Ignite Creation Date:
2024-05-05 @ 11:47 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00133783
Status:
UNKNOWN
Last Update Posted:
2005-10-26
First Post:
2005-08-23
Brief Title:
Pituitary Derived-Intermedin is an Estrogen-Modulated Factor for Reducing Blood Pressure
Sponsor:
Chang Gung Memorial Hospital
Organization:
Chang Gung Memorial Hospital
Study Overview
Official Title:
Intermedin is an Estrogen- Modulated Factor for Reducing Blood Pressure
Status:
UNKNOWN
Status Verified Date:
2005-05
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Calcitonin calcitonin gene-related peptides CGRPs adrenomedullin and amylin belong to a unique group of peptide hormones important for the regulation of calcium balance neurotransmission cardiovascular homeostasis and glucose metabolism We the investigators at Chang Gung Memorial Hospital recently identified intermedin as a novel peptide hormone belonging to this unique peptide ligand family Adrenomedullin is a 52-amino-acid peptide and is one of the most potent vasodilators Plasma adrenomedullin is elevated in a variety of pathological conditions such as hypertension renal failure heart failure and septic shock CGRPα and CGRPβ are 37-amino acid neuropeptides primarily release from sensory nerves and play important roles in regulating peripheral vascular tone and controlling blood flow in various organs Human mature intermedin encodes 40-amino-acid and is expressed mainly in the adrenocorticotrophs of the anterior and intermediate pituitary lobe Intermedin signals through calcitonin receptor-like receptor CRLRreceptor activity-modifying protein RAMP receptor complexes and CRLRRAMP signaling has been proven to be critical for vascular tone regulation Based on this finding we had documented that intraperitoneal administration of intermedin dose-dependently suppressed blood pressure in normal Sprague-Dawley rats In addition our preliminary in vitro and in vivo studies demonstrated that ovariectomy lead to a tenfold reduction of intermedin transcript expression in the pituitary in rats whereas subsequent estrogen treatment increased pituitary intermedin expression to a level similar to that of intact rats Taken together we propose that pituitary-derived intermedin is regulated by estrogen and exhibits potent hypotensive effects To address this hypothesis in Specific Aim 1 we will investigate the regulation of secretion and expression of intermedin in vitro and in vivo using cultured pituitary cells and oophorectomized rats In Specific Aim 2 we will study the molecular mechanism by which estrogen stimulates intermedin gene expression In Specific Aim 3 to demonstrate that the estrogen-dependent regulation of intermedin represents a critical link in the regulation of blood pressure in women we will study the relationship between blood pressure and blood intermedin levels using a cross-sectional study Our studies will provide a better understanding of the mechanisms by which sex hormones modulate blood pressure and open a new window for postmenopausal hypertension treatment
Detailed Description:
Specific Aim
Validation that intermedin represents an estrogen-regulated vasoactive hormone from the pituitary
Hypothesis
Intermedin is a mediator of the vaso-regulatory effects of estrogens
Rationale
In the Preliminary Study we showed that intermedin is a pituitary-derived hypotensive factor signaling through CRLRRAMP receptor complexes in vessel endothelium Based on studies of related hormones adrenomedullin and CGRP intermedin likely reduces blood pressure by exerting a vasodilator effect on vascular beds Earlier studies have shown that the neuropeptide αCGRP is predominately produced in the sensory neuron and serotonin can selectively reduce CGRP secretion by activating the endogenous serotonin type 1 5-HT1 receptor through the calcium signal pathway Deletion of the CGRP gene in mutant mice αCGRP-- leads to the elevation of mean arterial pressure heart rate peripheral vascular resistance and sympathetic nervous activity as compared to wild-type mice The other related peptide adrenomedullin ADM initially identified from pheochromocytoma has been shown to be expressed in various tissues including adrenal medulla cardiovascular tissues lung kidney and placenta Plasma ADM is elevated in various conditions including cardiovascular and renal disorders and septic shock and it has been hypothesized that ADM may be involved in the control of circulation and body fluid dynamics in various organs Studies of mice deficient for ADM showed that ADM is indispensable for cardiovascular development The homozygous knockout Adm-- mice exhibited an embryonic lethal phenotype
Earlier studies of the ADM gene promoter have revealed that in addition to two transcription factors nuclear factor for interleukin-6 expression NF-IL6 and activator protein 2 AP-2 the ADM gene expression is regulated by the hypoxia inducible factor-1 HIF-1 Under hypoxia conditions HIF-1 binds to the hypoxia response elements HRE in the ADM gene promoter to promote ADM gene expression Although outside the focus of the present study we have also detected putative HRE sequences in the intermedin gene promoter and demonstrated that hypoxia conditions stimulate intermedin gene promoter activity suggesting that HIF-1 could play a role in the regulation of intermedin gene expression Unlike intermedin the expression of CGRP and ADM is not actively stimulated by estrogens suggesting that these two related peptides are not directly associated with the cardiovascular effects of estrogens In females 17β-estradiol produced by ovaries is the chief circulating estrogen which increases vasodilatation and inhibits the response of blood vessels to injury Studies by Mercuro et al have shown that surgical-induced menopause causes an increase in peripheral vascular resistance and blood pressure Likewise a cross sectional study showed that there is a four- fold increase in the incidence of hypertension in postmenopausal women as compared to premenopausal individuals 40 in post menopausal women vs 10 in premenopausal women The rise in systolic blood pressure per decade was around 5mmHg greater in perimenopausal and postmenopausal women as compared with premenopausal women In addition to demographic studies studies have shown that estrogen could dilate coronary and brachial arteries in postmenopausal women A part of vasodilatation and hypotensive activities of 17β-estradiol could be explained by its ability to modulate the expression of genes known to influence vascular tone and structure such as ACE rennin and angiotension type I AT1 receptors However none of these genes have been shown to be specific direct targets for estrogen receptors and are responsible for the vasoprotective effects of estrogens Based on our findings that intermedin is a hypotensive factor and contains putative ERE sequence in the promoter region we propose that intermedin is a pituitary-derived blood pressure modulating factor directly regulated by ovarian estrogens Based on this understanding we further hypothesize that the down regulation of intermedin in aging individuals with estrogen deficiency could be responsible for postmenopausal hypertension Because there is no established animal model suitable for the study of naturally occurring menopause we will test our hypothesis by studying the relationship between plasma intermedin concentration and blood pressure among women in difference reproductive stages
Case Selection Measurement and Analysis of Biophysical and Biochemical Characteristics
Premenopausal and Postmenopausal Group
Eligible women who visit OBGYN physicians will be invited for an interview They will be questioned about general characteristics lifestyle habits smoking alcohol consumption physical activity and medical history During the interview blood pressure will be measured three times on the right arm while the participant is seated A woman is considered as post menopausal if her menses have naturally ceased for 12 months or more or if she has bilateral oophorectomy or hysterectomy without bilateral oophorectomy and aged more than 55 years Office BP will be measured using a mercury sphygmomanometer according to the recommendations of the American Society of Hypertension average the three BP readings after 5 min of quiet sitting position Biophysical and biochemical characteristics will be measured including the last menses period age BMI serum glucose AC and PC serum and urine creatinine plasma total cholesterol HDL LDL triglycerides FSH LH 17β-estradiol progesterone TSH intermedin and prolactin Blood specimens from individual subjects will be analyzed in a single assay to minimize variations Odds ratios ORs of elevated blood pressure and the corresponding 95 confidence intervals CIs will be computed after allowance for age Furthermore in order to take into account potential reciprocal confounding effects of variables considered factors significantly related with elevated blood pressure risk in the age adjusted analysis will be subsequently included in multiple logistic regression models fitted by the method of maximum likelihood Women asking for annually regular pap smear examinations without any medical disease will be eligible for this study group
The reproductive stages will be assigned as
Premenopausal no reported change in menstrual cycle pattern
Early peri-menopausal reported change in menstrual cycle frequency in preceding year with a bleed in the preceding 3 months
Late peri-menopausal no menses in the preceding 3-11 months
Postmenopausal no menses in the preceding 12 months
Surgically-Induced Menopausal Group
This protocol will include fertile women who suffer from ovarian pathology without other medical disease and are scheduled to undergo bilateral oophorectomy associated with or without hysterectomy Patients who suffer from uterine pathology and undergo hysterectomy only will serve as controls Blood pressure and all biochemical characteristics will be measured one week before surgery and 1 3 6 and 12 months after operation All individual measurements will be blinded as to the hysterectomizedoophorectomized status of the patients The entire data group will be reported as mean SE Differences in vascular parameters between oophorectomized women and controls and between values recorded prior to and following surgery will be assessed using paired and unpaired Students t-tests
ART Group
Women in ART treatment due to male or tubal factor will be included The day 3 hormone level E2 progesterone FSH LH TSH prolactin inhibin A inhibin B and activin and blood pressure will be measured one month before ART treatment After gonadotropin administration all the hormone and blood pressure changes will be measured and recorded at day 3 day 7 and the day before hCG injection as well as the day of oocyte retrieval All biophysical and biochemical characteristics will continue to follow up on the 15th day after embryo transfer and to the end of the first trimester in the pregnancy group
Validation that intermedin represents an estrogen-regulated vasoactive hormone from the pituitary
Hypothesis
Intermedin is a mediator of the vaso-regulatory effects of estrogens
Rationale
In the Preliminary Study we showed that intermedin is a pituitary-derived hypotensive factor signaling through CRLRRAMP receptor complexes in vessel endothelium Based on studies of related hormones adrenomedullin and CGRP intermedin likely reduces blood pressure by exerting a vasodilator effect on vascular beds Earlier studies have shown that the neuropeptide αCGRP is predominately produced in the sensory neuron and serotonin can selectively reduce CGRP secretion by activating the endogenous serotonin type 1 5-HT1 receptor through the calcium signal pathway Deletion of the CGRP gene in mutant mice αCGRP-- leads to the elevation of mean arterial pressure heart rate peripheral vascular resistance and sympathetic nervous activity as compared to wild-type mice The other related peptide adrenomedullin ADM initially identified from pheochromocytoma has been shown to be expressed in various tissues including adrenal medulla cardiovascular tissues lung kidney and placenta Plasma ADM is elevated in various conditions including cardiovascular and renal disorders and septic shock and it has been hypothesized that ADM may be involved in the control of circulation and body fluid dynamics in various organs Studies of mice deficient for ADM showed that ADM is indispensable for cardiovascular development The homozygous knockout Adm-- mice exhibited an embryonic lethal phenotype
Earlier studies of the ADM gene promoter have revealed that in addition to two transcription factors nuclear factor for interleukin-6 expression NF-IL6 and activator protein 2 AP-2 the ADM gene expression is regulated by the hypoxia inducible factor-1 HIF-1 Under hypoxia conditions HIF-1 binds to the hypoxia response elements HRE in the ADM gene promoter to promote ADM gene expression Although outside the focus of the present study we have also detected putative HRE sequences in the intermedin gene promoter and demonstrated that hypoxia conditions stimulate intermedin gene promoter activity suggesting that HIF-1 could play a role in the regulation of intermedin gene expression Unlike intermedin the expression of CGRP and ADM is not actively stimulated by estrogens suggesting that these two related peptides are not directly associated with the cardiovascular effects of estrogens In females 17β-estradiol produced by ovaries is the chief circulating estrogen which increases vasodilatation and inhibits the response of blood vessels to injury Studies by Mercuro et al have shown that surgical-induced menopause causes an increase in peripheral vascular resistance and blood pressure Likewise a cross sectional study showed that there is a four- fold increase in the incidence of hypertension in postmenopausal women as compared to premenopausal individuals 40 in post menopausal women vs 10 in premenopausal women The rise in systolic blood pressure per decade was around 5mmHg greater in perimenopausal and postmenopausal women as compared with premenopausal women In addition to demographic studies studies have shown that estrogen could dilate coronary and brachial arteries in postmenopausal women A part of vasodilatation and hypotensive activities of 17β-estradiol could be explained by its ability to modulate the expression of genes known to influence vascular tone and structure such as ACE rennin and angiotension type I AT1 receptors However none of these genes have been shown to be specific direct targets for estrogen receptors and are responsible for the vasoprotective effects of estrogens Based on our findings that intermedin is a hypotensive factor and contains putative ERE sequence in the promoter region we propose that intermedin is a pituitary-derived blood pressure modulating factor directly regulated by ovarian estrogens Based on this understanding we further hypothesize that the down regulation of intermedin in aging individuals with estrogen deficiency could be responsible for postmenopausal hypertension Because there is no established animal model suitable for the study of naturally occurring menopause we will test our hypothesis by studying the relationship between plasma intermedin concentration and blood pressure among women in difference reproductive stages
Case Selection Measurement and Analysis of Biophysical and Biochemical Characteristics
Premenopausal and Postmenopausal Group
Eligible women who visit OBGYN physicians will be invited for an interview They will be questioned about general characteristics lifestyle habits smoking alcohol consumption physical activity and medical history During the interview blood pressure will be measured three times on the right arm while the participant is seated A woman is considered as post menopausal if her menses have naturally ceased for 12 months or more or if she has bilateral oophorectomy or hysterectomy without bilateral oophorectomy and aged more than 55 years Office BP will be measured using a mercury sphygmomanometer according to the recommendations of the American Society of Hypertension average the three BP readings after 5 min of quiet sitting position Biophysical and biochemical characteristics will be measured including the last menses period age BMI serum glucose AC and PC serum and urine creatinine plasma total cholesterol HDL LDL triglycerides FSH LH 17β-estradiol progesterone TSH intermedin and prolactin Blood specimens from individual subjects will be analyzed in a single assay to minimize variations Odds ratios ORs of elevated blood pressure and the corresponding 95 confidence intervals CIs will be computed after allowance for age Furthermore in order to take into account potential reciprocal confounding effects of variables considered factors significantly related with elevated blood pressure risk in the age adjusted analysis will be subsequently included in multiple logistic regression models fitted by the method of maximum likelihood Women asking for annually regular pap smear examinations without any medical disease will be eligible for this study group
The reproductive stages will be assigned as
Premenopausal no reported change in menstrual cycle pattern
Early peri-menopausal reported change in menstrual cycle frequency in preceding year with a bleed in the preceding 3 months
Late peri-menopausal no menses in the preceding 3-11 months
Postmenopausal no menses in the preceding 12 months
Surgically-Induced Menopausal Group
This protocol will include fertile women who suffer from ovarian pathology without other medical disease and are scheduled to undergo bilateral oophorectomy associated with or without hysterectomy Patients who suffer from uterine pathology and undergo hysterectomy only will serve as controls Blood pressure and all biochemical characteristics will be measured one week before surgery and 1 3 6 and 12 months after operation All individual measurements will be blinded as to the hysterectomizedoophorectomized status of the patients The entire data group will be reported as mean SE Differences in vascular parameters between oophorectomized women and controls and between values recorded prior to and following surgery will be assessed using paired and unpaired Students t-tests
ART Group
Women in ART treatment due to male or tubal factor will be included The day 3 hormone level E2 progesterone FSH LH TSH prolactin inhibin A inhibin B and activin and blood pressure will be measured one month before ART treatment After gonadotropin administration all the hormone and blood pressure changes will be measured and recorded at day 3 day 7 and the day before hCG injection as well as the day of oocyte retrieval All biophysical and biochemical characteristics will continue to follow up on the 15th day after embryo transfer and to the end of the first trimester in the pregnancy group
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