Philippe Bouchard

Prediction of the individual follicle-stimulating hormone threshold for gonadotropin induction of ovulation in normogonadotropic anovulatory infertility: an approach to increase safety and efficiency

OBJECTIVE To predict the FSH response (threshold) dose in normogonadotropic, anovulatory infertile women undergoing gonadotropin induction of ovulation. DESIGN Prospective longitudinal clinical study. SETTING Specialist academic fertility unit. PATIENT(S) Normogonadotropic, oligoamenorrheic, infertile women who were resistant to clomiphene citrate or in whom clomiphene citrate therapy had failed. INTERVENTION(S) Daily exogenous FSH administration in a low-dose, step-up regimen. MAIN OUTCOME MEASURE(S) The FSH dose on the day of ovarian response (follicle growth > 10 mm in diameter). RESULT(S) Multivariate analysis was used to devise the following equation to predict the individual FSH response dose (75 to >187 IU/d) before initiation of therapy: [4 body mass index (in kg/m(2))] + [32 clomiphene citrate resistance (yes = 1 or no = 0)] + [7 initial free insulin-like growth factor-I (in ng/mL)] + [6 initial serum FSH level (in IU/L)] - 51. The SE of the predicted dose is 35 IU. CONCLUSION(S) The individual FSH response dose for gonadotropin induction of ovulation in anovulatory infertile women can be predicted on the basis of initial screening characteristics. The prediction model developed in this study may increase the safety and efficiency of low-dose gonadotropin protocols (step-up and step-down) by correctly determining the appropriate starting dose for a given patient.

Bone metastases of differentiated thyroid cancer: impact of early 131I-based detection on outcome

Bone is the second most frequent target of distant metastases in patients with differentiated thyroid cancer, and such forms carry a very poor prognosis. The impact of (131)I therapy in this setting is controversial. We describe the diagnostic circumstances and outcome of patients with bone metastases recently managed in two institutions. Among 921 consecutive thyroid cancer patients who had total thyroidectomy and (131)I ablation between January 2000 and December 2004 and who were subsequently monitored, bone metastases had been diagnosed in 16 patients. In three cases, the bone metastases were non-functioning (negative (131)I uptake) . These patients were treated with surgery and radiotherapy but progressed rapidly. The other 13 patients had functioning (positive (131)I uptake) bone metastases. In five of them, thyroid cancer was revealed by signs of distant involvement (bone pain, n = 4; dyspnea, n = 1). The bone metastases progressed in these five patients, despite local therapy and multiple courses of (131)I. The bone metastases in the remaining eight patients were discovered on the post-surgery (131)I therapy scan. Complementary radiological studies were negative except in one patient in whom one of the metastases (a 5 mm lesion of the right humerus) was visible on magnetic resonance imaging (MRI). Six of these patients showed a good response to (131)I therapy, with (131)I uptake and Tg levels becoming undetectable or showing a sharp fall. One patient refused (131)I therapy; bone metastases became visible on MRI within 1 year and the Tg level rose tenfold. The disease progressed in one patient despite (131)I therapy. Post-surgical (131)I ablation can contribute to early detection of bone metastases at a time when the Tg level may be only moderately elevated, when other radiological studies are negative, and when the disease is potentially curable by (131)I therapy.

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.

Fibroid growth and medical options for treatment

Although fibroids are common benign tumors, their impact on womens quality of life can be considerable. The most frequent symptoms are uterine bleeding, resulting in anemia, and pelvic pain. Fibroids can be of genetic or hormonal origin or arise from intrauterine events. Current options for medical treatment include control of estradiol and progesterone production or action and are discussed in this review. Although curative treatment of fibroids relies on surgical strategies, the current trend is for uterine-sparing treatment to preserve fertility and avoid unnecessary surgery. Currently approved medical treatments include intrauterine progestin delivery to reduce uterine bleeding, GnRH analogues, and, more recently, selective progesterone receptor modulators to control uterine bleeding and reduce fibroid volume.

Management of subclinical hypothyroidism in pregnancy - Are we too simplistic?

Guideline advice of many societies on the management of subclinical hypothyroidism in pregnancy suggests treatment when TSH serum levels exceed 2.5 mU/l. Justification of this procedure is based on limited experience, mainly from studies carried out in patients with positive thyroid-specific antibodies and higher TSH levels that classically define the condition in the non-pregnant state. Taking into account a lack of clear understanding of the regulation of thyroid hormone transport through the utero-placental unit and in the absence of foetal markers to monitor the adequacy of thyroxine treatment, this review attempts to discuss currently available data and suggests a more cautious approach.

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.

The future of women's contraception: stakes and modalities

The two main contraceptive methods are the combined pill and the intrauterine device. In several countries, sterilization is a commonly used alternative. The current goals of contraception remain to achieve effective, accessible, reversible, and well‐tolerated birth control for everyone. Despite progress, these goals have not been reached. To achieve these goals, it is mandatory to create new hormonal combinations and to discover new contraceptive targets. Recent innovations associate the development of new progestogens, selective progesterone receptor modulators, and the creation of new contraceptive combinations. Other innovations involve the use of natural estrogens but also optimizing existing treatment regimens and doses, as well as the development of new methods of emergency contraception. Finally, a major step will be to invent an efficient contraceptive that carries the lowest possible risk associated with methods protecting against sexually transmitted diseases. In the future, in relation to progress in the fields of genomics, proteomics, and immunology, new methods of contraception will be developed. These methods will be more targeted and will eventually be nonhormonal and independent of sexual activity.

Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma

STUDY QUESTION What are the consequences of radioactive iodine (RAI) therapy for testicular function? SUMMARY ANSWER A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities. WHAT IS KNOWN ALREADY Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function. STUDY DESIGN, SIZE, DURATION A longitudinal prospective multi-center study on testicular function performed in DTC patients before a single 131I ablative activity of 3.7 GBq (V0) and at 3 months (V3) and 13 months (V13) after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS Forty male patients, aged 18-55 years, with DTC participated. Hormonal analysis included FSH, LH, testosterone and inhibin B serum levels at V0, V3 and V13. Furthermore, sperm parameters, DNA fragmentation and sperm chromosomal abnormalities were evaluated at each time points. The differences in all parameters, between V0-V3, V0-V13 and V3-V13, were analyzed, using a Wilcoxon test. MAIN RESULTS AND THE ROLE OF CHANCE Prior to RAI administration, all patients had normal gonadal function. At V3, a statistically significant increase in FSH levels and a decrease in inhibin B levels were observed and sperm concentration, as well as the percentage of morphologically normal spermatozoa, were significantly decreased (P < 0.0001). These modifications were transient as both sperm concentration and normal morphology rate returned to baseline values at V13. However, at this later time point, FSH and inhibin B levels were still impacted by RAI administration but remained in the normal range. Although no DNA fragmentation was observed at V3 nor V13, our study revealed a statistically significant increase in the number of sperm chromosomal abnormalities both at V3 (P < 0.001) and V13 (P = 0.01). LIMITATIONS, REASONS FOR CAUTION Among the 40 patients included in the study, only 24 had all the parameters available at all visits. WIDER IMPLICATIONS OF THE FINDINGS Prospective studies with longer term follow up would be helpful to determine whether the chromosome abnormalities persist. These studies would be required before sperm banking should be suggested for all patients. However, sperm preservation for DTC patients who require cumulative radioiodine activities higher than 3.7 GBq should be proposed. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Programme Hospitalier de Recherche Clinique, AP-HP (No. P040419). The authors report no conflict of interest in this work. TRIAL REGISTRATION NUMBER NCT01150318.

Moduladores selectivos del receptor de la progesterona

Los moduladores selectivos del receptor de la progesterona (SPRM) ejercen una accion progestagena o antiprogestagena en funcion del tejido diana. Se usan en obstetricia para la interrupcion de embarazo y en ginecologia para la anticoncepcion de urgencia y el tratamiento medico de los miomas. Las perspectivas de desarrollo se centran en la anticoncepcion de larga duracion, el tratamiento de la endometriosis y la prevencion del cancer de mama. Los efectos endometriales especificos estan en evaluacion.

CHAPTER 26 – The Role of Gn-RH Antagonists in Supporting Ovarian Hyperstimulation Protocols

Gn-RH antagonists result from multiple amino acid substitutions from the native Gn-RH structure. Gn-RH antagonists are inactive but able to bind to Gn-RH receptors with high affinity. They behave as competitive inhibitors of Gn-RH by binding to its receptors and allow immediate suppression of gonadotropins and sex steroids. Their clinical applications are still being studied, particularly in assisted reproductive technologies (ART) where they are more user-friendly and allow a dramatic improvement in the risk of ovarian hyperstimulation syndrome (OHSS). The main concern of their use is a possible reduction of ongoing pregnancy rates in antagonist treated in vitro fertilization (IVF) cycles when compared with Gn-RH agonist treated cycles [ 1 ]. The mechanisms of this difference are still speculative and eventually related to abnormal endometrial maturation. In addition, the necessary learning curve inherent to the use of any new treatment may cause interference. Additional studies are necessary for treatment protocol optimization.