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Prolonged estrogen deprivation is associated with increased cardiovascular disease risk among women with primary ovarian insufficiency
O-269 Wednesday, November 1, 2017 12:00 PM
O-270 Wednesday, November 1, 2017 12:15 PM
PROLONGED ESTROGEN DEPRIVATION IS ASSOCIATED WITH INCREASED CARDIOVASCULAR DISEASE RISK AMONG WOMEN WITH PRIMARY OVARIAN INSUFFICIENCY. J. Christ,1,2 M. Gunning,2 G. Palla,3 R. Eijkemans,4 C. B. Lambalk,5 J. S. Laven,6 B. Fauser.2 1Cleveland Clinic Foundation, Cleveland, OH; 2University Medical Center, Utrecht, Utrecht, Netherlands; 3University of Pisa Medical Center, Pisa, Italy; 4Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands; 5Obstetrics & Gynecology, VU University Medical Center, Amsterdam, Netherlands; 6Div. Reproductive Medicine, Dept OBGYN, Erasmus Medical Center, Rotterdam, Netherlands.
AUTOLOGOUS GRAFTING OF FROZEN AND THAWED PREPUBERTAL TESTICULAR TISSUE PRODUCES FUNCTIONAL SPERM IN RHESUS MACAQUES. A. Fayomi,1 K. Peters,2 M. Sukhwani,3 4 5 6 C. Ramsey, C. Hanna, J. D. Hennebold, K. E. Orwig.7 1Department of Obstetrics, Gynecology and Reproductive sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA; 2Magee Womens Research Institute, Pittsburgh, PA; 3Ob Gyn, Magee-Womens Research Institite, Pittsburgh, PA; 4Assisted Reproductive technology Core, Oregon Health and Science University, Beaverton, OR; 5Division of Reproductive and Developmental Science, Oregon National Primate Research Center, Beaverton, OR; 6Reproductive & Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR; 7Ob/Gyn and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA.
OBJECTIVE: To evaluate the role of estrogen exposure and deficiency among women with primary ovarian insufficiency (POI) in predicting risk of cardiovascular disease (CVD). DESIGN: Cross-sectional study completed from 1996 to 2016. MATERIALS AND METHODS: 385 women with POI, as defined by amenorrhea and FSH >40 IU/L before the age of 40, were recruited. Women were screened at one of three referral centers (University Medical Center, Utrecht; Erasmus Medical Center, Rotterdam; VU University Medical Center, Amsterdam). Participants underwent a standardized intake questionnaire including extensive data on menstrual cyclicity, from which lifetime estrogen exposure and estrogen free period were estimated. A dual-energy x-ray absorptiometry scan was completed. Serum was analyzed for endocrine profiles and markers of cardiovascular disease. The Framingham 30 year risk of a cardiovascular event and the optimal risk of a cardiovascular event were calculated for each woman. Risk of CVD and optimal risk of CVD for each woman were compared with paired t-tests. The relevance of markers of hormone exposure was first assessed using Pearson’s correlation analyses and univariate linear regression analyses. Secondly multi-variable linear regression analyses controlling for body mass index (BMI), age, race, and smoking were completed to identify the independent effect of hormone exposure on risk factors for CVD. RESULTS: Women had an average lifetime estrogen exposure of 19.3 7.0 years and an estimated estrogen free period of 3.1 4.1 years. Women had a significantly greater 30 year risk of CVD than their calculated optimal risk (11.5 8.2% vs 6.3 3.0%, p<0.001). In univariate analyses Z-score associated with systolic blood pressure, and free androgen index associated with markers of dyslipidemia (p<0.05). In fully adjusted models, estrogen free interval and lifetime estrogen exposure independently associated with risk of cardiovascular disease such that for every year of estrogen deprivation risk of CVD increased by 0.20% and for every year of estrogen exposure risk declined by 0.16% (b (95% CI), 0.200 (0.052-0.348); -0.158 (-0.292-0.025), p<0.05). CONCLUSIONS: Prolonged estrogen deprivation is associated with increased risk of CVD, while prolonged estrogen exposure is associated with reduced risk of disease. These results support the early and continued use of estrogen replacement therapy in women with POI. FINANCIAL SUPPORT: Jacob Christ was supported by a Fulbright fellowship. References:
e392
ASRM Abstracts
OBJECTIVE: Testicular tissue freezing is an experimental fertility preservation option for prepubertal boys who are not able to cryopreserve sperm. The objective of this study was to demonstrate that fertilization competent sperm could be recovered from frozen/thawed grafts from prepubertal Rhesus macaques. DESIGN: Testicular tissue of five prepubertal Rhesus macaques was collected and cut into small pieces (2-5mm3, 15.341.54mg). Fresh or frozen/thawed tissues were grafted under the back skin (3 fresh & 3 frozen) and in the scrotum (1 fresh & 1 frozen). Four sites on the back and both scrotal sites were grafted with matrigel. Two sites on the back were grafted without matrigel. Grafts were recovered for analysis after 8-10 months. MATERIALS AND METHODS: Graft volume, follicle stimulating hormone (FSH) and testosterone (T) levels were monitored throughout the grafting period. At the end of the study, recovered grafts were weighed and fixed for immunofluorescence (IF; VASA, ACROSIN, GFRA1) or hematoxylin/ eosin (HE) staining. Portions of each graft were digested with collagenase to release sperm that were tested for fertilizing potential by intracytoplasmic sperm injection (ICSI). Quantitative results were expressed as mean standard error of the mean, and paired sample T-test was used to identify differences between treatment groups (p<0.05). RESULTS: HE and IF confirmed that donor tissues were immature (no spermatogenesis) at the time of grafting. Irrespective of the graft site or matrigel treatment, graft volume increased over time in the frozen/ thawed as well as fresh grafts. FSH and T levels increased after grafting, indicating progression through puberty and an intact hypothalamic, pituitary, gonadal axis. Graft weights from the scrotum were higher than from the back (P<0.01), but complete spermatogenesis was confirmed in all grafts with spermatids in more than 70% of seminiferous tubules. Irrespective of experimental group, millions of sperm were recovered per graft and sperm were competent to fertilize Rhesus oocytes, leading to preimplantation embryo development up to the hatching blastocyst stage, in vitro. CONCLUSIONS: Testicular tissue grafting is a mature technology that may be ready for the human fertility clinic. FINANCIAL SUPPORT: This work was supported by NICHD grant HD075795 References:
Vol. 108, No. 3, Supplement, September 2017
O-270 Wednesday, November 1, 2017 12:15 PM
PROLONGED ESTROGEN DEPRIVATION IS ASSOCIATED WITH INCREASED CARDIOVASCULAR DISEASE RISK AMONG WOMEN WITH PRIMARY OVARIAN INSUFFICIENCY. J. Christ,1,2 M. Gunning,2 G. Palla,3 R. Eijkemans,4 C. B. Lambalk,5 J. S. Laven,6 B. Fauser.2 1Cleveland Clinic Foundation, Cleveland, OH; 2University Medical Center, Utrecht, Utrecht, Netherlands; 3University of Pisa Medical Center, Pisa, Italy; 4Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands; 5Obstetrics & Gynecology, VU University Medical Center, Amsterdam, Netherlands; 6Div. Reproductive Medicine, Dept OBGYN, Erasmus Medical Center, Rotterdam, Netherlands.
AUTOLOGOUS GRAFTING OF FROZEN AND THAWED PREPUBERTAL TESTICULAR TISSUE PRODUCES FUNCTIONAL SPERM IN RHESUS MACAQUES. A. Fayomi,1 K. Peters,2 M. Sukhwani,3 4 5 6 C. Ramsey, C. Hanna, J. D. Hennebold, K. E. Orwig.7 1Department of Obstetrics, Gynecology and Reproductive sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA; 2Magee Womens Research Institute, Pittsburgh, PA; 3Ob Gyn, Magee-Womens Research Institite, Pittsburgh, PA; 4Assisted Reproductive technology Core, Oregon Health and Science University, Beaverton, OR; 5Division of Reproductive and Developmental Science, Oregon National Primate Research Center, Beaverton, OR; 6Reproductive & Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR; 7Ob/Gyn and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA.
OBJECTIVE: To evaluate the role of estrogen exposure and deficiency among women with primary ovarian insufficiency (POI) in predicting risk of cardiovascular disease (CVD). DESIGN: Cross-sectional study completed from 1996 to 2016. MATERIALS AND METHODS: 385 women with POI, as defined by amenorrhea and FSH >40 IU/L before the age of 40, were recruited. Women were screened at one of three referral centers (University Medical Center, Utrecht; Erasmus Medical Center, Rotterdam; VU University Medical Center, Amsterdam). Participants underwent a standardized intake questionnaire including extensive data on menstrual cyclicity, from which lifetime estrogen exposure and estrogen free period were estimated. A dual-energy x-ray absorptiometry scan was completed. Serum was analyzed for endocrine profiles and markers of cardiovascular disease. The Framingham 30 year risk of a cardiovascular event and the optimal risk of a cardiovascular event were calculated for each woman. Risk of CVD and optimal risk of CVD for each woman were compared with paired t-tests. The relevance of markers of hormone exposure was first assessed using Pearson’s correlation analyses and univariate linear regression analyses. Secondly multi-variable linear regression analyses controlling for body mass index (BMI), age, race, and smoking were completed to identify the independent effect of hormone exposure on risk factors for CVD. RESULTS: Women had an average lifetime estrogen exposure of 19.3 7.0 years and an estimated estrogen free period of 3.1 4.1 years. Women had a significantly greater 30 year risk of CVD than their calculated optimal risk (11.5 8.2% vs 6.3 3.0%, p<0.001). In univariate analyses Z-score associated with systolic blood pressure, and free androgen index associated with markers of dyslipidemia (p<0.05). In fully adjusted models, estrogen free interval and lifetime estrogen exposure independently associated with risk of cardiovascular disease such that for every year of estrogen deprivation risk of CVD increased by 0.20% and for every year of estrogen exposure risk declined by 0.16% (b (95% CI), 0.200 (0.052-0.348); -0.158 (-0.292-0.025), p<0.05). CONCLUSIONS: Prolonged estrogen deprivation is associated with increased risk of CVD, while prolonged estrogen exposure is associated with reduced risk of disease. These results support the early and continued use of estrogen replacement therapy in women with POI. FINANCIAL SUPPORT: Jacob Christ was supported by a Fulbright fellowship. References:
e392
ASRM Abstracts
OBJECTIVE: Testicular tissue freezing is an experimental fertility preservation option for prepubertal boys who are not able to cryopreserve sperm. The objective of this study was to demonstrate that fertilization competent sperm could be recovered from frozen/thawed grafts from prepubertal Rhesus macaques. DESIGN: Testicular tissue of five prepubertal Rhesus macaques was collected and cut into small pieces (2-5mm3, 15.341.54mg). Fresh or frozen/thawed tissues were grafted under the back skin (3 fresh & 3 frozen) and in the scrotum (1 fresh & 1 frozen). Four sites on the back and both scrotal sites were grafted with matrigel. Two sites on the back were grafted without matrigel. Grafts were recovered for analysis after 8-10 months. MATERIALS AND METHODS: Graft volume, follicle stimulating hormone (FSH) and testosterone (T) levels were monitored throughout the grafting period. At the end of the study, recovered grafts were weighed and fixed for immunofluorescence (IF; VASA, ACROSIN, GFRA1) or hematoxylin/ eosin (HE) staining. Portions of each graft were digested with collagenase to release sperm that were tested for fertilizing potential by intracytoplasmic sperm injection (ICSI). Quantitative results were expressed as mean standard error of the mean, and paired sample T-test was used to identify differences between treatment groups (p<0.05). RESULTS: HE and IF confirmed that donor tissues were immature (no spermatogenesis) at the time of grafting. Irrespective of the graft site or matrigel treatment, graft volume increased over time in the frozen/ thawed as well as fresh grafts. FSH and T levels increased after grafting, indicating progression through puberty and an intact hypothalamic, pituitary, gonadal axis. Graft weights from the scrotum were higher than from the back (P<0.01), but complete spermatogenesis was confirmed in all grafts with spermatids in more than 70% of seminiferous tubules. Irrespective of experimental group, millions of sperm were recovered per graft and sperm were competent to fertilize Rhesus oocytes, leading to preimplantation embryo development up to the hatching blastocyst stage, in vitro. CONCLUSIONS: Testicular tissue grafting is a mature technology that may be ready for the human fertility clinic. FINANCIAL SUPPORT: This work was supported by NICHD grant HD075795 References:
Vol. 108, No. 3, Supplement, September 2017