Treatment of the Adult and Transitional Patient

Supplements and Featured PublicationsAppropriate Use of Growth Hormone Therapy in Adults: A Collaborative Approach to Deliver Effective P
Volume 10
Issue 13 Suppl

Once the hurdles associated with testingand diagnosing adults withgrowth hormone deficiency (GHD)have been crossed, the challenge of determiningwhich adult patients should betreated with growth hormone (GH) replacementtherapy remains. In 1996, the US Foodand Drug Administration (FDA) approved recombinanthuman growth hormone (hGH)for the treatment of adult GHD secondary topituitary disease from known causes–pituitarytumor, pituitary surgical damage,hypothalamic disease, irradiation, trauma,and reconfirmed childhood GHD.1 This indicationencompasses most adult patients withGHD. In addition, hGH is now also indicatedfor the management of acquired immunodeficiencysyndrome—related cachexia. Interestabounds in using hGH for a host of otherindications, such as chronic fatigue syndrome,fibromyalgia, obesity, and enhancedathletic performance, none of which hasFDA approval. The potential for fad,unproved, and even cosmetic use of hGHhas forced many payers to implement precertificationrequirements for all patientswho are about to undergo therapy withhGH.1 All of the currently marketed hGHproducts are made using recombinantdeoxyribonucleic acid processes, eliminatingthe risk of contamination or diseasetransmission found with natural products.

For patients with documented GHD, hGHtherapy is the standard of care. However,economic considerations greatly influencethe initiation of treatment. Clinicians maybe reluctant to prescribe treatment for GHDbecause it requires substantial physiciantime and staff support to diagnose and justifyreimbursement. Patients may also bereluctant to undergo a treatment that isexpensive, time consuming, and inconvenient.The patient out-of-pocket costs may besignificant, resulting in a choice not to pursuetherapy. This is especially true in benefitsthat require coinsurance without anannual out-of-pocket cap. Patients should betold the goals of hGH therapy have specificand attainable end points, such as improvedlipid profile, increased bone mineral density,decreased fat mass, improved quality of life(QoL), and reduced mortality. The patientshould understand that the therapeutic benefitsof hGH are gradually achieved from severalmonths to more than a year aftertreatment. Accepted patient groups thatshould receive treatment include youngadults transitioning from pediatric care andyoung and middle-aged adults with recentonsetGHD. Patients older than 60 years ofage may glean only minimal benefits. In fact,because of preexisting medical conditions,older patients may be more susceptible tohGH side effects, such as fluid retention, theappearance of glucose intolerance, or worseningglycemic control in patients with diabetes.Generally, older adults are moresusceptible to the side effects of hGH therapycompared with young patients, especiallyat the start of treatment. Lower startingdoses will help minimize adverse events inthe older population. Starting therapy as ayoung adult decreases the duration of GHD(ie, decrease time to accrue consequencesthat may not be significantly reversible) andreduces the comorbid diagnosis. In theyoung adult patient, the medication is generallybetter tolerated and there is a betterchance to prevent or reverse the degenerativeconsequences of GHD. Waiting until thepatient's condition progresses raises thepotential for more advanced degenerativeconsequences and a greater number ofcomorbid diagnoses. The potential gain maybe less in the population with a higher risk ofpotentially serious side effects. Clinical judgmentis critical when it comes to startingtreatment with hGH, and greater caution isneeded when evaluating older patients whohave more complicated health profiles. Thefollowing case provides an example of theeffects of adult GHD and the restorativeactions of hGH therapy.

Case study: A 47-year-old man was in acar accident and suffered a head injury. Heexperienced central nervous system bleedingand was unconscious and placed on a ventilatorfor 3 weeks. He lost 30 lb in 3 weeks andwas unable to be taken off the ventilator.Diagnosed with panhypopituitarism, thepatient was treated with hormone replacementtherapy (glucocorticosteroids, thyroidhormone, androgens). Within 48 hours he wastaken off the ventilator, he entered rehabilitationfor 7 days, and then returned home.Several weeks after he was discharged, hereturned to work; however, his physical conditionworsened and he was extremely fatigued.He tried an exercise program but was unableto sustain a simple regimen. This scenariocontinued for months without any improvement,despite treatment with antidepressantsand continued attempts at graded exercise.Although he was in his mid-40s, the patientfelt like a frail octogenarian. An endocrinologistevaluated the patient. Provocative GHstimulation testing was performed revealingGHD, and he was prescribed hGH therapy. Hisability to read and retain material returnedcompletely. As the months progressed, hisstrength returned, the depression resolved,and he felt as if he had regained the energylevel he had before the car accident.

In a small, 10-year study that included 10adults with GHD, hGH treatment increasedlean body mass, improved lipid profiles(Table), reduced carotid artery thickness,and enhanced the patient's sense of well-being(Figure 1).2 Moreover, in a 2-yearstudy of 148 adults with GHD, hGH replacementtreatment significantly reduced theneed for sick leave and hospitalizations andalso bolstered QoL measures. These beneficialeffects were maintained throughout the2-year treatment period.3

In children and adults with GHD, hGHtreatment has been shown to significantlyimprove both high-density lipoprotein(HDL) serum concentrations and HDL/low-densitylipoprotein (LDL) ratios (Figure 2).4

In addition, hGH treatment in adults withGHD reverses the increases in carotid arteryintima media thickness seen in untreatedpatients (Figure 3).5 In a study that included 11 men with GHD and carotid intimathicknesses that significantly exceededthose of control subjects, hGH treatmentnormalized intima thickness after 6 monthsof treatment. These findings illustrate thathGH treatment in adults with GHD canreverse early harmful morphologic changesto the vasculature and perhaps reduce cardiovascularrisks.

Treatment with hGH has also been shownto reverse the attenuation in bone mineraldensity seen in GHD. In a randomized, placebo-controlled, 18-month study of 32 menwith adult-onset GHD, treatment with hGHincreased bone density and turnover in additionto increasing lean body mass.6 Thus,hGH therapy may prevent bone loss in adultswith GHD and possibly reduce the fracturerisk. In the transitional patient, hGH has alsobeen shown to improve bone mineral density,body composition, and lipid profiles.7

Together, these clinical findings stronglydemonstrate that adult and transitionalpatients with GHD can gain meaningful clinicalbenefits from hGH replacement therapy,and that this form of treatment should be astandard of care for those with legitimatereplacement needs.

The initial adult hGH dose is 0.1 to 0.3mg/day, which can be titrated monthly toachieve target insulin-like growth factor 1(IGF-1) levels and symptom reduction.Typical maintenance doses are 0.3 to 1.0mg/day; dose adjustments for weight are notusually necessary. Older patients may betreated with 50 μg/day to minimize adverseeffects. Women have greater GH requirementsthan men, especially women receivingoral estrogen therapy.8,9 The time toreach maintenance dose level in terms ofIGF-1 response typically varies from 3 to 6months, but can be longer. Body composition should improve with therapy, but totalbody weight may not substantially change.During treatment, side effects may dictatethe final hGH dose.

Although 90% of cases of GHD are causedby pituitary adenomas, irradiation, surgery,infiltrative disease, infection, or trauma, 10%are idiopathic and have normal radiographicstudies. Isolated GHD is being diagnosedwith greater frequency over time. This conditionis more difficult to diagnose andexplain. Therefore, payer guidelines may notinclude criteria or guidelines specific forapproval of isolated GHD.

Case study: A 54-year-old white manreports a 3-year history of not feeling well,increased abdominal girth, decreased musclemass and strength, moodiness, decreasedlibido, and anhedonia. The patient has amedical history significant for hyperlipidemiaand erythrocytosis. He is currentlytaking pravastatin sodium, aspirin, venlafaxinehydrochloride, niacin extended-releasetablets, dehydroepiandrosterone, and a multivitamin.His social history includes consumingno alcohol, using smokeless tobacco for 20years, and lifting weights regularly. He is marriedand a college graduate. His physical examinationrevealed that he is 6 ft, 3 in tall andweighs 231 lb. His blood pressure is 126/92mm Hg, his pulse is 80 bpm with flat affect,and he has minimal abdominal obesity. Thepatient's baseline laboratory values are: IGF-1, 213 mg/L (90-360); LDL cholesterol, 131mg/dL; HDL cholesterol, 61 mg/dL; normaltestosterone, prostate specific antigen, thyroid-stimulating hormone (TSH), free triiodothyronine(T3), and prolactin. The work-upfor GHD included an arginine stimulation testwith the following results: 0.1 mg/mL at 0 minutes,0.4 mg/mL at 30 minutes, 0.3 mg/mL at 60minutes, 0.3 mg/mL at 90 minutes, 0.3 mg/mLat 120 minutes, and 0.1 mg/mL at 150 minutes.His pituitary magnetic resonance imaging testis normal. A decision was made to treat basedon the physical examination and the failedarginine stimulation test. His insurance companydenied the claim because a destructivelesion of pituitary was not present and he didnot display childhood-onset GHD. In this case,the patient did not meet the payer guidelinesfor the use of hGH in adults, even though GHDwas supported by provocative testing. After anappeals process, therapy was initiated. Thepatient responded to therapy with increasedstamina and is being monitored for improvementin his hyperlipidemia.

Patients who have reached epiphysealfusion and who complete pediatric indicationsfor hGH represent a special categoryreferred to as "transitional patients." Thesepatients are typically in their mid-teens toearly 20s; however, a precise interval hasnot been established between the completionof hGH therapy in childhood and theinitiation of testing or continued hGH therapyin adolescence. These patients, especiallythose with idiopathic GHD, should undergoretesting to establish whether GHD has persistedinto adulthood, although the presenceof a structural pituitary defect, such as acraniopharyngioma in childhood, makes itlikely that GH deficiency will continue intoadulthood. In those transitional patientswith idiopathic GHD in childhood, however,the hypothalamic-pituitary unit may mature,thereby restoring normal GH levels insome patients.1

Case study: A 20-year-old man with panhypopituitarismsecondary to surgery at age 7for craniopharyngioma has not received GHfor several years. He receives testosterone(luteinizing hormone and follicle-stimulatinghormone were 0 when testosterone was low),thyroxin (TSH 0 regardless of thyroid dose),and hydrocortisone. He is not treated withdesmopressin acetate and his current IGF-1 is15 mg/dL (normal is 180-780 mg/mL).

The question remains as to whether thistransitional patient should be treated withGH now that his bone growth is complete.The results of a 2-year study of transitionalpatients demonstrated that these individualsare at risk for the same metabolic disturbancethat afflicts adult GHD patients andthat resumption of hGH treatment can amelioratethese effects.7 Those transitionalpatients with no other pituitary deficiencieswhose initial childhood diagnosis was partialGHD may need no further testing thanIGF-1. If this test is normal, it can beassumed that GH levels are also normal.Alternatively, if IGF-1 levels are low, provocativetesting should be considered.Those patients with multiple pituitary deficienciesand a low IGF should continuereceiving GH long term without the need forstimulation testing.

Transitional patients typically requirelarger doses of hGH than older patients withGHD.7 A Canadian/American study revealedthat 25 μg/kg/day affords better results interms of bone density and body compositionthan lower doses. This converts to 1.75mg/day for a 70-kg patient and 2.5 mg/dayfor a 100-kg patient. This dose, although welltolerated by younger patients, may be lesstolerated by older patients.8 For the transitionalpatient, the American Association ofClinical Endocrinologists guidelines recommenda starting dose of 0.4 to 0.8 mg/day,with increments of 0.2 to 0.4 mg/day every4 to 6 weeks until maintenance doses of1.2 to 2.0 mg/day are achieved. Thesemaintenance doses are much higher thanthe 0.2- to 0.5-mg/day dose recommendedfor a 50-year-old man and the 0.4- to1.0-mg/day dose recommended for a 50-year-old woman.1

Endocr Pract

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2. Gibney J, Wallace JD, Spinks T, et al. The effects of10 years of recombinant human growth hormone (GH)in adult GH-deficient patients. 1999;84:2596-2602.

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4. Attanasio AF, Lamberts SW, Matranga AM, et al.Adult growth hormone (GH)-deficient patients demonstrateheterogeneity between childhood onset andadult onset before and during human GH treatment.Adult Growth Hormone Deficiency Study Group. 1997;82:82-88.

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5. Pfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P,Clayton RN. Growth hormone (GH) treatment reversesearly atherosclerotic changes in GH-deficient adults. 1999;84:453-457.

Ann Intern Med.

6. Baum HB, Biller BM, Finkelstein JS, et al. Effects ofphysiologic growth hormone therapy on bone densityand body composition in patients with adult-onsetgrowth hormone deficiency. A randomized, placebo-controlledtrial. 1996;125:883-890.

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7. Underwood LE, Attie KM, Baptista J, GenentechCollaborative Study Group. Growth hormone (GH)dose-response in young adults with childhood-onset GHdeficiency: a two-year, multicenter, multi-dose, placebo-controlledstudy. 2003;88:5273-5280.

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8. Consensus guidelines for the diagnosis and treatmentof adults with growth hormone deficiency: summarystatement of the Growth Hormone Research SocietyWorkshop on Adult Growth Hormone Deficiency. 1998;83:379-381.

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9. Cook DM. Adult growth hormone deficiency syndrome:a personal approach to diagnosis, treatment andmonitoring. 1999;9:129-133.

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