Consequences of Reduced Growth Hormone Secretion on the Skin

GH declines with age in every animal species that has been tested to date. In humans, the amount of growth hormone after the age of 21 to 31 falls about 14% per decade, so that the total 24-hour growth hormone production rate is reduced by half by the age of 60. In numerical values, humans produce on a daily basis about 500 µg at 20 years of age, 200 µg at 40, and 25 µg at 80 [23]. The skin of adults with growth hormone deficiency (GHD) is thin, dry, and cool, rendering venous access difficult. These changes probably arise because of the loss of a direct anabolic influence of GH on skin cells exacerbated by reduced cardiac output. In addition, GH regulates eccrine sweat glands, and sweating is impaired in GHD, very likely contributing to poor exercise capacity.

Many of the undesirable changes that accompany aging mimic those manifest in the GHD syndrome,including central obesity,muscle atrophy, exercise intolerance, decreased metabolic rate, dyslipidemia, cardiovascular deterioration, osteopenia, thinning of skin, mild anemia, loss of vigor, sleep disturbances, and depression. Aging is thus a partial phenocopy of adult GHD. This has prompted speculation that pituitary somatotroph activity may be a pacemaker of aging and has raised the possibility that GH supplementation might retard geriatric deterioration because replacement therapy reverses most features of GHD in young adults.

Most organic adult GHD arises from pituitary lesions. The loss of GH secretion associated with aging alone results from hormonal changes upstream of the pituitary. Pituitary responsiveness to GHRH persists in aging, although the magnitude of GH release may decline somewhat. The practical implication of this difference is that GH secretagogues should be useful for stimulating GH secretion in normal older people whereas they are ineffective in most organic forms of adult GHD. At any age, including advanced ages; individuals with organic GHD have significantly lower measures of basal and stimulated GH secretion than do age-matched normal subjects [24].

A careful study of the aging face reveals it to be more than just surface textural wrinkling or loose skin. Changes in three-dimensional topography are responsible for the distinctive phenotypic presentation of the face throughout life. These geometric alterations are secondary to apportioning in the fat compartments and result in the fat dysmorphism characteristic of senescence. Redistributing this fat can rebalance the facial fat compartments and mimic the facial structure present in youth [22].

There is no single sign or symptom that is pathognomonic of GHD in adulthood or provides any biological end point for diagnosis. A low serum IGF-I in adults suggests GHD, but a normal value does not exclude the disease. The “gold standard” for establishing a biochemical diagnosis is the peak GH response to insulininduced hypoglycemia in an insulin tolerance test (ITT). Other GH stimuli such as arginine, glucagon, L-dopa, and clonidine are used in provocative tests, but none is as powerful as the ITT [25]. Despite vast clinical experience with the ITT, controversy remains over what peak GH value constitutes a diagnostic cutoff. Most patients respond to insulin-induced hypoglycemia with a peak GH greater than 5 ng/ml. “Severe GHD” is currently defined by a peak GH less than 3 ng/ml [26]. Because of the lack of standardization of GH assays, each laboratory should ideally establish its own diagnostic threshold values rather than blindly accepting these recommended cutoffs. The diagnosis of GHD is increasingly likely when additional anterior pituitary hormones are found to be deficient, as GH is one of the first of such hormones to be lost in adult hypopituitarism of most causes. Hence, isolated adult GHD should be confirmed with two biochemical tests. Although an ITT is safe when carefully administered, it is contraindicated in the setting of documented ischemic heart disease and seizure disorders [26]. Some investigators do not perform the ITT in anyone over 65 years of age because of potential occult cardiovascular disease (CVD) [25]. In such cases, arginine (or arginine plus GHRH) is probably the best alternative.

Unfortunately, distinguishing organic GHD from the hyposomatomedinemia of aging is a challenge. Although GH secretion is lower at any age in patients with organic GHD than in age-matched normal subjects, the spread between these groups diminishes with advancing age such that GH levels differ by only 13% between elderly adults with GHD and their normal peers [27]. Thus, confirming GHD in an older person may not be possible, especially if only one or no additional pituitary hormones are deficient [25]. The situation is similar for morbidly obese patients in whom GH secretion may be suppressed to a similar degree as in organic GHD. Even among people in whom the diagnosis of normal, age-related, hyposomatomedinemia is clear, the question remains whether such individuals might benefit from restoration of GH to youthful levels.