Biomechanical characteristics of the ovarian cortex in POI patients and functional outcomes after drug-free IVA.

PURPOSE: There is increasing evidence that the ovarian extracellular matrix (ECM) plays a critical role in follicle development. The rigidity of the cortical ECM limits expansion of the follicle and consequently oocyte maturation, maintaining the follicle in its quiescent state. Quiescent primordial, primary, and secondary follicles still exist in primary ovarian insufficiency (POI) patients, and techniques as in vitro activation (IVA) and drug-free IVA have recently been developed aiming to activate these follicles based on the Hippo signaling disruption that is essential in mechanotransduction. In this context, we analyze the effect of drug-free IVA in POI patients, comparing the relationship between possible resumption ovarian function and biomechanical properties of ovarian tissue. METHODS: Nineteen POI patients according to ESHRE criteria who underwent drug-free IVA by laparoscopy between January 2018 and December 2019 and were followed up for a year after the intervention. A sample of ovarian cortex taken during the intervention was analyzed by atomic force microscopy (AFM) in order to quantitatively measure tissue stiffness (Young's elastic modulus, E) at the micrometer scale. Functional outcomes after drug-free were analyzed. RESULTS: Resumption of ovarian function was observed in 10 patients (52.6%) and two of them became pregnant with live births. There were no differences in clinical characteristics (age and duration of amenorrhea) and basal hormone parameters (FSH and AMH) depending on whether or not there was activation after surgery. However, ovarian cortex stiffness was significantly greater in patients with ovarian activity after drug-free IVA: median E = 5519 Pa (2260-11,296) vs 1501 (999-3474); p-value < 0.001. CONCLUSIONS: Biomechanical properties of ovarian cortex in POI patients have a great variability, and higher ovarian tissue stiffness entails a more favorable status when drug-free IVA is applied in their treatment. This status is probably related to an ovary with more residual follicles, which would explain a greater possibility of ovarian follicular reactivations after treatment.

ALWAYS ICSI? A SWOT analysis.

PURPOSE: Intracytroplasmatic sperm injection (ICSI) is a common procedure used to improve reproductive results, even among couples without male factor infertility. However, the evidence available is still uncertain on the possible advantages and deficiencies that this procedure may have in patients with no formal indication for ICSI. METHODS: A SWOT (strengths, weaknesses, opportunities, threats) analysis examines the possible advantages and deficiencies of performing ICSI in these patients with no formal indication. RESULTS: The evidence suggests that ICSI is not justified for non-male factor infertile couples requiring in vitro conception. One of the major strengths associated to the procedure is the virtual elimination of cases further complicated by total fertilization failure and a combination between IVF and ICSI on sibling oocytes has been advised in the literature. Greater technical difficulties, higher costs and performing an unnecessary invasive technique in some cases represent some of the weaknesses of the procedure, and questions regarding safety issues should not be ruled out. CONCLUSION: Despite the widespread use of ICSI in patients without a formal diagnosis of male factor infertility, evidence demonstrating its effectiveness in this population is still lacking. Additional large and well-designed randomized controlled trials are needed to clarify definitive indications for ICSI in non-male factor infertility.

Hysteroscopic septum resection and reproductive medicine: A SWOT analysis.

Hysteroscopic septum resection in women with unfavourable reproductive and clinical outcomes has become common practice worldwide to improve reproductive results. No clear evidence on the possible advantages and drawbacks of this procedure has been published. In this opinion paper, based on a SWOT (strengths, weaknesses, opportunities, threats) analysis, the different aspects of this strategy are evaluated. Currently, no level 1 published evidence supports uterine resection in women with septate uterus. Clinical evidence from the studies analysed matches the more recent guidelines and suggests an improvement in reproductive outcomes after hysteroscopic resection of the septum, particularly in infertile women and women who have experienced recurrent miscarriages. In a patient with no history of infertility or prior pregnancy loss, it may be reasonable to consider septum incision after counselling about the potential risks and benefits of the procedure. Published clinical data in favour of the intervention, however, are based on studies with important methodological limitations. In this situation, the clinician and patient should reach an agreement together, based on the pros and cons of this intervention. Well-designed randomized controlled trials are required to confirm the clinical benefits and cost-effectiveness of this procedure.

Pregnancy after drug-free in vitro activation of follicles and fresh tissue autotransplantation in primary ovarian insufficiency patient: a case report and literature review.

BACKGROUND: The aim of this report was to describe a case of pregnancy after drug-free in vitro activation (IVA) of follicles and fresh tissue autotransplantation in primary ovarian insufficiency (POI) patient and to review the pertinent literature. METHODS: We present a case in wich a 32 - years old patient with POI became pregnant after IVA without tissue culture and with ovarian tissue transplantation. We also reviewed the literature using Pubmed database. CASE PRESENTATION: Pretreatment with estradiol/progesterone stopped the day before surgery. The removal of the ovarian cortex and autotransplantation were performed by laparoscopy in the same surgical act. Ovarian fragments were transplanted in contralateral ovary and peritoneal pocket near to the ovary. Immediately after surgery GnRH agonist together HMG injections started, leading the growth of 3 preovulatory follicles and the retrieval of two mature eggs. After IVF two embryos were transferred and singleton pregnancy was established and currently she is 25 weeks pregnant. RESULTS: A total of 51 patients with POI in whom an in vitro activation of ovarian tissue was performed, were collected from the revieew of the literature. In 29.4% of them, follicular development was obtained and in 4 of them a pregnancy. In all of them, a combined technique (fragmentation and activation) was performed in two laparoscopies. No case has been reported successfully after drug-free in vitro activation. CONCLUSIONS: This is the first report about a case with pregnancy after drug-free in vitro activation of follicles and fresh tissue autotransplantation in POI patient.

Ovarian response is associated with anogenital distance in patients undergoing controlled ovarian stimulation for IVF.

STUDY QUESTION: Is the length of the anogenital distance (AGD) a biomarker of ovarian reserve and response to controlled ovarian stimulation (COS)? SUMMARY ANSWER: Shorter AGD is associated with presence of poor ovarian response. WHAT IS KNOWN ALREADY: Organ development during prenatal life is influenced by the prevailing intrauterine environment, and it has been suggested that nutritional, environmental and toxic factors could affect ovarian reserve set prenatally. AGD is a biomarker of prenatal-hormonal environment and observational studies have shown an association between its length and reproductive parameters in both sexes. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study of 437 women treated with IVF/ICSI conducted in a tertiary-care university hospital between January and December 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women underwent their first COS for IVF/ICSI and reached criteria for oocyte retrieval. Based on the number of oocytes obtained, patients were divided into three groups: poor responders (≤3 oocytes) (n = 50), normoresponders (4-15 oocytes) (n = 332) and high responders (>15 oocytes) (n = 55). Before retrieval, the following patient data were recorded: age, body mass index (BMI), ovarian reserve markers (anti-Müllerian hormone [AMH], antral follicle count [AFC] and follicular stimulation hormone [FSH]), cause of infertility, total doses of gonadotropins used and ovarian sensitivity index (OSI). Patients with previous pregnancies, polycystic ovary syndrome (PCOS), endometriosis and previous ovarian or genital surgery were excluded. Anthropometric biomarkers of AGDAC (anus-clitoris) and AGDAF (anus-fourchette) were measured in all patients under sedation on the day of retrieval and before proceeding to oocyte pick-up. Multiple linear regression analyses were used to examine the association between both AGD and ovarian reserve markers, the total units of gonadotropins used, the number of oocytes obtained and the OSI. Logistic regression was used to predict poor response in COS for IVF/ICSI, while accounting for confounders such as age and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline FSH, AMH, AFC and age were significantly different among the three groups of ovarian response, as were the units of gonadotropin used, and the ovarian sensitivity index (OSI) (P < 0.001). Both AGDAC and AGDAF measurements were positively correlated with AMH levels (r = 0.38 and r = 0.21; P < 0.05), AFC (r = 0.41 and r = 0.20; P < 0.05), the OSI (r = 0.24 and r = 0.19; P < 0.05) and the number of oocytes retrieved (r = 0.29 and r = 0.28, respectively; P < 0.05). Conversely, there was a negative correlation between both AGD measurements and the doses of gonadotropins used (r= -0.19 and r= -0.15; P < 0.05). The area under the curve (AUC) for prediction of poor response of AGDAC was 0.70 (95% CI 0.66, 0.75), which was comparable to the classic ovarian reserve markers, such as AFC and AMH. AGDAF showed a significantly worse predictive capacity for poor ovarian response (AUC 0.60 [95% CI 0.55, 0.60]) than AMH and AFC. LIMITATIONS, REASONS FOR CAUTION: The population used for the study was a highly selected group of infertile women who underwent COS for IVF, so the findings of this research may not be applicable for general population. Besides, measurement or selection biases might have been possible and must be considered. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study suggest that in utero exposure to certain hormonal environments could affect the ovarian reserve set prenatally. STUDY FUNDING/COMPETING INTEREST(S): None. The authors have no competing interests to declare.

Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome.

Treatment with insulin-sensitizing agents is a relatively recent therapeutic strategy in women with polycystic ovary syndrome (PCOS) and insulin resistance. The key areas addressed in this review include PCOS and the development of type 2 diabetes mellitus and gestational diabetes, as well as the use of insulin-sensitizing agents, particularly metformin, in the management of infertility in obese and non-obese PCOS women. Treatment with metformin in PCOS women undergoing IVF and the use of metformin during gestation will be discussed. The challenge for the health care professional should be the appropriate utilization of pharmacotherapies to improve insulin sensitivity and lower circulating insulin levels resulting in beneficial changes in PCOS phenotype. Further research into the potential role of other insulin-sensitizing agents, such as pioglitazone and rosiglitazone, in the treatment of infertile women with PCOS is needed.

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.

Mioma uterino. Manifestaciones clínicas y posibilidades actuales de tratamiento conservador

Los miomas uterinos son los tumores más frecuentes del aparato reproductor femenino. Se estima que aparecen en un 25 per cent de mujeres en edad reproductiva y hasta en un 40 per cent de mujeres en edad inferior a los 50 años. En muchas ocasiones son tumores asintomáticos, pero lo más frecuente es que produzcan alteraciones menstruales (hipermenorreas y hemorragias intermenstruales), dolor abdominal y síntomas de compresión. Su relación con la fertilidad sigue siendo controvertida. Clásicamente, el tratamiento de elección ha sido quirúrgico, preferentemente la histerectomía en las pacientes que han completado su fertilidad y la miomectomía en las que desean conservarla. En la actualidad se utilizan tratamientos más conservadores, alguno de ellos, como la utilización de análogos de la hormona liberadora de gonadotropina (GnRH), con indicaciones y eficacia ya evaluadas, y otros, como la embolización arterial uterina, cuyos resultados preliminares son alentadores, pero con indicaciones todavía por especificar (AU)

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.

Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH.

BACKGROUND: It has been recently suggested that gonadotrophin-releasing hormone agonist down-regulation in some normogonadotrophic women may result in profound suppression of LH concentrations, impairing adequate oestradiol synthesis and IVF and pregnancy outcome. The aims of this study, where receiver-operating characteristic (ROC) analysis was used, were: (i) to assess the usefulness of serum LH measurement on stimulation day 7 (S7) as a predictor of ovarian response, IVF outcome, implantation, and the outcome of pregnancy in patients treated with recombinant FSH under pituitary suppression; and (ii) to define the best threshold value, if any, to discriminate between women with 'low' or 'normal' LH concentrations. METHODS: A total of 144 infertile women undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment were included. Seventy-two consecutive patients having a positive pregnancy test (including 58 ongoing pregnancies and 14 early pregnancy losses) were initially selected. As a control non-pregnant group, the next non-conception IVF/ICSI cycle after each conceptual cycle in our assisted reproduction programme was used. RESULTS: The median and range of LH values in non-conception cycles, conception cycles, ongoing pregnancies, and early pregnancy losses, clearly overlapped. ROC analysis showed that serum LH concentration on S7 was unable to discriminate between conception and non-conception cycles (AUC(ROC) = 0.52; 95% CI: 0.44 to 0.61) or ongoing pregnancy versus early pregnancy loss groups (AUC(ROC) = 0.59; 95% CI: 0.46 to 0.70). To assess further the potential impact of suppressed concentrations of circulating LH during ovarian stimulation on the outcome of IVF/ICSI treatment, the three threshold values of mid-follicular serum LH proposed in the literature (<1, < or =0.7, <0.5 IU/l) to discriminate between women with 'low' or 'normal' LH were applied to our study population. No significant differences were found with respect to ovarian response, IVF/ICSI outcome, implantation, and the outcome of pregnancy between 'low' and 'normal' S7 LH women as defined by those threshold values. CONCLUSIONS: Our results do not support the need for additional exogenous LH supplementation in down-regulated women receiving a recombinant FSH-only preparation.

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.

Mid-luteal serum inhibin-A concentration as a marker of endometrial differentiation.

BACKGROUND: Recent studies have indicated that the corpus luteum is a major source of circulating inhibin-A and serum concentrations of inhibin-A may reflect the human luteal function. The present prospective study was undertaken to determine the usefulness of mid-luteal serum concentrations of inhibin-A as markers of endometrial receptivity (as assessed by histological dating and alphavbeta3 integrin expression) and whether they are better predictors of endometrial function than serum progesterone. METHODS: Consecutive infertile women (experimental group, n = 50) with regular menstrual cycles, and fertile women who were requesting contraception and had regular menstrual patterns and normal secretory endometria (control group, n = 10) were included. In all women basal body temperature, luteal serum concentrations of oestradiol, progesterone, prolactin, and inhibin-A, and endometrial biopsies were used in the same cycle to assess luteal function. RESULTS: Out-of-phase mid-secretory endometria were detected in 17 of the 50 infertile women. Lack of alphavbeta3 integrin expression was detected in 27 of the 50 mid-luteal endometrial biopsies. Thus, hormonal concentrations were compared in the mid-luteal phase between the following eight groups of women: group 1 (n = 10), control fertile women; group 2 (n = 50), infertile women (all); subdivided into group 3 (n = 33), with in-phase biopsies; group 4 (n = 17), with out-of-phase endometria; group 5 (n = 23), expressing alphavbeta3 integrin in endometria; group 6 (n = 27), whose endometria did not express alphavbeta3 integrin; group 7 (n = 18), with both in-phase endometrial biopsy and alphavbeta3 integrin expression; and finally group 8 (n = 12), whose endometria were out-of-phase and did not express alphavbeta3 integrin. Mid-luteal serum concentrations of oestradiol, progesterone, prolactin, and inhibin-A of the seven infertile groups were similar to those of the control group of fertile women. No statistically significant difference between the infertile groups was observed for any hormonal parameter considered. CONCLUSION: Mid-luteal serum inhibin-A determination does not accurately reflect endometrial function/maturation and it is not a better indicator of endometrial luteal phase dysfunction than mid-luteal serum progesterone.

Follicular development and hormone concentrations following recombinant FSH administration for anovulation associated with polycystic ovarian syndrome: prospective, randomized comparison between low-dose step-up and modified step-down regimens.

The present study compared ovarian performance and hormone concentrations, after ovulation induction, in polycystic ovarian syndrome (PCOS) patients, using recombinant human FSH (rhFSH) in low-dose step-up and modified step-down regimens. Twenty-six women with clomiphene citrate-resistant chronic anovulatory infertility were treated with rhFSH in two consecutive cycles according to two different low-dose regimens: (i) the classic chronic low-dose step-up protocol, the starting dose being 75 IU; (ii) a modified step-down protocol where the starting dose was 300 IU followed by 3 days free of treatment, then rhFSH 75 IU daily was given and stepwise dose increments were performed exactly the same as in the step-up method. Each woman received both treatment approaches, in a randomized order, with an interval of > or = 1 month between treatments. The total number of follicles that were > 10, > 14 and > 17 mm in diameter on the day of human chorionic gonadotrophin (HCG) administration, and thus cycles with HCG cancelled, were significantly increased with the step-up approach. The total number of rhFSH ampoules tended to be higher with the step-down schedule despite the fact that both the mean duration of treatment and the threshold dose were similar with the two low-dose approaches. A physiological step-down approach for ovulation induction in PCOS patients may be more appropriate in order to avoid multifollicular cycles than the step-up approach.

Day 3 serum inhibin B and FSH and age as predictors of assisted reproduction treatment outcome.

Recent reports investigating the value of basal inhibin B determination as a predictor of ovarian reserve and assisted reproduction treatment have led to discordant results. This study was undertaken to further assess the relative power of day 3 inhibin B and follicle stimulating hormone (FSH) (defined before treatment) and the woman's age both as single and combined predictors of ovarian response and pregnancy in an in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programme. A total of 120 women undergoing their first cycle of IVF or ICSI was included. Forty consecutive cycles cancelled because of poor follicular response were initially selected. As a control group, the nearest completed IVF/ICSI cycles before and after each cancelled cycle (i.e. the closest cycles in temporal relationship to the index cycle) were used. Mean age and basal FSH concentrations were significantly higher in the cancelled than in the control group (P: < 0.01 and P: < 0.001 respectively), whereas basal inhibin B was significantly higher in the latter (P: < 0.05). The association of basal FSH (with an accuracy or predictive value of ovarian response of 79%) with cancellation rate was significant, independent of, and stronger than the effects of age and inhibin B (P: < 0.05). Any two or all three of these variables studied did not improve the predictive value of FSH alone. Woman's age was the only variable independently associated with pregnancy rate. It is concluded that the stronger predictors of success in patients undergoing their first IVF/ICSI treatment cycle are age and basal FSH rather than inhibin B. Basal FSH concentration was a better predictor of cancellation rate than age, but age was a stronger predictor of pregnancy rate.

Circulating levels of nitric oxide in successful and unsuccessful implantation after in vitro fertilization and embryo transfer. Relationship to estradiol and progesterone.

BACKGROUND: Nitric oxide (NO) may play an important role in embryo implantation and early embryo development. This study investigated the potential role of circulating nitric oxide (NO) measurement to predict the outcome of implantation and pregnancy after IVF and ET. METHODS: Two blood samples were collected from 237 IVF patients on days 13-14 and 20-21 after ET. Serum concentration of nitrite/nitrate (the two stable oxidation products of NO metabolism), estradiol (E2), progesterone and beta-hCG were measured on days 13-14 after ET and one week later. RESULTS: No significant differences were found with respect to nitrite/nitrate serum concentrations in conception versus non-conception cycles, viable versus abnormal pregnancies, and viable pregnancy group versus non-conception cycles, respectively, despite that significant differences were observed regarding E2 and progesterone values. Nitrite/nitrate serum concentrations were similar for singleton and multiple pregnancies at both study points. In viable pregnancies, no significant change was observed for nitrite/nitrate serum concentration from days 13-14 to 20-21 after ET. No correlation was found between nitrite/nitrate serum concentration and E2 or progesterone serum levels. CONCLUSIONS: Circulating levels of nitrite/nitrate are similar in successful and unsuccessful implantation after IVF and are unrelated to the outcome of pregnancy. This precludes the use of serum NO measurement as a marker of implantation and successful pregnancy in IVF.

Serum inhibin B determination is predictive of successful testicular sperm extraction in men with non-obstructive azoospermia.

Recent work indicates that serum inhibin B is a useful marker of spermatogenesis and inhibin B production sufficient to maintain detectable serum concentrations in adults depends on spermatogenic activity. The purpose of the present study was to investigate the usefulness of serum inhibin B measurement to predict the success of testicular sperm extraction (TESE) in 17 men with nonobstructive azoospermia to be treated by intracytoplasmic sperm injection (ICSI) (group 1). Two additional groups were used as positive controls; group 2 comprised 22 infertile men having obstructive azoospermia, and group 3, which included 29 semen donors having normal seminal parameters. Follicle stimulating hormone (FSH) was significantly higher (P < 0.01) and inhibin B significantly lower (P < 0.001), in group 1 as compared with groups 2 and 3. Serum inhibin B concentrations were significantly higher (P < 0.001) among successful TESE men as compared with those having failed TESE. In contrast, no differences were detected between these two groups with respect to serum FSH or testicular size. In addition, serum inhibin B but not FSH discriminated between successful and failed TESE in group 1 subjects as compared with control groups. According to the receiver operating characteristics curve analysis, the best inhibin B value for discriminating between successful and failed TESE was >40 pg/ml (sensitivity 90%, specificity 100%). It is concluded that inhibin B measurement is a useful non-invasive predictor of spermatogenesis and thus, all azoospermic males should have serum inhibin B concentrations determined in addition to FSH measurement and karyotyping prior to undergoing TESE.

Follicular fluid concentrations of adrenomedullin, vascular endothelial growth factor and nitric oxide in IVF cycles: relationship to ovarian response.

Marked granulosa cell proliferation along with important changes in the vascular bed of the ovary characterize IVF cycles associated with multiple follicular growth and maturation. The present report investigated follicular fluid (FF) and circulating concentrations of adrenomedullin, vascular endothelial growth factor (VEGF) and nitric oxide (NO) in 70 IVF patients (14 of whom became pregnant); these three vasoactive substances may be implicated in extensive ovarian tissue remodelling. Serum and FF concentrations of oestradiol and progesterone were also measured in the 70 IVF cycles studied. Follicular fluid concentrations of VEGF and adrenomedullin but not nitrite/nitrate (the two stable oxidation products of NO metabolism) were significantly higher (P < 0.0001) than the corresponding circulating concentrations. Follicular fluid concentrations of oestradiol and progesterone were not correlated with those of adrenomedullin, VEGF or nitrite/nitrate. No relationship existed between circulating concentrations of adrenomedullin, VEGF or nitrite/nitrate on the day of oocyte aspiration and parameters of ovarian response to gonadotrophin stimulation. In contrast, FF adrenomedullin concentration showed a direct relationship with day 3 FSH serum concentration (r = 0.53, P < 0.01) and the number of ampoules of gonadotrophin administered (r = 0.36, P < 0.005), but an inverse correlation with the total number of oocytes retrieved (r = -0.29, P < 0.01) and the number of mature oocytes (r = -0.25, P < 0. 05). A positive correlation was found for FF VEGF concentration and chronological age (r = 0.29, P < 0.05) and ampoules of gonadotrophins administered (r = 0.30, P < 0.05). There was no relationship between nitrite/nitrate FF concentrations and parameters of ovarian response. Neither serum concentrations nor FF concentrations of adrenomedullin, VEGF or nitrite/nitrate were correlated with IVF outcome. This study suggested for the first time that increased FF concentrations of adrenomedullin can be a marker of decreased ovarian response in IVF. Our results also provide further evidence favouring an association between FF VEGF and patient's age, while on the basis of our findings NO measurements are not a useful marker of ovarian response.

Day 5 inhibin B serum concentrations as predictors of assisted reproductive technology outcome in cycles stimulated with gonadotrophin-releasing hormone agonist-gonadotrophin treatment.

The present study investigates the usefulness of inhibin A, inhibin B and serum oestradiol concentrations obtained in the fifth day of gonadotrophin therapy in predicting ovarian response and assisted reproductive treatment outcome in women undergoing ovarian stimulation under pituitary desensitization. A total of 80 women undergoing their first cycle of in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment were studied. Twenty consecutive cycles which were cancelled because of a poor follicular response were initially selected. As a control group, 60 women were randomly selected from our assisted reproductive treatment programme matching by race, age, body mass index, and indication for IVF/ICSI to those in the cancelled group. For each cancelled cycle, three IVF/ICSI women who met the matching criteria were included. Basal follicle stimulating hormone (FSH) concentrations were significantly higher in the cancelled than in the control group, whereas basal inhibin B was significantly higher in the latter. Basal oestradiol concentrations were similar in both groups of patients. On day 5 of gonadotrophin therapy serum concentrations of oestradiol, inhibin A and inhibin B were significantly lower in the cancelled group as compared with controls. Logistic regression analysis showed that the association for day 5 inhibin B (with a predictive value of ovarian response of 91.03%) with cancellation rate was significant, independent of, and stronger than, the effects of any other hormone variable investigated. In addition, day 5 inhibin B concentrations were correlated directly with parameters of ovarian response, ovum retrieval and oocyte and fertilization outcome. However, day 5 inhibin B was not a better predictor of pregnancy than the other hormone variables studied on this day. It is concluded that inhibin B concentrations obtained early in the follicular phase during ovarian stimulation under pituitary suppression for assisted reproductive treatment are highly predictive of ovarian response.

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

PURPOSE: Our purpose was to determine prospectively, using receiver-operating characteristic (ROC) analysis, whether the ovarian reserve test with hMG could improve the predictive value of a woman's age and basal levels of follicle stimulating hormone (FSH), E2, and inhibin or any combination of them regarding ovarian response and pregnancy rate in IVF treatment following pituitary desensitization. METHODS: The hMG test was performed within 3 months of IVF treatment in 80 women undergoing the first cycle of IVF and consisted of 2 ampoules of hMG daily for 5 days starting on cycle days 2 to 3. Hormone and ultrasound evaluation was performed on cycle days 2 to 3 and 7 to 8. RESULTS: The mean age and basal FSH levels were significantly higher in the canceled (n = 28) than in the control (n = 52) group, whereas the basal inhibin level was significantly higher in the latter. Regarding ovarian response, the combination FSH plus inhibin had the better diagnostic accuracy (predictive value of 70%) among basal variables. When post-hMG parameters (alone or in combination) were analyzed, E2 alone, with a 77% diagnostic accuracy, emerged as the best predictive variable of cancellation in IVF cycles. When ROC analysis was used, the area under the ROC curve for E2 post-hMG (diagnostic accuracy of 84.5%) was significantly higher than that for the estimates based on the combination of basal FSH and inhibin (diagnostic accuracy of 71.3%). However, woman's age was the only variable independently associated with pregnancy rate. CONCLUSIONS: The predictive power of the hMG test of ovarian reserve is better than that of age and basal hormone values (FSH and inhibin) and it is based mainly on the E2 response to hMG treatment. However, given that age is the only predictor of pregnancy and considering the cost and discomfort of the hMG test, the usefulness, if any, of the test in predicting IVF performance in the daily clinical setting remains to be established.