis. Thromboses are rare but potentially serious with important sequellae. They are mostly observed in unusual sites such as head and neck vessels and the mechanism is still unknown although hypotheses have been proposed. This review is an update of our knowledge and an attempt to consider guidelines for the prevention and treatment of ART-associated thromboses, which frequently occur when the woman is pregnant. Prevention of severe ovarian hyperstimulation by appropriate stimulation procedures, detection of women at risk of hyperstimulation and of women at high risk of thrombosis should allow reduction of the risk of thrombosis, possibly by administration of a thromboprophylaxis at a timing and dose which can be only determined by extrapolation.