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Lin W.T.,Center for Reproductive Health | Lin W.T.,Harvard University | Beattie M.,University of California at San Francisco | Chen L.-M.,Center for Reproductive Health | And 5 more authors.
Cancer | Year: 2013

BACKGROUND: Germline mutations in BRCA1 and BRCA2 (BRCA1/2) are related to an increased lifetime risk of developing breast and ovarian cancer. Although risk-reducing salpingo-oophorectomy reduces the risk of both cancers, loss of fertility is a major concern. A recent study suggested an association between BRCA1 mutation and occult primary ovarian insufficiency. The objective of the current study was to determine whether BRCA1/2 mutation carriers have an earlier onset of natural menopause compared with unaffected women. METHODS: White carriers of the BRCA1/2 gene (n = 382) were identified within the Breast Cancer Risk Program Registry at the University of California at San Francisco and compared with non-clinic-based white women in northern California (n = 765). The 2 groups were compared with regard to median age at the time of natural menopause before and after adjustment for known risk factors, and the role of smoking within each group was examined using the Kaplan-Meier approach for unadjusted analyses and Cox proportional hazards regression analyses for adjusted analyses. RESULTS: The median age at the time of natural menopause in the BRCA1/2 carriers was significantly younger than among the unaffected sample (50 years vs 53 years; P <.001). The unadjusted hazard ratio for natural menopause when comparing BRCA1/2 carriers with unaffected women was 4.06 (95% confidence interval, 3.03-5.45) and was 3.98 (95% confidence interval, 2.87-5.53) after adjusting for smoking, parity, and oral contraceptive use. For BRCA1/2 carriers who were current heavy smokers (smoking ≥ 20 cigarettes/day), the median age at natural menopause was 46 years versus 49 years for nonsmokers (P =.027). CONCLUSIONS: The BRCA1/2 mutation was associated with a significantly earlier age at natural menopause, and heavy smoking compounded this risk. Because the relationship between menopause and the end of natural fertility is considered to be fixed, these findings suggest the risk of earlier infertility among BRCA1/2 carriers. Copyright © 2013 American Cancer Society.


Coticchio G.,Center for Reproductive Health | Sciajno R.,Center for Reproductive Health | Hutt K.,University of Minnesota | Bromfield J.,University of Kansas Medical Center | And 2 more authors.
Fertility and Sterility | Year: 2010

Objective: To determine whether Polscope analysis can predict different spindle and chromosome configurations of the oocyte metaphase II (MII) spindle. Design: Comparison of Polscope and confocal microscopy analysis of the MII spindle. Setting: Private IVF unit. Patient(s): Women undergoing IVF treatment for male or unexplained infertility. Intervention(s): Fresh and frozen-thawed mature oocytes were analyzed through the Polscope and, immediately afterward, fixed for confocal microscopy assessment. Main Outcome Measure(s): Comparison of retardance values, derived from Polscope analysis, between spindles with different microtubule and chromosome configurations, defined by confocal microscopy evaluation. Measurements of spindle longitudinal axis through the Polscope and confocal microscopy. Result(s): The mean retardance values of different categories of spindle configuration were not statistically significant in almost all cases, allowing only the identification of spindles with highly disorganized microtubules and chromosomes in frozen-thawed oocytes. In spindles with bipolar organization, the Polscope produced measurements of the spindle main axis which were in all cases statistically smaller compared with confocal microscopy evaluation. Conclusion(s): Retardance measurements have limited predictive value of the degree of spindle fiber order and chromosome position in routine clinical settings. Also, under the conditions tested, morphometric evaluation of the spindle through the Polscope is not consistent with confocal analysis. This suggests that the Polscope may still be a rather inefficient method for assessing the metaphase II spindle and, as a result, for noninvasive oocyte selection. © 2010 American Society for Reproductive Medicine.


O'Tierney-Ginn P.,Center for Reproductive Health | O'Tierney-Ginn P.,Case Western Reserve University | Presley L.,Center for Reproductive Health | Myers S.,Center for Reproductive Health | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: The sensitivity of the placenta to maternal insulin remains controversial. Early pregnancy may be a time of increased placental sensitivity to maternal insulin because insulin receptors are abundant on the syncytiotrophoblast in the first trimester but are far fewer at term. Hypothesis: Maternal insulin secretory response in early, but not late, pregnancy is positively associated with placental growth. Design: This is a secondary analysis of a cohort of women (n- 40) recruited before pregnancy. Outcome Measures: An iv glucose tolerance test was administered before pregnancy and in early (12-14 weeks) and late (34-36 weeks) pregnancy. Placental volume throughout gestation (in a subset of women via 3-dimensional ultrasound) and weight at birth were recorded. Results: Total insulin secretory response in early pregnancy was positively associated with placental volume in early pregnancy (R- 0.79, P- 0.04) and placental weight at term (R- 0.42, P- 0.007). Insulin secretory response before and in late pregnancy was not significantly associated with placental growth. Although neonatal fat mass was strongly correlated with placental weight at term (R- 0.449, P- 0.0003), maternal insulin secretory response was related to neonatal fat mass only at birth in male offspring (R- 0.59, P- 0.008). Conclusions: Maternal insulin secretory response in early pregnancy was strongly related to placental weight at birth. Thus, in early pregnancy, increased maternal insulin response as seen in obesity and gestational diabetes mellitus may be a key influence on placental growth, possibly due to the enhanced presence of placental insulin receptors on the maternal villous membrane early in gestation. © 2015 by the Endocrine Society.


News Article | November 1, 2016
Site: www.sciencedaily.com

Most of the research to understand the consequences of Zika virus infection has focused on how the virus affects pregnant women and causes severe birth defects in their developing fetuses. But a new study in mice suggests that Zika infection also may have worrisome consequences for men that interfere with their ability to have children. The research indicates that the virus targets the male reproductive system. Three weeks after male mice were infected with Zika, their testicles had shrunk, levels of their sex hormones had dropped and their fertility was reduced. Overall, these mice were less likely to impregnate female mice. The study is published Oct. 31 in Nature. "We undertook this study to understand the consequences of Zika virus infection in males," said Michael Diamond, MD, PhD, a co-senior author on the study and the Herbert S. Gasser Professor of Medicine. "While our study was in mice -- and with the caveat that we don't yet know whether Zika has the same effect in men -- it does suggest that men might face low testosterone levels and low sperm counts after Zika infection, affecting their fertility." The virus is known to persist in men's semen for months. The Centers for Disease Control and Prevention recommend that men who have traveled to a Zika-endemic region use condoms for six months, regardless of whether they have had symptoms of Zika infection. It is not known, however, what impact this lingering virus can have on men's reproductive systems. To find out how the Zika virus affects males, Diamond, co-senior author Kelle Moley, MD, the James P. Crane Professor of Obstetrics and Gynecology, and colleagues injected male mice with the Zika virus. After one week, the virus had migrated to the testes, which bore microscopic signs of inflammation. After two weeks, the testicles were significantly smaller, their internal structure was collapsing, and many cells were dead or dying. After three weeks, the mice's testicles had shrunk to one-tenth their normal size and the internal structure was completely destroyed. The mice were monitored until six weeks, and in that time their testicles did not heal, even after the mice had cleared the virus from their bloodstreams. "We don't know for certain if the damage is irreversible, but I expect so, because the cells that hold the internal structure in place have been infected and destroyed," said Diamond, who is also a professor of pathology and immunology, and of molecular microbiology. The structure of the testes depends on a type of cell called Sertoli cells, which maintain the barrier between the bloodstream and the testes and nourish developing sperm cells. Zika infects and kills Sertoli cells, the researchers found, and Sertoli cells don't regenerate. The testes normally produce sperm and testosterone, and as the mice's testes sustained increasing levels of damage, their sperm counts and testosterone levels plummeted. By six weeks after infection, the number of motile sperm was down tenfold, and testosterone levels were similarly low. When healthy females were mated with infected and uninfected male mice, the females paired with infected males were about four times less likely to become pregnant as those paired with uninfected males. "This is the only virus I know of that causes such severe symptoms of infertility," said Moley, a fertility specialist and director of the university's Center for Reproductive Health Sciences. "There are very few microbes that can cross the barrier that separates the testes from the bloodstream to infect the testes directly." No reports have been published linking infertility in men to Zika infection, but, Moley said, infertility can be a difficult symptom to pick up in epidemiologic surveys. "People often don't find out that they're infertile until they try to have children, and that could be years or decades after infection," Moley said. "I think it is more likely doctors will start seeing men with symptoms of low testosterone, and they will work backward to make the connection to Zika." Men with low testosterone may experience a low sex drive, erectile dysfunction, fatigue and loss of body hair and muscle mass. Low testosterone can be diagnosed with a simple blood test. "If testosterone levels drop in men like they did in the mice, I think we'll start to see men coming forward saying, 'I don't feel like myself,' and we'll find out about it that way," Moley said. "You might also ask, 'Wouldn't a man notice if his testicles shrank?' Well, probably. But we don't really know how the severity in men might compare with the severity in mice. I assume that something is happening to the testes of men, but whether it's as dramatic as in the mice is hard to say." Diamond and Moley said human studies in areas with high rates of Zika infection are needed to determine the impact of the virus on men's reproductive health. "Now that we know what can happen in a mouse, the question is, what happens in men and at what frequency?" Diamond said. "We don't know what proportion of infected men get persistently infected, or whether shorter-term infections also can have consequences for sperm count and fertility. These are things we need to know."


News Article | October 31, 2016
Site: www.eurekalert.org

Most of the research to understand the consequences of Zika virus infection has focused on how the virus affects pregnant women and causes severe birth defects in their developing fetuses. But a new study in mice suggests that Zika infection also may have worrisome consequences for men that interfere with their ability to have children. The research indicates that the virus targets the male reproductive system. Three weeks after male mice were infected with Zika, their testicles had shrunk, levels of their sex hormones had dropped and their fertility was reduced. Overall, these mice were less likely to impregnate female mice. The study is published Oct. 31 in Nature. "We undertook this study to understand the consequences of Zika virus infection in males," said Michael Diamond, MD, PhD, a co-senior author on the study and the Herbert S. Gasser Professor of Medicine. "While our study was in mice - and with the caveat that we don't yet know whether Zika has the same effect in men -- it does suggest that men might face low testosterone levels and low sperm counts after Zika infection, affecting their fertility." The virus is known to persist in men's semen for months. The Centers for Disease Control and Prevention recommend that men who have traveled to a Zika-endemic region use condoms for six months, regardless of whether they have had symptoms of Zika infection. It is not known, however, what impact this lingering virus can have on men's reproductive systems. To find out how the Zika virus affects males, Diamond, co-senior author Kelle Moley, MD, the James P. Crane Professor of Obstetrics and Gynecology, and colleagues injected male mice with the Zika virus. After one week, the virus had migrated to the testes, which bore microscopic signs of inflammation. After two weeks, the testicles were significantly smaller, their internal structure was collapsing, and many cells were dead or dying. After three weeks, the mice's testicles had shrunk to one-tenth their normal size and the internal structure was completely destroyed. The mice were monitored until six weeks, and in that time their testicles did not heal, even after the mice had cleared the virus from their bloodstreams. "We don't know for certain if the damage is irreversible, but I expect so, because the cells that hold the internal structure in place have been infected and destroyed," said Diamond, who is also a professor of pathology and immunology, and of molecular microbiology. The structure of the testes depends on a type of cell called Sertoli cells, which maintain the barrier between the bloodstream and the testes and nourish developing sperm cells. Zika infects and kills Sertoli cells, the researchers found, and Sertoli cells don't regenerate. The testes normally produce sperm and testosterone, and as the mice's testes sustained increasing levels of damage, their sperm counts and testosterone levels plummeted. By six weeks after infection, the number of motile sperm was down tenfold, and testosterone levels were similarly low. When healthy females were mated with infected and uninfected male mice, the females paired with infected males were about four times less likely to become pregnant as those paired with uninfected males. "This is the only virus I know of that causes such severe symptoms of infertility," said Moley, a fertility specialist and director of the university's Center for Reproductive Health Sciences. "There are very few microbes that can cross the barrier that separates the testes from the bloodstream to infect the testes directly." No reports have been published linking infertility in men to Zika infection, but, Moley said, infertility can be a difficult symptom to pick up in epidemiologic surveys. "People often don't find out that they're infertile until they try to have children, and that could be years or decades after infection," Moley said. "I think it is more likely doctors will start seeing men with symptoms of low testosterone, and they will work backward to make the connection to Zika." Men with low testosterone may experience a low sex drive, erectile dysfunction, fatigue and loss of body hair and muscle mass. Low testosterone can be diagnosed with a simple blood test. "If testosterone levels drop in men like they did in the mice, I think we'll start to see men coming forward saying, 'I don't feel like myself,' and we'll find out about it that way," Moley said. "You might also ask, 'Wouldn't a man notice if his testicles shrank?' Well, probably. But we don't really know how the severity in men might compare with the severity in mice. I assume that something is happening to the testes of men, but whether it's as dramatic as in the mice is hard to say." Diamond and Moley said human studies in areas with high rates of Zika infection are needed to determine the impact of the virus on men's reproductive health. "Now that we know what can happen in a mouse, the question is, what happens in men and at what frequency?" Diamond said. "We don't know what proportion of infected men get persistently infected, or whether shorter-term infections also can have consequences for sperm count and fertility. These are things we need to know."


Di Santo M.,Center for Reproductive Health | Tarozzi N.,Center for Reproductive Health | Nadalini M.,Center for Reproductive Health | Borini A.,Center for Reproductive Health
Advances in Urology | Year: 2012

Cryopreservation of human spermatozoaintroduced in the 1960'shas been recognized as an efficient procedure for management of male fertility before therapy for malignant diseases, vasectomy or surgical infertility treatments, to store donor and partner spermatozoa before assisted reproduction treatments and to ensure the recovery of a small number of spermatozoa in severe male factor infertility. Despite the usefulness of it, cryopreservation may lead to deleterious changes of sperm structure and function: while the effects of cryopreservation on cells are well documented, to date there is no agreement in the literature on whether or not cryopreservation affects sperm chromatin integrity or on the use of a unique and functional protocol for the freezing-thawing procedure. Therefore, sperm cryopreservation is an important component of fertility management and much of its successful application seems to affect the reproductive outcome of assisted reproduction technologies (ART): appropriate use of cryoprotectants before and sperm selection technologies after cryopreservation seem to have the greatest impact on preventing DNA fragmentation, thus improving sperm cryosurvival rates. Copyright © 2012 Marlea Di Santo et al.


Lassance L.,Center for Reproductive Health | Haghiac M.,Center for Reproductive Health | Minium J.,Center for Reproductive Health | Catalano P.,Center for Reproductive Health | Mouzon S.H.-D.,Center for Reproductive Health
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Low concentrations of estradiol and progesterone are hallmarks of adverse pregnancy outcomes as is maternal obesity. During pregnancy, placental cholesterol is the sole source of sex steroids. Cholesterol trafficking is the limiting step in sex steroid biosynthesis and is mainly mediated by the translocator protein (TSPO), present in the mitochondrial outer membrane. Objective: The objective of the study was to investigate the effects of maternal obesity in placental sex steroid biosynthesis and TSPO regulation. Design/Participants: One hundred forty-four obese (body mass index 30-35 kg/m2 ) and 90 lean (body mass index 19-25 kg/m2 ) pregnant women (OP and LP, respectively) recruited at scheduled term cesarean delivery. Placenta and maternal blood were collected. Setting: This study was conducted at MetroHealth Medical Center (Cleveland, Ohio). Main Outcome Measures: Maternal metabolic components (fasting glucose, insulin, leptin, estradiol, progesterone, and total cholesterol) and placental weight were measured. Placenta (mitochondria and membranes separated) and cord blood cholesterol values were verified. The expression and regulation of TSPO and mitochondrial function were analyzed. Results: Plasma estradiol and progesterone concentrations were significantly lower (P < .04) in OP as compared with LP women. Maternal and cord plasma cholesterol were not different between groups. Placental citrate synthase activity and mitochondrial DNA, markers of mitochondrial density, were unchanged, but the mitochondrial cholesterol concentrations were 40% lower in the placenta of OP. TSPO gene and protein expressions were decreased 2-fold in the placenta of OP. In vitro trophoblast activation of the innate immune pathways with lipopolysaccharide and longchain saturated fatty acids reduced TSPO expression by 2- to 3-fold (P < .05). Conclusion: These data indicate that obesity in pregnancy impairs mitochondrial steroidogenic function through the negative regulation of mitochondrial TSPO. © 2015 by the Endocrine Society.


Bianchi V.,Center for Reproductive Health | Lappi M.,Center for Reproductive Health | Bonu M.A.,Center for Reproductive Health | Borini A.,Center for Reproductive Health
Fertility and Sterility | Year: 2012

Objective: To update results on outcomes with frozen/thawed oocytes using a differential sucrose concentration during dehydration (0.2 M) and rehydration (0.3 M), combined with a one-step propanediol exposure. Design: Retrospective cohort study. Setting: Private IVF centers. Patient(s): Infertile couples undergoing IVF treatment. Intervention(s): Oocyte thawing cycles between May 2004 and December 2010. Main Outcome Measure(s): Survival, fertilization, and cleavage rates were reported to evaluate biological outcomes. Clinical pregnancy and implantation rates were analyzed as markers of efficiency. Result(s): Three hundred forty-two patients and 443 cycles were monitored; the survival was 71.8%, fertilization 77.9%, and of the embryos obtained 83.8% were classified as grade 1 and 2. Three hundred ninety-four transfers were performed, resulting in 90 pregnancies. The pregnancy rate per transfer was 22.8% and per patient was 26.3%, with 122 gestational sacs. The implantation rate per embryo was 13.5%. Patients were divided into three groups according to their age: ≤34 years (group A), 35-38 years (group B), and ≥39 years (group C). Biological outcomes were comparable in all three groups, whereas the pregnancy rate per transfer was higher in the first group (27.7% vs. 21.4% and 17.6%). The implantation rates per injected egg were 11.8%, 8.0%, and 7.5% for the three groups, respectively. Conclusion(s): The biological and clinical data obtained on 443 cycles are consistent with our previous results showing that slow freezing of oocytes can be a valid tool in IVF practice when performed with a suitable protocol. © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.


Prata N.,University of California at Berkeley | Bell S.,University of California at Berkeley | Quaiyum M.A.,Center for Reproductive Health
BMC Pregnancy and Childbirth | Year: 2014

Background: Bangladesh is one of the few countries that may actually achieve the fifth Millennium Development Goal (MDG) in time, despite skilled birth attendance remaining low. The purpose of this paper is to examine the potential role misoprostol can play in the decline of maternal deaths attributed to postpartum hemorrhage (PPH) in Bangladesh.Methods: Using data from a misoprostol and blood loss measurement tool feasibility study in Bangladesh, observed cause specific maternal mortality ratios (MMRs) were estimated and contrasted with expected ratios using estimates from the Bangladesh Maternal Mortality Survey (BMMS) data. Using Crystal Ball 7 we employ Monte Carlo simulation techniques to estimate maternal deaths in four scenarios, each with different levels of misoprostol coverage. These scenarios include project level misoprostol coverage (69%), no (0%), low (40%), and high (80%) misoprostol coverage. Data on receipt of clean delivery kit, use of misoprostol, experience of PPH, and cause of death were used in model assumptions.Results: Using project level misoprostol coverage (69%), the mean number of PPH deaths expected was 40 (standard deviation = 8.01) per 100,000 live births. Assuming no misoprostol coverage (0%), the mean number of PPH deaths expected was 51 (standard deviation = 9.30) per 100,000 live births. For low misoprostol coverage (40%), the mean number of PPH deaths expected was 45 (standard deviation = 8.26) per 100,000 live births, and for high misoprostol coverage (80%), the mean number of PPH deaths expected was 38 (standard deviation = 7.04) per 100,000 live births.Conclusion: This theoretical exercise hypothesizes that prophylactic use of misoprostol at home births may contribute to a reduction in the risk of death due to PPH, in addition to reducing the incidence of PPH. If findings from this modeling exercise are accurate and uterotonics can prevent maternal death, misoprostol could be the tool countries need to further reduce maternal mortality at home births. © 2014 Prata et al.; licensee BioMed Central Ltd.


Nadalini M.,Center for Reproductive Health | Tarozzi N.,Center for Reproductive Health | Di Santo M.,Center for Reproductive Health | Borini A.,Center for Reproductive Health
Journal of Assisted Reproduction and Genetics | Year: 2014

Purpose: To investigate whether the sperm fertilizing potential can be improved by selecting a non-apoptotic fraction using magnetic activated cell sorting (MACS), and to compare the results with the conventional swim-up method. Methods: Twenty five male patients attending the andrology laboratory for sperm DNA fragmentation analysis. The sperm were prepared by density gradient centrifugation (DGC) and subsequently divided into three aliquots. The first was further separated into Annexin V-negative (non-apoptotic) fraction using MACS, the second was further processed by swim-up, while the third was left unseparated as a control. The impact of the combination of DGC with the two sperm preparation techniques on sperm quality was evaluated by comparing 'rapid progressive' motility, normal morphology according to Tygerberg's strict criteria and DNA integrity (by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling [TUNEL]) for each aliquot. Results: Sperm preparation that combines DGC with conventional swim-up method can provide sperm of higher quality in terms of motility, morphology and extent of DNA fragmentation compared to the Annexin V-negative (non-apoptotic) fraction derived from the combination of DGC with MACS. Conclusions: Integrating MACS as a part of sperm preparation technique will not improve sperm fertilizing potential to the same extent as the traditional swim-up separation procedure. © 2014 Springer Science+Business Media.

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