Jean-Noël Hugues

Age and ovarian reserve are distinct predictive factors of cycle outcome in low responders.

The respective roles of age and ovarian reserve in predicting IVF outcome do not seem to be equivalent, as a high pregnancy rate seems to be preserved in the youngest women, despite low ovarian recruitment. The purpose of this study was to analyse the outcome of IVF/intracytoplasmic sperm injection (ICSI) procedures according to both age and ovarian reserve of patients with a low ovarian response to stimulation. A total of 163 IVF/ICSI cycles selected by a low response were analysed. The IVF outcome differed according to the womens age, with a cut-off value at 36 years. While the number of transferred embryos was similar, the pregnancy rate (PR) was 14.6% in younger patients but 4.9% (P < 0.04) in older ones. An elevated FSH was constantly associated with a poor cycle outcome. In contrast, when the FSH was normal, PR was significantly higher (P < 0.05) in women aged <36 (23.8%) than in women aged > or =36 (6.5%). This study shows that assisted reproduction outcome in women with a low ovarian response is primarily dependent on the ovarian status. The negative influence of age is relevant in patients with normal FSH. Therefore, even if the ovarian response to stimulation is low, patients aged <36 years with a normal FSH should proceed to oocyte retrieval.

Polycystic ovary syndrome (PCOS)

1. The Rotterdam classification should be used to define PCOS in the event of: menstrual cycle anomalies; amenorrhoea, oligomenorrhoea or long cycles, clinical and/or biochemical hyperandrogenism and ultrasound appearance of polycystic ovaries. 2. The presence of two of these three criteria is sufficient once all other diagnoses have been ruled out. 3. Diagnosis of hirsutism should not be based on the Ferriman-Gallway score. 4. The ultrasound definition of PCOS contains precise criteria that must be included in the report: presence of at least 12 follicles in each ovary measuring 2-9 mm in diameter, and/or increase in ovary size>10 ml. 5. Screening for elevated plasma LH no longer necessary. Testing for GnRH serves no purpose. 6. Routine screening for metabolic abnormalities should be carried out systematically based on weight, height and BMI, waist circumference, blood pressure and laboratory parameters: plasma glucose, triglycerides, HDL cholesterol. 7. In the case of obesity (BMI>30 kg/m(2)), oral glucose tolerance testing (OGTT) is recommended where fasting serum glucose is normal. 8. Clomiphene citrate (CC) remains the first-line therapy for ovulation induction. In patients with BMI>30, it should be preceded by improvement of metabolic status through appropriate lifestyle modifications.

A comparative study of high fixed-dose and decremental-dose regimens of gonadotropins in a minidose gonadotropin-releasing hormone agonist flare protocol for poor responders.

Selecting the most effective protocol for an IVF procedure is still a major challenge for women known as poor responders to controlled ovarian hyperstimulation (COH). Indeed, using the standard long-term GnRHagonist (GnRH-a) protocol in these patients requires a large amount of gonadotropins to obtain development of only few follicles. Moreover, the pregnancy rate (PR) remains inappropriately low because of poor oocyte and embryo quality. It was suggested that poor responders may take advantage of the initial endogenous gonadotropin “flare” induced by GnRH-a (1). Moreover, lowering the dose of agonist in short-term GnRH-a protocols may prove effective to decrease the requirement for gonadotropins and to induce an initial gonadotropin release with subsequent LH suppression (2).

Is intracytoplasmic morphologically selected sperm injection effective in patients with infertility related to teratozoospermia or repeated implantation failure

OBJECTIVE To evaluate the potential benefit of intracytoplasmic morphologically selected sperm injection (IMSI) in patients selected for either severe teratozoospermia or repeated implantation failure after conventional intracytoplasmic sperm injection (ICSI). DESIGN Prospective nonrandomized observational study. SETTING University hospital assisted reproduction unit. PATIENT(S) Four hundred seventy-eight patients were enrolled to evaluate ICSI and IMSI results for two indications. The first group (T) was composed of patients with severe teratozoospermia (<10% normal spermatozoa in fresh ejaculated and selected semen, according to David classification) and no or one previous ICSI failure. In the second group (IF), patients with at least two previous failed ICSI attempts were enrolled in absence of severe male factor (>10% normal spermatozoa in fresh ejaculated semen and >20% in selected sperm). INTERVENTION(S) ICSI/IMSI, biologic, and clinical data collection. MAIN OUTCOME MEASURE(S) Live-birth rate (LBR). RESULT(S) In group T, LBR was significantly higher when IMSI procedure was used compared with ICSI (38% [50/132] vs. 20% [25/126]). However, LBR observed in group IF was not significantly different between IMSI and ICSI procedures (21% [19/90] vs. 22% [28/130]). CONCLUSION(S) IMSI procedure is a valuable option for patients with severe teratozoospermia at their first or second attempts, but it does not improve pregnancy rate in patients with repeated ICSI failures in the absence of severe male factor.

Impact of endogenous luteinizing hormone serum levels on progesterone elevation on the day of human chorionic gonadotropin administration

OBJECTIVE To assess the relationship between endogenous LH serum levels after GnRH analogue administration and serum P elevation on the day of hCG administration (P hCG). DESIGN Retrospective study. SETTING Reproductive medicine center in a university hospital. PATIENT(S) A total of 708 patients undergoing a GnRH agonist or antagonist protocol for IVF intracytoplasmic sperm injection. INTERVENTION(S) Controlled ovarian stimulation. MAIN OUTCOME MEASURE(S) Serum P values according to GnRH analogue; correlation between serum LH measurements and P hCG values. RESULT(S) Serum P hCG values were significantly lower following the GnRH antagonist than agonist protocol. A positive correlation between serum P hCG and LH area under the curve or day 6 LH values was found in the GnRH agonist group and between P hCG and LH hCG levels in both GnRH analogue regimens. With multivariate analysis, P hCG values were positively correlated with serum E(2) levels on hCG administration day and with the total FSH dose in both GnRH analogue-treated groups. Additionally, the correlation between serum P hCG and LH hCG values was positive in patients treated with the GnRH agonist protocol. CONCLUSION(S) The lower serum P levels on hCG administration day following the GnRH antagonist protocol are mainly explained by lower granulosa cell steroidogenic activity. The correlation with serum LH hCG values was positive in the GnRH agonist-treated group.

Impact of androgens on fertility : physiological, clinical and therapeutic aspects

Ovarian androgen synthesis and regulation are essential to ensure adequate steroidogenesis and folliculogenesis. In primates, there is evidence for a direct impact on the number of small antral follicles and on the process of chronic anovulation. Therefore, serum androgen should be more carefully assessed in infertile women. Accurate measurements of serum androgen are required to better identify patients with androgen excess or deficiency. Medical or surgical interventions are able to decrease ovarian androgen excess and to reduce the risk of hyperstimulation. Conversely, androgen supplementation should be considered in women at risk of low ovarian response to gonadotrophins, related to androgen deficiency. This review supports a specific and broad role of androgen in reproductive physiology.

Pretreatment with estrogen does not affect IVF-ICSI cycle outcome compared with no pretreatment in GnRH antagonist protocol: a prospective randomized trial

OBJECTIVE To assess effects of estrogen pretreatment in GnRH antagonist protocol. DESIGN Prospective, randomized multicenter study. SETTING Ten private or university-based centers. PATIENT(S) A total of 472 patients undergoing IVF/ICSI. INTERVENTION(S) Randomization by sealed envelopes to receive 17β-estradiol (4 mg/d) or no pretreatment before daily recombinant FSH administration started on the first day of estrogen discontinuation or on cycle day 2 in nonpretreated women. MAIN OUTCOME MEASURE(S) The primary outcome measure was the number of retrieved oocytes. Secondary efficacy variables included total FSH dose, cycle duration, and outcome. RESULT(S) The mean numbers of retrieved oocytes (10.9 ± 5.7 vs. 10.2 ± 5.6) and obtained embryos (5.5 ± 3.7 vs. 4.8 ± 3.7) were not significantly different between women allocated to estrogen pretreatment (n = 238) and no pretreatment (n = 234). Total FSH amount (1,557 ± 408 vs. 1,389 ± 347 IU) and stimulation duration (10.8 ± 1.4 vs. 10.0 ± 1.5 days) were slightly but significantly increased in pretreated patients. Positive pregnancy tests, ultrasound pregnancy rate, and delivery rate per cycle were similar (36%, 33%, and 26.6%, respectively, vs. 38.2%, 35.4%, and 30%). CONCLUSION(S) These data confirm that estrogen pretreatment is associated with requirement of higher FSH doses and longer duration of stimulation without any significant increase in the number of retrieved oocytes. However, estrogen does not affect cycle outcome and therefore might be used in clinical practice for programming IVF retrievals during working days. CLINICAL TRIALS REGISTRATION NUMBER NCT01489852.

Assessment of theca cell function prior to controlled ovarian stimulation: the predictive value of serum basal/stimulated steroid levels

BACKGROUND Serum androgen levels correlate with ovarian sensitivity to follicle-stimulating hormone (FSH) but in practice, standard baseline serum testosterone (T) levels prior to in-vitro fertilization (IVF) may not be the most appropriate marker for determination. METHODS Infertile women enrolled in an IVF programme were included in this study. Serum T and Delta4-androstenedione (A), and the androgen precursor 17-hydroxyprogesterone (17-OHP) were measured before and 24 h after a gonadotrophin-releasing hormone agonist stimulation test (GAST). An early follicular phase antral follicle count (AFC) was also performed. Patients were subsequently enrolled in a long gonadotrophin-releasing hormone agonist protocol with a standard FSH dose (150 IU) for 7 days to assess the association between androgen levels and ovarian responsiveness to FSH. RESULTS The GAST elicited a significant increase in serum androgen levels that was well correlated with AFC. 17-OHP showed the greatest response to GAST and strongest correlation with AFC. The 17-OHP response to GAST differentiated patients with high ovarian reserve (OR) from those with low or normal OR as assessed by AFC, whereas only the estradiol response could differentiate those with low AFC. GAST-stimulated serum levels of 17-OHP were also correlated with ovarian response to FSH. Using receiver operating characteristic curve analysis, stimulated 17-OHP levels were predictive of the ovarian response to controlled ovarian stimulation, with similar power to that observed with AFC but lower power than with anti-Müllerian hormone. CONCLUSIONS Serum androgen levels following GAST are correlated with AFC and ovarian response to FSH. Serum T is a less sensitive marker of theca cell function than 17-OHP.

Chromosome 21 detection in human oocyte fluorescence in situ hybridization: possible effect of maternal age.

Purpose:The purpose of this study was to evaluate, among 100 uncleaved oocytes, the incidence of numerical and structural chromosome 21 and X abnormalities and to analyze the influence of various factors, such as in vitro (IVF) indications, follicle stimulation protocols, and womens age.Methods:We investigated 150 uncleaved oocytes from 128 patients after an IVF attempt. After cytogenetic analysis (Giemsa) 100 oocytes (66%) were selected for fluorescence in situ hybridization (FISH). Fluorescent probes for human chromosomes X and 21 were used simultaneously according to standard procedures for their hybridization and detection.Results and Conclusions:We analyzed by the FISH protocol 100 metaphase II oocytes with 22 to 25 chromosomes. Our results demonstrate a high rate of disomy for chromosome 21 in human oocytes. Among them, eight were disomic (8%) and three were nullosomic (3%) for chromosome 21. Only one disomy of chromosome X was noted. The various indications of IVF and the different folliculogenesis stimulating protocols did not seem to influence the results but suggested a correlation between the maternal age and the aneuploidy rate of chromosome 21.

Biological predictive criteria for clinical pregnancy after elective single embryo transfer

In this prospective observational study, the onset of a clinical pregnancy after elective single embryo transfer (eSET) was significantly associated with: 1) the womans age as well as the number of good- and top-quality embryos; and 2) the day of the embryo transfer (day 3>day 2). Good-quality embryos had the same ability to implant, regardless of the zygotic score, the day 1 early cleavage rate, the fragmentation degree, and the top-quality assessment, specifying the eligibility criteria for eSET.