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ACTH-secreting Pituitary Adenoma

Family member of survivor of pediatric Cushing disease

Christina Tatsi, M.D.

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

Background:

The pituitary gland produces hormones. A tumor in this gland can cause it to produce too much of the hormone cortisol. Too much cortisol in the body causes Cushing disease. This disease causes many problems. Some of these problems might persist after the disease is cured.

Objective:

To find out the long-term effects of exposure to high levels of cortisol during childhood and adolescence.

Eligibility:

People ages 10-42years who were diagnosed with Cushing disease before age 21 and are now cured and have normal or low cortisol levels

People related to someone with Cushing disease

Design:

Participants will be screened with a medical history.

Participants will complete an online survey. This will include questions about their or their child s physical and mental health.

All participants will be seen at 5 -year intervals after cure of Cushing disease (5yr, 10yr, 15yr, 20yr (last visit))

Participants who have a relative with Cushing disease will have a medical history and blood tests or cheek swabs.

Participants who have the disease will have:

Physical exam

Blood tests

Cheek swab

DXA scan: A machine will x-ray the participant s body to measure bone mineral content.

For participants who are still growing, a hand x-ray

Participants with the disease may also have:

Hormone stimulation test: Participants will get a hormone or another substance that will be measured.

Serial hormone sampling: Participants blood will be measured several times through a thin plastic tube in an arm vein.

Urine tests: Participants urine may be collected over 24 hours.

MRI: Participants may have a dye injected into a vein. They will lie on a table that slides into a machine. The machine will take pictures of the body.

Objective:

Cushing Disease (CD) describes the state of hypercortisolemia secondary to cortisol producing pituitary adenomas. The rarity of the disease (2-5 new cases per million, 1 out of 10 in children) and the subtle initial findings result in prolonged undiagnosed hypercortisolemia, that increases the risk for significant complications, including obesity, height deceleration, hyperlipidemia, hyperglycemia, hypertension, osteoporosis, immunodeficiency, and others. Although hypercortisolemia usually resolves after successful resection of the pituitary adenoma, the reversal of the abovementioned complications and the long-term effects of the previous prolonged exposure of the body to supraphysiologic levels of cortisol have not been clarified, especially when hypercortisolemia occurs during childhood.

Previous studies have addressed the possible complications after resolution of hypercortisolemia, but most of them refer to adult patients. Amongst the described complications, suppression of the pituitary hormones, such as the growth and thyroid hormone axes, and persistent increase of the body mass index (BMI) and abnormal fat distribution, have been described in limited number of pediatric patients followed for a few years after cure. Other complications, such as components of the metabolic syndrome or cardiovascular dysfunction, have not been extensively studied in children. Furthermore, equally important are the long-term effects of glucocorticoids on other aspects of health. For example, it has been previously described that the neurocognitive function of children with CD declines the first year after treatment. This can potentially result in impaired quality of life, lower education level, and lower job and life satisfaction in the future; however, the long-term neurocognitive sequelae of Cushing syndrome (CS) diagnosed in childhood have not been studied.

This study aims to provide novel insight on the long-term effects of hypercortisolemia on the developing child, their underlying pathogenetic mechanisms, their evolution over time, and the risk factors for developing them. This will assist in designing methods to closely monitor or prevent them in the future. Certain results of this study could potentially apply to children with iatrogenic CS, which is much more common due to the widespread use of pharmacologic doses of glucocorticoids in malignancies, autoimmune and atopic disorders.

Study population:

The study population will consist of patients that were previously successfully treated for CD before the age of 21 years. We aim to identify these patients through review of our current protocol 97-CH-0076 on "Clinical and genetic investigation of pituitary and hypothalamic tumors", which has been recruiting patients since 1997. We will also accept patients who have been diagnosed and successfully treated for pediatric CD at outside institutions after reviewing the medical records and confirming their diagnosis. The patients must not be hypercortisolemic at the time of their recruitment. Family members (any age) of patients with a family history of pituitary tumors and who will agree to participate in the DNA/linkage analysis study.

Design:

We will evaluate patients at specific intervals after cure at 5 (+/-1), 10 (+/-1), 15 (+/-1) and 20 (+/-1) years after documented resolution of hypercortisolemia.

The study will include an online survey offered to all patients, as well as an on-site short visit for those willing to travel to NIH.

The online survey will include questionnaires on assessment of various aspects of health: Current medical diagnoses, Medication use, History of endocrine disorders, Fertility, Quality of life, Behavioral and emotional symptomology, and Socioeconomic and Demographic information. The survey will be developed and distributed with the help of CTDB and will be sent with secure email to all the patients and/or their parents (for patients who are \<18yo at the time of evaluation) after consent and eligibility have been confirmed.

The short on-site visit at NIH will be offered to all the patients willing to travel. Blood tests, imaging studies (MRI pituitary/brain, DXA scan), and neurocognitive screening and patient reported outcome questionnaires will be performed.

Outcome measures:

The primary outcome measure of the study is the difference of the Body Mass Index (BMI) z-score of the patients previously treated for pediatric CD compared to the general population, as calculated by data derived from the NHANES study.

The secondary outcomes will be to describe the prevalence of other endocrine and non-endocrine abnormalities after successful treatment of CD in childhood, including: growth hormone, thyroid, gonadal, adrenal function; bone mineral density; glucose metabolism; lipid profile; cardiovascular abnormalities; immunologic changes; coagulation function; psychiatric diseases, behavioral symptomology; neurocognitive function; and quality of life.

Long-Term Follow-Up of Survivors of Pediatric Cushing Disease

Long-Term Follow-UP of Survivors of Pediatric Cushing Disease

The primary outcome measure of the study is the difference in the Body Mass Index (BMI) z-score of the patients previously treated for pediatric CD compared to the general population, as calculated by data derived from the NHANES study.

The secondary outcomes will be to describe the prevalence of other endocrine and non-endocrine abnormalities after successful treatment of CD in childhood, including: growth hormone, thyroid, gonadal, adrenal function; bone mineral density; glucose metabolism; lipid profile; cardiovascular abnormalities; immunologic changes; coagulation function; psychiatric diseases, behavioral symptomology; neurocognitive function; and quality of life.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Premature Birth

Infertility

Infertility, Female

Primary Ovarian Insufficiency

Menopause, Premature

Menopause

All Drugs and Chemicals

Hormones

Clarisa R Gracia, MD, MSCE

Postmenarchal female cancer patients scheduled to undergo cancer therapy may enroll in this study to assess changes in existing and novel surrogate measures of fertility potential before, during and after chemotherapy. Measures of fertility potential to be tested include ultrasound imaging for antral follicle counts and ovarian volumes, endocrine evaluation, and assessment of oxidative stress.

Eligible women are asked to complete a structured interview, questionnaires, a monthly menstrual diary, a brief physical examination, a blood test, and an abdominal or pelvic ultrasound at baseline and at 3 month intervals following start of chemotherapy through 6 months post end of treatment.

Within subject changes in continuous variables (hormones, urinary isoprostane levels, ovarian volume, AFC) will be compared using paired t-tests (nonparametric tests as appropriate). Non-Gaussian-distributed variables will be logarithmically transformed prior to analysis. In general, changes from baseline to every 3 month assessment will be compared individually as well as changes from baseline to post treatment. In addition, regression models for repeated measures will be used to describe the pattern of change in these outcomes over time. Additional models will be constructed to adjust for potential confounding variables including age, chemotherapy type, dose and duration of treatment, radiation treatment, gonadotropin releasing hormone agonist use, and hormone use. Finally, regression models will be used to evaluate the association between changes in urinary isoprostane levels over the study with changes in endocrine measures.

The Longitudinal Ovarian Reserve Study

The Effects of Cancer Treatment on Ovarian Function: A Longitudinal Study by the Oncofertility Consortium

20 mls blood will be obtained at stated timepoints for determining levels of Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estradiol (E2), Inhibin B, and Anti-mullerian Hormone (AMH). In menstruating girls and young women hormone measures will be obtained during the early follicular phase of the menstrual cycle (days 1-4). In women with irregular cycles the testing will be done spontaneously without regard for the bleeding pattern.

Ovaries will be measured in three dimensions. Uterine size and endometrial thickness will also be performed. The transvaginal approach is preferred, but transabdominal ultrasound will be performed in girls who do not feel comfortable with the transvaginal procedure.

Antral Follicle Counts by size (2-5 mm, 6-9 mm, and \>9 mm in diameter) will be determined.

24 hour urine collection will be analyzed to assess urinary 8,12-iso-iPF2alpha-VI isoprostane levels.

Subjects are asked to document menstrual bleeding in a diary, noting duration of each menstrual period in days, bleeding intensity (spotting, light, moderate, heavy, flooding, none), and intervals between periods.

The validated "Menopausal Symptom List" (MSL) will be used at each study visit to assess the presence or absence of menopausal symptoms during the past month, the frequency and severity of each symptom. Symptoms captured include: hot flashes, vaginal dryness, concentration/memory problems, irritability, mood swings, feeling sad, feeling anxious, trouble sleeping, aches, joint pain, headaches.

One of two well validated and widely used questionnaires will assess Quality of Life measures: For adolescents 20 years of age or younger, the Minneapolis-Manchester Quality of Life (MMQL) - Adolescent Form will be administered. This questionnaire assesses demographics, physical functioning, cognitive functioning, psychological functioning, body image, social functioning, outlook on life, and intimate relations in cancer survivors. The MMQL is a 46 item validated, standardized self-report instrument designed to assess health related quality of life in adolescent survivors of cancer.

Subjects over 20 years of age will be asked to complete a self report quality of life questionnaire entitled Assessing Quality of Life in Adult Cancer Survivors (QLACS). This questionnaire has been proven to be valid and reliable for comparing quality of life in adult cancer survivors and non-cancer patients.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Long-Term Follow-Up of Survivors of Pediatric Cushing Disease	NCT03831958	Cushing Disease		2 Years - 90 Years	National Institutes of Health Clinical Center (CC)
The Longitudinal Ovarian Reserve Study	NCT02395341	Effects of Chem...		15 Years - 45 Years	University of Pennsylvania

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