Growth Hormone Deficiency Replacement

How best to recognize and manage the condition

 

Adult growth hormone deficiency (GH deficiency) is a well-recognized clinical entity, with resultant abnormalities in substrate metabolism, remodeling of body composition, physical and psychosocial functioning. Improvement with growth hormone replacement has been well-documented and recognized, and this has been incorporated into clinical routines based on initial randomized clinical trials and now incorporated into guidelines.

Here, what primary care physicians and endocrinologists should know now about adult GH deficiency, based on the current literature. The experts also discuss research on weekly GH injection treatment, which is not yet available, but currently under study. If it gains approval for the U.S. market, it may be a game-changer, the researchers said.

Treatment guidelines

While the true prevalence and incidence rate of adult-onset GH deficiency is difficult to estimate accurately, a reasonable estimate can be determined from prevalence data for pituitary macroadenoma—that number is about 1 in 10,000. If cases of childhood-onset GH deficiency are added in, an overall prevalence reaches about 2-3 per 10,000.

As for etiology, pituitary adenomas are the most important cause of GH deficiency in adults. "People with pituitary disease are very likely to be GH deficient," says Roberto Salvatori, MD, professor of medicine and endocrinology at the Johns Hopkins School of Medicine. Another common cause is craniopharyngiomas. Together they account for 57% of cases.

Most cases of adult GH deficiency have an onset in adult years, but some of these are suffering from deficiencies that had onset in childhood.

In addition, other causes can lead to the deficiency, according to Murray Gordon, MD, director of the Alleghany Neuro-Endocrinology Center at Alleghany General Hospital, in Pittsburgh, Pennsylvania. "Another group, one that's somewhat underappreciated, are those who have had traumatic brain injury or a subarachnoid hemorrhage. That can lead to pituitary dysfunction."

Signs and symptoms

Among the clinical features of adult GH deficiency are many unspecific symptoms and signs. However, it's crucial for endocrinologists and primary care doctors (the latter may be less likely to encounter patients frequently) to recognize them. Among them:

  • Increase in body fat, especially central adiposity
  • Decreased muscle mass and muscle function
  • Poor thermoregulation, reduction in sweating
  • Decreased insulin sensitivity; worse glucose tolerance
  • Increase in total LDL cholesterol and Apo B
  • Decrease in HDL
  • Decreased exercise capacity
  • Bond density decrease
  • Increase in fracture risk
  • Depressed mood
  • Higher anxiety
  • Lack of energy
  • Social isolation
  • Less positive well-being

Diagnosis

Because GH is secreted in a pulsatile fashion, with the troughs falling below the assay detection limit of conventional radioimmunoassays, the diagnosis of GH can't be made by a baseline serum GH concentration. (However, a single GH serum measurement, taken at the exact time of the peak may actually rule out a diagnosis).

Dynamic stimulation testing is the next step. The gold standard is insulin tolerance testing. This should be a first choice, done between 8-10 am after an overnight fast and with the patient as relaxed as possible.

Administer insulin IV (0.05-0.15 /U/kg depending on BMI) and fasting blood glucose concentration to reach a blood glucose nadir of <2.2 mmol/L. Sample blood for GH every 15 minutes up to 90. A peak response of <3.0 ug/L is considered diagnostic for adult GH deficiency. That is independent of age and gender.

Another option, said Dr. Gordon, is the oral test, Macrilen (macimorelan). It stimulates GH secretion from the pituitary, and then levels are measured in the blood. While he agrees that the insulin tolerance test is still the gold standard, the Macrilen can fill an important niche due to its simplicity.

How common is it for someone with GH deficiency to also have type 2 diabetes? According to Dr. Salvatori, ''Those who have GH deficiency have visceral obesity, and that's a risk factor for type 2 diabetes." And with treatment, there can be a worsening of glucose control.

Benefits and risks

When treatment is initiated, ''The benefits include improved body composition, lower fat, particularly visceral fat, increased muscle mass, and lower cholesterol," Dr. Gordon said. "The other benefit is with quality of life. The feeling of well-being can improve. It may improve mood."

With GH treatment, Dr. Salvatori said, ''There is a risk of worsening glucose control. It may cause insulin resistance." On the plus side, however, it reduces visceral obesity.  As he said: "I don't not treat with GH if they have type 2 diabetes.''

Weekly injection of GH study

Soon, a weekly GH injection may be available. In a randomized phase 3 trial, researchers, including Dr. Gordon, report that once-weekly somapacitan is effective and well-tolerated in adults with GH deficiency.

Studied at clinics in 17 countries, 257 patients, all treatment naïve, completed the trial. They were randomized 2:2:1 to once-weekly somapacitan, daily GH, or once weekly placebo for 34 weeks. During the 52-week extension, they continued with somapacitan or daily GH. Novo Nordisk, maker of somapacitan, funded the study.

Results

At 32 weeks, the new injection significantly reduced truncal fat percentage (estimated difference: -1.53%[-2.68, -0.38] p =0.0090, demonstrating superiority compared with placebo and improving other parameters, including visceral fat and lean body mass. Improvement persisted at 86 weeks with both forms, daily and weekly.

"I think it's probably the greatest advance in the GH deficiency field in the last 10 years," Dr. Gordon said.  "It offers patients and their families an important therapeutic alternative." When it will be approved in the U.S. by the FDA and when it might be on the market, however, is unknown, as is the price point.

According to Dr. Salvatori, who reviewed the findings on once-weekly somapacitan, ''It's very promising. From the perspective of the patient, it may help them be more adherent," he said. "One of the biggest obstacles when you discuss GH treatment with the patient is the need for daily injections."

Dr. Gordon has consulted for Novo Nordisk and is on an advisory board for Corcept Therapeutics. Dr. Salvatori has no relevant disclosures.

 

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3-year Height Outcomes in Children Treated with Growth Hormone for Growth Hormone Deficiency and other Growth Hormone Disorders
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