Hyper-Responsiveness of Patients with Limb-Girdle Dystrophy to Human Growth Hormone

Self Cite

A B S T R A C T Previous studies showed hyperresponsiveness to human growth hormone (hGH) in men with myotonic or limb girdle dystrophies (MMD or LGD). Because polyamines may mediate some actions of hGH, we have nlow investigated polyamine metabolisimi in these and other dystrophies.Under metabolic balance study conditions, serum and urine levels of putrescine (Pu), spermidine (Sd), spermine (Smn), and cadaverine (Cd) were measured in six normal meni (36-44 yr), four men with MMD (38-44 yr), and three men with LGD (30-36 yr), before and durinig treatment with 0.532 U/kg body wt 314/d of hGH. Daily balances of N, P, and K were also monitored. In the normal subjects, hGH did not influence elemental balances or serum and urine polyamines. In MMD, hGH caused significant retention of N, P, and K (P < 0.005). Basal levels of Smn anid Cd were significantly elevated above niormal (P < 0.005), and Pu, Smn, and Cd increased two-to fourfold above basal during hGH treatment (P < 0.005). In LGD, hGH also caused retention of N, P, and K. Basal levels of nearly all the polyamiines (not serumi Pu) were significantly above normal in serum and urine (P < 0.05). During hGH treatmenit, all fotur polyamines rose significantly above basal (P < 0.005).Serum and urine polyaminie levels in five boys with Duchenne muscular dystrophy, age 8-13, did not differ from those in five age-matched normal boys.Skeletal muscle polyamines were measured in five men (31-40 yr) without muscle disease and in three meni with LGD (30-38 yr). Average concentrationis of Pu, Sd, Sm, and Cd were 46, 306, 548, and 61 nmol/g wet wt in LGD and 1, 121, 245, and 14 in the normnal subjects, respectively (P < 0.05 in each instance).Received for publication 9 Jutly 1979 and in revised form 14 September 1979. Polyamnines were determined in skeletal muscle, liver, kidnlley, and brain of male mice with hereditary muscular dystrophy and in age-and sex-mnatched normal controls. Pu, Sd, Sm, and Cd levels were two to three timiies higher than nonrnal in muscle, but did not differ in liver, kidney, and brain. Similar findings were made in miiale hamsters with hereditary dystrophy anid in their conitrols. The abnormality in hamster mnuscle polyamiinies appeared between 1 and 6 wk of age and( persisted or intensified until 30 wk.These data reveal abniormalities of polyamnine metabolism in men with MMD, in mnen with LGD, and in mice or hamsters with hereditary muscular dystrophy. The polyamine disorder could be related to dystrophic patients' hyperresponsiveness to hGH.

Section: Introductionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Abnormal Polyamine Metabolism in Hereditary Muscular Dystrophies

Rudman¹,

Kutner²,

Chawla³

et al. 1980

Self Cite

“…Nine children and adolescents with growth hormone deficiency and two adults with limb-girdle muscular dystrophy served as test sub-;jects. These two classes of patient were selected because of their hyperresponsiveness to exogenous hGH, compared with normal individuals (31,32). Criteria for deficiency of growth hormone, adrenocorticotropin (ACTH), and thyroid-stimulating hormone (TSH) were as previously described (31).…”

Section: Methodsmentioning

confidence: 99%

Metabolic Effects of Plasmin Digests of Human Growth Hormone in the Rat and Man

Mills¹,

Reagan²,

Rudman³

et al. 1973

Self Cite

A B S T R A C T As a first step in our study of structurefunction relationships among primate and non-primate growth hormones, human growth hormone (hGH) was subjected to the limited digestive activity of human plasmin. The lyophilized whole digest, containing less than 2% of unchanged hormone, had an average of 2. The digest also caused glucosuria in partially pancreatectomized rats treated with dexamethasone.These metabolic actions of plasmin-digested hGH in the array of animal tests were confirmed by comparable effects elicited in 11 human subjects (nine pituitary-deficient children and adolescents and two nondeficient adults). A single injection of the plasmin digest caused an increase in plasma free fatty acids and a fall in plasma amino acids. Seven daily injections caused positive balances of nitrogen, phosphorous, sodium, and potassium, gain in body weight, and in two of three subjects impairment of glucose tolerance. The potency of the plasmin digest in producing these metabolic effects in man was comparable to that of native hGH.Thus, 2-3 bonds in the hGH molecule can be cleaved by plasmin without impairing the hormone's growth-

“…As indicators of response, we measured increments in daily balances of N, P, Na, and K and in body weight (BW). The results of these ex-1 Previous studies (1,3) have shown that both categories are 5-10 times more responsive to the anabolic effects of HGH than normal individuals. The minimal effective dose for the anabolic effect of HGH in normals is 0.168-0.532 U/kg BW3/' daily, compared to 0.0532-0.168 U/kg BW3'4 for the patients cited.…”

mentioning

confidence: 86%

“…Adult subjects with myotonic and limb-girdle muscular dystrophies also are more sensitive than normals to the anabolic action of 0.015-0.15 U/kg BW"4 (1,3); the hormone consequently is being evaluated as a possible form of treatment for these types of dystrophy.…”

Section: Introductionmentioning

confidence: 99%

Diurnal Variation in the Responsiveness of Human Subjects to Human Growth Hormone

Rudman¹,

Freides²,

Patterson³

et al. 1973

Self Cite

A B S T R A C T The objective of this study was to compare the responsiveness of human subjects to the anabolic effects of human growth hormone (HGH) administered at 8 a.m. or at 11 p.m. Three doses of HGH were used: A, 0.0168 U/kg body weight (BW)"'4 per day; B, 0.0532 U/kg BW"/' per day; C, 0.168 U/kg BW"'4 per day. The effect of each dose on daily balances of N, P, Na, and K and on BW was measured. The subjects were of two groups: (a) seven GH-deficient children, of whom three were deficient in ACTH; and (b) three patients with limb-girdle dystrophy. ACTHdeficient patients in group (a) received exogenous cortisol at 7 a.m. In all 10 subjects, the anabolic effects of dose C, and sometimes of B and A, administered at 11 p.m. were significantly (P < 0.05) greater than when administered at 8 a.m. In these experiments plasma cortisol concentration averaged 3 times greater at 8 a.m. than at 11 p.m.In the next experiments, exogenous cortisol was administered to the three ACTH-deficient patients at 10 p.m. and the responsiveness to HGH injected at 11 p.m. vs. 8 a.m. was again compared. Under these conditions, when plasma cortisol concentration averaged 3 times greater at 11 p.m. than at 8 a.m., HGH injected at 8 a.m. caused significantly greater anabolic responses than HGH injected at 11 p.m.These findings indicate that the magnitude of the anabolic response to exogenous HGH is inversely related to the plasma cortisol concentration at the time of HGH injection.