Clinical and Reimbursement Issues in Growth Hormone Use in Adults

Transcription

1 Clinical and Reimbursement Issues in Growth Hormone Use in Adults Based on presentations by Beverly M.K. Biller, MD; Mary Lee Vance, MD; David L. Kleinberg, MD; David M. Cook, MD; and Terry Gordon, MD, MBA Presentation Summary Data published in the past decade have demonstrated that adults who are deficient in growth hormone (GH) experience deleterious clinical consequences without treatment. In 1996, the Food and Drug Administration approved the use of GH in adults who were GH deficient as a result of hypothalamic or pituitary disease. However, there are other conditions in adults for which GH treatment has also been approved (acquired immune deficiency syndrome [AIDS]-related wasting) or for which it is being considered, such as aging, catabolic states, and cardiomyopathy. Clinical issues revolve around the rationale for treatment; the diagnostic evaluation; the effects of GH therapy on body composition, bone density, lipids, and cardiac function; and appropriate dosing and follow up. Clearly, the use of GH in adults raises reimbursement issues as well. In this article, Dr. Beverly M.K. Biller provides an overview of the rationale for the treatment of adult-onset GH deficiency and reviews its etiology and clinical features as well as reimbursement and utilization issues related to treatment. Dr. Mary Lee Vance discusses various assays and criteria used in the diagnostic evaluation of the patient with adult-onset GH deficiency. Dr. David L. Kleinberg focuses on the effects of GH therapy on body composition, bone density, lipid profiles, and cardiac function, as well as on reimbursement issues regarding body composition studies. To complete the clinical portion of this session, Dr. David M. Cook addresses dosing and follow up. To address economic implications, Dr. Terry Gordon provides the payer s perspective on the diagnosis and treatment of adult-onset GH deficiency. Payer Highlights Managed care is amendable to working with employers to cover GH therapy in adults, thus working to remove the assumption that payers will deny all requests for such coverage. Clinicians question why they need to defend the use of GH in adults in the treatment of a particular clinical symptom when it is not required to obtain coverage of adrenal hormone, gonadal steroids, or thyroid hormone when they are prescribed as replacement therapy. Issues exist between payers and clinicians in regard to which diagnostic and/or follow-up tests for adults with GH deficiency should be reimbursed. VOL. 6, NO. 15, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S817

2 The use of growth hormone (GH) in adults raises clinical and economic issues regarding diagnostic evaluation, the nongrowth effects of treatment, dosing, follow up, and ongoing therapy. Although GH has been approved for use in adults with GH deficiency resulting from hypothalamic or pituitary disease and for those with wasting caused by AIDS, it is also being investigated for use in adults with other conditions. These include the treatment of aging ( somatopause ), respiratory failure, burns, and cardiomyopathy. The rationale for its use in those conditions differs. There is a gradual decline in GH production that occurs with aging. In contrast, catabolic states result in GH resistance. Patients with cardiomyopathy have normal GH function, so the mechanism of a potential beneficial effect is not yet clear. Research in those areas is under way, although some of the results are controversial. Causes and Clinical Features of GH Deficiency Etiology and Clinical Features. GH deficiency in adults has several Table 1. Etiology of Adult GH Deficiency Pituitary disease o Tumors o Postirradiation o Postsurgery o Apoplexy Hypothalamic disease Craniopharyngioma Posttrauma Postinfection Childhood-onset GH deficiency in adulthood GH = growth hormone. causes, which are listed in Table 1. A constellation of clinical features (Table 2) occurs in many patients with hypopituitarism who have adequate replacement of other pituitary hormones. Although a patient may not exhibit all of the features shown in Table 2, GH replacement therapy may correct the abnormalities listed. However, there are individual and gender-based differences in response to therapy, as well as differences in response based on the age of onset of GH deficiency. Rationale for the Treatment of Adult GH Deficiency Replacing what is missing ie, GH is the underlying rationale for the treatment of GH deficiency in children and adults. This concept is clearly illustrated by a case of a 57- year-old patient with panhypopituitarism that developed after he had undergone transsphenoidal surgery and radiation therapy 3 years earlier to treat a large, clinically nonfunctioning pituitary adenoma. The patient was receiving standard postsurgical therapy (thyroxine, testosterone, and prednisone) and presented to the neuroendocrine clinic for his annual examination. The patient was armed with an article in the American Association of Retired Persons newsletter about the use of GH to slow the aging process. Knowing that he had panhypopituitarism and that GH was produced in the pituitary, the patient concluded that he should be receiving GH as replacement therapy and asked for a prescription. His conclusion was on target because clinicians routinely prescribe cortisol as replacement therapy for patients who are cortisol deficient, thyroid hormone for patients who are thyroid-hormone deficient, and testosterone or estrogen as replacement for patients with hypogonadism. Another rationale underlying the recommendation for treatment of GH S818 THE AMERICAN JOURNAL OF MANAGED CARE SEPTEMBER 2000

3 ... CLINICAL AND REIMBURSEMENT ISSUES IN GROWTH HORMONE USE IN ADULTS... deficiency is related to the amelioration of the clinical features shown in Table 2. Patients with low levels of GH have abnormal body composition, decreased bone mineral density, abnormalities in serum lipid levels, diminished quality of life, and cardiovascular abnormalities. Each of these may be associated with significant morbidity, and some data have suggested an increase in cardiovascular mortality. Because treatment with GH can reverse these abnormalities, it can impact the associated morbidity. These potential metabolic and psychologic benefits of GH replacement are detailed later in this article. Insurance Issues. A major issue for clinicians who seek to obtain coverage for GH therapy for an adult with GH deficiency is the request by the payer to defend the use of GH based on the treatment of 1 particular clinical symptom. The payer wants to know which symptom will be ameliorated by treatment with GH and what will be offered as proof that the symptom is resolving and the patient is getting better. Clinicians question why this criterion is required to obtain coverage of GH replacement therapy when it is not required to obtain coverage of adrenal hormone, gonadal steroids, or thyroid hormone when they are prescribed as replacement therapy. Perhaps insurance companies may need to consider a prescription for GH replacement therapy as treatment that replaces a deficient substance, not as fixing 1 item on a long list of potential clinical variables that may be impacted differently in each treated patient. Another major insurance issue is utilization. Undertreatment with GH therapy is the reality for those with adult-onset GH deficiency. According to Bengtsson, a noted investigator in GH research, more than 85% of adults with GH deficiency in Sweden receive replacement therapy compared with less than 15% in the United States (BA Bengtsson, personal communication, 1999). There are many reasons for the low utilization rate of GH replacement therapy in adults in the United States, but 3 are related to insurance issues: Some clinicians are not aware that coverage is available, many patients are reluctant to ask for coverage, and some insurance companies are reluctant to reimburse for GH therapy. Some physicians and Table 2. Clinical Features of GH Deficiency Altered body composition o Increased fat mass o Decreased lean body mass o Decreased skeletal muscle strength o Decreased total body water Decreased bone mineral density o Multiple sites o Independent of gonadal status o Increased fracture rate Lipid metabolism abnormal o Increased LDL cholesterol level o Increased total cholesterol level opossible decrease in HDL cholesterol level Quality of life diminished o Social isolation o Decreased energy and mobility o Memory impairment o Mood impairment and/or lability o Sexual dysfunction Cardiac structure and function altered; possible increase in cardiovascular mortality o Decreased cardiac muscle thickness o Decreased left ventricular ejection fraction o Diastolic dysfunction o Endothelial dysfunction opossible relation to lipid/body composition changes GH = Growth hormone; LDL = low-density lipoprotein; HDL = high-density lipoprotein. VOL. 6, NO. 15, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S819

4 patients believe so strongly that a request for reimbursement for GH therapy will be denied that they will not ask for it. Diagnostic Evaluation of Adult GH Deficiency The diagnosis of GH deficiency in adults differs from that in children. Because adults have achieved their final height, growth rate and bone age are no longer factors in diagnosing GH deficiency. Challenges exist regarding which adults to test, the choice of the test and assays used, and cutoff levels. Adults who should be tested include those with a history of pituitary or hypothalamic disease (usually structural disease, but occasionally acquired hypogonadotropic hypogonadism), those with other hormone deficiencies, and those with childhood-onset GH deficiency. More than 90% of adults who are GH deficient have pituitary or hypothalamic disease, usually an adenoma, which is quite common in older adults. Those patients have undergone or will undergo pituitary surgery or radiation. Fewer than 10% of that patient population have childhoodonset GH deficiency. Those percentages, however, may change as a result of increased attention to treatment during the transition from childhood to adulthood. Endocrinologists who treat pediatric patients have had difficulty defining the best provocative test and cutoff values; those who treat adults face similar challenges. The overriding approach is to use common sense. For example, 90% or more of adults with 3 other pituitary hormone deficiencies will be GH deficient as well. It is also highly unlikely that an adult with a large pituitary tumor who presents with visual loss is producing adequate amounts of GH. Nevertheless, the Food and Drug Administration (FDA) requires a subnormal GH response to 1 stimulation test (as opposed to 2 tests in children) to confirm the diagnosis. Diagnostic Testing Criteria. When GH was first approved for use in adults, the type of stimulation test to be used in the diagnostic evaluation was not specified. The criterion for determining GH deficiency depended on the type of GH assay used. A GH level below 5 µg/l measured by radioimmunoassay or a level below 2.5 µg/l revealed by immunoradiometric assay was considered subnormal. This prompted the Growth Hormone Research Society to issue a consensus statement recommending the use of the insulin tolerance test (ITT) to induce hypoglycemia and setting the criterion as any GH value below 3 µg/l. 1 Although the ITT is considered the gold standard for the diagnosis of GH deficiency because it is the most rigorous, it is also the most difficult for the patient to undergo. It is contraindicated in those with angina, coronary artery disease, a history of a seizure disorder, or generalized debility, and is relatively contraindicated in those with known cortisol deficiency. The ITT is also used to identify patients who need glucocorticoid replacement as well. Because of these contraindications, the Growth Hormone Research Society s consensus statement also suggests an arginine plus GH-releasing hormone test as the most promising alternative, although this is not absolute. The tests described below are used in the outpatient setting to identify GH deficiency in adults. With the exception of oral clonidine, the results of these tests may be almost as reliable as those of the ITT in determining GH deficiency in adults. A 30-minute intravenous infusion of arginine is reliable and safe and is associated with minimal side effects. Oral levodopa (L-dopa) is reliable S820 THE AMERICAN JOURNAL OF MANAGED CARE SEPTEMBER 2000

5 ... CLINICAL AND REIMBURSEMENT ISSUES IN GROWTH HORMONE USE IN ADULTS... and safe and is associated with minimal side effects (eg, occasional nausea and mild orthostasis). A combination of arginine and L- dopa, either administered orally or intravenously, is reliable and produces only minimal side effects. The GH-releasing hormone and GH-releasing peptide tests, which are administered intravenously, provide reliable results and produce minimal side effects. However, they yield higher GH values than do the ITT and other tests. Therefore, higher cutoff points (eg, less than 15 µg/l) are recommended as diagnostic of GH deficiency. An intramuscular glucagon yields reliable results but can produce hypotension. Although oral clonidine is sometimes used for diagnostic testing in children, it is not suitable in adults because it is a poor stimulus for GH even in normal adults. Determining the serum insulinlike growth factor 1 (IGF-1) level has been proposed as a diagnostic test because it is well known to be a useful screening test in the opposite condition (ie, GH excess [acromegaly]). However, serum IGF-1 levels have been shown not to be reliable in the diagnosis of GH deficiency in adults because of the degree of overlap with values in normal subjects. However, it is a good test with which to monitor GH treatment. Coverage Issues. One of the major coverage issues regarding adult-onset GH deficiency is that insurance companies still tend to consider GH deficiency as a problem of achieving normal growth and height that affects children. As a result, the morbidity and premature mortality caused by untreated GH deficiency in adults are not given adequate consideration. Three large epidemiologic studies demonstrate that untreated GH-deficient adults die earlier of cardiovascular and cerebrovascular disease than do treated or normal adults. 2-4 GH replacement produces favorable clinical effects in GH-deficient adults and should be considered medically necessary for those individuals, as is thyroid replacement therapy in patients deficient in thyroid hormone. Clinicians must also deal with immediate denial by payers. It is extremely frustrating for clinicians who have submitted all necessary documentation for coverage to be denied and then to have to write letters of justification for coverage. Perhaps as a result, many clinicians are reluctant to prescribe GH for adults, and relatively few adults who need treatment actually receive it. Endocrinologists who treat adult patients should carefully document the diagnosis of GH deficiency and the results of the stimulation test. They must be vigilant in dealing with insurance companies to secure coverage for their patients and to keep GH use in adults within the purview of the medical profession rather than a treatment supplied in antiaging clinics, which is already happening in California, Nevada, and Florida. The cost of treatment is also an issue. Treatment with GH is far more expensive than that with thyroid hormone or other hormones usually prescribed for replacement. GH replacement therapy is not available in pharmacies and, in some cases, is not distributed directly by pharmaceutical companies. By obtaining GH from third-party payers, such as a home health agency, patients are paying 2 to 3 times the manufacturer s price. This increases the already high cost of healthcare. Effects of GH Therapy on Body Composition, Bone Density, Lipid Profiles, and Cardiac Function GH exerts favorable effects on body composition, bone density, lipid VOL. 6, NO. 15, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S821

6 abnormalities, and cardiac function as well as on several quality-of-life parameters such as physical strength, energy, the ability to perform the activities of daily living, and exercise capacity. GH deficiency produces a spectrum of symptoms. For many patients with GH deficiency, the most troublesome symptoms are related to quality-of-life parameters. Some report an enormous reduction in energy and/or exercise capacity, others report some diminution of those factors, and still others report no decrease. Signs that are relatively common in all patients with GH deficiency are increased amounts of body fat, decreased lean muscle mass, and decreased bone mineral density. However, these signs are more obvious in patients who have been GH deficient for some time than they are in those with GH deficiency of recent onset. Those with childhood-onset GH deficiency have more body fat, less lean body mass, and lower bone mineral density scores than do adults who have recently become GH deficient because of a pituitary tumor. Body Composition. The most solid data demonstrating the effects of GH on body composition in adults are from 9 placebo-controlled studies involving 392 GH-deficient patients who ranged in age from 21 to 68 years. Of those patients, 124 were female, 268 were male, 107 had childhood-onset GH deficiency, and 285 had adult-onset deficiency. The study participants were treated with doses of GH that ranged from 2.6 mg/kg/day to 26 mg/kg/day; the average dose was 0.5 mg/day, which is closer to the dose currently used in adults in the United States. Because a dose of 26 mg/kg/day in an adult can cause acromegaly, high doses (ie, overtreatment) should be avoided or used with great caution. Overall, these 9 studies indicated a mean increase in lean body mass of 3.4 kg and a mean decrease of 4.4% in body fat. 5 Moreover, in each of the studies, the lean body mass increased, usually within 6 months of treatment but maintained over a longer period of time, and the percentage of body fat decreased. The increased percentage of body fat in patients with GH deficiency is centered primarily around the abdomen and within the viscera. That pattern of fat distribution increases insulin resistance and the risk for adverse cardiovascular events. Several factors or methods, such as those listed below, are used to measure body composition. Total body water content Bioimpedance analysis Hydrodensitometry Total body potassium value Dual-energy X-ray absorptiometry (DEXA) scanning Skinfold measurements at selected sites Waist:hip ratio However, with each of these methods, body fat and lean mass percentages are either overestimated or underestimated because GH-deficient patients are relatively dehydrated before being treated with GH. After treatment, these patients become rehydrated or in some cases overhydrated, and water is measured as lean body mass. In fact, edema is a side effect of GH therapy. Body composition can be measured accurately by 4-compartment analysis in which DEXA machines with special software are used, but only a few centers in the United States can perform that testing. DEXA scanning without 4-compartment analysis is often performed to measure body composition, but that test varies from center to center, and the results are often difficult to analyze. When a DEXA scan is used to measure body composition, it is important that the same machine, methodology, S822 THE AMERICAN JOURNAL OF MANAGED CARE SEPTEMBER 2000

7 ... CLINICAL AND REIMBURSEMENT ISSUES IN GROWTH HORMONE USE IN ADULTS... and technician be used to conduct repeat scans of a particular patient to maximize the degree of reliability when comparisons are made. The waist:hip ratio can be used to determine body composition because that ratio decreases when fat around the middle is lost after GH therapy is initiated. One study indicated a significant decrease in the waist:hip ratio after 6 months of GH therapy and a further decrease in the ratio after 12 months of therapy, although the latter was not statistically significant. 6 Cardiopulmonary Function. Several studies have shown that treatment with GH improves cardiac function and increases maximum oxygen consumption. There is also evidence that the ability of the heart to pump blood is compromised in children who have been GH deficient for a long period of time. One study has indicated that GH produces a beneficial effect on the pumping ability of the heart by decreasing peripheral resistance. 7 Recent studies have shown that there is a very real and significant increase in coronary artery disease and other forms of cardiovascular disease in adults (particularly women) with GH deficiency. 8 To date, the effect of treatment with GH on cardiovascular morbidity and the life expectancy of GH deficient patients has not been studied. However, the effect of small replacement doses of GH on cardiopulmonary function is being evaluated and preliminary data are expected before the end of this year. Bone Density. Bone mineral density in adults with childhood-onset GH deficiency is impaired in the proximal and distal forearm and the lumbar spine. After treatment with GH, there is an increase in markers for both bone formation and resorption, but the net effect of such treatment is increased bone deposition and bone density. In 1 study, GH treatment increased bone mineral density by more than 4% over 18 months when compared with the results in controls who received placebo. 9 Lipids. There is little doubt that patients with GH deficiency exhibit lipid and lipoprotein abnormalities. A study by Attanasio and colleagues has shown a definite decrease in both total cholesterol and low-density lipoprotein (LDL) cholesterol and an increase in high-density lipoprotein (HDL) cholesterol as a result of GH therapy compared with the effect of placebo. 6 However, data from other studies have not completely supported the findings regarding the beneficial effects of GH on the level of HDL cholesterol. Reimbursement Issues. It is worthwhile to measure the body composition of the patient treated with GH because it is an objective way to measure changes in body composition during the course of treatment. However, payers do not reimburse for these measurements before or during GH therapy, but they do reimburse for measurements of bone mineral density. Dosing and Follow Up of Adults With GH Deficiency Although the focus of dosing and monitoring children with GH deficiency is linear growth, the focus in adults is on body composition changes and symptomatology. In adults, the symptoms of GH deficiency decreased energy, decreased exercise capacity, and not feeling well are often the impetus to seek GH therapy. Similarly, the increased energy and improvements in general well-being afforded by GH therapy are major reasons to continue therapy. Indeed, there is a very low dropout rate, about 3% to 4%, among adults on GH therapy. Even though GH is an injectable agent, patients continue with therapy because of their improved VOL. 6, NO. 15, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S823

8 physical well-being and favorable changes in body composition. Pediatric endocrinologists and pediatricians have known for years that GH deficient children lose abdominal and visceral fat and develop better muscle definition soon after they start therapy with GH. Computed axial tomography scans indicate that these children actually lose more visceral fat than subcutaneous fat in the truncal area. These findings have also been demonstrated in adults receiving GH. Selecting the appropriate GH dose for an adult presents a challenge and involves a good deal of trial and error. When endocrinologists first started using GH to treat adults with GH deficiency, they initiated therapy with doses of about 25 µg/kg/day, but it soon became apparent that adults could not tolerate that dose, because Table 3. Suggested Therapy Guidelines for Adults Requiring GH Replacement Therapy All men and all women on transdermal estrogen replacement therapy should begin treatment with 2 µg/kg/day GH, which should be increased every 4 to 6 weeks by 1 µg/kg/day until a high-normal IGF-1 concentration or symptom tolerance is achieved. Therapy for women who are taking oral estrogen should be initiated with a GH dose of 4 µg/kg/day that should be increased by 2 µg/kg/day every 4 to 6 weeks until a high-normal serum IGF-1 concentration or symptom tolerance is achieved. Do not begin any patient on a GH dose greater than 300 µg/day. Therapy in patients older than 55 years of age should be initiated with 100 µg/day, which should be increased every 4 to 6 weeks by 50-µg increments until a high-normal serum IGF-1 concentration or symptom tolerance is achieved. Be aware of and advise patients about the possibility of start-up symptoms and symptoms of intolerance before initiating therapy. GH = Growth hormone; IGF-1 = insulin-like growth factor 1. fluid retention and significant muscle and joint pain quickly developed. Growth is not an issue in adults with GH deficiency, and as a result, they generally require about one tenth of the pediatric dose, ie, 0.1 to 0.3 mg/day or 100 to 300 µg/day for adults as opposed to 1 to 3 mg/day or 1000 to 3000 µg/day for children. However, because adult patients represent a range of ages, usually from 20 to 80 years of age, and because GH production decreases by about 14% per decade, doses for adults should be further adjusted according to the patient s age. In addition, there are gender differences in response to GH therapy; women require higher doses than do men, presumably because of the influence of estrogen replacement. This is particularly evident in women who are taking oral estrogen replacement or birth control pills. There are 3 guiding principles regarding GH dose selection: Children need higher doses than adults. Women need higher doses than men. Younger adults need higher doses than older adults. These principles are illustrated in the cases that follow and in Table 3. Case 1. A 70-year-old man exhibiting panhypopituitarism resulting from a pituitary tumor and irradiation. He was deficient in all pituitary hormones and was receiving replacement therapy for all except GH. His major symptom was low energy. Stimulation tests revealed undetectable GH levels. He was started on a modest dose of GH but soon developed severe joint pain. The dose was decreased and the joint pain resolved, but the patient s energy level decreased again. The dose was increased to 80 µg/day. The patient s IGF-1 levels moved into S824 THE AMERICAN JOURNAL OF MANAGED CARE SEPTEMBER 2000

9 ... CLINICAL AND REIMBURSEMENT ISSUES IN GROWTH HORMONE USE IN ADULTS... the normal range, and his symptoms resolved. Case 2. A college student who is not in transition became GH deficient at age 19 for reasons that are not entirely clear. Her pretreatment IGF-1 levels were low and she was also deficient in thyroid-stimulating hormone and adrenocorticotropic hormone. She was started on a GH dose of 400 µg/day but did not begin to feel better, nor did her IGF-1 levels move into the midnormal range established for women of her age until her dose reached 2000 µg/day. Case 3. A 35-year-old woman became GH deficient after developing a nonfunctioning pituitary tumor. Three years earlier, when she was actively body building and participating in competitions, her body fat was a low 17%. Her body fat percentage was now increased, and her bone density at the spine and hip were below the values established for women her age. Her sex steroid levels and menstrual function were normal, however. After 2 years of GH therapy, at an average dose of 0.8 mg/day, her high energy level has returned, she is body building again, and her body composition and bone mineral density have improved. Case 4. An elderly woman with GH deficiency and a dilated cardiomyopathy had been receiving a maintenance dose of GH of 300 µg/day, and her heart condition had responded nicely. She was also receiving oral estrogen replacement therapy but wanted to switch to a transdermal preparation. Because the bioavailability of active drugs is higher with transdermal preparations than with oral formulations, she was switched from a modest dose of oral estrogen to a lower-dose estrogen patch. However, because estrogen influences GH effect (in fact, this patient s serum IGF-1 concentrations rose when she was switched from oral to transdermal estrogen) and because elderly women require lower GH doses than do younger women, her dose was lowered to 200 µg/day. Nevertheless, 200 µg/day proved to be excessive for this elderly woman, and her dose was further reduced to 100 µg/day. When trying to establish the appropriate GH dose for an adult, the endocrinologist should remember that there are 2 sets of symptoms associated with therapy: start-up symptoms and symptoms of excess. Therefore, it is especially important to start low and go slow before increasing the dose. This principle is best illustrated by the following case and in Table 3. Case 5. A 58-year-old man weighing exactly 100 kg (220 pounds) exhibited panhypopituitarism resulting from a nonfunctioning pituitary tumor and surgery. He was receiving replacement therapy for all of the other pituitary hormones and was started on GH at a dose of 100 µg/day. However, 7 days later he called to complain of severe muscle and joint pain, particularly in his shoulders, a typical start-up symptom. His dose was lowered to 50 µg/day, which he tolerated well, and then the dose was successfully increased by small increments over a period of time to a maximum of 300 µg/day, the highest dose he could tolerate. With higher doses, he developed persistent muscle and joint pain. Symptom tolerance is often a factor that determines the maintenance dose of GH. Elevated IGF-1 levels, carpal tunnel syndrome, signs of pituitary tumor growth, and the develop- VOL. 6, NO. 15, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S825

10 ment or redevelopment of muscle and joint pain are other determinants of the maintenance dose. Start-up symptoms, which usually include muscle and joint pain, headache, and blurred vision because of increased fluid retention, indicate the need to decrease the dose, which can then be gradually increased in small increments to a suitable maintenance dose. Symptoms of excess essentially, the redevelopment of start-up symptoms herald the need to reduce the dose. GH dosing in adults is clearly influenced by many variables: age, gender, endogenous estrogen, exogenous estrogen replacement and its route of administration, and obesity. In obese patients, the GH dose can be calculated on the patient s lean body mass rather than his or her weight, because basing the dose on an obese patient s weight invariably results in a dose that is too high. In general, 2 or 3 dosage adjustments are required every few weeks over the course of about 6 months to determine the appropriate maintenance dose for an individual patient. Monitoring Therapy. Endocrinologists can order many expensive assays to monitor GH therapy in adults with GH deficiency. However, in a cost-conscious healthcare environment, it is best to focus on necessary tests and on those most likely to be reimbursed. In the adult being treated with GH, the following tests are essential for appropriate monitoring: pituitary magnetic resonance imaging (at least during the year before and after therapy) and the evaluation of serum IGF- 1 concentrations, lipids, bone density, and body composition. Payer s Perspective on Diagnosis and Treatment of GH Deficiency in Adults Although different payers have different policies regarding reimbursement for GH therapy and monitoring in adults, they are generally amenable to working with employers, who can request what they want covered in their policies, and to providing necessary coverage for patients. Aetna, for example, provides coverage for GH treatment in adults who have become GH deficient because of pituitary surgery. Aetna also provides coverage for GH deficient adults when all of the following conditions have been met: The patient is already receiving full supplementation of other deficient hormones as required. The patient exhibits clinical features of somatotropin deficiency documented by any of the following: Severely reduced quality of life as assessed by the Growth Hormone Deficiency Assessment questionnaire Decreased bone density of less than 1 SD, which by World Health Organization criteria would predict increased risk for osteoporosis and fractures Aetna also provides coverage for GH in adults with Turner syndrome and those with AIDS-related wasting accompanied by involuntary weight loss. One of the major issues for payers is the lack of input from specialty societies for use in making complicated policy decisions. Payers need input about clinical matters and other issues from pediatric and adult endocrine societies and from expert groups involved in research and clinical practice pertaining to GH use. Thus far, the only specialty society that has consistently provided such input to payers is the American Heart Association.... REFERENCES Consensus guidelines for the diagnosis and treatment of adults with growth hormone S826 THE AMERICAN JOURNAL OF MANAGED CARE SEPTEMBER 2000

11 ... CLINICAL AND REIMBURSEMENT ISSUES IN GROWTH HORMONE USE IN ADULTS... deficiency: Summary statement of the Growth Hormone Research Society Workshop in Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998;83: Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336: Bates AS, Van t Hott W, Jones PJ, Clayton RN. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 1996;81: Bulow B, Hagmar L, Mikoczy Z, Nordstrom CH, Erfurth EM. Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol 1997;46: Newman CB, Kleinberg DL. Adult growth hormone deficiencies. Endocrinologist 1998;8: Attanasio AF, Lamberts SWJ, Matranga AM, et al. Adult growth hormone (GH) deficient patients demonstrate heterogeneity between childhood onset before and during human GH treatment. J Clin Endocrinol Metab 1997;82: Boqer RH, Skamina C, Bode-Boger SM, Brabant G, von zun Muhler A, Frolich JC. Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. A double-blind placebo-controlled study. J Clin Invest 1996;98: Bulow B, Hagman L, Erkilsson J, Erfunth EM. Hypopituitary females have a high incidence of cardiovascular mortality and an increased prevalence of cardiovascular risk factors. J Clin Endocrinol Metab 2000;85: Baum HBA, Biller BMK, Finkelstein JS, et al. Effects of physiologic growth hormone therapy on bone mineral density and body composition in patients with adult-onset growth hormone deficiency. Ann Intern Med 1996;81: VOL. 6, NO. 15, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S827