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A Longitudinal Investigation of the Endocrine and Neurobiologic Events Accompanying Puberty

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ClinicalTrials.gov Identifier: NCT01434368
Recruitment Status : Recruiting
First Posted : September 14, 2011
Last Update Posted : December 7, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:

Despite the clear importance of adolescence in the emergence of a number of disease states and processes, there is surprisingly little known about how the endocrine and metabolic events accompanying puberty in humans impact normal developmental neurobiology. Epidemiologic studies have identified sexual dimorphisms in the prevalence of several neuropsychiatric disorders, including depression, schizophrenia, and substance abuse. Many of these sex differences emerge during or shortly after puberty and are maintained until the 5th-6th decade of life. For example, the two-fold greater risk of unipolar depression in women compared with men does not appear until adolescence, and prior to puberty girls are not at increased risk relative to boys. Puberty is a structured, transitional process that can be influenced by both nutritional factors and environmental stressors; nonetheless, the variability in the timing and duration of puberty is largely determined by oligogenic inheritance. Basic neuroscience research has demonstrated that hormonal events accompanying puberty impact on many of the physiologic systems involved in the regulation of brain function (e.g., the appearance of new neurons in a brain-region specific pattern, neuronal remodeling, and the pruning of cortical connectivity). Additionally, not only does stress during puberty increase the risk of disturbances in affective adaptation during adulthood, but the events accompanying puberty modify stress responsivity (e.g., alterations in the duration and peak response of hypothalamic-pituitary-adrenal [HPA] axis hormones to stressors). Moreover, animal work has demonstrated that neural connectivity differs in a brain regional specific manner according to the stage of puberty (i.e., early versus late). In humans, puberty also occurs in stages, and although the endocrinology of puberty, surprisingly, has not been fully characterized with longitudinal data, studies have documented that the physical changes measured by Tanner stages I to V are accompanied by progressive increases in the secretions of both gonadal and adrenal steroids. Nonetheless, there remains considerable variability in the timing and duration of this otherwise highly structured reproductive transition.

We propose to perform a longitudinal, naturalistic study examining changes in brain structure and function, behavior, and stress responsivity in boys and girls across the pubertal transition. Because the pubertal transition is defined by a complex series of physiologic events that emerge sequentially over several years and involve changes in multiple endocrine and growth systems, and because there is also considerable variability in the timing of these events reflecting the influence of both genetic and environmental factors, puberty cannot by delineated by age of the participants as has been done in most imaging and other neurobiological studies of adolescence. The present study will formally bridge this gap by defining pubertal events per se in participants.

Participants will include healthy boys and girls whose pubertal status will be assessed, and in whom endocrine, metabolic, and brain imaging measures will be evaluated at eight - ten month intervals from age eight years (pre-puberty) until age 17 years (post-puberty). Reproductive endocrine, metabolic, and physical measures will be employed to characterize the stage and duration of pubertal development. Outcome measures will be derived via multimodal neuroimaging techniques, cognitive/behavioral assessments, metabolic measurements, and evaluations of HPA axis function. Additionally, the impact of genetic variation on the developmental trajectory of these parameters (both reproductive and CNS) will be determined.

This cross-institute proposal will employ a multidisciplinary approach to evaluating the effects on CNS function of the process of puberty in both boys and girls. This work will not only serve to inform research on the mechanisms by which sexual dimorphisms in neuropsychiatric disorders develop, it will also have important implications for the prevention and treatment of these disorders.


Condition or disease
Adolescent Developement Brain Developmental Biology

Detailed Description:

Despite the clear importance of adolescence in the emergence of a number of disease states and processes, there is surprisingly little known about how the endocrine and metabolic events accompanying puberty in humans impact normal developmental neurobiology. Epidemiologic studies have identified sexual dimorphisms in the prevalence of several neuropsychiatric disorders, including depression, schizophrenia, and substance abuse. Many of these sex differences emerge during or shortly after puberty and are maintained until the 5th-6th decade of life. For example, the two-fold greater risk of unipolar depression in women compared with men does not appear until adolescence, and prior to puberty girls are not at increased risk relative to boys. Puberty is a structured, transitional process that can be influenced by both nutritional factors and environmental stressors; nonetheless, the variability in the timing and duration of puberty is largely determined by oligogenic inheritance. Basic neuroscience research has demonstrated that hormonal events accompanying puberty impact on many of the physiologic systems involved in the regulation of brain function (e.g., the appearance of new neurons in a brain-region specific pattern, neuronal remodeling, and the pruning of cortical connectivity). Additionally, not only does stress during puberty increase the risk of disturbances in affective adaptation during adulthood, but the events accompanying puberty modify stress responsivity (e.g., alterations in the duration and peak response of hypothalamic-pituitary-adrenal [HPA] axis hormones to stressors). Moreover, animal work has demonstrated that neural connectivity differs in a brain regional specific manner according to the stage of puberty (i.e., early versus late). In humans, puberty also occurs in stages, and although the endocrinology of puberty, surprisingly, has not been fully characterized with longitudinal data, studies have documented that the physical changes measured by Tanner stages I to V are accompanied by progressive increases in the secretions of both gonadal and adrenal steroids. Nonetheless, there remains considerable variability in the timing and duration of this otherwise highly structured reproductive transition.

We propose to perform a longitudinal, naturalistic study examining changes in brain structure and function, behavior, and stress responsivity in boys and girls across the pubertal transition. Because the pubertal transition is defined by a complex series of physiologic events that emerge sequentially over several years and involve changes in multiple endocrine and growth systems, and because there is also considerable variability in the timing of these events reflecting the influence of both genetic and environmental factors, puberty cannot by delineated by age of the participants as has been done in most imaging and other neurobiological studies of adolescence. The present study will formally bridge this gap by defining pubertal events per se in participants.

Participants will include healthy boys and girls whose pubertal status will be assessed, and in whom endocrine, metabolic, and brain imaging measures will be evaluated at eight - ten month intervals from age eight years (pre-puberty) until age 17 years (post-puberty). Reproductive endocrine, metabolic, and physical measures will be employed to characterize the stage and duration of pubertal development. Outcome measures will be derived via multimodal neuroimaging techniques, cognitive/behavioral assessments, metabolic measurements, and evaluations of HPA axis function. Additionally, the impact of genetic variation on the developmental trajectory of these parameters (both reproductive and CNS) will be determined.

This cross-institute proposal will employ a multidisciplinary approach to evaluating the effects on CNS function of the process of puberty in both boys and girls. This work will not only serve to inform research on the mechanisms by which sexual dimorphisms in neuropsychiatric disorders develop, it will also have important implications for the prevention and treatment of these disorders.


Study Design

Study Type : Observational
Estimated Enrollment : 344 participants
Time Perspective: Prospective
Official Title: A Longitudinal Investigation of the Endocrine and Neurobiologic Events Accompanying Puberty
Study Start Date : September 13, 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Puberty
U.S. FDA Resources

Groups and Cohorts


Outcome Measures

Primary Outcome Measures :
  1. fMRI BOLD signal

Secondary Outcome Measures :
  1. Behavioral Measures [ Time Frame: 8 - 10 months ]
  2. DTI [ Time Frame: 8 - 10 months ]
  3. UFC and wakening salivary cortisol [ Time Frame: 8 - 10 months ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   8 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA - SAMPLE 1:

Child volunteers will qualify for inclusion if they meet the following criteria:

  • Good general health and normal IQ;
  • Age 8 years;
  • Body Mass Index (kg/m^2) between the 15th and 85th percentiles for age and sex according to the US Centers for Disease Control and Prevention 2000 growth charts;
  • A normal tempo of growth as determined by skeletal age within +/- 1.64 standard deviations of chronologic age according to the Greulich and Pyle radiographic atlas (i.e., no evidence for precocious puberty or abnormal delay of maturation); Research criteria for determining bone age will be performed by the collaborating pediatric endocrinologist. This criterion is required only for the initial entry into this study and is not one of the inclusion criteria for subsequent visits;
  • No history of significant neurologic or cognitive disorders. Examples include neonatal anoxic encephalopathy, seizure disorders, autism, and most learning disorders including attention deficit hyperactivity disorder;
  • Able to provide assent. Parents will provide consent.

EXCLUSION CRITERIA - SAMPLE 1:

Child volunteers will be excluded for the following reasons:

  • Presence of any medical condition that increases risk for MRI (e.g., pacemaker, metallic foreign body in eye or other body part, dental braces);
  • Presence or history of medical conditions known to affect cerebral anatomy;
  • Children who are not pre-pubertal as indicated by the presence of Tanner stage 2 development (i.e., areolar development in girls and testicular volume > 3 cc in boys);
  • Individuals who have, or whose parent or guardians have, current substance abuse or a psychiatric disorder or any other condition which, in the opinion of the investigators, would impede the ability to give informed consent or possibly hinder completion of the study; presence of any psychiatric disorder in the subject, sibling, or other first-degree relative;
  • Subjects who regularly use prescription medications (the use of over-the-counter medications will be reviewed on a case-by-case basis.);
  • For females who have reached menarche: Pregnancy, lactation, or inability or unwillingness to undergo pregnancy testing (a urine pregnancy test will be performed prior to all MRI and X-ray procedures for girls who have had the onset of menses);
  • Current or past use of psychiatric medication;
  • I.Q. < 70.

INCLUSION CRITERIA - SAMPLE 2:

Child volunteers will qualify for inclusion if they meet the following criteria:

  • Good general health and normal IQ;
  • Ages 12-13 years;
  • Body Mass Index (kg/m^2) between the 15th and 85th percentiles for age and sex according to the US Centers for Disease Control and Prevention 2000 growth charts;
  • A normal tempo of growth as determined by skeletal age within +/- 1.64 standard deviations of chronologic age according to the Greulich and Pyle radiographic atlas (i.e., no evidence for precocious puberty or abnormal delay of maturation); Research criteria for determining bone age will be performed by the collaborating pediatric endocrinologist. This criterion is required only for the initial entry into this study and is not one of the inclusion criteria for subsequent visits.;
  • No history of significant neurologic or cognitive disorders. Examples include neonatal anoxic encephalopathy, seizure disorders, autism, and most learning disorders including attention deficit hyperactivity disorder;
  • Able to provide assent. Parents will provide consent.

EXCLUSION CRITERIA - SAMPLE 2:

Child volunteers will be excluded for the following reasons:

  • Presence of any medical condition that increases risk for MRI (e.g., pacemaker, metallic foreign body in eye or other body part, dental braces);
  • Presence or history of medical conditions known to affect cerebral anatomy;
  • Individuals who have, or whose parent or guardians have, current substance abuse or a psychiatric disorder or any other condition which, in the opinion of the investigators, would impede the ability to give informed consent or possibly hinder completion of the study; presence of any psychiatric disorder in the subject, sibling, or other first-degree relative;
  • Subjects who regularly use prescription medications (the use of over-the-counter medications will be reviewed on a case-by-case basis.);
  • For females who have reached menarche: Pregnancy, lactation, or inability or unwillingness to undergo pregnancy testing (a urine pregnancy test will be performed prior to all MRI and X-ray procedures for girls who have had the onset of menses);
  • Current or past use of psychiatric medication;
  • I.Q. < 70.

INCLUSION/EXCLUSION CRITERIA - SAMPLE 3:

Inclusion and exclusion criteria for sample 3 will be identical as those for sample 2 with the exception that children between the ages of 8 and 17 will be included.

INCLUSION/EXCLUSION CRITERIA - SAMPLE 4:

Sample 4 participants will also be volunteering in Protocol #95-M-0150 Neurobiological Investigation of Patients with Schizophrenia Spectrum Disorders and Their Siblings, and/or Protocol #81-M-0126, The Evaluation of Women with Menstrually-Regulated Mood and Behavioral Disorders, in which they will also have signed consent and through which they will have been screened.

INCLUSION CRITERIA - SAMPLE 4:

  • Ages of 25 and 35 years.
  • Normal IQ.
  • No use of psychotropic substances in the last 3 months.
  • No psychiatric or severe chronic medical illness at the time of the study, and by history.

EXCLUSION CRITERIA - SAMPLE 4:

  • Presence of impaired hearing.
  • Pregnant or currently breast feeding. (a urine pregnancy test will be performed prior to MRI procedures in women)
  • Presence of a history head trauma with loss of consciousness in the last year or any evidence of functional impairment due to and persisting after head trauma.
  • Previous eye surgery with a prosthetic implant.
  • Presence of permanent tattooed makeup (eyeliner, lip, etc.) or general tattoos. Participants with tattoos will be excluded if those are in a dangerous location in the body or made with colors (e.g., dark blue and dark green) whose content in iron cannot be definitely ruled out by the investigators.
  • Presence of any non-organic implant or any other device such as: cardiac pacemaker, insulin infusion pump, implanted drug infusion device, cochlear, otologic, or ear implant, transdermal medication patch (Nitro), any metallic implants or objects, body piercing(s), bone/joint pin, screw, nail, plate, wire sutures or surgical staples, shunt.
  • Presence of cerebral or other aneurysm clips.
  • Presence of shrapnel or other metal imbedded in the body (such as from war wounds or accidents).
  • Previous employment in metal fields or with machines that may have left any metallic fragments in or near the eyes.
  • History of a severe accident in the past that may possibly have left metal in the body.
  • Psychological contraindications for MRI (e.g., suffer from claustrophobia);
  • I.Q. < 70.

INCLUSION/EXCLUSION CRITERIA - SAMPLE 5:

Inclusion and exclusion criteria for sample 5 will be identical as those for samples 1 and 2 (i.e., children will either be age 8-9 or between the ages of 12 and 13) with the exception that children with a tempo of growth that is considered abnormal as demonstrated by skeletal age greater than two standard deviations in advance of their chronologic age according to the Greulich and Pyle Radiographic Atlas will be included. These children will be matched for age, Tanner stage, race, ethnicity, and BMI with children currently enrolled in the longitudinal study.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01434368


Contacts
Contact: Peter J Schmidt, M.D. (301) 496-6120 peterschmidt@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
Investigators
Principal Investigator: Peter J Schmidt, M.D. National Institute of Mental Health (NIMH)
More Information

Additional Information:
Publications:
Responsible Party: National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier: NCT01434368     History of Changes
Other Study ID Numbers: 110251
11-M-0251
First Posted: September 14, 2011    Key Record Dates
Last Update Posted: December 7, 2017
Last Verified: November 24, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
Functional Magnetic Resonance Imaging (fMRI)
Normal Development
Puberty
Brain Function
Gonadal Steroids
Brain Structure
Healthy Volunteer
HV