Mathieu Leboeuf

Canadian Consensus Guideline on Continuous and Extended Hormonal Contraception, 2007

Abstract Objective To serve as a guideline for health care providers on the use of continuous and extended combined hormonal contraception regimens, to prevent pregnancy, and to delay menses that affect health-related quality of life. Options All combined hormonal contraceptive methods available in Canada that may be used in a continuous or extended regimen are reviewed, and the implications are discussed. Outcomes Efficacy of cited regimens and assessment of their side effects, patient safety, medical usage and non-contraceptive benefits, cost-effectiveness, and availability in Canada. Indications for patient counselling are also provided Evidence Medline, PubMed, and Cochrane Database were searched for articles published in English between 1977 and May 2007. Relevant publications and position papers from appropriate reproductive health and family planning organizations were also reviewed. Values The quality of evidence is rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs The guideline is intended to help reduce unintended pregnancies and improve health-related quality of life in women who find their menses problematic. Increased awareness and empowerment of women, their partners, and health care professionals will improve their ability to make appropriate choices between continuous or extended and cyclic usage of these regimens. Sponsors The development of this guideline has been supported by unrestricted grants from Bayer HealthCare Pharmaceuticals, Janssen Ortho, Organon Canada Ltd., Paladin Labs Inc., Pfizer Canada Inc., and Wyeth Pharmaceuticals.

The Human Aldose Reductase AKR1B1 Qualifies as the Primary Prostaglandin F Synthase in the Endometrium

CONTEXT Prostaglandins (PGs) E2 and PGF2α are produced in the endometrium and are important for menstruation and fertility. Dysmenorrhea is associated with increased production of PGF2α relative to PGE2, and the opposite is true for menorrhagia. The pathways leading to PGE2 biosynthesis are well described, but little is known for PGF2α. Aldoketoreductase (AKR)-1C3, the only PGF synthase identified in the human, cannot explain the production of PGF2α by endometrial cells. AKR1B1 appears to be an alternate candidate with promising therapeutic value. OBJECTIVE The objective of the study was to address whether AKR1B1 (gene ID 231) is a functional PGF2α synthase in the human endometrium and a valid therapeutic target for menstrual pain. DESIGN The design of the study was basic laboratory analyses to identify gene expression and protein levels associated with PGF2α production in endometrial tissues and endometrial cells from cycling women aged between 23 and 52 yr undergoing biopsies or hysterectomy for diverse gynecological disorders. RESULTS AKR1B1 is expressed at a high level during the menstrual cycle during the secretory phase and in both epithelial and stromal cells, whereas AKR1C3 was found only in epithelial cells. Purified recombinant AKR1B1 protein, gene silencing, and transient transfection experiments all concur to demonstrate that this enzyme is a functional PGF synthase. Ponalrestat, a specific inhibitor developed to block AKR1B1 activity, reduced PGF2α production in response to IL-1β in both cultured endometrial cells and endometrial explants. CONCLUSIONS The human aldose reductase AKR1B1 currently associated with diabetes complications is also a highly functional PGF synthase responsible for PGF2α production in the human endometrium and a potential target for treatment of menstrual disorders.

Low abdominal subcutaneous preadipocyte adipogenesis is associated with visceral obesity, visceral adipocyte hypertrophy, and a dysmetabolic state.

Subcutaneous adipose tissue expansion through adipogenesis is increasingly recognized as a major determinant of body fat distribution and obesity-related cardiometabolic alterations. Our objective was to assess whether adipogenic rates of cultured human primary preadipocytes from the visceral and subcutaneous compartments relate to visceral obesity and cardiometabolic alterations. We recruited 35 women undergoing gynecological surgery and assessed body fat distribution by CT as well as fasting plasma lipids and glycemia. Fat samples from the greater omentum and abdominal subcutaneous (SC) compartments were used to assess mature adipocyte cell size and establish primary preadipocyte cultures. Differentiation was induced using adipogenic media and adipogenic rates were assessed using Oil Red O (ORO) absorbance/DNA content ratio and glyceraldehyde 3-phosphate dehydrogenase (G3PDH) activity/DNA of differentiated cells. We found a lower adipogenic capacity of omental (OM) preadipocytes than SC preadipocytes originating from the same women (P < 0.05). Whereas only OM cell size was different among groups of low vs high OM adipogenic rate, SC adipogenic rates were clearly related to increased OM cell size and dyslipidemia when women were separated on median value of either ORO/DNA or G3PDH activity/DNA ratios. When matched for BMI, women with low SC preadipocyte adipogenic rates had a higher visceral adipose tissue area (P < 0.01), omental adipocyte hypertrophy (P < 0.05), higher VLDL-lipid content (P < 0.01) and higher fasting glycemia (P < 0.05) than those with low SC adipogenic rates. In conclusion, low abdominal subcutaneous preadipocyte differentiation capacity in vitro is associated with visceral obesity, visceral adipocyte hypertrophy, and a dysmetabolic state.

Macrophage Migration Inhibitory Factor Is Involved in a Positive Feedback Loop Increasing Aromatase Expression in Endometriosis

Immune-endocrine interplay may play a major role in the pathogenesis of endometriosis. In the present study, we have investigated the interaction between macrophage migration inhibitory factor (MIF), a major pro-inflammatory and growth-promoting factor markedly expressed in active endometriotic lesions, and estradiol (E(2)) in ectopic endometrial cells. Our data showed a significant increase of MIF protein secretion and mRNA expression in endometriotic cells in response to E(2). MIF production was blocked by Fulvestrant, an estrogen receptor (ER) antagonist, and induced by ERα and ERβ selective agonists propyl-pyrazole-triol (PPT) and diarylpropionrile (DPN), respectively, thus demonstrating a specific receptor-mediated effect. Cell transfection with MIF promoter construct showed that E(2) significantly stimulates MIF promoter activity. Interestingly, our data further revealed that MIF reciprocally stimulates aromatase protein and mRNA expression via a posttranscriptional mRNA stabilization mechanism, that E(2) itself can upregulate aromatase expression, and that inhibition of endogenous MIF, using MIF specific siRNA, significantly inhibits E(2)-induced aromatase. Thus, the present study revealed the existence of a local positive feedback loop by which estrogen acts directly on ectopic endometrial cells to upregulate the expression of MIF, which, in turn, displays the capability of inducing the expression of aromatase, the key and rate-limiting enzyme for estrogen synthesis. Such interplay may have a considerable impact on the development of endometriosis.

Soluble Human IL-1 Receptor Type 2 Inhibits Ectopic Endometrial Tissue Implantation and Growth : Identification of a Novel Potential Target for Endometriosis Treatment

Endometriosis is often associated with a chronic pelvic immuno-inflammatory process, which is closely related to disease pathogenesis and major symptoms. Our studies led to the detection of a marked imbalance between IL-1 and its natural inhibitor IL-1 receptor type 2 (IL1R2) in women with endometriosis. This points to a deficiency in the local control of IL-1 that, in view of the cytokines elevated levels and potent proinflammatory, angiogenic, and growth-promoting effects, may contribute to endometriosis development. Using an in vivo model in which human endometrial tissue was inoculated into nude mice and left to establish before any further treatment, our data showed that sIL1R2 interferes with the capability of endometrial tissue to invade, grow, disseminate, and stimulate angiogenesis into the host tissue. sIL1R2 significantly down-regulated the expression of major cell adhesion receptors (αv and β3 integrins), matrix metalloproteinases (MMP-2 and -9), and vascular endothelial cell growth factor. Interestingly, treatment with sILR2 (5 μg/kg) led to a concomitant upregulation of matrix metalloproteinases natural inhibitors (TIMP1 and TIMP2) and down-regulation of BclII, a potent anti-apoptotic protein. This creates an imbalance between pro- and anti-proteolytic and apoptotic factors and may further contribute to IL1R2 growth-inhibitory effects. This study provides evidence that sIL1R2 alters ectopic endometrial tissue growth, remodeling, and survival in vivo and may represent an interesting potential therapeutic tool.

Identification of multiple and distinct defects in prostaglandin biosynthetic pathways in eutopic and ectopic endometrium of women with endometriosis

OBJECTIVE To investigate prostaglandin (PG) biosynthesis and catabolism pathways in eutopic and ectopic endometrium of women with endometriosis. DESIGN Retrospective study. SETTING Human reproduction research laboratory. PATIENT(S) Forty-five women with endometriosis and 29 normal controls. INTERVENTION(S) Endometrial and endometriotic tissue samples were obtained during laparoscopic surgery. MAIN OUTCOME MEASURE(S) Cyclo-oxygenases (Coxs 1 and 2), PGE2 synthases (microsomal [m] PGES 1 and 2 and cytosolic [c] PGES), PGF2α synthases (aldoketoreductase [AKR]-1C3 and AKR-1B1), and the PG catabolic enzyme 15-hydroxyprostaglandin dehydrogenase messenger RNA expression by quantitative real-time polymerase chain reaction and protein localization by immunohistochemistry. RESULT(S) This study showed a marked increase in the key PG biosynthesis enzymes Cox-2, mPGES-1, mPGES-2, cPGES, and AKR-1C3 in ectopic endometrial tissue of women with endometriosis, particularly in the earliest and most active stages of the disease, without a noticeable change in the expression of the PG catabolic enzyme 15-hydroxyprostaglandin dehydrogenase. Meanwhile, the significant increase in rate-limiting Cox-2 expression upstream was correlated downstream by a significant stage- and cycle phase-dependent decrease in the terminal specific synthase mPGES-2, thereby revealing the presence of counter-regulatory mechanisms, which operate in the eutopic endometrium of women with endometrium but seem to be lacking in the ectopic implantation sites. CONCLUSION(S) This study reveals for the first time multiple defects in PG biosynthesis pathways, which differ between eutopic intrauterine and ectopic endometrial tissues and may, owing to the wide spectrum of PG properties, contribute to the initial steps of endometrial tissue growth and development and have an important role to play in the pathogenesis and symptoms of this disease.

Missed Hormonal Contraceptives: New Recommendations

OBJECTIVE To provide evidence-based guidance for women and their health care providers on the management of missed or delayed hormonal contraceptive doses in order to prevent unintended pregnancy. EVIDENCE Medline, PubMed, and the Cochrane Database were searched for articles published in English, from 1974 to 2007, about hormonal contraceptive methods that are available in Canada and that may be missed or delayed. Relevant publications and position papers from appropriate reproductive health and family planning organizations were also reviewed. The quality of evidence is rated using the criteria developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS This committee opinion will help health care providers offer clear information to women who have not been adherent in using hormonal contraception with the purpose of preventing unintended pregnancy. SPONSORS The Society of Obstetricians and Gynaecologists of Canada. SUMMARY STATEMENTS: 1. Instructions for what women should do when they miss hormonal contraception have been complex and women do not understand them correctly. (I) 2. The highest risk of ovulation occurs when the hormone-free interval is prolonged for more than seven days, either by delaying the start of combined hormonal contraceptives or by missing active hormone doses during the first or third weeks of combined oral contraceptives. (II) Ovulation rarely occurs after seven consecutive days of combined oral contraceptive use. (II) RECOMMENDATIONS: 1. Health care providers should give clear, simple instructions, both written and oral, on missed hormonal contraceptive pills as part of contraceptive counselling. (III-A) 2. Health care providers should provide women with telephone/electronic resources for reference in the event of missed or delayed hormonal contraceptives. (III-A) 3. In order to avoid an increased risk of unintended pregnancy, the hormone-free interval should not exceed seven days in combined hormonal contraceptive users. (II-A) 4. Back-up contraception should be used after one missed dose in the first week of hormones until seven consecutive days of correct hormone use are established. In the case of missed combined hormonal contraceptives in the second or third week of hormones, the hormone-free interval should be eliminated for that cycle. (III-A) 5. Emergency contraception and back-up contraception may be required in some instances of missed hormonal contraceptives, in particular when the hormone-free interval has been extended for more than seven days. (III-A) 6. Back-up contraception should be used when three or more consecutive doses/days of combined hormonal contraceptives are missed in the second and third week until seven consecutive days of correct hormone use are established. For practical reasons, the scheduled hormone-free interval should be eliminated in these cases. (II-A) 7. Emergency contraception is rarely indicated for missed combined hormonal contraceptives in the second or third week of the cycle unless there are repeated omissions or failure to institute back-up contraception after the missed doses. In cases of repeated omissions of combined hormonal contraceptives, emergency contraception may be required, and back-up contraception should be used. Health care professionals should counsel women in these situations on alternative methods of contraception that do not demand such stringent compliance. (III-A).

Promotion of angiogenesis and proliferation cytokines patterns in peritoneal fluid from women with endometriosis

Studies have long sought specific cytokines that could characterize endometriosis. Either due to variations between study designs regarding the assessment criteria for the cytokine or to low power resulting from small sample size, no factor proved to be sufficiently specific to endometriosis. In other clinical fields, a combination of several markers proved to be more powerful than a single-molecule approach. As well, in the context of endometriosis, simultaneous assessment of several cytokines present in the peritoneal fluid might help in unveiling patho-physiological processes, thus contributing to a better understanding of the condition. Therefore, the objective of this study was to investigate peritoneal fluid cytokines-derived of endometriotic women. For this retrospective case-control study, peritoneal fluid samples were obtained at laparoscopy and assessed by multiplex. Our data showed distinct patterns of peritoneal fluid cytokine concentrations in endometriotic women most notably a marked increase in EGF, FGF-2, IL-1α, MIP-1β, TGFα, PDGF-AA, PDGF-BB, MCP-3, sCD40L, Gro Pan, IL-17α, MDC and Rantes. The overall effect of fertility status revealed a significant difference for only one cytokine, namely MDC. Furthermore, FLT-3L and IP-10 levels were decreased in endometriosis patients, the former in both menstrual cycle phases and the latter in the secretory phase. A significant inverse Pearson correlation (p<0.05) was noted between pro-angiogenic cytokines EGF and FGF and the anti-angiogenic cytokine IP-10 in endometriosis patients at stages III-IV and in the secretory phase. These changes may exacerbate the local peritoneal angiogenic and proliferative reaction observed in women with endometriosis, and contributes to its pathophysiology.

Macrophage migration inhibitory factor is involved in ectopic endometrial tissue growth and peritoneal-endometrial tissue interaction in vivo: a plausible link to endometriosis development.

Pelvic inflammation is a hallmark of endometriosis pathogenesis and a major cause of the diseases symptoms. Abnormal immune and inflammatory changes may not only contribute to endometriosis-major symptoms, but also contribute to ectopic endometrial tissue growth and endometriosis development. A major pro-inflammatory factors found elevated in peritoneal fluid of women with endometriosis and to be overexpressed in peritoneal fluid macrophages and active, highly vascularized and early stage endometriotic lesions, macrophage migration inhibitory factor (MIF) appeared to induce angiogenic and inflammatory and estrogen producing phenotypes in endometriotic cells in vitro and to be a possible therapeutic target in vivo. Using a mouse model where MIF-knock out (KO) mice received intra-peritoneal injection of endometrial tissue from MIF-KO or syngeneic wild type (WT) mice and vice versa, our current study revealed that MIF genetic depletion resulted in a marked reduction ectopic endometrial tissue growth, a disrupted tissue structure and a significant down regulation of the expression of major inflammatory (cyclooxygenease-2), cell adhesion (αv and β3 integrins), survival (B-cell lymphoma-2) and angiogenic (vascular endothelial cell growth) factorsrelevant to endometriosis pathogenesis, whereas MIF add-back to MIF-KO mice significantly restored endometriosis-like lesions number and size. Interestingly, cross-experiments revealed that MIF presence in both endometrial and peritoneal host tissues is required for ectopic endometrial tissue growth and pointed to its involvement in endometrial-peritoneal interactions. This study provides compelling evidence for the role of MIF in endometriosis development and its possible interest for a targeted treatment of endometriosis.

Perceived Benefits and Barriers to Family Planning Education among Third Year Medical Students

Abstract Purpose: The purpose of the current study is to explore third- year medical students’ interest in learning about family planning, exposure to family planning (contraception and abortion) and perceived barriers and benefits to family planning education in their obstetrics and gynecology rotation. Method: We conducted four focus groups with 27 third-year medical students near the end of their rotation in obstetrics and gynecology. Results: Students desired education in family planning but perceived limited exposure during their rotation. Most students were aware of abortion but lacked factual information and abortion procedural skills. They felt systemic and faculty-related barriers contributed to limited exposure. Students discussed issues such as lack of time for coverage of contraception and abortion in the curricula and rotation itself. Perceived benefits of clinical instruction in family planning included increased knowledge of contraceptive management and abortion the ability to care for and relate to patients, opportunity for values clarification, and positive changes in attitudes towards family planning. Conclusions: Medical students who desire full education in family planning during their obstetrics and gynecology rotation may face barriers to obtaining that education. Given that many medical students will eventually care for reproductive-age women, greater promotion of opportunities for exposure to family planning within obstetrics and gynecology rotations is warranted.