by Beverly M.K. Biller, M.D
NEPTCC Newsletter MGH Neuroendocrine Center Bulletin Volume
11, Issue 1, Spring / Summer 2005
Since 1996, growth hormone (GH) replacement in adults has been approved by US Food and Drug Administration. Growth hormone replacement in adults has been shown to improve body composition, bone density, cardiovascular risk markers, and quality of life. The current indications for the use of GH in adults include either a history of pituitary disease or a history of childhood onset growth hormone deficiency (GHD) which persists in adulthood. The goal of diagnostic testing for GHD is to determine which patients are truly deficient and might benefit from replacement, and which patients continue to make normal amounts of GH despite their pituitary disease, therefore having no need for GH replacement.
Consensus guidelines by the Growth Hormone Research Society and the American Association of Clinical Endocrinologists indicate that the diagnosis should be established in patients with an appropriate clinical history by demonstrating a peak GH concentration of less than 3-5 mcg/L following insulin-induced hypoglycemia (insulin tolerance test, ITT)1,2. However, the ITT is not frequently performed in the United States because it is labor intensive, has potential risks, and is contraindicated in some patients. A recent study of over 800 patients being tested for adult GHD showed that only 11.4% were evaluated with insulin tolerance tests 3. A multi-center study was designed to determine whether another stimulation test might have the same diagnostic accuracy as the ITT without the associated risk.
This study, conducted at Massachusetts General Hospital, Oregon Health Sciences University, University Hospital of Cleveland, Cedars Sinai Medical Center, and New York University Medical Center evaluated five stimulation tests for the diagnosis of GHD 4. Thirty-nine patients with adult onset hypothalamic-pituitary disease and multiple pituitary hormone deficiency were compared with 34 control subjects carefully matched for age, sex, body mass index, and estrogen use. Subjects underwent stimulation testing on five separate mornings approximately a week apart including ITT, arginine (ARG), L-dopa, ARG + L-dopa, and ARG + growth hormone releasing hormone (GHRH). Blood was sampled for GH every 20-30 minutes for 2.5 hours and samples were measured in a central laboratory.
Cut points were chosen to allow three different diagnostic options. A cut point was chosen which provided 95% sensitivity, another was selected to afford 95% specificity, and an additional cut point termed CART was chosen to minimize misclassification of patients in either direction. The results showed that the ARG-GHRH test achieved the same diagnostic accuracy as the ITT. Receiver operating characteristic (ROC) curves for peak serum GH responses to ITT and ARG-GHRH are shown in Figure 1. A perfect test, one which would discriminate completely between diseased and normal subjects, would demonstrate a line along the left side and upper part of the box, coinciding with the left upper corner, and would be associated with a ROC area of 1.0. In contrast, a test that is unable to discriminate between diseased versus normal groups would result in a diagonal line from the left lower to the right upper corner of the box, corresponding to a ROC area of 0.5. Both the ITT and the ARG-GHRH test demonstrate excellent discrimination between groups, with ROC areas under the curve of 0.962 and 0.968 (NS) respectively. The superscripts a, b and c denote cut points which provide CART (minimization of misclassification), 95% sensitivity, and 95% specificity values, respectively.
The ARG-GHRH test represents an ideal alternative to the ITT in making the diagnosis of GHD in most adults.
TIn contrast, the ROC curve for the L-dopa test shows a significantly lower ability to discriminate between the patients and the normal subjects, with a substantially lower ROC area under the curve of 0.906, compared with ITT or ARG-GHRH. In addition, this test was not able to achieve 95% specificity, so there is no cut point labeled c.
The choice of a high sensitivity versus a high specificity cut point may depend on the clinical setting. In patients with panhypopituitarism, a number of studies have demonstrated a very high probability of GHD. For example, patients who are deficient in 3 or 4 other pituitary hormones have been shown to have a greater than 95% probability of being deficient in GH 5, 6. In such patients, clinicians might prefer to use a test with at least 95% sensitivity, thereby limiting the chance of a false negative result, in order not to misclassify a deficient patient as having normal GH secretion. Because patients with panhypopituitarism have such a high probability of GHD, some insurance companies have approved GH replacement without requiring stimulation testing. In contrast, in a patient with no other pituitary hormone deficiencies, the risk of GHD is less than 50%. In such a patient, a clinician is likely to seek high specificity. Choosing a cut point with high specificity would limit the chance of a false positive test, which would be important for avoiding the unnecessary use of GH replacement in someone with adequate GH production. Alternatively, the cut points derived by CART analysis provide a balance between high sensitivity and specificity, and might be preferred by some clinicians.
While insulin-like growth factor-1 (IGF-1) is diagnostically useful for the GH excess state of acromegaly, it is not as accurate in the diagnosis of GHD. This is because there is substantial overlap at the low end of the normal range between normal people and patients subsequently confirmed to have GH deficiency. Thus, IGF-1 has low sensitivity for the diagnosis of GHD when it is in the lower half of the normal range. It has been suggested that an IGF-1 level below a certain cut point might be useful for the diagnosis of GHD, particularly in childhood onset or younger adult-onset GHD patients 7, 8. Because serum IGF-1 levels decline with age, the diagnostic utility of this measurement is particularly low in older patients 9,10. Several studies have shown specific IGF-1 levels below which normal subjects almost never fall. These levels have typically been in the 70-80 mcg/L range 3, 4. However, choosing a specific IGF-1 cut point below which all subjects are classified as GHD must take into account other variables that affect IGF-1 such as nutrition, liver disease, and the IGF-1 assay employed. It may be clinically useful to measure an IGF-1 as a screening test in patients with possible GHD. If the level returns very low, in the absence of other causes of low IGF-1, the diagnosis may be established if the patient is also deficient in three or more other pituitary hormones. Some insurance companies have accepted this combination of panhypopituitarism and a frankly low IGF-1 as sufficient for the diagnosis of GHD. However, it is important to note that if a screening IGF-1 level returns in the lower half of the normal range, this does not exclude the possibility of GHD, and further stimulation testing should be performed. If a screening IGF-1 is in the high end of the normal range for age and sex, then the probability of GHD is quite low, and clinical judgment should be used as to whether to pursue stimulation testing.
In summary, the ARG-GHRH test represents an ideal alternative to the ITT in making the diagnosis of GHD in most adults. There are several caveats regarding clinical situations where this test may not be accurate. Patients who have had recent radiation, and may have hypothalamic damage (but not yet pituitary dysfunction), may have a falsely normal response to GHRH. The same situation may be seen in patients with other sources of hypothalamic GHD including childhood-onset subjects without organic disease. In such patients, an alternative test, such as ITT or ARG + L-dopa with a more stringent cut point (such as 0.25 mg/L, 95% specificity) might be advisable. The use of clinical history, including the presence of panhypopituitarism and a low IGF-1 may also assist in making the diagnosis of growth hormone deficiency. Establishing the presence or absence of GHD using accurate diagnostic tests will allow replacement therapy to be offered to the appropriate patients.
Figure 1. Receiver-operating characteristic (ROC) curves for peak serum GH responses to ITT, ARG-GHRH, and L-DOPA. The ROC curve plots the true positive rate (sensitivity) against the false-positive rate (1-specificity) for different cut-points. A test with perfect discrimination between multiple pituitary hormone deficiencies (MPHD) patients and matched control subjects (100% sensitivity and 100% specificity) would coincide with the left upper corner of the box, and be associated with a ROC area of 1.0. In contrast, a test providing no discrimination between groups would result in a diagonal line from the left lower to the right upper corner of the box (sensitivity = 1-specificity), and correspond to a ROC area of 0.5. The arrows and superscripts indicate the location on the ROC curves of the three diagnostic cut-points defined as follows: a, minimize misclassification of MPHD patients and control subjects; b, 95% sensitivity for GHD; and c, 95% specificity for GHD. The area under the curve (AUC) for each ROC curve is shown. The ITT and ARG-GHRH tests are statistically equivalent for diagnostic accuracy. Reprinted with permission from The Endocrine Society.
- American Association of Clinical Endocrinologists. Endocr Pract. 1998; 4:165-73.
- Growth Hormone Research Society J Clin Endocrinol Metab. 1998; 83:379-81.
- Hartman ML, et al. J Clin Endocrinol Metab. 2002; 87:477-85.
- Biller BMK, et al. J Clin Endocrinol Metab. 2002; 87:2067-79.
- Aimaretti G, et al. J Clin Endocrinol Metab. 1998; 83:1615-8.
- Toogood AA, et al. Clin Endocrinol. 1994; 41:511-6.
- Hilding A, et al. J Clin Endocrinol Metab. 1999; 84:2013-9.
- Span JP, et al. J Endocrinol Invest. 2001; 22:446-50.
- Ghigo E, et al. Eur J Endocrinol. 1996; 134:352-6.
- Toogood AA, et al. J Clin Endocrinol Metab. 1996; 81:460-5.
~ RESEARCH STUDIES AVAILABLE ~
Patients may qualify for research studies in the Neuroendocrine and Pituitary Tumor Clinical Center. We are currently accepting the following categories of patients for screening to determine study eligibility. Depending on the study, subjects may receive free testing, medication and/or stipends.
~ Physicians' Pituitary Information Service ~
with questions about pituitary disorders may contact:
Dr. Biller or Dr. Klibanski at
(617) 726-3965 within the Boston area or toll free at (888)
or e-mail to firstname.lastname@example.org
~ MGH Neuroendocrine and Pituitary Tumor Clinical Center
Services Available ~
Facilities The Neuroendocrine Center is located on the 1st floor (Suite 112) of Zero Emerson Place at the Massachusetts General Hospital. A test center is available for complete outpatient diagnostic testing, including ACTH (Cortrosyn) stimulation; Insulin tolerance; CRH stimulation; Oral glucose tolerance and growth hormone reserve testing. Testing for Cushing's syndrome can also be arranged, including bilateral inferior petrosal sinus ACTH sampling for patients with ACTH-dependent Cushing's syndrome.
Speakers The Neuroendocrine Center offers speakers on a wide variety of topics. Lectures, rounds, and small symposia can be arranged.
Neuroendocrine Clinical Conference A weekly interdisciplinary conference is held to discuss all
new patients referred to the Neuroendocrine Center and to review patient management issues. It is a multidisciplinary conference, attended by members of the Neuroendocrine, Neurology, Neurosurgery, Psychiatry and Radiation Medicine services. Physicians are welcome to attend and present cases.
Neuroendocrine Lecture Series A bimonthly conference is held on didactic and research topics
related to Neuroendocrinology. Attendance is open to all interested medical personnel.
Physicians’ Pituitary Information Service Physicians with questions may contact Dr. Biller or
Dr. Klibanski at (617) 726-3965 within the Boston area or toll free at (888) 429-6863, or e-mail to
Scheduling Outpatient clinical consultations for patients with pituitary disorders can be arranged by calling the Neuroendocrine Center Office at (617) 726-7948.