Parathyroid hormone related protein.
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Bone Neoplasms↗
Biomedical subjects
D A Heath
Publications and source records attributed to D A Heath.
Pregnancy associated osteoporosis.
OBJECTIVE: Previous literature reports have suggested that osteoporosis associated with pregnancy is a rare event. We have examined the prevalence of this condition and compiled data on the largest group of such patients in the literature. PATIENTS AND DESIGN: With the help of the National Osteoporosis Society 35 women with pregnancy associated osteoporosis were identified. These women were matched with a control group from our already established computer data bank for age, weight, height and calcium status. Detailed questionnaires were sent to the osteoporotic sufferers enquiring about their present condition, past medical and drug history, and their menstrual, lactational and obstetric histories. They were also asked to complete a detailed dietary history to establish their calcium status. A questionnaire was also completed by the parents of these women and the parents of the control group, asking specifically about fracture history. RESULTS: Twenty-nine women had idiopathic osteoporosis associated with pregnancy, while in six, the condition may have resulted from drug therapy or associated diseases. Pain occurring late in the first full term pregnancy was the most common presentation. The natural history was for the condition to improve with time. There was a significantly higher prevalence of adult related fractures (P < 0.02) occurring at an earlier age in the mothers of these women compared to a control population. CONCLUSION: We have identified 35 women who have developed osteoporosis during or shortly after pregnancy and in only six of them could a recognized underlying cause be suggested. These findings would suggest that idiopathic osteoporosis associated with pregnancy may be more common than the current literature suggests. The higher prevalence of fractures in the mothers of our population compared to controls raises the question of a possible associated genetic factor in the aetiology of this condition.
Adult↗
Effects of the Booroola gene (FecB) on body weight, ovarian development and hormone concentrations during fetal life.
The aim of this study was to determine whether the FecB gene influenced some aspects of fetal development in sheep. Carrier (BB/B+) and non-carrier (++) female fetuses were recovered at specific times of gestation, namely, days 40, 55, 75, 90, 95 and 135. The results showed that the FecB gene influenced litter size, body weight and ovarian development during fetal life. The mean litter sizes were larger (P < 0.05) and body weights were lighter (P < 0.05) at most gestational ages in BB/B+ than in ++ fetuses. Morphometric studies of the ovary showed that the development of the BB/B+ ovaries was retarded: the ++ genotype had more oogonia at day 40 (P < 0.01), more germ cells entering meiosis at day 55, more primordial follicles developing at days 75, 90 and 95 (P < 0.05), a greater loss of germ cells by atresia at day 90 (P < 0.01) and more growing follicles (P < 0.01) and more antral follicles (P < 0.05) at day 135. Differences between the BB/B+ and ++ genotypes in the plasma concentrations of immunoreactive (i) inhibin, i-FSH, bioactive (b)-FSH or (i)-LH were not apparent at any age except for i-LH at day 75 (BB/B+ > ++; P < 0.05). Likewise no differences were noted in the contents of ovarian or adrenal oestradiol or i-inhibin except for i-inhibin in the adrenal at day 75 (++ > BB/B+, P < 0.01). No differences between the genotypes were noted in the i-inhibin contents of the mesonephros at day 40. In mid- to late but not early gestation (i.e. days 40 and 55) significant correlations (i.e. P < 0.05) were noted between litter size and body weight at days 75, 90 and 135, and between litter size and ovary weight, ovary volume, adrenal weight and pituitary weight at day 135. To eliminate the effect of litter size, equal numbers of BB/B+ and ++ embryos were transferred to respective recipient ewes, and fetuses were recovered at the equivalent of days 40 and 90 of gestation. The results showed that the genotypic difference in fetal body weight at day 40 (++ > BB, P < 0.001) and in number of oogonia at day 90 (++ > BB/B+, P < 0.05) were independent of litter size.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Gonadotrophin-releasing hormone and the control of ovulation rate by the FecB gene in Booroola ewes.
Booroola sheep carry a FecB gene that confers high fecundity. The aims of the present studies were to determine in homozygous carriers (BB) and non-carriers (++) of the Booroola FecB gene whether there are FecB differences in the secretory characteristics of GnRH in hypophyseal-portal blood of ovariectomized ewes (Expt 1) and whether differences in ovulation rate would occur following the administration of PMSG and pulsatile GnRH to ovary-intact Booroola ewes with hypothalamic-pituitary disconnection (HPD) (Expt 2). In Expt 1, no FecB gene-specific differences were noted for GnRH with respect to pulse frequency, pulse amplitude or overall secretion rate. Irrespective of genotype there were 1.9 +/- 0.2 GnRH pulses h-1 (n = 20 ewes; 10 BB and 10 ++ animals) and 1.9 +/- 0.1 pulses of immunoreactive (i) LH h-1. In Expt 2, ovulation was induced in the HPD ovary-intact animals on three occasions (e.g. 56, 393 and 423 days after HPD surgery) using a PMSG (200 or 400 iu)-GnRH pulse (250 ng i.v. for 96 h)-GnRH bolus (10 micrograms i.v.) regimen after pretreating the animals with GnRH pulses (250 ng i.v. for 14 days). On all occasions the ovulation rates were significantly higher (P < 0.05) in BB ewes (n = 6 or 7) than in ++ animals (n = 7). No differences between the genotypes were noted with respect to the mean concentrations of progesterone in plasma notwithstanding the differences in ovulation rates.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of chronic FSH administration on ovarian follicular development, ovulation rate and corpora lutea formation in sheep.
This study in ewes examined the effects on ovarian function of a pulsatile regimen of ovine FSH (NIADDK-oFSH-17) administered over a 24- to 28-day period beginning on day 1 of the oestrous cycle (day 0 = oestrus). The FSH (1.66 micrograms or 5.00 micrograms) was administered i.v. over a 1-min interval once every hour throughout the treatment period. In other ewes ovine LH (NIDDK-oLH-23) was administered (10 micrograms once every 2 h) for 24-28 days together with oFSH (1.66 micrograms/h). Compared with untreated controls (n = 19 ewes), FSH alone at both doses (n = 10 ewes/dose) as well as the FSH + LH treatment (n = 10) led to significant increases in the plasma concentrations of FSH (P < 0.01), ovarian weight (P < 0.05) and ovulation rate (P < 0.01) but there was no change in the mean weight of individual corpora lutea (CL). Exogenous FSH at the high but not the low dose alone or with LH stimulated a significant overall increase in plasma inhibin concentrations (P < 0.05). The geometric mean (and 95% confidence limits) ovulation rates in the high FSH (i.e. 5.00 micrograms/h), low FSH (i.e. 1.66 micrograms/h), low FSH + LH, and control treatment groups were 15.3 (9.3, 24.8), 3.7 (2.1, 6.0), 3.7 (2.5, 5.8) and 1.4 (1.2, 1.7) respectively. The FSH or FSH + LH treatments did not alter the total numbers of antral follicles (> or = 1 mm diameter). However, the high but not the low FSH or low FSH + LH treatment led to significant increases in the mean numbers of large follicles (i.e. > 4.5 mm diameter; P < 0.01) and a higher proportion of non-atretic antral follicles. Highly significant linear relationships were found between the mean plasma concentrations of FSH or inhibin and the ovulation rate (FSH: r = 0.74, P < 0.0001; inhibin: r = 0.93, P < 0.0001). Highly significant linear relationships were also found between the plasma concentrations of FSH or inhibin and the number of large follicles (i.e. > 4.5 mm diameter; FSH, r = 0.78, P < 0.0001; inhibin, r = 0.80, P < 0.0001) and between the plasma concentrations of inhibin and the number of granulosa cells in large follicles (r = 0.78, P < 0.0001). After the high FSH but not the low FSH treatment there were significant increases in both FSH- and LH-induced responsiveness in granulosa cells with respect to cyclic AMP synthesis in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
In pursuit of a dubious principle.
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Euthanasia↗
Immunochemical characterisation of parathyroid hormone-related protein from tumour and non-tumour cells.
The molecular forms of parathyroid hormone-related protein (PTHRP) in conditioned media from the BEN human lung cancer cell line, rat parathyroid cells (PT-r) and human keratinocytes were studied by gel-filtration chromatography with assay of PTHRP by immunoassays and bioassay. Immunoreactivity (1-86 and 1-34) and bioactivity (1-34) in conditioned media eluted as a coincident major peak (approx. molecular mass 19-22 kDa) and there was evidence of amino-terminal species in the molecular mass range 10-16 kDa in BEN and keratinocyte media. Western blotting of PTHRP affinity purified by monoclonal antibodies directed at regions 1-34 or 37-67, identified a major species in all cell cytosols and media with an apparent molecular mass of 24-25 kDa, consistently slightly larger than recombinant PTHRP(1-141) (mobility of 21 kDa) which may represent an intact or native form of PTHRP. Additional amino-terminal species were identified in medium from keratinocytes (16 and 7 kDa), BEN cells (18 and 14 kDa) and PT-R cells (17 kDa), suggesting that processing occurs at the C-terminus and within the mid-region to form a range of amino-terminal fragments.
Animals↗
Long-term thyroxine treatment and bone mineral density.
Studies of the effect of thyroxine replacement therapy on bone mineral density have given conflicting results; the reductions in bone mass reported by some have prompted recommendations that prescribed doses of thyroxine should be reduced. We have examined the effect of long-term thyroxine treatment in a large homogeneous group of patients; all had undergone thyroidectomy for differentiated thyroid cancer but had no history of other thyroid disorders. The 49 patients were matched with controls for age, sex, menopausal status, body mass index, smoking history, and calcium intake score; in all subjects bone mineral density at several femoral and vertebral sites was measured by dual-energy X-ray absorptiometry. Despite long-term thyroxine therapy (mean duration 7.9 [range 1-19] years) at doses (mean 191 [SD 50] micrograms/day) that resulted in higher serum thyroxine and lower serum thyrotropin concentrations than in the controls, the patients showed no evidence of lower bone mineral density than the controls at any site. Nor was bone mineral density correlated with dose, duration of therapy, or cumulative intake, or with tests of thyroid function. There was a decrease in bone density with age in both groups. We suggest that thyroxine alone does not have a significant effect on bone mineral density and hence on risk of osteoporotic fractures.
Absorptiometry, Photon↗
Hypercalcaemia: changing causes over the past 10 years.
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Humans↗
Comparison and investigation of bone mineral density in opposing femora by dual-energy X-ray absorptiometry.
A dual-energy X-ray absorptiometry (DXA) machine was used to measure the bone mineral density (BMD) of both femora in 760 female volunteers. Each volunteer completed a questionnaire and exclusion criteria were applied such that only 480 of these were considered normal subjects. The remaining 280 women failed to comply with the criteria and were considered 'abnormal'; their BMD results were analysed separately. Two abnormal subgroups, one with previous long bone fractures and one with radiologically diagnosed osteopenia, were studied. BMD values for femoral neck, Ward's triangle and trochanter were compared between the two femora in all the above groups. No dominance relationship was found when comparing left to right femur, averaged over any population studied, but large differences were found between the femora in individual volunteers. There was a high correlation between BMD in opposing femora of 0.91, 0.91 and 0.84 for the femoral neck, Ward's triangle and trochanter respectively. However, in normal subjects the percentage variation in these regions ranged up to 34%, 64% and 80% respectively at the different femoral sites. In addition, the normal population was divided into two subgroups, one in which the density difference between the femora was large, and the other in which the difference was statistically insignificant. The analytical and anatomical variations between these two groups were investigated. Only part of the difference appeared to be due to analytical problems and it seems that there is a genuine difference in femoral density. Poor correlation for femoral neck percentage density difference was found with average BMD, age, height and weight in the normal population.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorptiometry, Photon↗
The molecular defect in a family with mild atypical osteogenesis imperfecta and extreme joint hypermobility: exon skipping caused by an 11-bp deletion from an intron in one COL1A2 allele.
We have investigated a family with an autosomal dominantly inherited connective-tissue defect causing extreme joint hypermobility, premature osteoporosis and late-onset fractures. Analysis of collagenous proteins from affected individuals showed a deletion in some alpha 2(I) chains. Peptide mapping localized this to the CB peptide alpha 2CB4, which covers the N-terminal one-third of the protein chain. Polymerase chain reaction amplification and sequencing of cDNA derived from this region of the mRNA identified a heterozygous deletion of the 54 bp comprising exon 9. Similar analysis of the genomic DNA revealed an 11-bp deletion from bp3 to bp13 of IVS-9. This disrupts the consensus 5' splice signal (GTAAGT) and leads to exon skipping. In a family study of 13 affected and unaffected family members using both heteroduplex formation and direct analysis for the deletion, all of the affected, but no unaffected individuals, were found to carry the deletion. This generated a positive Lod score of 2.6 with the Liped programme.
Alleles↗
Concentrations of immunoreactive inhibin in ovarian and peripheral venous plasma and follicular fluid of Booroola ewes that are homozygous carriers or non-carriers of the FecB gene.
No gene-specific differences were found during either the luteal or follicular phases of the oestrous cycle in the venous secretion rates of ovaries or in concentrations of immunoreactive inhibin in peripheral plasma between Booroola ewes that were homozygous carriers (BB) or non-carriers (++) of the FecB gene. In three experiments in which concentrations of plasma inhibin and follicle-stimulating hormone (FSH) were compared, gene-specific differences were noted for FSH (P less than 0.05), but no significant correlations were noted between FSH and inhibin for either genotype. Granulosa cells and follicular fluid, but not theca interna, stroma or corpora lutea, were the major intra-ovarian sites of inhibin; no gene-specific differences were noted for inhibin concentrations in follicular fluid or in any of the intra-ovarian tissues. The mean concentrations of inhibin in follicular fluid remained constant irrespective of follicular diameter whereas the mean total contents of inhibin increased significantly with increasing diameter (P less than 0.05). Inhibin secretion rates were four times higher in ovaries with oestrogen-enriched follicles (i.e. greater than or equal to 50 ng oestradiol ml-1) than in ovaries with no such follicles (P less than 0.01). Moreover, inhibin concentrations were higher in follicular fluid of oestrogen-enriched follicles than in those with low oestrogen (i.e. less than 50 ng ml-1; P less than 0.05). Ovariectomy resulted in a significant reduction in concentrations of immunoreactive inhibin from plasma (P less than 0.01). The residual plasma inhibin in some Booroola ewes was not associated with genotype. It is concluded that, although antral follicles are a major source of inhibin in Booroola ewes, immunoreactive inhibin is not associated with the FecB gene and is not responsible for the gene-specific differences in concentrations of FSH in plasma.
Analysis of Variance↗
Expression of the genes for alpha inhibin, beta A inhibin and follistatin in the ovaries of Booroola ewes which were homozygotes or non-carriers of the fecundity gene FecB.
Ovine cDNA probes for the alpha and beta A inhibin subunits and for follistatin were used to investigate the mRNA species for these hormones in ovaries obtained during the luteal phase of the oestrous cycle, from Booroola ewes which were homozygous carriers (BB) or non-carriers (++) of the FecB gene. BB ewes had significantly higher concentrations of peripheral FSH and LH immunoreactivity than ++ ewes, but the peripheral inhibin immunoreactivity and ovarian inhibin and progesterone secretion rates were not significantly different between genotypes. No gene-specific differences in the number or size of mRNA transcripts detected by Northern blotting were noted for any of these genes. A single alpha inhibin mRNA species at 1.5 kb was observed in the follicle RNA from ++ and BB ovaries. Low amounts of alpha inhibin hybridization were discerned occasionally in ++ and BB stroma and also in BB, but not in ++, corpora lutea. The beta A inhibin gene was expressed only in the follicles from both ++ and BB ovaries. At least three beta A inhibin transcripts were observed; one at 7.5 kb and at least two between 1.4 and 5.0 kb. The follistatin cDNA probe detected two major transcripts at 2.7 and 1.5 kb and a minor band at 0.5 kb in both follicle and corpora lutea RNA. Densitometry of the Northern blots revealed no significant gene-specific differences in the levels of alpha inhibin and follistatin gene mRNA transcripts.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Bioactive and immunoreactive FSH and immunoreactive inhibin concentrations in the ovine fetus.
The bioactive (B) and immunoreactive (I) pituitary contents/concentrations of FSH, together with the plasma concentrations of B-FSH, I-FSH and I-inhibin were determined in ovine fetuses at days 55, 75, 90 and 135 of gestation (day 145 = term). The pituitary contents and concentrations of B-FSH and I-FSH increased in both sexes with gestational age. The female fetuses had significantly (P < 0.01) higher pituitary contents/concentrations of B-FSH and I-FSH than the male fetuses at days 75 and 135. The pituitary B/I ratios of FSH were not significantly different with age or sex. The plasma concentrations of B-FSH remained relatively constant from days 75 to 135, with no significant differences between sexes or with age. In contrast, the plasma concentrations of I-FSH reached a peak at day 90 and then declined towards term in both sexes. At all gestational ages except day 55, the female fetuses had significantly (P < 0.05) higher plasma concentrations of I-FSH than the males. In both sexes, the plasma B/I ratios of FSH were lowest at day 90 and had increased again by day 135, with the male fetuses having significantly (P < 0.05) higher B/I ratios compared with the female group at days 75 and 135 but not at day 90. At all gestational ages, the plasma concentrations of I-inhibin declined throughout gestation in the female fetuses, whereas in the males they reached a nadir at day 75 and then increased towards term. The concentrations of I-inhibin were significantly (P < 0.01) higher in the male fetuses compared with the females.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Production of parathyroid-hormone-related protein by cholesteatoma cells in culture.
Specimens of cholesteatoma were removed at surgery from five patients who had evidence of bone resorption. Parathyroid-hormone-related protein (PTHrP) was detected, by radioimmunoassay, in conditioned media from keratinocyte cultures derived from all five samples. Concentrations of PTHrP in conditioned media from secondary cultures were higher for the cholesteatoma cells than for normal keratinocytes from controls matched for age and sex. Thus, production of PTHrP by cholesteatoma may be a contributory factor in the bone destruction commonly associated with this disorder.
Adolescent↗
Conservative management of primary hyperparathyroidism.
The personal management of patients seen with primary hyperparathyroidism over the past 10 years has been reviewed; 248 cases were identified of which 122 have been managed conservatively. These patients were mainly asymptomatic. Apart from 4 who developed renal stones, which were spontaneously passed, there was no clinical or biochemical evidence that patients sustained adverse consequences by conservative management. These studies support the need for further studies of the conservative management of asymptomatic hyperparathyroidism.
Adult↗
In vivo and in vitro precision for bone density measured by dual-energy X-ray absorption.
An investigation was made into some of the major sources of error influencing the bone mineral density (BMD) measurements of the lumbar vertebrae, the femoral neck and the greater trochanter. The effect on accuracy and reproducibility of the following parameters was investigated: influence of patient positioning, patient size, scan speed, the technique of scan analysis and the temporal variation in instrument performance. The in vitro precision, both long-term and short-term, was assessed using aluminium phantoms supplied by the manufacturer. For the spine phantom, the precision expressed as a percentage coefficient of variation (%CV) was found to be 0.4% (10 scans) in the short term and 0.55% (15 scans) in the long term. Measured precision (short-term) for the three regions of the femur phantom analysed by the software was 1.3% for the neck of femur, 1.7% for Ward's triangle and 0.6% for the trochanter. Long-term precision was 1.0%, 1.9% and 1.1% respectively. No statistically significant difference was found between long- and short-term results. Short-term in vitro precision on a low density anthropological phantom was 4.1%, 4.2%, 2.4% and 0.61% for neck of femur, Ward's triangle, trochanter and spine respectively. In vivo short-term precision for the lumbar spine (L2-L4), measured by scanning four normal volunteers five times in one session, was found to be 0.8 +/- 0.25%. In vivo precision for the femur, measured on seven volunteers was 1.6 +/- 0.8% for the neck of femur, 3.2 +/- 1.7% for Ward's triangle and 2.2 +/- 1.1% for the trochanter.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorptiometry, Photon↗
Primary hyperparathyroidism and renal osteodystrophy.
Primary hyperparathyroidism is a common condition infrequently complicated by renal stones and overt bone disease. Most cases are asymptomatic or have vague, nonspecific symptoms. There is considerable debate as to whether mild or asymptomatic cases should be managed surgically or conservatively. Important chromosomal abnormalities have now been demonstrated in some parathyroid adenomas. Renal osteodystrophy remains a difficult condition to treat once it is fully established. The use of vitamin D metabolites in the early stages of renal failure and the maintenance of a normal serum calcium and phosphate appear to prevent the development of secondary hyperparathyroidism. Further studies are required to ascertain the optimum way of using vitamin D metabolites and how best to reduce serum phosphorus.
Chromosomes, Human, Pair 11↗