Joana Peñarrubia

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.

Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study

OBJECTIVE To produce age-related normograms for serum antimüllerian hormone (AMH) level in infertile women without polycystic ovaries (non-PCO). DESIGN Retrospective cohort analysis. SETTING Fifteen academic reproductive centers. PATIENT(S) A total of 3,871 infertile women. INTERVENTION(S) Blood sampling for AMH level. MAIN OUTCOME MEASURE(S) Serum AMH levels and correlation between age and different percentiles of AMH. RESULT(S) Age-related normograms for the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles of AMH were produced. We found that the curves of AMH by age for the 3rd to 50th percentiles fit the model and appearance of linear relation, whereas the curves of >75th percentiles fit cubic relation. There were significant differences in AMH and FSH levels and in antral follicle count (AFC) among women aged 24-33 years, 34-38 years, and ≥39 years. Multivariate stepwise linear regression analysis of FSH, age, AFC, and the type of AMH kit as predictors of AMH level shows that all variables are independently associated with AMH level, in the following order: AFC, FSH, type of AMH kit, and age. CONCLUSION(S) Age-related normograms in non-PCO infertile women for the 3rd to 97th percentiles were produced. These normograms could provide a reference guide for the clinician to consult women with infertility. However, future validation with longitudinal data is still needed.

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.

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.

Follicular Development and Hormonal Levels Following Highly Purified or Recombinant Follicle-Stimulating Hormone Administration in Ovulatory Women and WHO Group II Anovulatory Infertile Patients

Purpose:Our purpose was to compare ovarian performance and hormonal levels, after ovulation induction, in both normal ovulatory women undergoing intrauterine insemination (group 1) and World Health Organization (WHO) group II anovulatory infertile patients (group 2), using two different gonadotropin drugs.Methods:Patients (n = 20 per group) were treated during consecutive cycles, using the same stimulation protocol, with highly purified urinary FSH (HP-FSH) in the first treatment study cycle and recombinant FSH (rFSH) in the second one. Patients in group 1 were treated according to a late low-dose technique, and WHO group II anovulatory patients (group 2) received chronic low-dose FSH therapy.Results:Compared with HP-FSH, treatment with rFSH in group 2 required significantly less ampules of drug to induce follicular development but resulted in significantly higher plasma levels of estradiol and inhibin A on the day of human chorionic gonadotropin injection. No differences were found when both treatment modalities were compared in group 1.Conclusions:rFSH is more efficacious than urinary HP-FSH for ovulation induction in WHO group II anovulatory infertile patients as assessed by follicular development, hormonal levels, and the amount of FSH required.

Hormonal profiles in successful and unsuccessful implantation in IVF–ET after combined GnRH agonist/gonadotropin treatment for superovulation and hCG luteal support

The luteal phase of in vitro fertilization-embryo transfer (IVF-ET) cycles has come under great scrutiny as the cause for the discrepancy between fertilization rates (> 70%) and pregnancy rates (around 20%) in most IVF programs is sought. The effects of the various stimulation protocols on the subsequent hormonal events of the luteal phase are both important and controversial but information regarding cycles where ovarian stimulation has been carried out with gonadotropins under pituitary suppression is scanty. The effect of high levels of estrogen in the late follicular phase and around the time of implantation is a matter of concern. As combined gonadotropin-releasing hormone analog (GnRH-a) gonadotropin treatment for superovulation is associated with supraphysiological ovarian steroid levels, both in the follicular and luteal phase of IVF cycles, we compared preovulatory (estradiol), midluteal (estradiol, progesterone and prolactin) and late luteal (estradiol and progesterone) hormone levels in on-going pregnancies, abortions and non-conception cycles in 222 patients accomplishing their first IVF-ET attempt who received such ovarian stimulation therapy. For both successful and unsuccessful implantation cycles, estradiol on the day of human chorionic gonadotropin (hCG) administration correlated positively with progesterone and estradiol levels and negatively with the progesterone/estradiol ratio in the midluteal phase. Mean peak follicular estradiol, midluteal estradiol and progesterone levels, mean mid- and late luteal progesterone/estradiol ratio, and mean midluteal prolactin concentration, were similar in the three groups studied. The mean late luteal estradiol and progesterone in the on-going pregnancy group were significantly higher than in non-conception cycles (p < 0.005 and p < 0.001, respectively) as a reflection of trophoblastic hCG production. Forty-eight patients (21.6%) had hyperprolactinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Day-5 inhibin B serum concentrations and antral follicle count as predictors of ovarian response and live birth in assisted reproduction cycles stimulated with gonadotropin after pituitary suppression

OBJECTIVE To investigate the usefulness of day-5 inhibin B and antral follicle count (AFC) in predicting ovarian response and live birth in the first cycle of assisted reproduction. DESIGN Prospective cohort study. SETTING University hospital. PATIENT(S) Ninety-eight infertile women treated with in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) comprising 72 normal responders and 26 poor responders. INTERVENTION(S) Ovarian stimulation with gonadotropin-releasing hormone agonist-gonadotropin treatment. MAIN OUTCOME MEASURE(S) Basal ultrasonographic (AFC, total ovarian volume) and basal (follicle-stimulating hormone, estradiol, and inhibin B) and stimulation day-5 (estradiol, inhibin B) hormone parameters. RESULT(S) The AFC had the best predictive value among the basal variables for outcome of ovarian stimulation. Among the dynamic hormone measurements, day-5 inhibin serum measurement emerged as the best predictive variable of poor response in IVF-ICSI cycles, but it was not statistically significantly better than basal AFC. The association of day-5 inhibin B with live-birth rate was statistically significant and stronger than the effect of any other variable investigated. CONCLUSION(S) Basal AFC and day-5 inhibin B have similar predictive properties for ovarian response in assisted reproduction cycles stimulated with gonadotropin after pituitary suppression, but day-5 inhibin B is a superior predictor of live birth.

Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain

Abstract Background: Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene mutation have been postulated as a possible cause of recurrent miscarriage (RM). There is a wide variation in the prevalence of MTHFR polymorphisms and homocysteine (Hcy) plasma levels among populations around the world. The present study was undertaken to investigate the possible association between hyperhomocysteinemia and its causative genetic or acquired factors and RM in Catalonia, a Mediterranean region in Spain. Methods: Sixty consecutive patients with ≥3 unexplained RM and 30 healthy control women having at least one child but no previous miscarriage were included. Plasma Hcy levels, MTHFR gene mutation, red blood cell (RBC) folate and vitamin B12 serum levels were measured in all subjects. Results: No significant differences were observed neither in plasma Hcy levels, RBC folate and vitamin B12 serum levels nor in the prevalence of homozygous and heterozygous MTHFR gene mutation between the two groups studied. Conclusions: In the present study RM is not associated with hyperhomocysteinemia, and/or the MTHFR gene mutation.

A pharmacokinetic and endocrine comparison of recombinant follicle-stimulating hormone and human menopausal gonadotrophin in polycystic ovary syndrome

Elevated LH concentrations are frequently encountered in patients with polycystic ovary syndrome (PCOS) and increased LH (either endogenous or superimposed through the use of HMG) may have detrimental effects on reproductive function. In spite of this, FSH-only products and HMG have been used indiscriminately for ovulation induction - on the basis that the administration of HMG to patients with PCOS, who are not receiving GnRH agonists, does not result in significant increases in serum LH concentrations as judged by daily single blood samples. However, both endogenous and exogenous LH have a relatively short terminal half-life and studies have reported normal serum LH, but abnormal urinary LH and emphasized that early morning urinary measurements are more informative than those in serum because they reflect nocturnal LH secretion. Therefore, the present study was undertaken to perform a pharmacokinetic and endocrine comparison of recombinant human FSH and HMG in PCOS patients including LH measurements in the urine. Five PCOS patients receiving s.c. recombinant human FSH (rhFSH) and five PCOS patients receiving i.m. HMG for ovulation induction according to a chronic low-dose step-up regimen underwent blood and urine sampling at the following study points: Point 0 was the day of HCG injection; Points 1 to 5 corresponded to days HCG -1 to -2; -3 to -4; -5 to -6; -7 to -8; and -9 to -10; respectively. Serum hormone measurements included oestradiol, FSH, LH, progesterone, inhibin A, androstenedione, testosterone, and free testosterone index. FSH and LH were also measured daily in 8-h urine samples reflecting overnight renal urine secretion. Hormone concentrations calculated as the area under the curve showed that both FSH and LH concentrations in urine were significantly higher in HMG group than in group rhFSH. It is concluded that both LH and FSH concentrations significantly accumulate in the urine of PCOS patients receiving HMG for ovulation induction in a chronic low-dose protocol as compared with rhFSH treatment.

Ovulation side and ovarian cancer

Previous reports have suggested a predilection for right-sided ovulation and that epithelial ovarian cancer arises more commonly in the right ovary, thus establishing a possible causal relationship between ovulation and ovarian cancer. However, evaluation of ovulation patterns in consecutive cycles has produced contradictory results and there are no reports corroborating a higher incidence of right-sided ovarian cancers. We reviewed the records of 293 patients with epithelial ovarian cancer and found no significant difference between the frequency of tumors in the right and left ovaries. We also prospectively analyzed the side of ovulation in 41 unselected consecutive patients undergoing 156 in vitro fertilization cycles without ovarian stimulation. Follicular development was carefully monitored by daily ultrasonic scan and estradiol and LH plasma determinations. Eight-two ovulations (52%) were on the right (not statistically significant). Thus our results bring into question previous studies suggesting a link between the side of ovulation and epithelial ovarian cancer.