Francisco Fábregues

Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial

BACKGROUND Studies in macaques have indicated that androgens have some synergistic effects with FSH on folliculogenesis. This study investigated the usefulness of pretreatment with transdermal testosterone in low-responder IVF patients. METHODS Randomized clinical trial including 62 infertile women who had a background of the first IVF treatment cycle cancelled because of poor follicular response. Patients were randomized in two treatment groups in their second IVF attempt. In patients in Group 1 (n = 31), transdermal application of testosterone preceding standard gonadotrophin ovarian stimulation under pituitary suppression was used. In Group 2 (n = 31 patients), ovarian stimulation was carried out with high-dose gonadotrophin in association with a minidose GnRH agonist protocol. The primary end-point was the incidence of low-responder patients. The main secondary outcome was the incidence of patients reaching ovum retrieval. RESULTS The percentage of cycles with low response was significantly lower in Group 1 than in Group 2 (32.2 versus 71% 95% confidence interval for the difference, 15.7-61.6; P < 0.05). The number of patients with ovum retrieval tended to be higher in Group 1 than in Group 2 (80.6 versus 58.1% P = 0.09), the difference reaching statistical significance (81.2 versus 41.1%; P < 0.05) when only patients having normal basal FSH levels (16 and 17 patients in Groups 1 and 2, respectively) were considered. CONCLUSIONS Pretreatment with transdermal testosterone may improve the ovarian sensitivity to FSH and follicular response to gonadotrophin treatment in previous low-responder IVF patients. This approach leads to an increased follicular response compared with a high-dose gonadotrophin and minidose GnRH agonist protocol.

Risk Factors Associated with Fetal Losses in Treated Antiphospholipid Syndrome Pregnancies: A Multivariate Analysis

PROBLEM: Pregnancies in women with antiphospholipid syndrome (APS) are associated with obstetric complications despite treatment. The present study analyzes risk factors and evaluates fetal outcome in a large sample of treated APS pregnancies.
 METHOD OF STUDY: Seventy‐seven pregnancies in 56 women were included. Twelve selected variables potentially related to the outcome of treated pregnancies were analyzed in a multivariate logistic regression model.
 RESULTS: Treated women delivered 65 live infants at 24–41 weeks gestation (mean 36.7±0.5) but two neonatal deaths occurred. There were seven first‐trimester miscarriages (9%) and five intrauterine fetal demises (6.5%). Thus, the probability of having a live baby under treatment was 82% (95% CI 71.3–89.6%), a figure significantly greater (P<0.001) than that observed before therapy (25.7%; 95% CI 18.7–33.7%). Variables related with fetal outcome in the multivariate model were: preconceptional use of aspirin and abnormal umbilical artery Doppler velocimetry at 23–26 weeks gestation.
 CONCLUSIONS: The present report shows that in treated APS pregnancies: i) aspirin treatment started preconceptionally is an independent and significant prognostic factor associated with favorable fetal outcome; and ii) abnormal velocity waveforms in the umbilical artery predict adverse outcome of pregnancy.

Inhibin, follicle-stimulating hormone, and age as predictors of ovarian response in in vitro fertilization cycles stimulated with gonadotropin-releasing hormone agonist-gonadotropin treatment.

OBJECTIVE Our purpose was to determine the relative power of basal inhibin and follicle-stimulating hormone (defined before treatment) and the womans age both as single and combined predictors of ovarian response in an in vitro fertilization program where pituitary desensitization was routinely used. STUDY DESIGN The study was a retrospective analytic investigation of 120 women undergoing the first cycle of in vitro fertilization. Forty consecutive cycles canceled because of poor follicular response were initially selected. As a control group, the nearest completed in vitro fertilization cycles before and after each canceled cycle (i.e., the closest cycles in temporal relationship to the index cycle) were used. RESULTS The mean age and basal follicle-stimulating hormone level were significantly higher in the canceled than in the control group, whereas the basal inhibin level was significantly higher in the latter. Follicle-stimulating hormone and inhibin alone, with an accuracy (predictive value of ovarian response) of 70%, were better predictors of cancellation than age was. Any two or all three of these variables studied did not improve the predictive value of follicle-stimulating hormone or inhibin alone. CONCLUSION Age is a poorer predictor than pretreatment basal follicle-stimulating hormone and inhibin levels for ovarian response in in vitro fertilization cycles stimulated with gonadotropin-releasing hormone agonist-gonadotropin treatment. Basal follicle-stimulating hormone and inhibin have similar predictive properties and could therefore be used interchangeably.

Ovarian responses to recombinant FSH or HMG in normogonadotrophic women following pituitary desensitization by a depot GnRH agonist for assisted reproduction

At present, there is considerable debate about the utility of supplemental LH in assisted reproduction treatment. In order to explore this, the present authors used a depot gonadotrophin-releasing hormone agonist (GnRHa) protocol combined with recombinant human FSH (rhFSH) or human menopausal gonadotrophin (HMG) in patients undergoing intracytoplasmic sperm injection (ICSI). The response to either rhFSH (75 IU FSH/ampoule; group rhFSH, 25 patients) or HMG (75 IU FSH and 75 IU LH/ampoule; group HMG, 25 patients) was compared in normo-ovulatory women suppressed with a depot triptorelin injection and candidates for ICSI. A fixed regimen of 150 IU rhFSH or HMG was administered in the first 14 days of treatment. Treatment was monitored with transvaginal pelvic ultrasonographic scans and serum measurement of FSH, LH, oestradiol, androstenedione, testosterone, progesterone, inhibin A, inhibin B and human chorionic gonadotrophin (HCG) at 2-day intervals. Although oestradiol serum concentrations on the day of HCG injection were similar, both the duration of treatment and the per cycle gonadotrophin dose were lower in group HMG. In the initial 16 days of gonadotrophin treatment, the area under the curve (AUC) of LH, oestradiol, androstenedione and inhibin B were higher in group HMG; no differences were seen for the remaining hormones measured, including the inhibin B:inhibin A ratio. The dynamics of ovarian follicle development during gonadotrophin treatment were similar in both study groups, but there were more leading follicles (>17 mm in diameter) on the day of HCG injection in the rhFSH group. The number of oocytes, mature oocytes and good quality zygotes and embryos obtained were significantly increased in the rhFSH group. It is concluded that in IVF patients undergoing pituitary desensitization with a depot agonist preparation, supplemental LH may be required in terms of treatment duration and gonadotrophin consumption. However, both oocyte, embryo yield and quality were significantly higher with the use of rhFSH.

Combined laparoscopic surgery and pentoxifylline therapy for treatment of endometriosis-associated infertility: a preliminary trial

BACKGROUND Surgical treatment has modest efficacy for the treatment of infertility associated with early-stage endometriosis. Immunomodulation with pentoxifylline is considered as a new strategy potentially useful in treating endometriosis. Thus, this study investigated the usefulness of combined laparoscopic surgery and pentoxifylline therapy in the treatment of infertility associated with minimal to mild endometriosis. METHODS A prospective, randomized, controlled blind trial was conducted. Patients entered the study immediately after laparoscopic surgery and were randomly assigned to the treatment with either oral pentoxifylline (800 mg/day) (pentoxifylline group, n = 51) or an oral placebo (placebo group, n = 53). Patients were then observed for pregnancy for 6 months. RESULTS Among 98 patients finally considered in the evaluation of the results, the 6 month overall pregnancy rates were 28 and 14% in the pentoxifylline and placebo groups, respectively. Thus, an absolute difference of 14% (95% CI -2 to 30) (Chi-squared test, P = 0.1) in the cumulative probability of pregnancy in 6 months after laparoscopic surgery in patients receiving pentoxifylline versus placebo post-operatively was observed. CONCLUSION Our findings provide preliminary clinical evidence to suggest the new experimental treatment approaches, toward endometriosis, that are based on immunomodulation deserve further attention. Well-designed multicenter trials are warranted to confirm or refute our results.

Is luteinizing hormone needed for optimal ovulation induction

The role of luteinizing hormone in the natural menstrual cycle is not disputed. There are, however, a variety of opinions regarding the potential role of exogenous luteinizing hormone in ovulation induction and whether it is actually needed. The recent introduction into clinical practice of recombinant gonadotropins has been paralleled by recent advances in the knowledge of the endocrine and paracrine mechanisms that regulate human folliculogenesis. On this basis, this review analyses whether or not all patients need luteinizing hormone for follicular growth stimulation. In addition, new opportunities for improved treatment are considered as a result of the availability of recombinant human luteinizing hormone both in patients with ovulatory disorders and those undergoing multiple follicular development for assisted reproduction.

The effect of exogenous luteinizing hormone (LH) on oocyte viability: evidence from a comparative study using recombinant human follicle-stimulating hormone (FSH) alone or in combination with recombinant LH for ovarian stimulation in pituitary-suppressed women undergoing assisted reproduction.

Purpose: The purpose of this prospective, randomized study was to compare ovarian response and oocyte and embryo yields in women undergoing ovulation induction for IVF/ICSI using recombinant human FSH (rhFSH) alone or in combination with recombinant human LH (rhLH).Methods: Patients were randomized to receive rhFSH alone (group F; n = 13) or rhFSH + rhLH (group L; n = 15). rhFSH was administered according to a step-down protocol; patients assigned to group L received rhLH at a fixed dose of 75 IU (1 ampoule) throughout the treatment period.Results: The total dose of rhFSH, number of growing follicles, and serum concentrations of estradiol (E2) on the day of hCG administration were similar in both treatment groups. However, the percentage of metaphase II oocytes and fertilization rate were significantly higher in group F than in group L. The lower fertilization rates associated with rhLH were also seen in a subgroup of patients from group L who had undergone a previous ART cycle stimulated with FSH only and thus acted as their own controls. However, when in vitro fertilization (IVF) and intracytoplasmic sperm injection cycles were considered separately, differences in fertilization rates were statistically significant only for oocytes treated by conventional IVF.Conclusions: This study shows that the addition of recombinant LH to recombinant FSH in pituitary-suppressed women undergoing ART does not improve the ovarian response and even may have a negative impact on oocyte maturation and fertilization.

Ovarian reserve test with human menopausal gonadotropin as a predictor of in vitro fertilization outcome.

AbstractPurpose: Our purpose was to determine prospectively, usingreceiver-operating characteristic (ROC) analysis, whetherthe ovarian reserve test with hMG could improve thepredictive value of a womans age and basal levels of folliclestimulating hormone (FSH), E2, and inhibin or anycombination of them regarding ovarian response and pregnancy ratein IVF treatment following pituitary desensitization. Methods: The hMG test was performed within 3 months ofIVF treatment in 80 women undergoing the first cycle ofIVF and consisted of 2 ampoules of hMG daily for 5 daysstarting on cycle days 2 to 3. Hormone and ultrasoundevaluation was performed on cycle days 2 to 3 and 7 to 8. Results: The mean age and basal FSH levels weresignificantly higher in the canceled (n = 28) than in the control(n = 52) group, whereas the basal inhibin level wassignificantly higher in the latter. Regarding ovarian response, thecombination FSH plus inhibin had the better diagnosticaccuracy (predictive value of 70%) among basal variables.When post-hMG parameters (alone or in combination) wereanalyzed, E2 alone, with a 77% diagnostic accuracy,emerged as the best predictive variable of cancellation inIVF cycles. When ROC analysis was used, the area underthe ROC curve for E2 post-hMG (diagnostic accuracy of84.5%) was significantly higher than that for the estimatesbased on the combination of basal FSH and inhibin(diagnostic accuracy of 71.3%). However, womans age was theonly variable independently associated with pregnancy rate. Conclusions: The predictive power of the hMG test ofovarian reserve is better than that of age and basal hormonevalues (FSH and inhibin) and it is based mainly on the E2response to hMG treatment. However, given that age is theonly predictor of pregnancy and considering the cost anddiscomfort of the hMG test, the usefulness, if any, of the testin predicting IVF performance in the daily clinical settingremains to be established.

Recombinant human follicle-stimulating hormone for ovulation induction in polycystic ovary syndrome: a prospective, randomized trial of two starting doses in a chronic low-dose step-up protocol.

AbstractPurpose: The aim was to compare the follicular response to 37.5 and 50 IU of recombinant follicle-stimulating hormone (FSH) as starting doses for ovulation induction in patients with polycystic ovary syndrome (PCOS). Methods: Prospective, randomized, crossover study including 15 women with clomiphene citrate-resistant chronic anovulatory infertility. Patients were treated with subcutaneous recombinant FSH at starting doses of 37.5 IU and 50 IU, respectively, according to a low-dose step-up protocol. Each woman received both treatments, in a randomized order, with an interval of ≥1 month between treatments. Results: All treatment cycles were ovulatory after an appropriate follicular response and hormone levels were similar with both treatments, although the total quantity of FSH required and the mean daily dose required to induce identical follicular development were significantly lower with a starting dose of 37.5 IU FSH. The mean duration of treatment to achieve ovulation was approximately 13 days with both treatments but treatment periods ≥20 days were required in some patients. Conclusions: In women with PCOS, a starting dose of 37.5 IU recombinant FSH may be adequate to induce follicular growth. However, the use of low starting doses may result in some cases in increased treatment periods and need for monitoring.

Outcome from consecutive assisted reproduction cycles in patients treated with recombinant follitropin alfa filled-by-bioassay and those treated with recombinant follitropin alfa filled-by-mass

Recent advances in manufacturing procedures for r-hFSH have resulted in a preparation (follitropin alfa) that is highly consistent in both isoform profile and glycan species distribution. As a result, follitropin alfa can be reliably quantified and vials can be filled by mass. This study compared the clinical results in a well-established assisted reproduction programme during the crossover from standard follitropin alfa filled-by-bioassay (FSH-bio) to follitropin alfa filled-by-mass (FSH-mass). The study included the last 125 patients treated with FSH-bio and the first 125 patients receiving FSH-mass for ovarian stimulation in their first assisted reproduction treatment cycle. Patient baseline characteristics were almost identical in the two groups. The duration of ovarian stimulation was significantly shorter in the FSH-mass group. The number of patients receiving the HCG injection and undergoing oocyte retrieval, follicular development and the serum concentration of oestradiol on the day of HCG injection were similar for the two treatment groups. The oocyte yield and the fertilization rates were similar in both groups of patients. However, embryo quality and implantation rates were significantly higher in the FSH-mass group. Accordingly, in spite of the mean number of embryos transferred being significantly lower in the FSH-mass group, there was a trend for higher clinical pregnancy rates in this group of patients. It is concluded that the new formulation of FSH-mass is more effective than the standard FSH-bio in terms of embryo quality, implantation rates, and number of days of stimulation.