Diagnosing and Treating Growth Hormone Deficiency: What Are the Obstacles, and How Can They Be Overcome?

[Click here to get started]    
[Go to Main Page]

Question: What is the best algorithm to confirm a diagnosis of adult growth hormone (GH) deficiency In clinical practice?
Answer: The first thing we think of as clinicians is: What symptoms are associated with adult GH deficiency? And the major symptom is decreased energy, which is the impetus the patient has to seek some sort of answer as to why he or she has lost energy.

The second thing that patients identify is a decrease in their thinking power. I will ask patients how their brain function is. Right away they’ll say, “I’m just not the person I used to be,” especially if they have a cognitively demanding job and have to do a lot of multitasking. Often they just can’t do it anymore. More commonly, people who like to read find that they no longer get pleasure out of it because things go in one ear and out the other—their comprehension is diminished.

Next, you have to determine the reason for the patient’s having GH deficiency. The major reason in adults, of course, would be a pituitary tumor, and this would be associated with pituitary surgery, pituitary irradiation, and the tumor itself pressing or destroying normal pituitary function. There is a gradual decrease in pituitary function in a predicted fashion, along with a dropout of hormones. And the pituitary is most sensitive, with any injury or insult, to loss of GH, followed by the gonadotropins—luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—then thyroid-stimulating hormone (TSH), and finally the toughest one to destroy by any process would be adrenocorticotropic hormone (ACTH).
In addition to pituitary tumor, a history of head trauma is associated with hypopituitarism. Head trauma is usually a rapid deceleration injury, which includes being thrown out of an automobile and suddenly hitting the ground or hitting the dashboard. It has been well documented that some head injuries that are seemingly inconsequential will, in time, demonstrate decreased function. For instance, someone might say, “Well, I just fell down the stairs and bumped my head a little bit, but ever since that time I just haven’t been the same.” And that last phrase is the key portion of the history—“ever since that time,” be it a head injury or an automobile injury—there has been some precipitating incident that leads to GH deficiency.

In addition to head trauma, subarachnoid or subdural hemorrhages can also be associated with GH deficiency. Another cause can be irradiation of the brain, for a tumor other than a pituitary tumor, which hits the hypothalamus. The hypothalamus is much more susceptible to irradiation injury than is the pituitary. So, here we have a context.

Last but not least, physicians who are thinking about this symptom complex will also find patients who have an idiopathic cause of GH deficiency. And so, a complex of decreased energy, decreased thinking, body composition changes—which mostly include loss of muscle and increase in fat, especially visceral fat or abdominal fat, or increase in waist circumference—is what drives the patient to seek medical attention.

In the context of young adult patients, there are two groups in which we might consider a diagnosis of GH deficiency. The first group includes those patients who were born with midline defects. For example, patients who had a cleft palate repaired or a single incisor in the front as child are at an increased risk for hypopituitarism; these patients can develop GH deficiencies and are often undiagnosed until young adulthood. 1. The second group in whom reviewing endocrine function in young adulthood might be appropriate includes patients who were treated for a hematologic malignancy during childhood, especially those who received cranial irradiation. 2. GH deficiencies in this cohort can occur slowly. The bottom line is that it may be worthwhile to ask adult patients if they were either born with a midline defect or if they were treated with radiation and/or chemotherapy for an illness during their childhood.

After we have thought about the symptoms associated with GH deficiency, especially in a context, we screen the patient with an analysis of the major axes of anterior pituitary functions. We screen for GH deficiency with insulin-like growth factor 1 (IGF-1), and then we screen for LH and serum testosterone in males. In females, the screening would be for LH and then FSH. This is especially helpful in a postmenopausal woman, where the LH and FSH should be very high. If it’s low, then you have good evidence of hypogonadotrophic hypogonadism. In a young woman, just stopping menstrual periods after pituitary surgery, for example, would be enough evidence that she is gonadotropin deficient. To test for thyroid, we would look at TSH and free T4, and then for ACTH it would be a cosyntropin stimulation test—not 24-hour urine cortisol. And to reiterate, all of this is in the context of a known reason for pituitary injury.

Once you have these test results, if you have a low IGF-1 and three other hormone axes of the anterior pituitary that are deficient (ie, of the gonadotropins, TSH, ACTH, and antidiuretic hormone [ADH]), you don’t have to go any further. You’ve made your diagnosis. You most likely have MRI evidence of what’s going on—namely, that you’ve had a pituitary tumor and there’s surgical evidence in the tumor bed, something like that; or you have an atrophied pituitary, so-called empty sella, and you have MRI evidence of something wrong with the pituitary. If you have only one or two axes that are deficient or just a low IGF-1, and you’re considering GH deficiency, then you need to confirm the diagnosis of adult GH deficiency with a stimulation test.

The stimulation tests currently used in adults are the insulin tolerance test and glucagon stimulation test. I would have said 2 years ago that the major tests for adults would be arginine plus GH-releasing hormone, but GH-releasing hormone has been removed from the market. So, we no longer have that as a diagnostic tool. We have the insulin tolerance test, which neither physicians nor patients like. That leaves us with glucagon test or using arginine alone. We tend not to use arginine alone because it is not a very good stimulus.

With these tests, you have to use associated reference points for peak cutoff values after the stimulation. For example, for glucagon, 3 ng/mL or above is normal. So, if it stimulates just a little bit and gets to 3.0 ng/mL, that is still considered normal. A value of 2.9 ng/mL or below would be abnormal, and you’ve confirmed your deficiency. For insulin tolerance tests, the cutoff point is 5 ng/mL. I would look at these cutoff points and references for testing in the major consensus guidelines that have been published: American Association of Clinical Endocrinologists guidelines,3 2007 GH Deficiency Consensus Workshop Participants guidelines,4 and the Endocrine Society Clinical Practice Guideline.

Question: What are the current overall recommendations and indications for the use of GH in adults, including those who are transitioning from pediatric treatment?
Answer: We will first look at the patient who transitions from the pediatric indication to the adult indication. They’ve received GH as a child, and they have finished the indication, which is to say that growth has stopped. And there is no magic age for that; some patients will have stopped growth at age 15 and others at 16, 17, or 18 years. It’s not a matter of epiphyseal fusion. It’s not a matter of their age. It’s a matter of whether they’ve stopped growing as a response to GH. At this point, the pediatrician stops GH and transitions the patient to adult care. For adults, we would treat anyone who is GH deficient.

However, it is important to note that major negative changes in body composition related to fat and muscle can occur if GH is stopped rather than transitioning to adult dosing during young adulthood after growth is completed. More specifically stopping GH once growth has stopped is associated with increased body fat around the waist and a loss of muscle mass, which can lead to the increased fatigue.6 These changes can happen quite rapidly, well less than 6 months after stopping GH; it is difficult to reverse when GH is restarted. As a consequence, transitioning to adult dosing but not stopping GH has become fairly routine.

Now, having said all of this, the major morbidities associated with each of those age groups differ. In the transition patient, the major reason to treat would be a bone disorder or bone osteopenia; in essence, decreased development of the bones. So, the major reasons for continuing GH in the transition cohort are to increase bone mineral density (BMD) and to prevent negative changes in body composition.6 BMD peaks at about 25 years of age; normal maximum density is not likely to be reached if GH is stopped at the ending of growth and resumed later in adulthood. For the patient aged 30 to 60 years, the major indication to treat would be cardiovascular risk factors. The patient may have high cholesterol, an increase in visceral fat, high C-reactive protein, or high interleukin-6—all of which can indicate an increased cardiovascular risk.

In patients age 60 years and older, we are looking primarily at a decreased quality of life. Usually, if you develop GH deficiency after age 60 or close to that age, you don’t have the bony indication. You don’t have osteoporosis or osteopenia. And although you do have the increased cardiovascular risk factors, they’re not as important a reason to treat as they would be in the middle age group.

In summary, we treat everyone who actually is proven to be GH deficient as an adult. But as far as indications, the major things that will surface are broken down into age groups. In the transition patient, or the patient up to age 30, we are talking about a bony indication. From 30 to 60 years of age, the indication is for a compilation of cardiovascular risk factors. And then above 60 years, it’s a matter of quality of life. But all ages have a decreased quality of life, which is improved by GH replacement therapy.

Question: How do you manage adult patients on recombinant GH after they develop malignancy or diabetes or those who are at risk for recurrence of a pituitary tumor?
Answer: GH therapy is clearly contraindicated in patients who have malignancies, and the development of a malignancy in a patient receiving GH therapy is a definite reason to stop GH. Physicians sometimes have concerns that therapy with GH can actually induce malignancies; so, I want to clarify that there is no evidence that this is the case.

The question is, in a patient with a history of malignancy, after what period of time would you consider replacing GH? And that’s a very arbitrary number, as it is really disease-related. For example, with lymphoma, we have more clear-cut evidence that patients are cured, and the interval is probably shorter than it is for breast cancer or lung cancer. But the typical figure that’s used is that they are cancer-free for 5 years or longer when starting GH. If I see a patient who has had a malignancy, I like to get a green light from the oncologist, who will confirm that he/she is comfortable that the patient has been disease-free for a sufficient amount of time.

Diabetes is another potential contraindication for GH therapy. This is not an absolute contraindication, as it does not apply to diabetes in all of its stages. From an absolute standpoint, diabetic proliferative retinopathy is a contraindication to GH therapy. However, dosage adjustments are important in the patient with comorbid GH deficiency and diabetes. In diabetic patients being started on GH therapy, it may be necessary to use more antidiabetic therapy or more insulin for a time until they lose visceral fat and become more insulin sensitive. Patients with GH deficiency who also suffer from diabetes need to start GH therapy at a very low dose. For a diabetic adult or someone with a BMI over 30 kg/m2, 0.1 mg/day is a standard dose to start.

Frequently, the patient with pituitary tumor has a pituitary remnant, or there may be concern expressed by the neurosurgeon about the possibility of a pituitary remnant. And, physicians often wonder if there is a concern that GH will induce recurrence of a pituitary tumor. The answer to that is no. In fact, it may even be protective against a recurrence of a pituitary tumor. This has been well studied by a number of large series looking at the rate of pituitary tumor recurrence in control patients with pituitary tumors untreated with GH and those treated with GH. So, experience tells us that we do not need to be concerned about recurrence of a pituitary tumor in patients treated with hGH. Having said there is not an increased worry over recurrence with GH therapy, patients are at possible risk for recurrence due to the natural history of recurrence. The key is that the risk of recurrence is not increased with GH therapy.

1. Datani M, Preece M. Lancet. 2004;363:1977-1987.
2. Gurney JG et al. Cancer. 2006;107:1303-1312.
3. Cook D et al. Endocrine Practice. 2009;15:580-586.
4. Ho KKY. Eur J Endocrinol. 2007;157:695-700.
5. Molitch M, Vigersky R. J Clin Endocrinol Metab. 2006;91:1621-1634.
6. Savage MO et al. Eur J Endocrinol. 2004;151:S61-S65.

[Click here to get started]    

[Go to Main Page]