Immunosuppressive drugs and fertility.

Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. This review aims to summarize the main gonadal side effects of immunosuppressants, to detail the effects on fertility and pregnancy of each class of drug, and to provide recommendations on the management of patients who are seen prior to starting or who are already receiving immunosuppressive treatment, allowing them in due course to bear children. The recommendations for use are established with a rather low level of proof, which needs to be taken into account in the patient management. Methotrexate, mycophenolate, and le- and teri-flunomide, cyclophosphamide, mitoxanthrone are contraindicated if pregnancy is desired due to their teratogenic effects, as well as gonadotoxic effects in the case of cyclophosphamide. Anti-TNF-alpha and mTOR-inhibitors are to be used cautiously if pregnancy is desired, since experience using these drugs is still relatively scarce. Azathioprine, glucocorticoids, mesalazine, anticalcineurins such as cyclosporine and tacrolimus, ß-interferon, glatiramer-acetate and chloroquine can be used during pregnancy, bearing in mind however that side effects may still occur. Experience is limited concerning natalizumab, fingolimod, dimethyl-fumarate and induction treatments. Conclusion: At the time of prescription, patients must be informed of the possible consequences of immunosuppressants on fertility and of the need for contraception. Pregnancy must be planned and the treatment modified if necessary in a pre-conception time period adapted to the half-life of the drug, imperatively in relation with the prescriber of the immunosuppressive drugs.

First intention IVF protocol for polycystic ovaries: does oral contraceptive pill pretreatment influence COH outcome?

BACKGROUND: Morphological aspect of polycystic ovaries (PCO) is a very common finding in an IVF center population: this includes PCOS patients identified in 18-25% of the couples presenting with infertility and so called "sonographic PCO only" the prevalence of which has been estimated as high as 33% in asymptomatic patients. Finding the optimal first intention IVF protocol for polycystic ovaries patients is still challenging in order to improve the controlled ovarian hyperstimulation (COH) outcome while avoiding ovarian hyperstimulation syndrome (OHSS). It has been suggested that women with PCO would benefit from a longer period of pituitary down-regulation. The purpose of this study was to compare an extended duration of OCP pretreatment with a classic GnRH agonist protocol. METHODS: A single center prospective non-randomized study was performed from January 2009 to December 2010 in the Lille University Hospital including 113 women diagnosed with PCO(S) according to the Rotterdam ultrasonographic criteria and undergoing their first IVF attempt. Comprehensive hormonal and ultra-sonographic assessments were collected during COH in these patients. LH and androgen suppression and dynamics of follicular growth were compared between the two protocols as well as the COH outcome in terms of oocyte/embryo number and quality, implantation and pregnancy rates. RESULTS: No significant difference was observed between the two groups concerning dynamics of follicular growth and hormonal values. Clinical and ongoing pregnancy rates were significantly lower in the OCP group despite same oocyte and embryo quality. Nevertheless, the cumulative pregnancy rate did not differ between the two groups. The incidence of OHSS was not statistically significant. CONCLUSIONS: Extended duration of OCP pretreatment, as a first intention IVF protocol for PCO patients, does not improve the pattern of follicular growth nor the oocyte and embryo quality.

Quintuplets after a transfer of two embryos following in vitro fertilization: a proved superfecundation.

OBJECTIVE: To report a genetically proved superfecundation of quintuplets after transfer of two embryos in IVF procedure and successful completion of the pregnancy after fetal reduction. DESIGN: Case report. SETTING: Academic reproductive medicine center. PATIENT(S): A 31-year-old woman, gravida 0, who underwent her second IVF cycle after three IUIs. INTERVENTION(S): After 5 years of primary infertility, three IUIs, and one IVF, the patient underwent her second IVF cycle with transfer of two fresh embryos on day 2. MAIN OUTCOME MEASURE(S): Development of five separate embryonic sacs. Fetal reduction to twins at 12 weeks of gestation. Successful pregnancy and delivery. Deoxyribonucleic acid analysis of the three reduced embryos, the live-born twins, and their parents. RESULT(S): Analysis of the seven DNA samples, because all were different, confirmed the superfecundation and disproved the zygote's division after transfer. Fetal growth restriction motivated preterm delivery by cesarean section. Both twins were in good health. CONCLUSION(S): Superfecundation can explain high-order multiple pregnancy and can be proved by DNA analysis. Couples must be informed because of the implications of fetal reduction for ethical issues, risks of pregnancy loss, fetal growth restriction, preterm delivery, and its consequences.

Serum inhibin B during controlled ovarian hyperstimulation: an additional criterion for deciding whether to proceed with egg retrieval.

OBJECTIVE: To determine the predictive value of the inhibin B increment during controlled ovarian hyperstimulation (COH) for differentiating between poor and normal responders and for deciding whether to continue or stop an IVF attempt. DESIGN: Prospective study. SETTING: Assisted reproduction unit at a university hospital. PATIENT(S): A total of 110 women undergoing IVF for idiopathic, tubal, and/or male infertility. INTERVENTION(S): Blood samples were collected on days 6 and 8 of COH. Inhibin B and E(2) assays were performed. MAIN OUTCOMES MEASURE(S): The degree of inhibin B increment was defined as Delta IB = day-8 value minus day-6 value. We analyzed the correlation of day-6 and day-8 inhibin B values and Delta IB with the number of oocytes retrieved. The predictive value of each parameter was determined by using the receiving operator characteristics curve analysis. RESULT(S): The Delta IB correlated best with the number of oocytes retrieved (r = 0.5) and with the number of embryos obtained (r = 0.26), independently of age. From the receiving operator characteristics curve analysis, a Delta IB cutoff value of 300 pg/mL discriminated poor (few than four oocytes retrieved, n = 16) from normal (more than four oocytes retrieved, n = 94) responders, with a sensitivity of 70% and a specificity of 94%. CONCLUSION(S): The degree of inhibin B increment during COH provides additional information for predicting ovarian response to COH. An increment >300 pg/mL is required to rule out the eventuality of a poor ovarian response.

Oligoanovulation with polycystic ovaries but not overt hyperandrogenism.

OBJECTIVES: By requiring a minimum of two of three items [hyperandrogenism (HA), oligoanovulation (OA), and polycystic ovaries (PCO) at ultrasound], the Rotterdam definition recognizes four PCO syndrome (PCOS) phenotypes: HA+OA+PCO (full-blown syndrome), HA+OA (former National Institutes of Health definition), HA+PCO (ovulatory PCOS), and OA+PCO. However, the latter phenotype is controversial, and it is not known to what extent it shares similarities with the others. DESIGN: The study was a comparative analysis of hormonal, metabolic, and ultrasound parameters obtained from patients and controls that were consecutively included in a database. PATIENTS AND METHODS: Sixty-six patients having OA+PCO without hirsutism or elevated serum androstenedione and testosterone levels were compared with 118 normally cycling nonhyperandrogenic age-matched women without PCO (controls). These patients (phenotype D) were also compared with patients with HA+OA+PCO (phenotype A, n = 246), HA+OA (phenotype B, n = 27), and HA+PCO (phenotype C, n = 67). RESULTS: Patients with phenotype D had higher mean values of waist circumference and higher mean levels of serum testosterone, androstenedione, and LH than controls. Conversely, they had lower mean serum levels of FSH and SHBG (P < 0.05 for each parameter). Variance analysis disclosed significant group effects between the different patients' phenotypes for all parameters, except age, BMI, and FSH. After multiple comparisons with post hoc analysis, phenotype D had milder endocrine and metabolic abnormalities than phenotype A, although it did not differ from phenotype C, except for androgen data, by definition. Phenotypes A and B were statistically similar, except for the ultrasound data, by definition. CONCLUSION: Oligoanovulatory patients with PCO but without HA have mild endocrine and metabolic features of PCOS.

Obesity and serum luteinizing hormone level have an independent and opposite effect on the serum inhibin B level in patients with polycystic ovary syndrome.

OBJECTIVE: To elucidate whether the negative effect of obesity on the serum inhibin B level that we previously reported is specific or not to polycystic ovary syndrome (PCOS) and whether it may explain the wide interindividual variability in serum inhibin B levels found in patients with PCOS. DESIGN: Prospective study. SETTING: Reproductive endocrinology unit of an academic medical center. PATIENT(S): One hundred thirty-four consecutive patients with PCOS (mean age, 27.4 +/- 4.7 years; mean body mass index [BMI], 28.3 +/- 7.6 kg/m(2); BMI > 25, 53%) and in 78 control women (mean age, 30.1 +/- 4.1 years; mean BMI, 24.3 +/- 4.9; BMI > 25, 34%). INTERVENTION: Blood sampling was performed in the early follicular phase in patients and in control women. MAIN OUTCOME MEASURE(S): BMI and waist circumference (WC), serum levels of inhibin B, LH, FSH, E(2), androstenedione, T, fasting insulin, and leptin were assessed in all subjects. RESULT(S): No difference was observed in the mean inhibin B level between patients and controls. The BMI and WC correlated negatively with inhibin B in patients with PCOS and in controls, with similar regression slopes, thus indicating that the influence of obesity on inhibin B is not specific to PCOS. In addition, we found a positive relationship between serum LH and inhibin B levels in PCOS. There was no significant interaction between the effects of BMI and LH on the serum inhibin B levels by analysis of variance (ANOVA). The mean serum inhibin B level in patients with PCOS with high serum LH (i.e., >the 90th percentile of LH in controls) was significantly higher than in those patients with normal LH or in controls. The highest mean inhibin B level was noted in nonobese patients with PCOS with high LH levels (121.0 +/- 51.2 pg/mL), while nonobese patients with PCOS with normal LH levels and obese patients with normal LH or high LH levels had similar mean levels (94.5 +/- 40.0, 84.9 +/- 34 and 91.6 +/- 51.7 pg/mL, respectively). CONCLUSION(S): We confirm that obesity has a negative effect on inhibin B serum level, which is not specific to PCOS. Obesity and excess LH, acting oppositely and independently on inhibin B production, may explain the discrepancies between the previous reports studying serum inhibin B level in patients with PCOS. Further work is required to elucidate the mechanisms underlying the antagonistic effects of LH and obesity on inhibin B production in patients with PCOS.