Nathalie Chabbert-Buffet

Steroid profiling in preeclamptic women: evidence for aromatase deficiency

OBJECTIVEnExperimental data have revealed the critical role played by 2-methoxy-estradiol, a metabolite of 17β-estradiol, in the pathophysiology of preeclampsia. We used gas chromatography/mass spectrometry to measure a whole panel of hormonal steroids in the plasma from women during the third trimester of their pregnancy.nnnSTUDY DESIGNnThe population study consists of 24 pregnant patients with different outcomes: normal, or complicated by isolated preeclampsia or by severe preeclampsia with Hemolysis Enzyme Liver Low Platelets (HELLP) syndrome.nnnRESULTSn17β-estradiol was reduced by 50% in isolated preeclampsia, and by 70% in severe preeclampsia with HELLP syndrome (normal: 8.54 ± 0.9 ng/mL; isolated preeclampsia: 4.65 ± 1.0 ng/mL; severe preeclampsia with HELLP syndrome: 2.64 ± 0.4 ng/mL), as is estrone. Downstream, 2-methoxy-estradiol was decreased only in severe preeclampsia with HELLP syndrome. The concentrations of estrone and 17β-estradiol precursors were comparable between groups, suggesting that placental aromatase is deficient in preeclampsia.nnnCONCLUSIONnThe gradual decrease of estrogen levels with increasing severity of preeclampsia suggests an impairment of placental steroidogenesis.

Comparison of a 24-day and a 21-day pill regimen for the novel combined oral contraceptive, nomegestrol acetate and 17β-estradiol (NOMAC/E2): a double-blind, randomized study

BACKGROUND Nomegestrol acetate/17β-estradiol (NOMAC/E(2)) is a new monophasic oral contraceptive combining NOMAC (2.5 mg), a highly selective progesterone-derived progestogen, with E(2) (1.5 mg), which is structurally identical to endogenous estrogen. The objective of this study was to compare the effects on ovarian activity of two different NOMAC/E(2) regimens. METHODS This was a double-blind, randomized study. Healthy, premenopausal women (aged 18-38 years, previous menstrual cycle length 28 ± 7 days) were randomized by computer-generated code to once-daily NOMAC/E(2) for three consecutive 28-day cycles: either 24 days with a 4-day placebo interval (n = 40) or 21 days with a 7-day placebo interval (n = 37) per cycle. Follicular growth (primary outcome measure), plasma hormone profiles and bleeding patterns were assessed. RESULTS There was no evidence of ovulation during treatment with either NOMAC/E(2) regimen. The largest follicle diameter was significantly smaller in the 24-day group than in the 21-day group [mean (SD) mm in cycle 2: 9.0 (3.0) versus 11.3 (5.3) (P = 0.02); in cycle 3: 9.2 (3.0) versus 11.5 (6.0) (P = 0.04)]. Mean FSH plasma levels were significantly lower in the 24-day versus the 21-day group on Day 24 of cycles 1 and 2. Withdrawal bleeding duration was significantly shorter in the 24-day than in the 21-day group [mean (SD) days after cycle 1: 3.5 (1.3) versus 5.0 (2.6) (P = 0.002); after cycle 2: 3.9 (1.6) versus 4.8 (1.7) (P = 0.03)]. CONCLUSIONS The 24-day NOMAC/E(2) regimen was associated with greater inhibition of follicular growth and shorter duration of withdrawal bleeding than the 21-day regimen, suggesting the shorter pill-free interval results in a greater margin of contraceptive efficacy and tolerability, and fewer withdrawal symptoms.

Inhibition of ovulation by NOMAC/E2, a novel monophasic oral contraceptive combining nomegestrol acetate and 17β-oestradiol: A double-blind, randomised, dose-finding pilot study

Objectiveu2003To explore the optimal dose of the progestogen, nomegestrol acetate (NOMAC), required in a monophasic oral contraceptive, in combination with 1.5u2009mg 17β-oestradiol (E2), to inhibit ovulation. Methodsu2003A double-blind, randomised study assessing 41 normally cycling women (aged 18–35 years) over two screening cycles, one control cycle and one consecutive treatment cycle; 38 women completed the treatment period. Subjects received 0.625u2009mg NOMAC/1.5u2009mg E2 (nu200a=u200a9), 1.25u2009mg NOMAC/1.5u2009mg E2 (nu200a=u200a10), 2.5u2009mg NOMAC/1.5u2009mg E2 (nu200a=u200a10) or 2.5u2009mg NOMAC alone (nu200a=u200a9) for 21 days. Resultsu2003During the treatment cycle, ovulation was suppressed in all treatment groups. The lowest plasma E2 levels were observed with 2.5u2009mg NOMAC given alone. Addition of 1.5u2009mg E2 to 2.5u2009mg NOMAC resulted in statistically significant increases in E2 levels and decreases in mean follicle-stimulating hormone and luteinising hormone levels. In the three NOMAC/E2 combination groups, a statistically significant inverse correlation was found between E2 plasma levels and NOMAC dose. Conclusionu2003The dose of 2.5 mg NOMAC was confirmed to be optimal to inhibit both ovulation and follicular maturation. The antigonadotropic effect of 2.5u2009mg NOMAC was reinforced when combined with 1.5u2009mg E2.

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).

Soluble endoglin in preeclamptic patients with or without HELLP syndrome

OBJECTIVEnThe pathogenesis of the HELLP (hemolysis, enzyme liver, low platelets) syndrome is unknown. Recently soluble endoglin (sEng) was identified as a cause of the appearance of schistocytes and liver pathology in an animal model of preeclampsia (PE).nnnSTUDY DESIGNnWe explored the value of sEng in 82 women who delivered in a context of normal pregnancy (NP, n = 10), PE (n = 49), or HELLP (n = 23).nnnRESULTSnsEng was elevated in pathological pregnancies (66.7 +/- 62 and 75.7 +/- 48 pg/mL in PE and HELLP, respectively, vs 5.29 +/- 1.25 in NP, P < .001 for both comparisons) and was correlated with an increase in transaminases (r(2) = 0.17; P = .05), but it was not statistically different between PE and HELLP.nnnCONCLUSIONnAlthough recent literature findings demonstrated a role of sEng in the pathophysiology of HELLP syndrome in animal models, we found that, at the time of delivery, sEng was not specifically elevated in preeclamptic patients with HELLP.

From Pregnancy to Preeclampsia: A Key Role for Estrogens

Preeclampsia (PE) results in placental dysfunction and is one of the primary causes of maternal and fetal mortality and morbidity. During pregnancy, estrogen is produced primarily in the placenta by conversion of androgen precursors originating from maternal and fetal adrenal glands. These processes lead to increased plasma estrogen concentrations compared with levels in nonpregnant women. Aberrant production of estrogens could play a key role in PE symptoms because they are exclusively produced by the placenta and they promote angiogenesis and vasodilation. Previous assessments of estrogen synthesis during PE yielded conflicting results, possibly because of the lack of specificity of the assays. However, with the introduction of reliable analytical protocols using liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry, more recent studies suggest a marked decrease in estradiol levels in PE. The aim of this review is to summarize current knowledge of estrogen synthesis, regulation in the placenta, and biological effects during pregnancy and PE. Moreover, this review highlights the links among the occurrence of PE, estrogen biosynthesis, angiogenic factors, and cardiovascular risk factors. A close link between estrogen dysregulation and PE occurrence might validate estrogen levels as a biomarker but could also reveal a potential approach for prevention or cure of PE.

Complex US adnexal masses during pregnancy: Is pelvic MR imaging accurate for characterization?

OBJECTIVEnTo retrospectively evaluate the accuracy of pelvic magnetic resonance (MR) imaging for the characterization of complex sonographic adnexal masses discovered in women during pregnancy.nnnSTUDY DESIGNnThe study population comprised 31 pregnant women (median age: 32 years (range: 19-42); mean gestation age of 16 weeks) referred to our institution for MR imaging for characterization of an adnexal mass discovered incidentally during routine ultrasound (US) for other indications. The population comprised of 31 women, with 36 adnexal lesions (mean size: 103mm [range: 20-290]), of which 27 were benign and 9 were malignant masses. Prospective US and MR reports were reviewed to determine the presence of a benign or malignant lesion. Two radiologists (R1 and R2) blinded to the final outcome, retrospectively evaluated the MR images using the criteria based on the ADNEXMR-SCORE and classified the lesion as benign or malignant. The reference standard was surgical pathology or at least a 1-year imaging follow-up.nnnRESULTSnProspective US and MR imaging correctly identified the diagnosis in 27/36 (75%) (95% confidence interval (CI): 58.9%-86.2%) and in 32/36 (88.9%) (95% CI: 74.6%-95.6%) of lesions, respectively. MR imaging with ADNEXMR-SCORE allowed a correct diagnosis in 32/36 (88.9%) (95% CI: 74.6%-95.6%) of lesions for R1 and in 30/36 (83.3%) (95% CI: 68.1%-92.1%) of lesions for R2. The sensitivities and specificities of MR imaging using the MR ADNEXMR-SCORE were 100% (95% CI: 70.1%-1000%) for both readers and 85.1% (95% CI: 67.5%-94%) and 77.7% (95% CI: 59.2%-89.4%) for R1 and R2, respectively. No malignancy was classified as benign using MR criteria. The reproducibility between the two readers was almost perfect, with a kappa of 0.914.nnnCONCLUSIONnMR imaging is highly accurate for the characterization of complex adnexal masses incidentally discovered during pregnancy.nnnCLINICAL RELEVANCEnMR imaging can accurately characterize adnexal masses in pregnancy and could be useful in opting for expectant management until delivery.

The inconvenience due to women’s monthly bleeding (ISY) survey: a study of premenstrual symptoms among 5728 women in Europe

Abstract Objectives: The aim of the ISY study was to investigate the prevalence of menstrual-related symptoms prior to and/or during menstrual or withdrawal bleeding among women from 12 European countries. Methods: A 15-min quantitative online survey was conducted in two waves from February to September 2015 among 5728 women aged between 18 and 45 years, with an equal distribution of women using a combined hormonal contraceptive, including regular combined oral contraceptives (COCs) (CHC group, nu2009=u20092739) and women using a non-hormonal contraceptive or no contraceptive (non-HC group, nu2009=u20092989). Results: The prevalence of at least one menstrual-related symptom was high in CHC users (93%) and in non-HC users (95%) (pu2009<u2009.0001) and the average number of symptoms reported was 5.3 vs. 5.9, respectively, (pu2009<u2009.0001). Pelvic pain, bloating/swelling, irritability and mood swing were reported in more than half of the women in both groups. Although generally modest, symptom severity was higher in non-HC users, except for headache. Overall, during the last four cycles, 60–75% of women did not require a treatment for most symptoms but headaches and pelvic pain. Mood swings/irritability, water retention/weight gain, lack of energy/mood swings and lack of energy/irritability were common symptoms that frequently co-occurred. No associations were reported between symptoms and age, educational qualifications or women’s desire to reduce the frequency of menstruation. Conclusions: Premenstrual and menstrual symptomatology was less frequent, less numerous and less severe (except for headache) in women using CHCs; however, it remains a common concern. Reducing the frequency of menstrual periods could reduce withdrawal-related symptoms.

Pharmacology of Hormone Replacement Therapy in Menopause

Menopause represents the final stage of the continuous process of reproductive aging in a woman’s life, marking the end of her fertility. According to the World Health Organization (WHO), the natural menopause is defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity (WHO Report, 1996). Preceded by endocrine and menstrual cycle changes described as “menopausal transition”, natural menopause occurs at an average age of approximately 51 years, although a high inter-individual variability is supported by results from epidemiological studies. However, occurrence of menopause outside the estimated normal age interval (45-55 years) is associated with increased morbidity, either when a late or on the contrary, a premature cessation of menstruation appears. A late menopause implies a longer exposure to estrogens and a possible increased risk for breast (Colditz, 1993; Kelsey & Bernstein, 1996) and endometrial cancer (Dossus et al., 2010; McPherson et al., 1996) or for venous thromboembolism (Simon et al., 2006). On the other hand, women entering menopause earlier are facing a hypo-estrogenic state for a longer period compared to women undergoing normal menopause. That is the case for about 1% of women, which are confronted with the diagnosis of primary ovarian insufficiency (POI). POI is defined by the presence of amenorrhea associated with elevated follicle-stimulating hormone (FSH) levels in the menopausal range in women younger than 40 years (Bachelot et al., 2009). Women facing a premature cessation of the ovarian function were shown to be at increased risk for premature death, cardiovascular disease, neurologic disease, mood disorders, osteoporosis or psychosexual dysfunction (Shuster et al., 2010). As the main rationale for these disorders was linked to hormonal changes, maintaining a certain level of ovarian steroids for a given period of time arose as an essential condition for conserving life quality in women (Wilson, [1966]). Accentuated by the increasing life span, researches related to menopause and its treatment have provided scientific community with an increased body of data during the last decades. However, different aspects regarding the benefit/risk balance or the ideal doses and routes of administration of hormone replacement therapy (HRT) in menopausal women remain uncertain (Grodstein et al., 1997; Rossouw et al., 2002).

Propensity score to evaluate prognosis in pregnancy-associated breast cancer: Analysis from a French cancer network

PURPOSEnTo compare the prognosis of pregnancy associated breast cancer occurring during pregnancy (BCP) to non-pregnancy associated breast cancers (non-BCP) in young women managed at a national expert center.nnnMETHODSnRetrospective cohort study of a prospective database using propensity score matching (PSM) analysis with known prognostic factors.nnnRESULTSnWe analyzed data of 49 patients with BCP and 104 with non-BCP diagnosed between 2002 and 2017u202fat Tenon University Hospital (Paris, France). The BCP tumors were often locally advanced (lymph node metastases in 59%), of high grade (55%) and highly proliferative (67% with Ki67u202f≥u202f20%). After PSM, breast cancer-free survival (pu202f=u202f0.45) and breast cancer specific survival (pu202f=u202f0.81) were similar in the two groups. The recurrence rate was 12% vs 18% (pu202f=u202f0.45) and the death rate was 6% vs 8% (pu202f=u202f0.74) for the BCP and non-BCP groups, respectively. No difference in recurrence type was observed between the groups (pu202f=u202f0.60).nnnCONCLUSIONSnAfter PSM for known prognostic factors, the prognosis of BCP patients did not differ from that of young patients with non-BCP.