Reproductive endocrinology

A. Nazzaro, A. Salerno, L. Di Iorio, G. Landino, S. Marino, E. Pastore, F. Fabregues, A. Iraola, G. Casals, M. Creus, S. Peralta, J. Penarrubia (+661 others)
2013 Human Reproduction  
Study question: This study aims to compare the efficacy of mid-follicular recombinant LH (rLH) supplementation for ovarian stimulation in gonadotrophinreleasing hormone-antagonist (GnRH-a) protocol for IVF/ICSI cycles in normogonadotrophic women Summary answer: r-LH supplementation in GnRH-a cycles improve implantation and pregnancy rates probably via an improvement in oocyte quality and/or uterine receptivity. What is known already: The role of LH during ovarian stimulation in IVF is
more » ... ial and previous reports on this topic have revealed conflicting outcomes, mostly ought to the heterogeneity of the studies in terms of design, sample size, inclusion criteria, GnRH analogue protocol,type of LH administered (recombinant human LH (r-HLH), human menopausal gonadotrophin (HMG), dose, beginning, duration of treatment) Study design, size, duration: 422 patients without ovulatory dysfunction, aged ,40 years and at their first IVF/ICSI cycle were divided into two groups matched by age according to two ovarian stimulation schemes: Group I (n ¼ 211): r-FSH alone and Group II (n ¼ 211): r-FSH + r-LH . All women were synchronized with vaginal estroprogestinic device Participants/materials, setting, methods: Pituitary down regulation and ovarian stimulation were carried out by the following fixed scheme: three daily administration of GnRH-a starting on day two of the menstrual cycle followed by five days of r-FSH administration (225 IU/day) alone, on day six the all women restarted daily GnRH-a administration and were randomized to receive r-FSH alone or r-FSH + r-LH (r-LH 150 IU/day) for the remainder of the stimulation. Follicular maturation was triggered with 250 mg of r-hCG. Data were analyzed using InStat version 3.0 (GraphPad Software, San Diego, California, USA). The Student's t, Mann-Whitney and x2 tests were utilized when appropriate. The level of significance was set at P , 0.05 Main results and the role of chance: The number of oocytes collected, the number of oocytes in metaphase II and fertilization rate were significantly lower in the Group I than in Group II (P ¼ 0.036, P ¼ 0.0014 and P ¼ 0.017, respectively). The mean number of embryos produced per cycle, the mean high grade number of embryos and the mean number of frozen embryos per cycle were statistically lower (P ¼ 0.0092; P¼ 0.0086; P ¼ 0.0008, respectively) in Group I than in Group II. The cumulative implantation rate (fresh + thawed embryos) and clinical pregnancy rate were significantly lower (P ¼ 0.04 and P ¼ 0.03, respectively) in Group I than in Group II. Limitations, reason for caution: none Wider implications of the findings: The beneficial effect of r-HLH on implantation and pregnancy outcomes in our population could be explained by two different mechanisms. Firstly, the embryo quality seems to be superior in the rLH supplemented group; secondly, rLH supplementation may have a beneficial effect on the endometrium, which could promote embryo implantation. Although larger studies are required to further investigate these findings, r-HLH supplementation for normogonadotrophic women aged ,40 years undergoing ICSI/IVF cycles is recommended as it may have a beneficial action on implantation and pregnancy rates. Study question: Have previously tested doses of recombinant follicle-stimulating hormone (rFSH) been too low in experimental studies regarding the asparagi-ne680serine polymorphism in the FSH receptor (FSHR) gene? Summary answer: Yes, in accordance with previous in vivo findings, we found that the less common FSHR variant with serine in amino acid position 680 exhibited notably lower activity in vitro compared to the FSHR with asparagine in the same position. What is known already: The asparagine680serine variant in the FSHR gene has previously been shown to affect reproductive function in women, so that those carrying serine in amino acid position 680 require higher doses of rFSH than those with asparagine in the same position during hormonal treatment prior to in vitro fertilization. However, so far in vitro studies on 0.03-10 mIU/mL rFSH have failed to show differences in FSHR activity between the receptor variants. Abstracts i311 Downloaded from by guest on 30 July 2018 Study design, size, duration: Eukaryotic kidney cells (COS-1), lacking endogenous FSHR, were used in a reporter assay in which the capability of the wild type asparagine-containing FSHR was compared to the serine-containing FSHR with respect to stimulation of the release of cAMP, which is a downstream signaling molecule in the FSHR signaling pathway. Participants/materials, setting, methods: Genetic variants of the FSHR , /SSF . were cloned into the pCMV6-XL5 vector and transiently transfected into COS-1 cells. Cells were stimulated with 0-400 mIU/mL rFSH (Gonal-F) and subsequently cAMP concentration was measured with ELISA and adjusted for total protein concentration. The experiment was performed 3 times in duplicates. Main results and the role of chance: As in previous studies, there were no differences in cAMP response between the FSHR variants, when cells were stimulated with 0-10 mIU/mL rFSH. However, in response to doses above 10 mIU/mL rFSH, the serine-containing receptor displayed approximately 5 times lower response than the wild type asparagine-containing receptor. Limitations, reason for caution: The COS-1 cells are of primate origin. The results may therefore not be directly applicable on humans. Wider implications of the findings: The results from this study may, at least partly, explain the need for higher rFSH doses for ovulation prior to in vitro fertilization in women carrying serine instead of asparagine in amino acid position 680. On the other hand, women with asparagine-containing FSHRs may be those at increased risk of developing ovarian hyperstimulation syndrome. Study question: Whether or not the prevalence of abnormal lipid profile of polycystic ovary syndrome (PCOS) alters in the same population according to the different diagnostic criteria? Summary answer: The prevalence of abnormal lipid profile in PCOS under Androgen Excess and PCOS (AE-PCOS) Society criteria was higher than that of and non-hyperandrogenic PCOS (oligomenorrhea with appearance of polycystic ovary on transvaginal ultrasonography). What is known already: The diagnosis of PCOS still remains controversial, as it is based on signs, symptoms and laboratory findings that are not unanimously recognized. It is indicated that PCOS is a multifactorial condition that is associated with dyslipidemia and insulin resistance. The current study gives the prevalence rates of insu in women with PCOS under contrasting diagnostic criteria. Study design, size, duration: In this retrospective cohort study, the medical records of 8908 consecutive women between ages of 18 and 45 years were reviewed. The study was conducted in the gynecological outpatient department of Inonu University, Turgut Ozal Medical Centre, between 2009 and 2012. Of 1047 women with PCOS under Rotterdam criteria were included. Participants/materials, setting, methods: The consecutive women between the ages of 18 and 45 years were included. Post-menopausal women, women with incomplete medical data, a history of hysterectomy or bilateral oophorectomy, systemic disease, taking medication and pregnant women were excluded. Totally, 7872 subjects were included and of 1047 women with PCOS were recruited for final analyses. Main results and the role of chance: The prevalence of PCOS under Rotterdam, AE-PCOS Society criteria and non-hyperanderogenic PCOS were 13.2%, 8.7% and 4.6%, respectively. While the prevalence of high triglycerides (TG) was 21.7% in the whole study group, within the patients diagnosed as PCOS according to AE-PCOS Society criteria and non-hyperandrogenic PCOS, it was 23.5% and 14.2%, respectively (P ¼ 0.04). The prevalence of low high-density lipid (HDL) in the group under AE-PCOS Society criteria was higher than that of nonhyperandrogenic PCOS (60.6% versus 40.8%, respectively; P , 0.01); however, the prevalence of low HDL was 56.8% in the whole study group. In terms of prevalence of high total cholesterol and low-density lipid (LDL) parameters, there were no statistically significant differences between the groups (18.5% versus 15.0% and 14.8% versus 11.9%; P ¼ 0.48% and P ¼ 0.53, respectively). Limitations, reason for caution: Even though women living at a similar environment, a potential selection bias due to undetermined differences between our study sample and the background community. Wider implications of the findings: A diagnosis of PCOS in combination of anovulation with hyperanderogenism has the most long-term metabolic impact. Current results can be generalized to Caucasian populations and may present variations in other populations according to race and ethnicity. Study question: The aim of this study was to evaluate serum AMH levels in women with polycystic ovary syndrome (PCOS) for setting up the diagnostic cut-off value, and to investigate affecting factors to AMH levels in women with PCOS with and without hyperandrogenism. Summary answer: Serum AMH in women with PCOS was significantly increased compared with eumenorrheic asymptomatic volunteers, however, not different between women with hyperandrogenism or not. In women with hyperandrogenism, serum AMH was well correlated with LH, T, and fasting insulin level. In women without hyperandrogenism, AMH was not correlated with any parameters. What is known already: Serum AMH levels are elevated in women with PCOS, and proposed as a marker for diagnosis and surveillance of PCOS therapy. There is an independent effect of race and ethnicity. There were some reports the relationship of AMH with obesity, LH, hyperandtorgenemia. Study design, size, duration: This is a case control study performed from January 2012 to November 2012. Sixty eight women with PCOS, fifty five age-matched normogonadotropic regularly menstruating women were enrolled for this study. Participants/materials, setting, methods: All women in study group had secondary amenorrhea and PCO morphology, divided into two groups depend on hyperandrogenism (HA+ and HA-). Sera were collected on the progesterone induced cycle day 2 or 3 for determining the levels of AMH, FSH, LH, E2, T, DHEA-s, TSH, prolactin, and 75g OGTT. Main results and the role of chance: Mean serum AMH level was markedly increased in the PCOS group (12.7 + 4.9 ng/mL) compared with control (4.8 + 2.1 ng/mL; P , 0.001). Cut-off value for predicting PCOS was 8.21 ng/ mL with sensitivity of 82.4%, and specificity of 94.5% by ROC curve (AUC 0.937, P , 0.001). Serum AMH levels were not significantly different between HA+ and HA-group. In HA+ group, AMH was well correlated with LH (r¼ 0.692), T (r¼ 0.725), and fasting insulin (r¼ -0.893), however, not correlated with BMI, waist hip ratio, fasting or 2hr blood sugar level after 75g OGTT, FSH, E2, TSH, prolactin, or DHEA-s. In HA-group, AMH was not correlated with any parameters. Serum AMH levels were not significantly different between obese and normal BMI women either. Limitations, reason for caution: . Wider implications of the findings: The diagnostic cut-off of serum AMH was 8.21 ng/mL in this study, higher then other reports. It was possibly by ethical differences. There were inconsistent reports about the relationship of AMH with endocrinological and clinical parameters. In our study, serum AMH was not influenced by hyperandrogenemia, LH, or obesity. Only in hyperandrogenemia subgroup, AMH was well correlated with LH, T and fasting insulin. It might reflect the differences in pathophysiology between the two subgroups. Study funding/competing interest(s): NO Trial registration number: NO P-470 The role of ethnicity and body weight in determination of AMH levels in women diagnosed with subfertility i312 Abstracts Downloaded from by guest on 30 Study question: What are the roles of the ethnicity and the body weight in determination of AMH levels in infertile women? Summary answer: It appears that ethnicity does not play significant role in determination of AMH levels in subfertile women. However obese women appear to have higher AMH levels compared to their lean counterparts, which remained statistically significant following controlling for age, PCOS status, ethnicity and the causes of infertility. What is known already: Female ovarian reserve is largely determined by genetic factors and therefore it is believed that female ethnicity may play a role in determining AMH levels. However data based on large cohort of subjects is currently not available. Similarly, effect of body weight on AMH is unknown. Study design, size, duration: This is first observational study that has evaluated effect of ethnicity and body weight on AMH levels using large cohort of subjects. ANOVAwith quadratic adjustment for age (and diagnosis of PCOS, causes of infertility and history of reproductive surgery) was used to estimate effect size and statistical significance. Participants/materials, setting, methods: All women (20-45 years) referred for management of infertility (01.10.2008-18.10.2010) and had AMH measurements using DSL ELISA were included (n ¼ 3488). Distribution of ethnicity was as follows: 1973 White British, 150 Other White, 106 Black, 174 Asian Indian, 322 Asian Pakistani, 32 Chinese. 731 women did not report their ethnicity. Main results and the role of chance: When compared to White British there were no significant differences in AMH levels of Other White, Asian Indian, Asian Pakistani and Chinese women following adjustment for age and PCOS status whilst Black women had significantly higher hormone levels (p ¼ 0.008). However this significance was lost following adjustment for BMI (p ¼ 0.26). Obese women (BMI 30-40) had significantly higher AMH levels compared to lean women (BMI 20-25), which remained statistically significant following adjustment for age, PCOS status and ethnicity (p ¼ 0.007). The analysis of the interaction of these two confounding factors suggests that the effect of ethnicity on AMH appears to be the consequence of obesity, whilst the effect of obesity is independent of the ethnicity. Limitations, reason for caution: This data is based on heterogeneous infertile population; which includes 'healthy'sub-population (n ¼ 330) consisting of women with no history of reproductive pathology and whose partner/husbands diagnosed with azoospermia. The data for all possible confounding factors (causes of infertility, reproductive surgery) were collected and the analysis included adjustment for these factors. Wider implications of the findings: Currently women's age and diagnosis of PCOS are only known factors which affects AMH levels. This study suggests that BMI is independent factor that affects AMH levels and therefore future research studies should take this into account when controlling the trials and/or in adjustment for the confounding factors. Participants/materials, setting, methods: Of all 1129 patients, 280 received hormonal supplementation, with GnRH agonist co-treatment (group A), whereas 849 patients only received hormonal supplementation (group B). Demographic characteristics, indication for fertility treatment and endometrial thickness at day of planning, did not differ significantly between the 2 groups. Main results and the role of chance: Forty-one cycles did not result in an embryo transfer in group A (14.6%) and 116 in group B (13.7%) (p ¼ 0.69). Premature Abstracts i313 Downloaded from by guest on 30 July 2018 progesterone rise occurred in 1.9% in group B (16/849), versus 0% in group A (0/ 280), which is significantly different (p ¼ 0.02). Regarding secondary outcome parameters, 77/280 (27.5%) had a positive pregnancy test after transfer in group A, 237/849 (27.9%) in group B (p ¼ 0.94). Mean number of embryos transferred (1.41 in group A (SD 0.49) versus 1.43 in group B (SD 0.50)) was comparable (p ¼ 0.81). Limitations, reason for caution: Given the retrospective design of this trial, results must be interpreted with caution. Future randomized trials are needed to confirm our findings. Wider implications of the findings: Our results confirm the outcomes from previous smaller studies suggesting low cancellation rates and promising pregnancy rates in women undergoing artificially prepared frozen embryo transfer cycles with or without the use of a GnRH agonist. The low cancellation rate due to premature progesterone rise implies that the use of a GnRH agonist should not be routinely recommended, since it does not increase pregnancy rates whereas it increases patients' burden and costs related to medication. Study question: Does combined oral contraceptive (COC) use alter serum prostate-specific antigen (PSA) levels in patients with polycystic ovary syndrome (PCOS)? Summary answer: Use of COC seems to significantly increase serum PSA levels in patients with PCOS. Therefore, PSA should not be used for the monitoring of PCOS patients on COC treatment. What is known already: Universal pathology in PCOS is androgen excess that is responsible for signs and symptoms of hyperandrogenism. Several studies have demonstrated a significant reduction in ovarian androgen production during the use of COCs. PSA has been detected in female serum using ultrasensitive assays and has been proposed as a marker of androgen excess in hirsute women. However, the results are conflicting. In most of the study, significant decrease in serum PSA concentrations has been demonstrated in hirsute women on antiandrogen treatment. However, similar PSA decrease was not reported after COC treatment in several small studies. Moreover, in a study it was stated that COCs may increase serum PSA levels. Study design, size, duration: Seventy women who had a new diagnosis of PCOS between January 2011 and April 2012 were included in this prospective study. Participants/materials, setting, methods: PCOS was defined by the 2003 Rotterdam criterias. All patients with PCOS were treated with a COC containing 0.035 mg ethinylestradiol and 2 mg cyproterone acetate for 6 months. Serum PSA levels, ovarian volume, antral follicule count, serum testosterone level and HOMA index were measured before and after the treatment. Main results and the role of chance: The median serum PSA levels were 0.040 (range 0.02-0.09) ng/ml and 0.060 (range 0.02-0.09) ng/ml before and after COC use, respectively. Serum PSA levels significantly increased after the treatment (p , 0.001). Serum PSA levels were not correlated to ultrasonographic, laboratory and demographic parameters. Limitations, reason for caution: The main limitation of our study was the absence of control group. However, it might be the secondary outcome of the study, because our primary outcome was to evaluate the effect of COC use on serum PSA levels in patients with PCOS. The follow-up period might be longer than 6 months. However, in most of the studies clinical and laboratory changes were evaluated after 3 or 6 cycles of COC treatment. Wider implications of the findings: The present study seems to be the largest prospective trial revealing the effect of COC use on serum PSA levels in women with PCOS. Our results suggest that use of COC may increase serum PSA level of PCOS women. Therefore, PSA should not be used as a monitoring marker of PCOS patients receiving COC. Study question: What is the likelihood of clinical pregnancy and live birth rates in women with extremely low anti-Müllerian hormone (AMH) levels. Summary answer: Our results confirmed that even without supplementation, the likelihood of live birth is still a reasonable reason to begin treatment in women with extremely low live birth rates. What is known already: Anti-Mullerian hormone (AMH) is an established marker of ovarian reserve and predicts both high and low responses in controlled ovarian stimulation cycles. A current diagnostic issue for clinicians is the treatment of women with extremely low AMH levels. In that group of patients, we expect poor ovarian response, which can lead to cycle termination, thus lowering the probability of pregnancy. Study design, size, duration: We retrospectively analyzed a computer database of women with extremely low AMH ( ,0.4 ng/ml) levels treated with intracytoplasmic sperm injection (ICSI) in our IVF unit between May 2007 and January 2011. Participants/materials, setting, methods: During the study period, 194 cycles of 106 women were investigated. The median age of all patients included in the study population was 37 years. We divided women into three age categories: ,35, 35-39, and .39, Clinical pregnancy rate and live birth rate was recorded. Main results and the role of chance: The mean AMH levels in all women/cycles were 0.25 + 0.12 ng/ml. Fourteen clinical pregnancies were recorded (7.2% per cycle start and 13.2% cumulative) and 14 live births in 13 women (one pair of twins). Four live births occurred after the first cycle, seven live births occurred after the second cycle, two live births occurred after the third cycle, and one live birth occurred after the fourth cycle. Only one woman miscarried. When evaluated according to age, we found significantly higher clinical pregnancy and live birth rates in women younger than 35 years [9 (23.7%)] compared to women between 35 and 39 years [3 (10.3%)] and older than 39 years[1 (2.6%)]. Limitations, reason for caution: Small group. Two center study. Wider implications of the findings: It seems clear that clinicians should communicate the probability of live birth when the woman has extremely low AMH levels to allow both the couples and the doctors to either begin treatment (when a low probability of live birth is accepted) or present other possibilities to achieve pregnancy (e.g., oocyte donation program). Study question: Which of the common clinical determinants, including patient age; levels of anti-Müllerian hormone (AMH), inhibin B, and follicle-stimulating hormone (FSH); antral follicle count (AFC); and number of oocytes retrieved, is the best marker in predicting live births in women undergoing in vitro fertilization. Summary answer: In this assessment of various indices (i.e., age; levels of AMH, inhibin B, and FSH; AFC; and quantity of oocytes retrieved) for predicting live births for IVF patients, AMH, AFC and the quantity of oocytes retrieved constituted the most reliable determinants. i314 Abstracts Downloaded from by guest on 30
doi:10.1093/humrep/det221 fatcat:l2bdsdbcb5aj5njnljn4ls2fea