Fertility Weekly
A Weekly Digest on Fertility & Human Reproductive Science
April 7, 2014
News
Ectopic Pregnancy
Following ...
Advising Editor: Mark Perloe, M.D., Medical Director, Georgia Reproductive Specialists
News Editors: J. Mitchell, K. Holco...
Fertility Weekly - April 7, 2014 - Page 3
and effective (Carson and Buster, 1993; Lipscomb et al., 1999; Stovall et al., 1...
Page 4 - Fertility Weekly - April 7, 2014
low doses, may cause reduced sperm counts in some men. In this population, count...
Fertility Weekly - April 7, 2014 - Page 5
The current study was part of a larger ongoing project; only those who fulfilled...
Page 6 - Fertility Weekly - April 7, 2014
(CYP11A1), and act as a key enzyme in androgen synthesis, 17 - hydroxylase/17, 2...
Fertility Weekly - April 7, 2014 - Page 7
Endometrial Hyperplasia
LG-IUS vs. Oral Progestogen Treatment
Use of the levonor...
Page 8 - Fertility Weekly - April 7, 2014
independently correlated with treatment modality and regression outcome. Therefo...
Fertility Weekly - April 7, 2014 - Page 9
Days 1, 6, and the day of hCG triggering. On days 1, 6 and on the day of hCG tri...
Page 10 - Fertility Weekly - April 7, 2014
In this prospective study, Ulku Ozdemir and colleagues compared cycle propertie...
Fertility Weekly - April 7, 2014 - Page 11
"A demonstration of reduction in IVF clinical pregnancies in women with stage I...
Page 12 - Fertility Weekly - April 7, 2014
(COH). The advantages of antagonist treatment are the short stimulation period ...
Page 13
Conference Abstracts . . . April 7, 2014
Information About Research Worldwide . . . Compiled by Vinaya Kasibhatla
...
Page 14 - Fertility Weekly - April 7, 2014
“Cyclophosphamide Triggers Follicle Activation Causing Ovarian Reserve 'Burn Ou...
Fertility Weekly - April 7, 2014 - Page 15
“A Novel Method for Cryopreservation of Very Low Count Human Spermatozoa.”A. St...
Page 16 - Fertility Weekly - April 7, 2014
embryos were compared utilizing Fisher's exact test. Main results and the role ...
Fertility Weekly - April 7, 2014 - Page 17
samples on site. Pre-weighed sample jars were provided and semen volume determi...
Page 18
International Calendar . . . April 7, 2014
Conferences, Symposia, Meetings Worldwide. *New Listing
April 1-3, 2014...
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Fertility Week - April 2014 Sample Issue

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Fertility Week - April 2014 Sample Issue

  1. 1. Fertility Weekly A Weekly Digest on Fertility & Human Reproductive Science April 7, 2014 News Ectopic Pregnancy Following IVF. Effects of Methotrexate Administration. . . p. 2 Semen Parameters. Effects of Finasteride Use in Infertile Males. . . p. 3 PCOS. Evaluation of Ovarian Function in 35- to 40-year-old Women with Disease. . . p. 4 Human Polycystic Ovaries. Protein Expression of LHCG Receptor and 17α-hydroxylase/17- 20- lyase. . . p. 5 Endometrial Hyperplasia. LG-IUS vs. Oral Progestogen Treatment. . . p. 7 Endocrinology. Endocrine Effects of hCG Supplementation to Recombinant FSH during COS for IVF. . . p. 8 Ovulation Induction. Letrozole with Gonadotropins is Effective for Patients with Previous CC Cycle Failure. . . p. 9 MORE NEWS . . . pp. 10 - 12 Conference Abstracts Authors’ Abstracts from Meetings Worldwide. . . pp. 13 - 17 International Calendar Upcoming Events. . . pp. 18 www.fertilityweekly.com Cryopreservation Effects on Human Sperm mRNAs Cryopreservation alters transcripts that are markers of spermatozoa quality and of pregnancy success, states a study from Spain. Spermatic mRNAs may possibly be clinical markers associated with semen quality and pregnancy success (Galeraud- Denis et al., 2007; Garrido et al., 2009). Cryopreservation, which is widely used for conserving sperm to be used later for assisted reproductive technologies (ART), can produce changes in transcripts (Garcia-Herrero et al., 2011), DNA damage (DiSanto et al., 2012) and/or epigenetic modifications (Chao et al., 2012). "Our results demonstrated that the used cryopreservation protocol, which is routinely employed in clinical practice, alter transcripts considered as spermatozoa quality markers and markers for pregnancy success," wrote Valcarce et al. ("Effect of cryopreservation on human sperm messenger RNAs crucial for fertilization and early embryo development," CB, 2013; 67:84-90). Human semen samples were obtained from young men 24 to 28 years old. Morphology and counting of spermatozoa were conducted; phase contrast microscopy was used on fresh samples. Samples that met the standards of the WHO (2010) were selected: 12 samples classified as normozoospermic were studied initially, nine of them were used for the cryopreservation assay (n = 9) and three of which were used in the comparison of cryopreservation and vitrification protocols study (n = 3). Each sperm sample (n = 9) was cryopreserved using the same protocol. Samples were diluted 1:1 in cryoprotective medium, after which the mixture was equilibrated during 10 min at room temperature (RT) and loaded in 0.5 ml French straws. Straws were then exposed horizontally to liquid nitrogen vapors for 30 min. Straws were plunged into liquid nitrogen and stored until use, at which point thawing was carried out at RT for 5 min. Cell viability after cryopreservation was confirmed under microscopy, after which RNA isolation was performed. Vitrification was performed in parallel to cryopreservation in three new normozoospermic samples using the protocol of Isachenko et al. (2012). RNA was extracted from fresh, cryopreserved, and vitrified samples, after which they were centrifuged. RNA quantity and purity were then determined in a spectrometer. For each of the fresh, cryopreserved and vitrified
  2. 2. Advising Editor: Mark Perloe, M.D., Medical Director, Georgia Reproductive Specialists News Editors: J. Mitchell, K. Holcomb; Medical Editor: V. Kasibhatla Page 2 samples, complementary DNA was synthesized from 1 µg of RNA using a commercial kit. The final reaction was incubated in a thermocycler. Researchers focused on two sets of genes for transcript analysis: those reported as possible male fertility markers and those associated with pregnancy success. Genes studied for the first group wereBCL2-interacting killer (BIK), FSHβ polypeptide (FSHB), protamine 1 (PRM1), protamine 2 (PRM2) and mesoderm specific transcript homolog (mouse) (PEG1/MEST); genes studied for the second group were activin A receptor type II like 1 (ACVRL1), adducing 1 alpha (ADD1), androgen receptor (AR), arylhydrocarbon receptor nuclear translocator (ARNT), and endothelial PAS domain protein (EPAS1). Primer pairs described by Cavalcanti and colleagues (2011) for four genes proposed as reference genes were also studied. Quantitative PCR assays for fresh and cryopreserved samples for each male (n = 9) were simultaneously performed. Two-step RT-PCR analysis was conducted using specific primer pairs for the four reference genes proposed by Calvalcanti et al. (2011) as well as for BIK and ADD1. Statistical analysis utilized SPSS v.20.0 software and one-way ANOVA. Two variables were generated with the mean value of each of the nine males for each gene (fresh, Ct_gene_f, and cryopreserved, Ct_gene_c) to compare transcripts population before and after freezing. Fresh semen samples showed earlier Ct ("threshold cycle") than cryopreservation samples, indicating a decrease in the presence of transcripts after cryopreservation. Some of the studied males showed the same delay in Ct values after cryopreservation. RT-CPR assay corroborated results obtained by qPCR assay. After cryopreservation, the amount of final product for β-ACT, ATP5B, GAPD, and HSPCB could be stable or variable, depending on the subject, but study transcripts showed band variation. Protamine 1 (PRM1) and 2 (PRM2) had very early Ct, and also had the earliest amplification in cryopreserved samples. Remaining transcripts had later Ct values, especially in samples that were cryopreserved. Researches quantified transcripts and analyzed results using Ct values, taking into account the variability of reference genes. Significant differences were found for PRM1, PRM2, and PEG1/MEST within the group of transcripts associated with sperm quality, and AD-D1 within the group who achieved pregnancy. The amount of transcripts (later Ct) in both cryopreservation and vitrification was observed. One-way ANOVA revealed significant differences in PRM1 and PRM2 between fresh and vitrified samples. The two freezing methods showed no significant differences. qPCR analysis showed PCR efficiencies from 90% to 110% for all primers used. "Based on the genes analyzed, cryopreservation significantly affects four of the five studied transcripts proposed as fertility markers and two to five mRNAs proposed as successful pregnancy markers," wrote Valcarce et al. Address correspondence to V. Robles, Department of Molecular Biology and INDEGSI, University of Leon, 24071 Leon, Spain; e-mail: v.robles@unileon.es. Ectopic Pregnancy Following IVF Effects of Methotrexate Administration Methotrexate (MTX) may be used as the first line treatment for ectopic pregnancy (EP) without compromising in vitro fertilization (IVF) cycle outcome, according to research from the United States. EP can be diagnosed earlier now, thanks to more sensitive assays for β-hCG assays and higher resolution ultrasound. An earlier diagnosis allows the option of medical management. One alternative to surgical management in asymptomatic EP is MTX, which has proven safe Since 1995, published weekly for subscribers internationally by Fertility Weekly, Inc. 2451 Cumberland Parkway, Suite 3374, Atlanta, GA 30339 USA, Telephone: (888) 662-5048, or (404) 419-6701, Fax: (404) 419-6702, email: subs@fertilityweekly.com. Internet: info@fertilityweekly.com World Wide Web: http://www.fertilityweekly.com. US$699 a year North America, US$799 a year all other countries. Copyright ©2007 Fertility Weekly. All rights reserved. This information shall not, in whole or in part, be redistributed, reproduced, or put into a computer without prior written permission. Possession or distribution of an illegal photocopy of all or part of this information - even for internal use - is PROHIBITED BY LAW (17 U.S.C. 504) and will result in civil or criminal prosecution. Report offenses to the publisher. This information is not medical advice and is subject to change as knowledge advances. ISSN 1086-1068.
  3. 3. Fertility Weekly - April 7, 2014 - Page 3 and effective (Carson and Buster, 1993; Lipscomb et al., 1999; Stovall et al., 1991). The researchers' objective in this study was to determine the effect s of MTX on the future fertility of women undergoing IVF. "Our data do not demonstrate an adverse impact of MTX administration in the setting of IVF and demonstrated that patients who were treated with MTX had similar antral follicle counts, FSH levels, number of oocytes retrieved, and overall good outcomes after treatment," stated Boots et al. ("Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness?" F&S, 2013;100(6):1590-1593). Included in the study were patients who underwent IVF in a single large private practice and were diagnosed with an EP that was treated with MTX between January 2007 and December 2010. EP was diagnosed based in β-hCG level and transvaginal ultrasound. Methotrexate was administered using the single dose protocol (50 mg/m2 on day 0 and repeated on day 7 if β-hCG levels did not fall by 15% between days 4 and 7) (Stovall et al., 1991). Age, day 3 FSH, antral follicle count, IVF stimulation parameters, and time from MTX administration to the first day of the subsequent IVF cycle were compared between cycles. Those cycles that took place within 90 days of MTX were compared to those that occurred > 90 days after MTX administration. Comparisons were also carried out before and after 180 days. Statistical analysis utilized paired t-test and analysis of variance (ANOVA). Data were given as mean ± SD, and P < 0.05 was considered significant. In all, 66 women met the authors' inclusion criteria and were included in the study. Ovarian reserve parameters, like FSH and antral follicle count, did not differ before and after MTX. Other parameters that were similar before and after MTX were days of stimulation, peak E2 levels, number of oocytes retrieved, fertilization rate, and embryo development. The dose of gonadotropin required was higher after MTX administration (P < 0.01). Forty-seven (71%) of the patients were given a single dose of MTX and 19 (29%) needed a second dose. Four women (6%) failed MTX and required surgical management. Mean time from MTX administration and baseline evaluation for the subsequent IVF cycle was 187 ± 159.1 days. Fifty-seven of the 66 women who underwent stimulation made it to ET. Twenty-three (40.4%) underwent day 3 transfer, but transferal took place on day 5 for 34 (59.6%) women. Thirty-one of the 57 women (54%) achieved pregnancy; 20 had clinical pregnancies, 9 had biochemical pregnancies, and 2 had recurrent EPs. Averaged across all ages, the pregnancy rates were comparable to the practice's general statistics. "Methotrexate remains the first line of therapy for medical management of asymptomatic EP and does not compromise ovarian reserve, ovarian responsiveness, or IVF success in subsequent cycles," Boots et al. concluded. Address correspondence to Eve C. Feinberg, MD, Fertility Centers of Illinois, 767 Park Ave West, Suite 190, Highland Park, Illinois 60035; e-mail: eve.feinberg@integramed.com. Semen Parameters Effects of Finasteride Use in Infertile Males Finasteride use may reduce the sperm counts in some men, state researchers in Canada. Finasteride is approved at a 5 mg/day dose for treating benign prostatic hyperplasia, and at a dose of 1 mg/day for treating androgenic alopecia (Laborde and Brannigan, 2010); the latter use has resulted in more reproductive-age men taking finasteride. Finasteride increases the ratio of testosterone (T) to dihydrotestosterone (DHT) by inhibiting 5α-reductase. Studies have shown that 5α-reductase is present in human testis, but it seems that DHT is not essential for spermatogenesis (Aumuller et al., 1996). According to the U.S. Food and Drug Administration, finasteride does not adversely affect male fertility (Administration USFaD, 2011). Finasteride at high doses (5 mg) has a reversible negative effect on semen parameters (Amory et al., 2007), while low-dose (1 mg) finasteride in healthy men with normal spermatogenesis shows no effects in semen parameters (Overstreet et al., 1999). In this study, researchers M.K. Samplaski and colleagues aimed to determine the extent to which semen parameters improve following finasteride discontinuation. "Finasteride, even at
  4. 4. Page 4 - Fertility Weekly - April 7, 2014 low doses, may cause reduced sperm counts in some men. In this population, counts improved dramatically for the majority of men after finasteride discontinuation," wrote Samplaski and colleagues ("Finasteride use in the male infertility population: effects on semen and hormone parameters," F&S, 2013;100(6):1542-1546). Study subjects were men taking finasteride who presented for fertility evaluations from 2008 - 2012 at the same clinic and were identified by a prospectively collected database. The data base was made of up men with normospermia, oligospermia, and azoospermia; data were reviewed retrospectively. Data analysis was conducted for semen and hormone parameters while taking finasteride and after discontinuation. All of the men completed the Sexual Health Inventory for Men (SHIM) and Androgen Deficiency in the Aging Male (ADAM) questionnaires (Morley et al., 2000). Blood and semen samples were collected at different laboratories, all of which used validate methodologies and performed their own quality control procedures to assess semen samples for volume and analyze them for sperm count, sperm concentration, and motility using computer-assisted semen analysis, following 1999 WHO criteria (1999). Statistical analysis was carried out using a paired, two-tailed Student's t-test, with P < 0.05 considered significant. Twenty-seven men were taking low-dose finasteride (1 mg/day) for androgenic alopecia at the time of presentation; 24 men were evaluated. Mean patient age was 37 years, and mean reported dosage was 1.04 mg/day over mean treatment duration of 57.4 months. Mean time between measurements was 6.45 months. Mean SHIM and ADAM scores at presentation were 23.5 and.1.23, respectively. Fourteen men had semen analysis while taking finasteride and also after its discontinuation. Twelve had a single semen analysis after discontinuation. Two of the 14 had two semen analyses performed after discontinuation; the two analyses were averaged for the two analyses for these men; mean time between measurements was 6.45 months. For the 14 men, ejaculate volume did not change while they were taking finasteride and after discontinuation, but sperm concentration increased significantly. Sperm motility increased, but not to a significant degree. Sperm morphology also showed no significant changes. A significant increase was noted in sperm count after finasteride discontinuation (an average of 11.6-fold higher); the increase was most dramatic in men with severe oligospermia, initially. "Our study indicates that finasteride is associated with subfertility in some men and that the adverse effect of finasteride is reversible for most of the men who present with infertility," concluded Samplaski et al. Address correspondence to Keith Jarve, MD, Department of Surgery, Mount Sinai Hospital, University of Toronto, 60 Murray Street, 6th floor, Box 19, Toronto, Ontario, Canada M5T 3L9; e-mail: kjarvi@mtsinal.on.ca. PCOS Evaluation of Ovarian Function in 35- to 40-year-old Women with Disease For ages 35 to 40 years, women with polycystic ovary syndrome (PCOS) have gonadotropin secretion that differs from that of women without the disease, according to a study from Chile. Research suggests that some features of PCOS may improve with aging (Elting et al., 2000; Brown et al., 2011; Carmina et al., 2012). In addition, during their reproductive age, women with PCOS have significantly higher ovarian volume, number of antral follicles, and other ovarian reserve markers (Piltonen et al., 2005; Mulders et al., 2004; Hudecova et al., 2009). The aim of this study was to evaluate gonadotrophin secretion, ovarian steroid production, and ovarian reserve in PCOS women during the onset of reproductive decline, in order that their ovarian function at this age might be characterized. "These observations suggest that during late reproductive age, gonadotrophin secretion in women with PCOS is clearly different from that observed in control women and may also differ from that of younger PCOS patients," stated de Guevara et al. ("Evaluation of ovarian function in 35- to 40-year-old women with polycystic ovary syndrome," EJOGR, 2013;170:165-170).
  5. 5. Fertility Weekly - April 7, 2014 - Page 5 The current study was part of a larger ongoing project; only those who fulfilled inclusion criteria were included in this study. Study subjects were 40 women with PCOS, ages 35 - 40 years, and 35 control women (Cw) attending preventive medical examinations, matched for age, weight and BMI (range 20 - 35 kg/m2 ). PCOS diagnosis was made according to NIH consensus criteria (Zawadzky and Dunaif, 1992) when patients were in early reproductive age. The patients took part in previous studies; inclusion criteria were previously described (Sir- Petermann et al., 2009; Crisosto et al., 2012). Controls and PCOS women were studied 3 - 7 days after menstruation; those without menstrual bleeding underwent ultrasound examination and had serum progesterone (P) evaluation. On day 3, PCOS and control women underwent complete physical examinations, and transvaginal ultrasounds were conducted. Ovarian volume was then calculated, and the total number of 2 to 9 mm follicles from both ovaries was determined. On day 4, all participants underwent a GnRH analogue test with 10 µg/kg leuprolide acetate as previously described (Ibanez et al., 1997; Sir-Petermann et al., 2007). Serum LH and FSH were measured before and 3 h after leuprolide. Serum testosterone, androstenedione, 17-OHP and oestradiol concentrations were determined at baseline and 24 h after leuprolide (day 5). SHBG, progesterone, AMH and inhibin B were measured in the fasting sample prior to leuprolide administration (day 4). FAI was then calculated. Oral glucose tolerance tests were performed after a 12-h overnight fast. Blood samples were drawn for glucose and insulin concentration measurements before and 30, 60, 90 and 120 min after the glucose load. Assays were used to determine hormone levels. Statistical analysis utilized STATA 1.0 software and included Shapiro-Wilk test, Mann- Whitney test, and χ2 test. Data were given as median and range, and P < 0.05 was considered significant. Clinical characteristics of the control and PCOS groups differed significantly (P < 0.05) in the percentage of women with regular menses (100% vs. 22.5%, respectively), parity (2 vs. 1, respectively), and hirsutism (2.0 vs. 12, respectively). PCOS women (PCOSw) had significantly higher basal and peak levels of 17-OH progesterone, androstenedione, and testosterone. SHBG levels were significantly lower in PCOSw than Cw. Peak oestradiol was significantly higher in PCOS women than controls, as well (199.0 vs. 127.9; P < 0.05). Basal and post-stimulation LH concentrations were similar in the two groups, but basal and post- stimulation FSH levels were significantly lower in the PCOS group. AMH concentrations were significantly higher in PCOSw. PCO morphology was seen by ultrasound (Rotterdam criteria, 2004), in 55.0% of PCOSw studied. Ovarian volume was 5.6 cc in controls vs. 10.0 cc in PCOS women (P < 0.05). Number of follicles was also significantly higher in PCOS at 14 vs. 7 in the controls (P < 0.05). "Our data show that, during the 35- to 40-year-old period, women with the classical form of PCOS identified during early reproductive age have a reproductive profile that is clearly different from that observed in healthy women," wrote the researchers. Address correspondence to Laboratory of Endocrinology, Department of Medicine, West Division, school of medicine, Las Palmeras 299, Interior Quinta Normal, Casilla 33052, Correl 33, Zip Code 8320000, Santiago, Chile; e-mail: tsir@med.uchile.cl, tsir@vtr.net (T. Sir- Petermann). Human Polycystic Ovaries Protein Expression of LHCG Receptor and 17αααα-hydroxylase/17- 20- lyase The proportion of theca cells from anovulatory polycystic ovaries (PCOs) that express LHCG receptor protein (HCGR) is higher in polycystic ovaries (PCO) than in normal ovaries, reports a multi-center study. Androgen excess is the biochemical marker of polycystic ovary syndrome (PCOS). Luteinizing hormone (LH), which is the major endocrine factor, drives androgen secretion of theca cells. Theca cells have higher expression of mRNA for LHCG receptor (LHCGR) compared with control theca cells. In addition, theca cells exhibit over-expression of steroidogenic factors, such as steroidogenic acute regulatory protein (STAR), cholesterol side-chain cleavage
  6. 6. Page 6 - Fertility Weekly - April 7, 2014 (CYP11A1), and act as a key enzyme in androgen synthesis, 17 - hydroxylase/17, 20-lyase (CYPA1) (Gilling-Smith et al., 1997; Jakijuik et al., 2001; Wickenheisser et al., 2005). The goal of the current multi-center study by F.V. Comim and colleagues was to determine whether expression of LHCGR protein and key enzymes in the androgen biosynthetic pathway differ between normal human and polycystic ovarian tissue. "LHCGR and 17α-17-20 - lyase (CYP17A1) protein levels are increased in polycystic ovaries (PCOs)," wrote Comim et al. ("Increased protein expression of LHCG receptor and 17{{alpha/17-20- lyase in human polycystic ovaries," HR, 2013;28(11):3086-3092). Archived human ovary sections were removed from patients aged < 50 years. Three groups were defined: normal women, ovulatory PCO, and anovulatory PCO, as described previously in detail (Stubbs et al., 2005, 2007). Twenty-six human ovaries were obtained from women with ovulatory PCOS (n = 11), anovulatory PCOS (n = 5) and normal women without PCOS (n = 10). Follicle stages were classified as previously described (Stubbs et al., 2005, 2007). Atresia in antral follicles was defined according to Gougeon's (1996) classification. LHCGR, CYP17A1, 3βHSD5 was determined by immunohistochemistry using a protocol previously described in studies of non-primate animal models (Teerds and Dorrington, 1995; Peters et al., 2001; Schoemaker et al., 2002). Sections were examined with a microscope, and images were captured with a digital camera. Pictures were taken at the same microscope settings for each experiment and at 10, 20, 40 or 60 times magnification. Statistical analysis utilized Excel (.xls), Instat 3, and Prism6 software. Student's t-test, Mann-Whitney test, Kruskal-Wallis test, and Dunn's multiple comparison test were performed, as appropriate. Normally distributed data were given as mean ± SD, and skewed data were given as median plus interquartile range (IQR). P ≤ 0.05 was considered significant. In total, 96 follicles were analyzed: 25 from normal ovaries, 58 from ovulatory PCO, and 13 from anovulatory PCO. The proportion of cells that stained for LH in follicles was similar for ovulatory women with PCO and normal women. A higher proportion of theca cells from anovulatory PCO expressed LHCGR compared with controls (P = 0.04). The authors identified immunoreactivity for CYP17A1 protein in the cytoplasm of thecal cells, theca-lutein and granulosa-lutein cells of the corpus luteum, and some in dispersed interstitial cells in ovarian stroma. Altogether, 26 follicles (1206 theca cells) in normal ovaries and 58 follicles (3052 theca cells) from PCO were analyzed. Proportions of theca cells that expressed CYP17A1 were similar between controls and PCO, but staining intensity increased in follicles from both PCO groups compared with normal ovaries. The proportion of strong staining (++) for CYP17A1 in theca cells from PCO follicles was (mean, IQR) 0.34 (0.19 - 0.50) compared with 0.13 (0.04 - 0.25) in normal ovaries (P = 0.01). Density of expression, as measured in optical density arbitrary units, was significantly higher in PCO theca cell layers than in ovaries in normal women. Theca cells and theca-Lutein cells displayed immunolabelling for 3βHSD11 protein, which was also faintly observed in antral GCs. For the present study, 9 follicles (274 theca cells) in normal ovaries, along with 60 follicles (1506 theca cells) in PCO ovaries were examined. Similar proportions of theca cells in normal and PCO ovaries expressed 3βHSDII protein. Quantification of 3βHSD11 protein staining confirmed that the level of expression was similar in PCO (0.16 ± 0.03) and controls (0.13 ± 0.03). Positive labelling for 17βHSD type 5 were identified in theca and GCs in antral follicles, and theca-lutein and granulosa-lutein cells in corpus luteum. A total of 23 follicles (1948 theca cells) in ovaries from normal women and 68 follicles (4860 thecal cells) in PCO ovaries were analyzed. Expression of 17βHSD5 protein was similar in theca cells from PCO and normal ovaries. "The key findings of this study were the increased expression of both LHCGR and CYP17A1 protein in PCO compared with normal ovaries, emphasizing the importance of both factors in the etiology of androgen excess in PCOS," concluded Comim et al. Address correspondence to S. Franks, Institute of Reproductive and Development Biology, Imperial College London, London, UK; e-mail: s.franks@imperial.ac.uk.
  7. 7. Fertility Weekly - April 7, 2014 - Page 7 Endometrial Hyperplasia LG-IUS vs. Oral Progestogen Treatment Use of the levonorgestrel-releasing intrauterine system (LNG-IUS) leads to higher regression rates and lower hysterectomy rates than are achieved with oral progestogens in the treatment of endometrial hyperplasia (EH), according to a study from the United Kingdom. EH is the precursor of endometrial carcinoma, which is the most common gynecological malignancy in the western world (Bray et al., 2005). Hysterectomy has traditionally been recommended for CH cases, but may not be the best option in sight of the potential risks, particularly for older or obese patients and those with significant co-morbidities. In these cases such as these, medical management is recommended (Clark et al., 2006). A national survey showed that over 85% of gynecologists treat CH with the LNG-IUS or oral progestogens (Gallos et al., 2011). A meta-analysis of observational studies showed oral treatment is inferior to LNG-IUS in treatment of EH (Gallos et al., 2010). This study aimed to determine and compare the regression and hysterectomy rates for women treated with LNG-IUS and those treated with oral progestogens for EH. "The LNG-IUS achieves higher regression and lower hysterectomy rates than oral progestogens in the treatment of complex and atypical hyperplasia," wrote Gallos et al. ("LNG-IUS versus oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study," HR, 2013;28(11):2966-2971). This study included all women diagnosed with CH or ACH who underwent treatment with LNG-IUS or oral progestogens in a tertiary referral hospital. Women were reviewed in the authors' gynecology outpatient clinic after diagnosis and were offered the LNG-IUS, oral progestogens (3 - 6 months) or hysterectomy as part of routine clinical practice. Women who were diagnosed with ACH were offered a hysterectomy. Those women who declined surgery or were medically unfit to undergo surgery were offered either the LNG-IUS or oral progestogens. Recruitment for women treated with LNG-IUS was prospective and ran from August 1998 to December 2010. Prospective recruitment for women treated with oral progestogens began in August 2008. Women with CH and ACH who were treated with oral progestogens from August 1998 until August 2008 were invited for long-term follow-up, which has continued until now. Statistical analysis utilized Mann-Whitney U-test, Pearson χ2 test, logistic regression analysis to compute odds ratios (ORs) with their 95% confidence intervals (CIs), Cox proportional hazards model, and Kaplan-Meier estimates. STATA v.12.1 software was used for analysis. After the authors' exclusions were made, the study group was made up of 250 women int he LNG-IUS group and 94 in the oral progestogen group. After exclusions, the final group consisted of 250 women in the LNG-IUS group and 94 in the oral progestogen group. Mean length of follow-up was 66.9 ± 35.1 months in the LGN-IUS group and 87.2 ± 54.5 months in the oral progestogen group; treatment lasted for 3 (29.8%, 28/94), 6 (63.8%, 60/94), or 12 months (6.4%, 6/94). Baseline characteristics were evaluated for the two groups and were found to be similar for all variables except age and menopause. Women in the LNG-IUS group were older (mean 52.7 years ± SD 10.6 vs. 48.5 ± 11.6, P = 0.001) and more often menopausal (52.4%, 131/250 vs. 33%, 31/94, P < 0.001. BMI and endometrial thickness were not available for all women. Hyperplasia regressed in 94.8% and 84% of LNG-IUS and oral progestogen patients, respectively (P = 0.001). Regression rates were significantly higher with LNG-IUS treatment than oral progestogen treatment for CH (OR = 3.03, 95% CI 1.1 - 8.35, P = 0.032), but not for ACH (OR = 3.73, 95% CI 0.85 - 16.44, P = 0.082). Regression rates were greater for CH than ACH for the LNG-IUS group (96.5, 221/229 vs. 76.2%, 16/21, P < 0.001) and the oral progesterone group (90.1%, 73/81 vs. 46.2%, 6/13; P < 0.001). Hysterectomy rates were significantly lower in the LNG-IUS group versus the oral group during follow-up (22.1% 55/250 vs. 37.2%, 35/94, ($% = 0.48, 95% CI 0.29 - 0.8, P < 0.004). Ten women were diagnosed with cancer during follow-up; 6 were originally treated with LNG-IUS (6/250, 2.4%) and 4 with oral progestogens (4/94, 5.3%, P = 0.361). Logistic regression showed age to be
  8. 8. Page 8 - Fertility Weekly - April 7, 2014 independently correlated with treatment modality and regression outcome. Therefore, the authors adjusted the OR for the outcomes of EH regression and hysterectomy. Regression was higher with LNG-IUS at 12, 18 and 24 months' follow-up (hazard ratio 1.48, 95% CI 1.14 - 1.04, P = 0.002). After 12 months of follow-up, the chance of regression fell to 57.4% with the LNG-IUS and 38.9% with oral progestogens; the proportions diagnosed with cancer were 4.4% and 11.1%, respectively. Regression was achieved in24 months in 93.2% of LNG-IUS women and 91.1% of oral progestogen women by the same point in time. Survival analysis showed that hysterectomy was less likely to occur in women treated with LNG-IUS from 12 up to 60 months of follow-up (hazard ratio 0.56, 95% CI 0.37 - 0.86, P = 0.007). "This study finds that complete regression of EH occurs more often in women treated with the LNG-IUS compared with women treated with oral progestogens, with fewer hysterectomies," concluded Gallos et al. Address correspondence to Ioannis D. Gallos, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham Women's hospital Birmingham B15 2TG, UK; e-mail: ioannis.gallos@nhs.net. Endocrinology Endocrine Effects of hCG Supplementation to Recombinant FSH during COS for IVF Human chorionic gonadotrophin (hCG) supplementation to recombinant FSH during controlled ovarian stimulation (COS) resulted in a dose-related response for androgens, progesterone, and 17-OH-progesterone, states a study from Belgium. Studies have shown that LH/hCG influences steroidogenesis in the production of androgens and oestradiol during COS (Filicori et al., 2005; Smitz et al., 2007), but the effect of the LH component on preovulatory progesterone levels is a subject of debate. It seems that increases in progesterone, even slight ones, result in impaired endometrial receptivity (Labarta et al., 2011; Ubaldi et al., 1997; Van Baerenbergh et al., 2011) and lower live birth rates (Bosch et al., 2010; Devroey et al., 2012; Ochsenkuhn et al., 2012; Xu et al., 2012). The goal of the current study was to analyze the endocrine response in relation to the ∆-4 and ∆-5 pathways of ovarian steroidogenesis after different doses of hCG supplementation. "Supplementation with hCG resulted in a dose-dependent increase in the levels of both progesterone and 17-OH-progesterone. The augmentation of both hormones in relation to increasing hCG supports the concept that addition of hCG does not lower, but rather increases, preovulatory progesterone levels," wrote Thuesen et al. ("Endocrine effects of hCG supplementation to recombinant FSH throughout controlled ovarian stimulation for IVF: a dose-response study," CE,2013;79:708-715 Included in the study were 62 patients who were randomized, along with 60 patients for the per protocol (PP) analysis. Patients were 'standard' patients scheduled for IVF. Women were 35 - 37 years old. A detailed description of the study population and the clinical outcome of the study was published previously (Thuesen et al., 2012). On cycles Days 2 - 5, patients were assessed for eligibility and had endocrine testing (s-FSH, s-LH, s-AMH). Down-regulation was confirmed, after which patients were randomized to one of four treatment arms: (i) control arm (Dose 0): 150 IU/day of rFSH alone, (ii) hCG low dose (Dose 50): 150 IU/day of rFSH + 50 IU/day of hCG, (iii) hCG medium dose (Dose 100): 150 IU/day of rFSH + 100 IU/day of hCG and (iv) hCG high dose (Dose 150): 150 IU/day of rFSH + 150 IU/day of hCG. Subjects were treated with rFSH 150 IU/day in a fixed-dose regimen on Day 1 of stimulation. On Day 1 of stimulation, supplementation with different doses of hCG began. HCG at 10,000 IU s.c. was administered to initiate final follicle maturation once ≥ 3 follicles of }}>=}} 17 - 18 mm diameter were observed. Oocytes were retrieved 36 h post-hCG, after which IVF was performed. Transfer of one embryo was conducted on Day 3 after oocyte retrieval. Blood samples were drawn for assays of baseline FSH, LH and AMH on cycle Days 2 - 5. HCG and oestradiol, FSH and LH were measured prior to the daily drug injection in stimulation Days 1, 3, and 6 and every second day thereafter until the day of hCG. Progesterone was measured on
  9. 9. Fertility Weekly - April 7, 2014 - Page 9 Days 1, 6, and the day of hCG triggering. On days 1, 6 and on the day of hCG triggering, 17- OH-progesterone, DHEA, androstenedione, testosterone, SHBG and AMH were determined. Sample size calculation and randomization were described previously (Thuesen et al., 2012). Statistical analysis utilized analysis of variance (ANOVA), Kruskal-Wallis test, Bonferroni correction, the Greenhouse-Geisser correction, and logarithmic transformation. Data were given as mean and 95% confidence interval. P < 0.05 was considered significant, and SPSS v.18.0 software for Windows was used. Randomization of the 62 included patients into hCG dose groups was: Dose 0 (n = 16), Dose 50 (n = 15), Dose 100 (n = 16), and Dose 150 (n = 15). Results are based on the 60 patients who fulfilled PP criteria. The treatment groups did not differ significantly in demographics, clinical and sonographic characteristics, and endocrine profile at screening on cycle Days 2 - 5 as previously stated (Thuesen et al., 2012). The number of different-sized follicles in the four groups did not differ significantly. The authors compared multiple time-points in the four groups and found an overall significant effect of time for all the different hormones. The hCG dose significantly affected the hormone level during stimulation for progesterone, 17-OH-progesterone, androstenedione, testosterone, and FAI. Serum progesterone levels on the day of hCG differed significantly between treatment arms. Progesterone increments increased significantly with increasing doses of hCG from 49% (CI: 18 - 90%) in Dose 0 to 160% (95 - 247%) in Dose 150 (P = 0.02). Levels of 17-OH- progesterone increased significantly with increasing dose of hCG compared with the Dose 150 group; a significant dose-related increase with increments was detected from 223% (CI: 132 - 350%) in Dose 0 to 614% (CI: 320 - 1113%) in Dose 150 (P = 0.02). DHEA levels did not differ between groups; however, on the day of hCG trigger, DHEA increased 6 - 20% compared with the start of stimulation in all dose groups (P = 0.75). Androstenedione increased significantly with higher hCG doses; the incremental increase was 91% (CI: 48 - 145%) to 340% (CI: 242 - 468%) from Dose 0 to Dose 150 (P < 0.001). Testosterone increments increased significantly when hCG dose was increased, ranging from 95% (CI: 50 - 153%) in Dose 0 to 338% (CI: 188 - 467%) in Dose 150 (P < 0.01). FAI levels followed the same pattern; an incremental increased occurred from 48% (CCI: 20 - 81%) in Dose 0 to 186% (CI: 86 - 317%) in Dose 150 (P < 0.01). Peak preovulatory levels of oestradiol were twice as high in Dose 100 and Dose 150 compared with Dose 0 (P = 0.09). AMH levels did not differ between groups at any point during stimulation. Serum hCG (OI/l) layers on the day of hCG trigger were Dose 0: < 0.1, Dose 50: 3.1 (CI 2.6 - 3.6), Dose 100: 5.5 (CI: 4.1 - 7.4) and Dose 150: 11.0 (CI 8.9 - 13.6) (P < 0.001) (Thuesen et al., 2012). FSH and LH levels did not vary between groups. "Supplementation with doses of hCG up to 150 IU/day from the first day of stimulation resulted in a dose-dependent response for androstenedione testosterone, progesterone and 17-OH- progesterone, whereas the aromatase system producing oestrogens seemed saturated with androgen precursors using hCG doses above 100 IU/day," concluded the researchers. Address correspondence to Lea Thuesen, The Fertility Clinic, Rigshpitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; e-mail: lea@theussen.com. Ovulation Induction Letrozole with Gonadotropins is Effective for Patients with Previous CC Cycle Failure Using letrozole in addition to gonadotropins is effective for ovulation induction (OI) in patients with a history of clomiphene citrate (CC) cycle failure, state researchers in Turkey. Aromatization is the final phase of estrogen synthesis and is a good place for selectively inhibiting estrogen synthesis for OI (Hong and Chen, 2006). There has been a recent increase in the use of aromatase inhibitors for OI (Requena et al., 2008). Because it does not cause estrogen receptor blockage, it causes no adverse effects on the endometrium and cervical mucus (Casper, 2003; Mitwally and Casper, 2004). In addition, one study demonstrated the safety of letrozole for infertility treatment in regards to congenital anomaly (Tulandi et al., 2006).
  10. 10. Page 10 - Fertility Weekly - April 7, 2014 In this prospective study, Ulku Ozdemir and colleagues compared cycle properties of OI with gonadotropin by itself or in combination with letrozole in patients with a history of CC failure ("Letrozole Usage Adjuvant to Gonadotropins for Ovulation Induction for Patients with Clomiphene Citrate Failure," Arch Gynecol Obstet, 2013;288:445-448). "Adding letrozole to gonadotropin in OI cycles decreases total gonadotropin dose and induction duration without any adverse effects on endometrial thickness," wrote Ozdemir et al. A total of 40 patients with three or more CC cycle failures were included in this study. Twenty patients received 2.5 mg letrozole on days three through seven of the menstrual cycle and rFSH beginning on day give. The remaining 20 patients received only rFSH beginning on day three. The groups were compared in regards to OI duration, gonadotropin dose, endometrial thickness, estradiol (2) levels on day of hCG administration and follicle count. The total rFSH dose, the E2 levels on day of hCG and >18 mm follicle count was much lower and OI duration was considerably shorter in the rFSH + letrozole group. The mean endometrial thickness was similar between the two groups. "Letrozole seems to be an effective agent for OI," wrote Ozdemir et al. "The decrement of gonadotropin dose and E2 levels, high monoovulation rates, short half life, no antiestrogenic effects, clearance before implantation from the body (half life is approximately 48 h) are the advantages of letrozole when compared to CC." Address correspondence to A.N. Cakir Gungor, Dr. Zekai Tahir Burak Education and Research Hospital, Ankara, Turkey; E-mail: dr-aysecakir@hotmail.com Endometriosis Stage III/IV Associated with Poor IVF Treatment Outcome Patients with severe endometriosis have poor in vitro fertilization (IVF) treatment outcomes, state researchers in the United Kingdom. Research shows that up to five percent of fertile women and up to 40% of infertile women have endometriosis (Ozkan et al., 2008; Houston et al., 1987). Women with endometriosis frequently have to turn to IVF to conceive; more than one third of IVF patients have endometriosis (Damewood, 1989). Studies have shown that the severity of endometriosis may direct affect the success of IVF (Olivennes, 2003; Pal et al., 1998). However, the relationship between endometriosis and IVF outcomes is unclear (Revised American Fertility Society Classification of Endometriosis, 1985; Barnhart et al., 2002). To further examine the above information, H.M. Harb and colleagues conducted a study in which they sought to determine the relationship between endometriosis and IVF outcome ("The Effect of Endometriosis on in Vitro Fertilization Outcome: A Systematic Review and Meta- analysis," British Journal of Obstetrics and Gynecology, 2013;120:1308-1320). "The presence of severe endometriosis (stage III/IV) is associated with poor implantation and clinical pregnancy rates in women undergoing IVF treatment," wrote Harb et al. The authors conducted literature reviews using MEDLINE, EMBASE, Cochrane Library and Web of Science (inception, December, 2012). Selection criteria included studies that compared IVF outcome in women with and without endometriosis. Patients were grouped according to stage of endometriosis. The outcomes examined included fertilization, implantation, clinical pregnancy, and live birth rates. Study selection was performed independently by two reviewers. Quality assessment was performed using the Newcastle- Ottawa Quality Assessment Scale. Data extraction was performed independently by two reviewers. A meta-analysis was conducted of relative risks (RR) from individual studies. Twenty-seven observational studies with a total of 8,984 women were included. Meta- analysis of these studies revealed that fertilization rates were lower in stage I/II of endometriosis [RR=0.93, 95% confidence interval (95% CI) 0.87-0.99, P=0.03]. Lower implantation rates [RR=0.79, 95% CI 0.67-0.93, P=0.006] and clinical pregnancy rates [RR=0.79, 95% CI 0.69- 0.91, P=0.0008] in patients with stage III/IV endometriosis who were undergoing IVF treatment.
  11. 11. Fertility Weekly - April 7, 2014 - Page 11 "A demonstration of reduction in IVF clinical pregnancies in women with stage III/IV endometriosis does not necessarily mean that treatment of endometriosis will restore the clinical pregnancy rates to the level expected in women without endometriosis," wrote Harb et al. "Therefore, this evidence does not justify advocating medical or surgical treatment of endometriosis for these women, as a favourable risk benefit analysis of intervention in this clinical context is currently absent." Address correspondence to Prof. A. Coomarasamy, School of Clinical and Experimental Medicine, University of Birmingham, Academic Department, 3rd Floor, Birmingham Women's Hospital Foundation Trust, Metchley Park Road, Edgbaston, Birmingham B15 2TG, UK; E- mail: a.coomarasamy@bham.ac.uk ICSI Message Carried by Sperm Cannot be Altered Intracytoplasmic sperm injection (ICSI) yields a higher fertilization rate for men with obstructive azoosermia (OA) versus men with non-obstructive azoospermia (NOA), though clinical pregnancy and miscarriage rates are similar in the two groups, state researchers in Turkey. Azoospermia is characterized by the absence of spermatozoa in the ejaculate following the examination of centrifuged semen on two or more occasions (Donoso et al., 2007). Azoospermia is divided in OA and NOA. Sperm can be retrieved in almost all men with OA, but only in half of men with NOA when no preliminary selection of patients regarding histopathology has been performed (Tournaye et al., 1997). ICSI offers a way for azoospermic men to have biological children; however, the success rates according to etiology of azoospermia are unclear. In this retrospective study, Ayse Celikten and colleagues sought to compare the results of ICIS cycles in OA and NOA patients ("Intracytoplasmic Sperm Injection Outcomes of Obstructive and Nonobstructive Azoospermic Men," Arch Gynecol Obstet, 2013;288:683-686). "ICSI overcomes the obstacles related to the sperm in its function as a carrier but it cannot alter the message carried by the male gamete," reported Celikten et al. A total of 211 azoospermic men were included this study. First ICSI cycle parameters were examined. The main outcome measures included the average fertilization rate, implantation rate, pregnancy, and miscarriage rates. The patients with OA had higher fertilization and biochemical pregnancy rates than did the patients with NOA. However, clinical pregnancy and miscarriage rates were similar between the two groups. "Adequate fertilization, cleavage and pregnancy rates are to be expected when ICSI is performed to azoospermic men with a normal sperm production, such as OA ones," wrote Celikten et al. "However, lower fertilization rates are achieved when ICSI performed with sperm from men with NOA." Address correspondence to A.N.C. Gungor, Dr. Zekai Tahir Burak Women Health and Research Hospital, Ankara, Turkey; E-mail: dr_aysecakir@hotmail.com IVF-ICSI GnRH Agonist Treatment Yields Lower Pregnancy Rates than Antagonist Treatment GnRH agonist treatment results in higher serum estradiol (E2) and progesterone levels and produces lower pregnancy rates compared to antagonist treatment, state researchers in Turkey. In vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) has been used for many years and treatment success is dependent upon a number of factors. Retrieved oocyte number (RON) and follicular maturation are important to a successful pregnancy. The use of GnRH agonists in controlled ovarian hyperstimulation (COH) increased pregnancy rates (Fleming et al., 1982). Later, GnRH antagonists were introduced for controlled ovarian hyperstimulation
  12. 12. Page 12 - Fertility Weekly - April 7, 2014 (COH). The advantages of antagonist treatment are the short stimulation period and low gonadotrophin dosages (Nikolettos et al., 2001). Some researchers have reported lower clinical pregnancy rates with GnRH antagonist cycles (Al-Inany and Aboulghar, 2002), while others suggest live birth rates are higher with antagonist treatment compared to agonist protocol (Kolibianakis et al., 2006; Al-Inany et al., 2011). Due to the conflicting results of previous reports, Mustafa Kara and colleagues conducted a study in which they compared GnRH agonist and antagonist protocols ("Comparison of GnRH Agonist and Antagonist Protocols in Normoresponder Patients Who Had IVF-ICSI," Arch Gynecol Obstet, 2013;288:1413-1416). "GnRH agonist treatment seems to be associated with higher serum E2 and progesterone levels and resulted in lower pregnancy rates than antagonist treatment," reported Kara et al. A total of 195 women were treated with agonist or antagonist protocol based on the clinician's and patient's preference. GnRH agonist (n=77 patients) and antagonists (n=118 patients) were administered. Retrieved oocyte number (RON), metaphase two oocyte number (MON), E2 and progesterone levels on day of hCG, as well as fertilization rate were significantly higher in the agonist group compared to the antagonist group (P<0.05). Implantation rate (IR), clinical pregnancy rate (CPR), and ongoing pregnancy rate (OPR) were significantly higher in the antagonist group compared to the agonist group (P<0.05). However, no significant difference was observed between the two groups regarding total FSH. "In conclusion, although the higher RON and MON yielded in the agonist treatment, CPR and OPR were better in antagonist group," wrote Kara et al. "Having lower serum E2 and progesterone levels on hCG day could play a key role in antagonist cycle to obtain more successful IVF outcome than agonist cycle," continued the authors. "Our results demonstrate that lower E2 and P may increase the IVF-ICSI success." Address correspondence to M. Kara, Department of Obstetrics and Gynecology, Bozok University Medical Faculty, Adnan Menderes Boulevard No 44, 66200 Yozgat, Turkey; E-mail: opdrmustafakara@hotmail.com or Mustafa.kara@bozok.edu.tr Subscribe Now! Get Fertility News and Research Every Week Fertility Weekly Subscription Form Yes! I want to access timely & comprehensive international information in Fertility Weekly (1 year – 45 issues) Enter my subscription as follows: PDF: Worldwide – One year, single user, Email delivery PDF..............$659 PRINT: North America – One year, print publication ................................$699 All others – One year, print publication.........................................$799 PRINT & PDF: North America – One year, print and Email PDF.........................$739 All others – One year, print and Email PDF................................$839 Multi-copy and multi-year discount available. Please fax, call or Email subs@fertilityweekly.com Here is my check for US$ ________ , made payable to: Fertility Weekly, Inc. 2451 Cumberland Pkwy Suite 3374 Atlanta, 30339 GA USA Charge my: Visa MC Amex Discover ____________________________ ______/______ Card # Expiration Date ___________________________________________________ Signature Four Easy Ways You Can Order! 1. Mail this order form with payment to: Fertility Weekly, Inc. 2451 Cumberland Parkway, Suite 3374 Atlanta, GA 30339 USA 2. Charge your order by calling 1-888-662-5048 (404-419-6701 outside US & Canada) 3. Sign-up at www.fertilityweekly.com 4. Fax this order form to 404-419-6702 _________________________________________________ Name _________________________________________________ Institute/Company/Organization _________________________________________________ Address _________________________________________________ Address 2 _________________________________________________ City State/Province _________________________________________________ Zip/Postal Code Country _________________________________________________ Phone Fax Money-Back Guarantee If you are not completely satisfied with your subscription, you may cancel and we’ll refund your money on all unmailed issues. 1. 2. 3.
  13. 13. Page 13 Conference Abstracts . . . April 7, 2014 Information About Research Worldwide . . . Compiled by Vinaya Kasibhatla “Increased Breast Cancer Risk after Multiple Implantation in IVF: A Cohort Study.”1E. Groeneveld, 2I.M. Krul, 2M. Spaan, 2A.W. van den Belt-Dusebout, 2T.M. Mooij, 1M.J. Lambers, 1J.W.R. Twisk, 2M. Hauptmann, 3C.W. Burger, 1P.G.A. Hompes, 2F.E. van Leeuwen, 1C.B. Lambalk, and on behalf of. 1VUMC, Amsterdam, The Netherlands, 2The Netherlands Cancer Institute, Amsterdam, The Netherlands, 3Erasmus Medical Centre, Rotterdam, The Netherlands. According to an abstract presented by the authors at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology in London, England, July 7-10, 2013, "Study question: Are women who were treated with IVF and gave birth to multiples at increased risk to develop breast cancer compared with mothers of singletons and women who remained nulliparous? Summary answer: IVF-treated women who gave birth to multiples are at increased risk of breast cancer compared with mothers of singletons and nulliparous women. Our study indicates that it is not the multiple pregnancy itself, but a maternal trait that is related to increased implantation potential and increased breast cancer risk. What is known already: Increased concentrations of estrogens and alpha-fetoprotein during a multiple pregnancy have been linked to contradictory epidemiologic evidence of both an increased and decreased subsequent risk of maternal breast cancer. The observed differences in breast cancer risk are generally assigned to the multiple pregnancy itself. Instead, a maternal trait causally related both to increased implantation potential and to an altered risk of breast cancer may be involved. Study design, size, duration: We used data from a large Dutch nationwide cohort of 19,861 women who received IVF or ICSI treatment between 1983-1995: the OMEGA study. Between 1997-1999 patients received a questionnaire inquiring about subfertility treatment, reproductive history (number of pregnancies), pregnancy outcome (singleton/twin, alive/stillborn, date of delivery) and (family) history of cancer. Participants/materials, setting, methods: We selected patients who filled in the risk questionnaire completely. Breast cancer cases between 1989-2009 were ascertained through linkage with the population-based Netherlands Cancer Registry (NCR). Hazard ratios (HR) and 95% confidence intervals (95%CI) for breast cancer risk were calculated using Cox proportional hazard models with time dependent variables. Main results and the role of chance: We included 12,589 women with complete risk factor questionnaires of whom 1,688 gave birth to multiples, 6,027 to singletons and 4,874 remained nulliparous. Mean duration of follow-up was 16.7 years. Breast cancer diagnosis was confirmed in 317womenofwhom105were nulliparous, 155 gave birth to singletons and 57 to multiples. Mothers of multiples were at increased breast cancer risk compared with mothers of singletons (HR 1.44 95%CI 1.06-1.97; adjusted for year of IVF treatment, number of IVF cycles, height and age first birth). Remarkably, only multiple pregnancies conceived after complete implantation of all transferred embryos (n = 415) were associated with increased breast cancer risk (n = 14, HR 1.86 95%CI 1.01-3.43), whereas multiple pregnancies conceived after incomplete implantation (n = 580) were not (n = 18, HR 1.31 95%CI 0.76-2.25). Limitations, reason for caution: The majority of women were premenopausal when they were diagnosed with breast cancer, therefore these conclusions do not account for postmenopausal breast cancer. Wider implications of the findings: These results need to be ascertained in larger studies before women with complete multiple implantation after IVF should be advised for routine screening imaging at an earlier age than is recommended for the general population."
  14. 14. Page 14 - Fertility Weekly - April 7, 2014 “Cyclophosphamide Triggers Follicle Activation Causing Ovarian Reserve 'Burn Out'; AS101 Prevents Follicle Loss and Preserves Fertility.”1H.Roness, 1L.Kalich-Philosoph, 1A.Carmely, 1M. Fishel-Bartal, 1H. Ligumsky, 1S. Paglin, 1I.Wolf, 1H.Kanety, 2B. Sredni, and 1D. Meirow. 1Sheba Medical Center, Ramat-gan, Israel, 2Bar Ilan University, Ramat-gan, Israel. According to an abstract presented by the authors at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology in London, England, July 7-10, 2013, "Study question: The mechanism behind chemotherapy-induced ovarian reserve destruction in young cancer patients is unknown. Understanding the mechanism behind follicle loss will enable the development of attenuating agents that can preserve fertility in young cancer patients. Summary answer: Cyclophosphamide (Cy) activates dormant follicle growth via the PI3K/AKT signaling pathway, leading to depletion of ovarian reserve. AS101 suppresses this pathway and prevents apoptosis of large follicles, inhibiting follicle activation and rescuing fertility in mice. What is known already: Chemotherapy drugs cause a reduction in primordial follicle (PMF) stockpiles, diminished ovarian weight, and ovarian atrophy. Chemotherapy is thought to destroy dormant PMFs via induction of apoptosis in the pre-granulosa cells and the oocyte, and via damage to ovarian stromal components. However, studies do not demonstrate apoptosis in vivo, in the dormant PMF population, only in granulosa cells of large preantral and small antral follicles. Study design, size, duration: Studies were conducted on 8 week and 5 day old female Balb/C mice. Treatments were intraperitoneal Cy 75-200mg/kg, AS101 10ug/mouse, and PBS for controls. Time course was 1, 3, and 7 days for ovarian analysis, and 26 weeks for the mating study. Total number of mice = 95. Participants/materials, setting, methods: Ovarian analysis endpoints: - differential follicle counts - immunohistochemical staining for TUNEL, Caspase 3, Ki67, AKTt, mTOR, Foxo3, rpS6; -Western blotting for AKT, mTOR, rpS6, and Foxo3; - AMH plasma levels. Mating study endpoints: - Pregnancy incidence - Litter size, total number of pups - Histology Main results and the role of chance: TUNELand Caspase3 staining showed that Cy does not destroy dormant PMFs by directly inducing apoptotic cell death. Apoptosis was observed only in growing follicles. Follicle counts and Ki67 staining showed that, shortly after Cy treatment, early growing follicles were undergoing proliferation. Analysis of the PI3K/PTEN/Akt pathway showed increased phosphorylation of activation proteins 24 hours post Cy treatment. Co- treatment Participants/materials, setting, methods: All patients continued treatment with CC for more than six ovulatory cycles with dosages varying from 50mg to 150mg per day on cycle days 3-7. Follicle monitoring was not done. Primary outcome was ongoing pregnancy. Main results and the role of chance: The 98 women who fulfilled the inclusion criteria underwent between one and six additional cycles with CC. For 34 of 98 women (35%), treatment resulted in an ongoing pregnancy, one of which was a twin pregnancy. 8 women (8%) conceived but had a miscarriage. The ongoing pregnancy rate per cycle was 9.3%. The median time to pregnancy was a total of 9 cycles. Limitations, reason for caution: The study was retrospective. Wider implications of the findings: If these results are confirmed in a prospective setting, continued treatment with CC after six cycles should be considered as the first choice treatment in women with WHO type II anovulation. Whether earlier use of gonadotrophins or intrauterine insemination is more cost-effective, should be studied in randomized clinical trials."
  15. 15. Fertility Weekly - April 7, 2014 - Page 15 “A Novel Method for Cryopreservation of Very Low Count Human Spermatozoa.”A. Stein, S. Hadar, E. Kaisler, B. Fisch, and H. Pinkas. Helen Schneider Hospital for Women Rabin Medical Center Beilinson Hospital, Infertility and IVF Unit, Petach Tikva, Israel. According to an abstract presented by the authors at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology in London, England, July 7-10, 2013, "Study question: To develop an efficient cryopreservation method for very low sperm count samples. Summary answer: The present data suggest that the employment of vitrification straw - Cryolock (AL-RAD, Israel) can be a useful tool for freezing very small number of human sperm cells. What is known already: The growing use of various surgical methods for testicular sperm retrieval in azoospermic patients, raises the need for an efficient cryopreservation method of very low count human spermatozoa. Current sperm cryopreservation methods are associated with loss of a considerable proportion of spermatozoa. A simple and useful sperm cryopreservation method can be beneficial not only for azoospermic man but for cases of extreme oligozoospermia as well Study design, size, duration: Our prospective study included 20 samples from very severe male factor patients and 10 TESE samples. Using cryolock (AL-RAD,Israel) a devise usually used for oocyte or embryo vitrification, the efficiency of two cryoprotectants and two freezing protocols was studied. Each experiment designed on the basis of results achieved previously Participants/materials, setting, methods: sperm was mixed with Test yolk buffer (TYB) or HEPES- glycerol - glucose solution (final ratio 1:1 vol/vol). 5 µl mixture aliquot was than placed on two cryolocks. One plunged directly into liquid nitrogen (LN) and the other exposed to LN vapors. Thawing: cryolock tip was immersed directly into warm medium Main results and the role of chance: In all twenty OTA samples, sperm were detected post thawing. Better survival rate was found when using TYB as cryoprotectant and exposure to liquid nitrogen vapor compared to HEPES- glycerol-glucose solution followed by directly plunging into liquid nitrogen (95%vs. 35%respectively) P< 0.0001. Based on this, very few spermatozoa (10-50 sperms) (15 samples) and TESE samples were frozen using only TBY as cryoprotectant and exposure to LN vapor. After thawing, sperm were identified in all 15 samples and at least one motile spermatozoon was detected in 14/15 samples (93%). Moreover, In 9 out of 10 frozen/thawed TESE samples (90%) sperm cells were found in the culture dish under the microscope, and in four (44%) of them, at least one motile spermatozoon was detected post thawing. Limitations, reason for caution: No limitation and no special equipment are needed. Wider implications of the findings: The present data suggest that Cryolock can be a useful tool for freezing not only female gametes or embryos but also for cryopreservation of very small number of human sperm cells. These findings can benefit men with extreme OTA samples as well as patients undergoing TESE/microTESE. However, further studies concerning various technical aspects are needed to improve the yield of this method for cryopreservation of individual sperm cells." “Euploid Embryos are Far More Likely to Undergo Blastulation than Aneuploid Embryos when Based on Single Blastomere Array Comparative Genomic Hybridization (CGH).”M. Vega, M. Keltz, and A. Breborowicz. Continuum Reproductive Center St. Luke's-Roosevelt Hospital Center, Obstetrics and Gynecology, New York, U.S.A. According to an abstract presented by the authors at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology in London, England, July 7-10, 2013, "Study question: Is blastulation rate associated with euploid embryo status? Summary answer: Euploid embryos appear to be three times more likely to undergo blastulation than aneuploid embryos among six to eight cell embryos undergoing blastomere biopsy and array CGH for Pregestational Genetic Screening (PGS). What is known already: Recent studies on trophoectoderm biopsies show a higher rate of euploid embryos at the blastocyst stage than the euploid rate previously reported from cleavage stage blastomere biopsies. However, it has historically been thought that aneuploid embryos are just as likely to undergo blastulation as euploid embryos. Study design, size, duration: Retrospective cohort study was performed on 44 cycles between January 2011 and December 2012 that underwent IVF and day three single cell blastomere biopsy with array CGH and PGS. Participants/materials, setting, methods: Subjects underwent IVF-ICSI and CGH at a university hospital based IVF center. All cleavage- stage embryos underwent single cell blastomere biopsy and fixation for microarray CGH and results were reported for all embryos on day 5. The percent of both euploid and aneuploid
  16. 16. Page 16 - Fertility Weekly - April 7, 2014 embryos were compared utilizing Fisher's exact test. Main results and the role of chance: Mean patient age among the 44 cycles was 37.2 (range 28-42).A total of 463 embryos were produced in 44 cycles from which 382 (82.5%) six to eight embryos were biopsied. Overall blastulation rate for all biopsied embryos was 32.0% which was not significantly different from a matched control group that did not undergo biopsy. The number of euploid and aneuploid embryos after biopsy was 106 (27.7%) and 276 (72.3%), respectively. 84 (79.2%) of the euploid embryos and 66 (23.9%) of the aneuploid embryos progressed to blastocyst stage. (p < 0.0001). However only 58/106 (54.7%) of the euploid embryos formed fully expanded or hatching blastocysts by day 5, and therefore would not have been able to undergo trophoectoderm biopsy. Limitations, reason for caution: Limitations include retrospective design and somewhat small study group. Additionally mosaicism in single cell biopsy could affect our outcomes. Wider implications of the findings: Our results suggest that euploid embryos are far more likely to undergo blastulation than aneuploid embryos. However there are still many aneuploid blastocysts that would be transferred in cycles without PGS. One advantage of day three biopsy is that only half of the euploid embryos in this study advanced enough for trophoectoderm biopsy on day five." “SIEDY Scale 3, a New Instrument to Detect Psychological Component in Subjects with Erectile Dysfunction.”1,3GIOVANNI CORONA, 1ELISA BANDINI, 1GIULIA RASTRELLI, 1HELEN CASALE, 2EMMANULE A JANNINI, 1EDOARDO MANNUCCI, 1GIANNI FORTI AND 1MARIO MAGGI. 1University of Florence, Florence Italy; 2University of L'Aquila, L'Aquila, Italy; 3Azienda Usl, Maggiore-Bellaria Hospital, Bologna, Italy. According to an abstract presented by the authors at the 10th International Congress of Andrology in Melbourne, Australia, February 23-26, 2013, "Background: We previously developed and validated a structured interview (SIEDY) dealing with the organic (Scale 1), relational (scale 2) and psychological (Scale 3) components of erectile dysfunction (ED). Objectives: To identify a pathological threshold for SIEDY Scale 3 and its correlates. Methods: A pathological threshold of SIEDY scale 3 score in predicting subjects with a medical history of psychopathology and using psychiatric drugs was identified through receiver operating characteristic (ROC) curve analysis, in a sample of 484 patients (Sample A). Sensitivity and specificity, along with possible interactions with biological and psychological correlates were verified in a further sample of 1275 patients (Sample B). Findings: In sample A, 39 (8%) and 60 (12.4%) subjects reported a positive medical history for psychiatric disturbances or for the use of psychotropic medication, respectively. The association with both conditions was present in 28 (5.8%) subjects. ROC curve showed that SIEDY scale 3 score predicts psychopathology with an accuracy of 69.5 ± 5.9% (p < 0.002), when a threshold of three was chosen. When the same threshold was applied in Sample B, it identified a higher ranking in free-floating anxiety, somatized anxiety and depressive symptom subscales, even after adjustment for confounders. In the same sample, pathological Scale 3 score was related to a higher risk of psychopathology, to the use of psychotropic drugs as well as with smoking and alcohol abuse, and elevated BMI. Conclusions: SIEDY represents an easy tool for the identification of patients with a relevant intra-psychic component who should be considered for psychological/psychiatric treatment." “Implementation of WHO 5th Ed. Laboratory Procedures for the Examination and Processing of Human Semen in a Clinical Pathology Laboratory.”1JULIE SELISKY-NATOLI, 1FENG-PING DONG AND 1,2ROBERT MCLACHLAN. 1Healthscope IVF Pathology-Reproductive Laboratories, Clayton, Australia; 2Monash IVF Healthbridge Private Hospital, Hawthorn, Australia. According to an abstract presented by the authors at the 10th International Congress of Andrology in Melbourne, Australia, February 23-26, 2013, "Aim: To assess practicality of implementing the (WHO) 5th Edition 2010 procedures for assessing human semen within a busy ART-associated laboratory performing approximately 2500 analyses annually across several sites. Methods and Results: Procedures were modified to prioritise time critical assessments including motility, pH and vitality, with sperm concentration, morphology, neutrophilic polymorphous leucocytes (WBC) and sperm antibodies assessed later. Sample availability was managed by allocation of morning appointments with patients producing
  17. 17. Fertility Weekly - April 7, 2014 - Page 17 samples on site. Pre-weighed sample jars were provided and semen volume determined by weight. Due to constraints of staff time, it was found necessary to adapt WHO 5th Edition guidelines as follows: reducing the number of sperm profiles counted for normal range vitality and morphology (from 400 to 200), a sperm antibody screening test where 100 sperm profiles for each antibody class were tested and then if >50% binding detected further profiles were counted (200 total), introduction of conversion factors for calculating sperm concentration to reduce potential error, WBC testing using Leucoscreen rapid detection kit rather than detection by ortho-toluidine blue procedure. Despite these modifications, the WHO assessment procedure has reduced laboratory throughput by approximately 20%. Conclusion: Implementing WHO 5th Edition procedures into a clinical service is achievable but some modifications were applied to normal range samples where reduced precision would be of no clinical importance. Nonetheless, the procedures still led to a 20% reduction in sample throughput. Laboratories claiming to use WHO methods ought make known any modifications to the strict WHO guidelines." “The Role of Sperm DNA Testing in the Clinic.”A. Giwercman, M. Bungum, and K. Oleszczuk. Skane University Hospital Malmo, Dept of Clinical Sciences Lund University Reproductive Medicine Centre Entrance 74, Malmo, Sweden. According to an abstract presented by the authors at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology in London, England, July 7-10, 2013, "Traditional sperm parameters, including number, motility and morphology have rather low predictive value in the context of assessment of male fertility and also in selection of methods for assisted reproduction technology (ART). For that reason, there is an ongoing search for alternative, more clinically and biologically meaningful parameters of semen quality. During the past few decades a lot of attention has been given to impairment of Sperm DNA integrity, including single and double strand breaks as well as aberrant protamination. There is overwhelming evidence showing that men from infertile couples have increased percentage of spermatozoa with impairment of sperm chromatin integrity. The remaining questions are: a) what is the biology behind these changes? b) does determination of sperm DNA integrity provide clinically useful information? c) can we treat, and thereby improve fertility, of men with sperm DNA defects? d) is the health of the offspring conceived by IVF/ICSI affected by sperm DNA strand breaks? There is a number of methods for determination of sperm DNA integrity and the results of these different tests usually show a moderate correlation, indicating that they are not assessing the same aspect of sperm chromatin status. In general, the most clinically useful information has been provided by the COMET assay and the Sperm Chromatin Structure Assay (SCSA).These tests seem to be most powerful in assessment fertility in vivo (spontaneous pregnancy and intrauterine insemination) and possibly even in deciding whether to use standard IVF or ICSI. Some studies have even indicated that the embryo quality, fertilisation rate and miscarriage rate. More clinical data are, however, needed in order to fully establish the role of sperm DNA testing in the clinical routine. It also remains to be elucidated whether treatment, with e.g. antioxidants, of men with high percentage of spermatozoa with DNA strand breaks leads to an improvement of fertility. An emerging issue to be investigated is also the question of safety of IVF/ICSI using gametes with high level of DNA impairment." Since 1995, published weekly for subscribers internationally by Fertility Weekly, Inc. 2451 Cumberland Parkway, Suite 3374, Atlanta, GA 30339 USA, Telephone: (888) 662-5048, or (404) 419-6701, Fax: (404) 419-6702, email: subs@fertilityweekly.com. Internet: info@fertilityweekly.com World Wide Web: http://www.fertilityweekly.com. US$699 a year North America, US$799 a year all other countries. Copyright ©2007 Fertility Weekly. All rights reserved. This information shall not, in whole or in part, be redistributed, reproduced, or put into a computer without prior written permission. Possession or distribution of an illegal photocopy of all or part of this information - even for internal use - is PROHIBITED BY LAW (17 U.S.C. 504) and will result in civil or criminal prosecution. Report offenses to the publisher. This information is not medical advice and is subject to change as knowledge advances. ISSN 1086-1068.
  18. 18. Page 18 International Calendar . . . April 7, 2014 Conferences, Symposia, Meetings Worldwide. *New Listing April 1-3, 2014, THE GRACE HOTEL 77 YORK STREET SYDNEY NSW 2000 AUSTRALIA, "7th World Congress on Mild Approaches in Assisted Reproduction." Information: Phone : +61 3 9645 6311; Email : ismaar2014@wsm.com.au. April 4-6, 2014, BRISBANE CONVENTION CENTRE, QUEENSLAND, AUSTRALIA, "5th Asia Pacific Initiative on Reproduction (ASPIRE 2014)." Information: Phone: +65 6292 0723; Fax: +65 6292 4721; Email: info@aspire-reproduction.org; Website: http://www.aspire-reproduction.org/Events/Pages/ASPIRECongresses.aspx. April 4-8, 2014, INTERCONTINENTAL BUCKHEAD ATLANTA, ATLANTA, GA, USA, "American Society of Andrology 32nd Annual Meeting." Information: Phone: 847/619-4909; Fax: 847/517-7229; E-Mail: info@andrologysociety.org; Website: http://andrologysociety.org/meetings/2014/2014%20ASA%20Program%20Schedule.pdf. April 10-13, 2014, VALENCIA, SPAIN, "2nd Biomarker Meeting in Personalised Reproductive Medicine." Information: Email: spain@comtecmed.com; Website: http://www.comtecmed.com/biomarker/2014/Default.aspx. April 30 - May 3, 2014, SAO PAOLO,BRAZIL, "12th World Congress on Endometriosis." Information: WCE2014 Congress Secretariat, Phone: +44(0)20 7808 5171; Email WCE2014@tfigroup.com; Website: http://endometriosis.ca/world-congress/wce2014/. May 1-4, 2014, CANCUN CENTER CONVENTIONS & EXHIBITIONS, CANCUN, MEXICO, "14th World Congress on the Menopause." Information: Phone: +39 06 8546198; Fax +39 06 85389063; Website: http://www.imscancun2014.com/information/. May 28-31, 2014, LISBON, PORTUGAL, "13th Congress of the European Society of Contraception and Reproductive Health." Information: Phone: +32 2 582 08 52; Fax: +32 2 582 55 15; Email: congress@escrh.eu; Website: http://www.escrh.eu/events/esc-events/2014. June 2-5, 2014, ALLEGRIA HOTEL, LONG BEACH , NY, USA, "34th Annual Meeting of American Society for Reproductive Immunology." Information: Phone: (847) 247-6905; E-mail: stephohr@gmail.com; Website: http://www.theasri.org/meetings/34th-annual-meeting. June 21-24, 2014, CHICAGO, IL, USA, "ICE/ENDO 2014." Information: Email: societyservices@endo-society.org; Website: www.endo- society.org/meetings/Annual/index.cfm. June 29-July 2, 2014, MUNICH, GERMANY, "ESHRE 2014." Information: Congress Secretariat, European Society of Human Reproduction and Embryology; Phone: +32 (0)2 269 09 69; Email: info@eshre.eu Web: http://www.eshre.eu/annual_meeting/page.aspx/11. July 19-23, 2014, GRAND RAPIDS, MICHIGAN, USA, "Society for the Study of Reproduction's 47th Annual Meeting; Fertility: A Global Challenge." Information: Email: ssr@ssr.org; Phone: (608) 256-2777; Fax: (608) 256-4610; Website: http://www.ssr.org/Meetings.shtml. September 2-4, 2014, EDINBURGH, UNITED KINGDOM, "World Congress of Reproductive Biology 2014." Information: Email: wcrb@portland-services.com; Website: http://www.wcrb2014.org/Edinburgh.aspx. September 2-4, 2014, EDINBURGH, ENGLAND, "World Congress on Reproductive Biology 2014." Information: Contact: SRF Meetings Team; E-mail: conferences@portlandpress.com Web: http://www.srf-reproduction.org/Meetings/WCRB2014.aspx. September 11-14, 2014, HILTON QUEBEC & QUEBEC CITY CONVENTION CENTRE, QUEBEC CITY, QUEBE, "Canadian Fertility and Andrology Society Annual Meeting." Information: Email: info@cfas.ca; Phone: 514-524-9009; Fax: 514-524-2163; Website: http://www.cfas.ca/index.php?option=com_content&view=article&id=1177&Itemid=721. October 18-22, 2014, HONOLULU, HI, USA, "70th Annual Meeting of the ASRM." Information: Conference Organiser, American Society for Reproductive Medicine; Email: asrm@asrm.org; Website: http://www.asrm.org/Upcoming_Meetings/. October 31, 2014 - November 3, 2014, SHANGHAI,CHINA, "6th International Conference on the Epididymis." Information: Phone: 86-21-54920000; Fax: 86-21-54921011; Email: liudan@sibcb.ac.cn; Website: http://www.sibcb.ac.cn/cpMeetings023.asp. May 20-22, 2015, MADRID,SPAIN, "10th European Congress on Menopause and Andropause." Information: Phone: +49 (0)30 24603-0; Fax: +49 (0)30 24603-310; Email: info@emas-online.org; Website: www.emas-online.org. October 1-4, 2015, MARRIOTT HARBOURFRONT HOTEL, HALIFAX, NOVA SCOTIA, "Canadian Fertility and Andrology Society, 61st Annual Meeting - Halifax 2015." Information: Email: info@cfas.ca; Phone: 514-524-9009; Fax: 514-524-2163; Website: http://www.cfas.ca/index.php?option=com_content&view=article&id=1278&Itemid=782.

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