A Longitudinal Investigation of the Endocrine and Neurobiologic Events Accompanying Puberty

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01434368
First received: September 13, 2011
Last updated: June 25, 2014
Last verified: May 2014
  Purpose

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
Adolescent Developement
Brain
Developmental Biology

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: A Longitudinal Investigation of the Endocrine and Neurobiologic Events Accompanying Puberty

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • fMRI BOLD signal

Secondary Outcome Measures:
  • Behavioral Measures [ Time Frame: 8 - 10 months ] [ Designated as safety issue: No ]
  • DTI [ Time Frame: 8 - 10 months ] [ Designated as safety issue: No ]
  • UFC and wakening salivary cortisol [ Time Frame: 8 - 10 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 244
Study Start Date: September 2011
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.

  Eligibility

Ages Eligible for Study:   8 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • Sample 1

INCLUSION CRITERIA:

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/m2) between the 15th and 85th percentiles for age and sex according to the US Centers for Disease Control and Prevention 2000 growth charts (103);
  • 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 (102) (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:

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.

Sample 2

INCLUSION CRITERIA:

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/m2) between the 15th and 85th percentiles for age and sex according to the US Centers for Disease Control and Prevention 2000 growth charts (103);
  • 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 (102) (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:

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.

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.

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, in which they will also have signed consent and through which they will have been screened.

INCLUSION CRITERIA:

  • 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:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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
Investigators
Principal Investigator: Peter J Schmidt, M.D. National Institute of Mental Health (NIMH)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT01434368     History of Changes
Other Study ID Numbers: 110251, 11-M-0251
Study First Received: September 13, 2011
Last Updated: June 25, 2014
Health Authority: United States: Federal Government

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

ClinicalTrials.gov processed this record on July 10, 2014