Ignite Creation Date:
2024-05-05 @ 5:15 PM
Last Modification Date:
2024-10-26 @ 9:30 AM
Study NCT ID:
NCT00419913
Status:
TERMINATED
Last Update Posted:
2008-04-02
First Post:
2007-01-07
Brief Title:
A Trial of Dehydroepiandrosterone DHEA Treatment for in Vitro Fertilization IVF
Sponsor:
Center for Human Reproduction
Organization:
Center for Human Reproduction
Study Overview
Official Title:
A Randomized Placebo-Controlled Trial of Dehydroepiandrosterone DHEA Treatment for Two Months Before Starting Ovulation Induction for in Vitro Fertilization IVF
Status:
TERMINATED
Status Verified Date:
2008-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Failure to recruit sufficient participants
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Our long term goal is to elucidate the role of DHEA on follicular dynamics in the human ovary and to better understand the interaction of DHEA supplementation with other treatments for ovulation induction especially among older reproductive age women
The specific hypothesis behind the proposed research is that DHEA is a regulator of follicular dynamics acting in the early pre-gonadotropin dependent stage of initial primordial follicle recruitment and growth
The specific hypothesis behind the proposed research is that DHEA is a regulator of follicular dynamics acting in the early pre-gonadotropin dependent stage of initial primordial follicle recruitment and growth
Detailed Description:
Specific Aims
The ability of women to respond to ovulation inducing medications also called ovarian reserve declines with age Navot Bergh et al 1991 Scott Leonardi et al 1993 Toner and Flood 1993 Scott and Hofmann 1995 Scott 1996 ASRM 2002 When attempting in-vitro fertilization IVF older women produce few oocytes Chuang Chen et al 2003 Orvieto Bar-Hava et al 2004 and yield few normal embryos even when exposed to maximal gonadotropin stimulationOrvieto Bar-Hava et al 2004 As a result reproductive success for women over 40 years old is significantly reduced compared to younger women Older ovaries have few antral follicles high rates of follicular degeneration atresiaFaddy 2000 and increased resistance to ovulation inductionFilicori 1999 Chuang Chen et al 2003 Kupesic Kurjak et al 2003 A delay in onset of atresia could salvage follicles for later ovulation
Our long term goal is to elucidate the role of DHEA on follicular dynamics in the human ovary and to better understand the interaction of DHEA supplementation with other treatments for ovulation induction especially among older reproductive age women
The specific hypothesis behind the proposed research is that DHEA is a regulator of follicular dynamics acting in the early pre-gonadotropin dependent stage of initial primordial follicle recruitment and growth That hypothesis is based on the following observations First at physiological doses DHEA increases serum levels of the insulin-like growth factor IGF-lCasson Santoro et al 1998 DHEA is produced by the ovarian thecaBurger 2002 increased concentration of follicular DHEA is associated with increased aromatase activityFranks Mason et al 2000 and DHEA is a prohormone that is converted in peripheral tissues to estrogensHaning Hackett et al 1993 Second DHEA exposed rats simulate polycystic ovary syndrome PCORoy Mahesh et al 1962 and have a higher percentage of meiotically active oocytes and less evidence of atresiaAnderson Lee et al 1997 Women chronically exposed to androgens can develop PCO-like ovariesAmirikia Savoy-Moore et al 1986 Women with anovulatory PCO have less evidence of follicle atresiaFranks Mason et al 2000 Third Casson et al Casson Lindsay et al 2000 found a small increase in follicle number and E2 response to ovulation induction after two months of DHEA 80 mgday administration to five women with proven ovarian resistance to stimulation
Preliminary data Barad and Gleicher reported a patient with a history of severely decreased ovarian reserve who dramatically increased her oocyte production over nine cycles of treatment while taking DHEA and ovulation inductionBarad and Gleicher 2005 The dramatic increase in oocyte production seen in this patient did not occur until after four months of DHEA treatment 75 mgday This treatment duration is in keeping with the interval required for normal follicular initiation of recruitment and growthGougeon 1986 and raises that possibility that the Casson et al did not treat their subjects long enough to achieve maximum effect Our case report was followed by a case control study that showed increased oocyte production and improved embryo quality among 25 DHEA treated patients whose pre-treatment cycle acted as controlBarad and Gleicher 2005
More recently we showed that DHEA treated patients with significant decreased ovarian reserve have higher pregnancy rates compared to controlsBarad Brill et al 2006
Based on these observations the experimental focus of this project is on the interaction of DHEA adjuvant treatment with gonadotropin treatment during ovulation induction The specific aims are designed to provide a comprehensive assessment of this effect
1 DHEA treatment will increase pregnancy rates among women 40 to 45 years old
2 DHEA treatment will increase antral follicle counts
3 DHEA will lead to increased anti-mullerian AMH hormone levels
4 DHEA treatment will increase mean and peak follicular phase estradiol
5 DHEA treatment will increase the number of oocytes retrieved in IVF cycles compared to placebo
Research Plan
Placebo controlled randomized trial of 2 months of DHEA pretreatment prior to ovulation induction for IVF-ET
Hypothesis 1
Two months of DHEA pretreatment will improve the chance of pregnancy and lead to greater oocyte and embryo yields relative to placebo treated control patients
Hypothesis 2
Embryos produced following 2 months of pretreatment with either DHEA alone OR with DHEA plus supplemental FSH 150 units per day will result in embryos with better morphology
Hypothesis 3a-c
Two months of DHEA pretreatment will result in a increased antral follicle counts increased AMH b increased mean and peak estradiol and c increased oocyte production
Recruitment plan
New patients presenting for treatment
Possible print magazine or Radio advertisement
References
Amirikia H R T Savoy-Moore et al 1986 The effects of long-term androgen treatment on the ovary Fertil Steril 452 202-8
Anderson E G Y Lee et al 1997 Polycystic ovarian condition in the dehydroepiandrosterone-treated rat model hyperandrogenism and the resumption of meiosis are major initial events associated with cystogenesis of antral follicles Anat Rec 2491 44-53
ASRM 2002 Aging and infertility in women a committee opinion Fertil Steril 781 215-9
Barad D H Brill et al 2006 Dehydroepiandrosterone DHEA Increases Pregnancy Rates in Women with Diminished Ovarian Reserve
A Case Controlled Study Submitted for Publication Barad D and N Gleicher 2005 Effect of dehydroepiandrosterone DHEA on oocyte and embryo yields embryo grade and cell number in IVF Human Reproduction In Press
Barad D and N Gleicher 2005 Increased Oocyte Production after Treatment with Dehydroepiandrosterone Fertil Steril 843 756
Burger H G 2002 Androgen production in women Fertil Steril 77 Suppl 4 S3-5
Casson P R M S Lindsay et al 2000 Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders a case series Hum Reprod 1510 2129-32
Casson P R N Santoro et al 1998 Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein a six-month trial Fertil Steril 701 107-10
Chuang C C C D Chen et al 2003 Age is a better predictor of pregnancy potential than basal follicle-stimulating hormone levels in women undergoing in vitro fertilization Fertil Steril 791 63-8
Faddy M J 2000 Follicle dynamics during ovarian ageing Mol Cell Endocrinol 1631-2 43-8
Filicori M 1999 The role of luteinizing hormone in folliculogenesis and ovulation induction Fertil Steril 713 405-14
Franks S H Mason et al 2000 Follicular dynamics in the polycystic ovary syndrome Mol Cell Endocrinol 1631-2 49-52
Gougeon A 1986 Dynamics of follicular growth in the human a model from preliminary results Hum Reprod 12 81-7
Haning R V Jr R J Hackett et al 1993 Plasma dehydroepiandrosterone sulfate serves as a prehormone for 48 of follicular fluid testosterone during treatment with menotropins J Clin Endocrinol Metab 765 1301-7
Kupesic S A Kurjak et al 2003 Three-dimensional ultrasonographic ovarian measurements and in vitro fertilization outcome are related to age Fertil Steril 791 190-7
Navot D P A Bergh et al 1991 Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility Lancet 3378754 1375-7
Orvieto R I Bar-Hava et al 2004 Results of in vitro fertilization cycles in women aged 43-45 years Gynecol Endocrinol 182 75-8
Roy S V Mahesh et al 1962 The effect of dehydroepiandrosterone and D4-androstenedione on the reproductive organs of female rats Production of cystic changes in the ovary Nature 196 42-43
Scott R T Jr 1996 Evaluation and treatment of low responders Semin Reprod Endocrinol 144 317-37
Scott R T Jr and G E Hofmann 1995 Prognostic assessment of ovarian reserve Fertil Steril 631 1-11
Scott R T M R Leonardi et al 1993 A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population Obstet Gynecol 824 Pt 1 539-44
Toner J P and J T Flood 1993 Fertility after the age of 40 Obstet Gynecol Clin North Am 202 261-72
The ability of women to respond to ovulation inducing medications also called ovarian reserve declines with age Navot Bergh et al 1991 Scott Leonardi et al 1993 Toner and Flood 1993 Scott and Hofmann 1995 Scott 1996 ASRM 2002 When attempting in-vitro fertilization IVF older women produce few oocytes Chuang Chen et al 2003 Orvieto Bar-Hava et al 2004 and yield few normal embryos even when exposed to maximal gonadotropin stimulationOrvieto Bar-Hava et al 2004 As a result reproductive success for women over 40 years old is significantly reduced compared to younger women Older ovaries have few antral follicles high rates of follicular degeneration atresiaFaddy 2000 and increased resistance to ovulation inductionFilicori 1999 Chuang Chen et al 2003 Kupesic Kurjak et al 2003 A delay in onset of atresia could salvage follicles for later ovulation
Our long term goal is to elucidate the role of DHEA on follicular dynamics in the human ovary and to better understand the interaction of DHEA supplementation with other treatments for ovulation induction especially among older reproductive age women
The specific hypothesis behind the proposed research is that DHEA is a regulator of follicular dynamics acting in the early pre-gonadotropin dependent stage of initial primordial follicle recruitment and growth That hypothesis is based on the following observations First at physiological doses DHEA increases serum levels of the insulin-like growth factor IGF-lCasson Santoro et al 1998 DHEA is produced by the ovarian thecaBurger 2002 increased concentration of follicular DHEA is associated with increased aromatase activityFranks Mason et al 2000 and DHEA is a prohormone that is converted in peripheral tissues to estrogensHaning Hackett et al 1993 Second DHEA exposed rats simulate polycystic ovary syndrome PCORoy Mahesh et al 1962 and have a higher percentage of meiotically active oocytes and less evidence of atresiaAnderson Lee et al 1997 Women chronically exposed to androgens can develop PCO-like ovariesAmirikia Savoy-Moore et al 1986 Women with anovulatory PCO have less evidence of follicle atresiaFranks Mason et al 2000 Third Casson et al Casson Lindsay et al 2000 found a small increase in follicle number and E2 response to ovulation induction after two months of DHEA 80 mgday administration to five women with proven ovarian resistance to stimulation
Preliminary data Barad and Gleicher reported a patient with a history of severely decreased ovarian reserve who dramatically increased her oocyte production over nine cycles of treatment while taking DHEA and ovulation inductionBarad and Gleicher 2005 The dramatic increase in oocyte production seen in this patient did not occur until after four months of DHEA treatment 75 mgday This treatment duration is in keeping with the interval required for normal follicular initiation of recruitment and growthGougeon 1986 and raises that possibility that the Casson et al did not treat their subjects long enough to achieve maximum effect Our case report was followed by a case control study that showed increased oocyte production and improved embryo quality among 25 DHEA treated patients whose pre-treatment cycle acted as controlBarad and Gleicher 2005
More recently we showed that DHEA treated patients with significant decreased ovarian reserve have higher pregnancy rates compared to controlsBarad Brill et al 2006
Based on these observations the experimental focus of this project is on the interaction of DHEA adjuvant treatment with gonadotropin treatment during ovulation induction The specific aims are designed to provide a comprehensive assessment of this effect
1 DHEA treatment will increase pregnancy rates among women 40 to 45 years old
2 DHEA treatment will increase antral follicle counts
3 DHEA will lead to increased anti-mullerian AMH hormone levels
4 DHEA treatment will increase mean and peak follicular phase estradiol
5 DHEA treatment will increase the number of oocytes retrieved in IVF cycles compared to placebo
Research Plan
Placebo controlled randomized trial of 2 months of DHEA pretreatment prior to ovulation induction for IVF-ET
Hypothesis 1
Two months of DHEA pretreatment will improve the chance of pregnancy and lead to greater oocyte and embryo yields relative to placebo treated control patients
Hypothesis 2
Embryos produced following 2 months of pretreatment with either DHEA alone OR with DHEA plus supplemental FSH 150 units per day will result in embryos with better morphology
Hypothesis 3a-c
Two months of DHEA pretreatment will result in a increased antral follicle counts increased AMH b increased mean and peak estradiol and c increased oocyte production
Recruitment plan
New patients presenting for treatment
Possible print magazine or Radio advertisement
References
Amirikia H R T Savoy-Moore et al 1986 The effects of long-term androgen treatment on the ovary Fertil Steril 452 202-8
Anderson E G Y Lee et al 1997 Polycystic ovarian condition in the dehydroepiandrosterone-treated rat model hyperandrogenism and the resumption of meiosis are major initial events associated with cystogenesis of antral follicles Anat Rec 2491 44-53
ASRM 2002 Aging and infertility in women a committee opinion Fertil Steril 781 215-9
Barad D H Brill et al 2006 Dehydroepiandrosterone DHEA Increases Pregnancy Rates in Women with Diminished Ovarian Reserve
A Case Controlled Study Submitted for Publication Barad D and N Gleicher 2005 Effect of dehydroepiandrosterone DHEA on oocyte and embryo yields embryo grade and cell number in IVF Human Reproduction In Press
Barad D and N Gleicher 2005 Increased Oocyte Production after Treatment with Dehydroepiandrosterone Fertil Steril 843 756
Burger H G 2002 Androgen production in women Fertil Steril 77 Suppl 4 S3-5
Casson P R M S Lindsay et al 2000 Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders a case series Hum Reprod 1510 2129-32
Casson P R N Santoro et al 1998 Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein a six-month trial Fertil Steril 701 107-10
Chuang C C C D Chen et al 2003 Age is a better predictor of pregnancy potential than basal follicle-stimulating hormone levels in women undergoing in vitro fertilization Fertil Steril 791 63-8
Faddy M J 2000 Follicle dynamics during ovarian ageing Mol Cell Endocrinol 1631-2 43-8
Filicori M 1999 The role of luteinizing hormone in folliculogenesis and ovulation induction Fertil Steril 713 405-14
Franks S H Mason et al 2000 Follicular dynamics in the polycystic ovary syndrome Mol Cell Endocrinol 1631-2 49-52
Gougeon A 1986 Dynamics of follicular growth in the human a model from preliminary results Hum Reprod 12 81-7
Haning R V Jr R J Hackett et al 1993 Plasma dehydroepiandrosterone sulfate serves as a prehormone for 48 of follicular fluid testosterone during treatment with menotropins J Clin Endocrinol Metab 765 1301-7
Kupesic S A Kurjak et al 2003 Three-dimensional ultrasonographic ovarian measurements and in vitro fertilization outcome are related to age Fertil Steril 791 190-7
Navot D P A Bergh et al 1991 Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility Lancet 3378754 1375-7
Orvieto R I Bar-Hava et al 2004 Results of in vitro fertilization cycles in women aged 43-45 years Gynecol Endocrinol 182 75-8
Roy S V Mahesh et al 1962 The effect of dehydroepiandrosterone and D4-androstenedione on the reproductive organs of female rats Production of cystic changes in the ovary Nature 196 42-43
Scott R T Jr 1996 Evaluation and treatment of low responders Semin Reprod Endocrinol 144 317-37
Scott R T Jr and G E Hofmann 1995 Prognostic assessment of ovarian reserve Fertil Steril 631 1-11
Scott R T M R Leonardi et al 1993 A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population Obstet Gynecol 824 Pt 1 539-44
Toner J P and J T Flood 1993 Fertility after the age of 40 Obstet Gynecol Clin North Am 202 261-72
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None