title: Parathyroid hormone secretory pattern, circulating activity, and effect on bone turnover in adult growth hormone deficiency.
abstract: Adult growth hormone deficiency (AGHD) is associated with osteoporosis. Reports have associated parathyroid hormone (PTH) circadian rhythm abnormalities with osteoporosis. Furthermore, there is evidence of relative PTH insensitivity in AGHD patients. Factors regulating PTH circadian rhythm are not fully understood. There is evidence that serum phosphate is a likely determinant of PTH rhythm. The aim of this study was to investigate PTH circadian rhythm and its circulating activity and association with bone turnover in untreated AGHD patients compared to healthy individuals. We sampled peripheral venous blood at 30-min and urine at 3-h intervals during the day over a 24-h period from 1400 h in 14 untreated AGHD patients (7 M, 7 W; mean age, 49.5 +/- 10.7 years) and 14 age (48.6 +/- 11.4 years; P = NS) and gender-matched controls. Cosinor analysis was performed to analyze rhythm parameters. Cross-correlational analysis was used to determine the relationship between variables. Serum PTH (1-84), phosphate, total calcium, urea, creatinine, albumin, type I collagen C-telopeptides (CT(x)), a bone resorption marker, and procollagen type I amino-terminal propeptide (PINP), a bone formation marker, were measured on all samples. Nephrogenous cyclic adenosine monophosphate (NcAMP), which reflects the renal activity of PTH, was calculated from plasma and urinary cAMP. Urinary calcium and phosphate were measured on all urine samples. Significant circadian rhythms were observed for serum PTH, phosphate, CT(x), and PINP in AGHD and healthy subjects (P < 0.001). No significant rhythm was observed for serum-adjusted calcium. PTH MESOR (rhythm-adjusted mean) was significantly higher (P < 0.05), whereas the MESOR values for phosphate, CT(x) (P < 0.05), and PINP (P < 0.001) were lower in AGHD patients than in controls. AGHD patients had significantly lower 24-h NcAMP (P < 0.001) and higher urinary calcium excretion (P < 0.05). Maximum cross-correlation between PTH and phosphate (r = 0.75) was observed when PTH was lagged by 1.5 h in healthy individuals, suggesting that changes in phosphate precede changes in PTH concentration. PTH/CT(x) and PTH/PINP showed maximum correlation when CT(x) (r = 0.68) and PINP (r = 0.71) were lagged by 3 h. In AGHD patients, compared to controls the maximum correlation between PTH/phosphate (r = 0.88, P = 0.007), PTH/CTx (r = 0.61, P = 0.027), and PTH/PINP (r = 0.65, P = 0.028) was observed when the lag time was reduced by 1.5 h in all variables, with changes in PTH and phosphate occurring at concurrent time points. Our data suggest decreased end-organ sensitivity to the effects of PTH in AGHD patients, resulting in a significantly lower NcAMP, low bone turnover, and higher calcium excretion in the presence of significantly higher PTH concentrations. We have also demonstrated that changes in serum phosphate precede those of PTH, which in turn precede changes in bone resorption and formation in healthy individuals. This relationship was altered in AGHD patients. These results suggest a possible role for GH in regulating PTH secretion and the bone remodeling process.
authors.affiliation: Department of Diabetes and Endocrinology, Royal Liverpool University Hospital, Prescot Street Liverpool, L7 8XP, UK. DRAAHMAD@Yahoo.com
authors.forename: A M
authors.initials: AM
authors.lastname: Ahmad
authors.forename: M T
authors.initials: MT
authors.lastname: Hopkins
authors.forename: W D
authors.initials: WD
authors.lastname: Fraser
authors.forename: C G
authors.initials: CG
authors.lastname: Ooi
authors.forename: B H
authors.initials: BH
authors.lastname: Durham
authors.forename: J P
authors.initials: JP
authors.lastname: Vora
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001861:Bone Regeneration / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D016001:Confidence Intervals; D005260:Female; D019382:Human Growth Hormone / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D007018:Hypopituitarism / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009010:Monte Carlo Method; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000502:physiology*; D010710:Phosphates / Q000378:metabolism
chemical_list: D010281:Parathyroid Hormone; D010710:Phosphates; D019382:Human Growth Hormone; D002118:Calcium