Elevation in serum parathyroid hormone (PTH) often accompanies vitamin D deficiency and renal impairment. PTH elevation in renal failure is viewed as an unfavorable development. Evidence is increasing that PTH elevation may be associated with increased morbidity and mortality. In many instances these PTH effects appear to be independent of vitamin D status. PTH mediates its effects through the ubiquitous type 1 PTH/PTH-related peptide receptor, which is notably present in the cardiovascular system. Increased PTH may promote cardiovascular disease through diminished cardiac contractility, enhanced coronary risk, and cardiac valvular and vascular calcification. High PTH levels appear to be linked to the metabolic syndrome and are aligned with hyperlipidemia, decreased insulin sensitivity, and, perhaps, decreased insulin secretion. Increased PTH also is associated with neuroendocrine activation, increased sympathetic activity, and endothelial stress. The relation between PTH and vitamin D is complex and may show significant threshold variations, especially when calcium intake, age, and race are considered. Moreover, evidence is increasing that fragments of PTH may not only be hormonally active but also may have opposing effects to PTH. Despite these caveats, PTH values provide useful clinical diagnostic and prognostic information in monitoring many chronic ailments such as heart and renal failure and multiple sclerosis.

Background: Lithium is the most effective long-term treatment for bipolar disease. It has, however,been associated with hypercalcemia and hyperparathyroidism. The aim of the study is to research howlithium associated hyperparathyroidism(LHPT)affects bone mineral density. Method: A sub-analysis was performed on an ongoing randomized prospective study evaluating the operation results from parathyroidectomy versus watchful waiting in 22patients with LHPT. The patients were followed-up for 2 years and their blood samples, bone mineral density (BMD) and FRAX assessment were analysed. The data from LHPT patients was also compared to a separate group of patients with primary hyperparathyroidism (PHPT) corresponding in age.Results: In comparing LHPT patients with PHPT apparent differences in the biochemical profile were detected, including elevated values of ionized Ca in PHPT (p=0.001), lower excretion of 24h urinary calcium in LHPT (p=0.003) and significantly higher values of PTH excretion in PHPT. LHPT showed tendencies to having better BMD (p=0.176). At 2-year follow-up of 8 LHPT patients, biochemicalvalues improved, suggesting cure, including lower risks of skeletal fractures. Discussion: The biochemical features in LHPT are distinctive from PHPT. However, each case is unique, and thebiochemicalvariety issimilar to PHPT. Confounding factors include age, sex, renal function and stability of the bipolar condition. Conclusions:The present study illustratesthat LHPT differs biochemically from PHPT. In comparison to PHPT, LHPT patients tend to have reduced BMD and the present study could not confirm the previous postulation that lithium could be protective of the skeleton. In conclusion, casesof LHPT should be assessed individually, since the clinical course is diverse. In patients risking fracture, parathyroidectomy should be considered.

Background: Lithium is the most effective long-term treatment for bipolar disease. It has, however,been associated with hypercalcemia and hyperparathyroidism. The aim of the study is to research howlithium associated hyperparathyroidism(LHPT)affects bone mineral density. Method: A sub-analysis was performed on an ongoing randomized prospective study evaluating the operation results from parathyroidectomy versus watchful waiting in 22patients with LHPT. The patients were followed-up for 2 years and their blood samples, bone mineral density (BMD) and FRAX assessment were analysed. The data from LHPT patients was also compared to a separate group of patients with primary hyperparathyroidism (PHPT) corresponding in age.Results: In comparing LHPT patients with PHPT apparent differences in the biochemical profile were detected, including elevated values of ionized Ca in PHPT (p=0.001), lower excretion of 24h urinary calcium in LHPT (p=0.003) and significantly higher values of PTH excretion in PHPT. LHPT showed tendencies to having better BMD (p=0.176). At 2-year follow-up of 8 LHPT patients, biochemicalvalues improved, suggesting cure, including lower risks of skeletal fractures. Discussion: The biochemical features in LHPT are distinctive from PHPT. However, each case is unique, and thebiochemicalvariety issimilar to PHPT. Confounding factors include age, sex, renal function and stability of the bipolar condition. Conclusions:The present study illustratesthat LHPT differs biochemically from PHPT. In comparison to PHPT, LHPT patients tend to have reduced BMD and the present study could not confirm the previous postulation that lithium could be protective of the skeleton. In conclusion, casesof LHPT should be assessed individually, since the clinical course is diverse. In patients risking fracture, parathyroidectomy should be considered.

INTRODUÇÃO: A criopreservação de tecido paratireóideo é empregada no tratamento cirúrgico do hiperparatireoidismo secundário nos pacientes com doença renal crônica. Entre a captação do tecido e a criopreservação, realizada em laboratório especializado, o tecido é preservado em solução para cultura de células a 4°C (solução para transporte). Não há dados que demonstrem por quanto tempo o tecido paratireóideo humano pode permanecer viável nesta solução, antes de ser criopreservado. Este estudo objetiva avaliar o período de tempo que o tecido da glândula paratireóide hiperplásica de humanos pode permanecer na solução para transporte, sem apresentar danos ultra-estruturais. MÉTODOS: Estudo prospectivo que incluiu 11 pacientes submetidos a paratireoidectomia total com autoimplante heterotópico e criopreservação de fragmentos de tecido paratireóideo. Parte do tecido destinado para exame anatomopatológico foi selecionado para preservação em solução para transporte. Foram definidos 5 períodos relacionados ao tempo de permanência dos fragmentos de paratireóide na solução para transporte. No tempo 1, o material foi fixado a fresco, sem contato com a solução para transporte, este tempo serviu para controle. No tempo 2, os fragmentos de tecido permaneceram imersos na solução para transporte por 2 horas, no tempo 3, este período foi de 6 horas, e os tempos 4 e 5, corresponderam a preservação dos fragmento de paratireóide na solução para transporte por 12 e 24 horas respectivamente. Ao final de cada período os fragmentos foram removidos da solução de transporte e fixados com glutaraldeído a 2%, seguido por preparo do material para cortes ultrafinos. A análise por microscopia eletrônica avaliou a adesão celular e a integridade das membranas plasmáticas, dos núcleos e das mitocôndrias, além da presença de edema celular e de vacúolos. RESULTADOS: Dos 11 casos estudados, 10 apresentaram achados ultraestruturais compatíveis com a normalidade nos fragmentos de tecido que permaneceram na solução para transporte por até 12 horas. Em apenas um destes casos, houve preservação das características morfológicas do tecido por 24 horas, na solução para transporte. Em um caso os achados caracterizaram sinais de dano celular irreversível em todos os períodos, inclusive no tempo inicial, em que o tecido foi fixado a fresco, sem contato com a solução para transporte. As alterações das mitocôndrias representaram os danos ultra-estruturais mais constantes nos casos estudados. CONCLUSÃO: A análise da ultra-estrutura do tecido da glândula paratireoide hiperplásica de humanos permite concluir que ocorre manutenção adequada da integridade estrutural do tecido que permanece na solução com meio de cultura de células a 4°C.até cerca de 12 horas após sua retirada do organismo, na maioria dos casos. / BACKGROUND: The cryopreservation of parathyroid tissue is employed in the surgical treatment of secondary hyperparathyroidism in patients with chronic kidney disease. During the period between surgical resection and cryopreservation of tissue, which requires a specialized laboratory, the tissue is stored in a cell culture solution, at 4 °C (solution for transport from the operating room to the laboratory). There is no data showing for how long the human parathyroid tissue can remain viable in this solution, before being cryopreserved. The present study evaluates the time that the tissue of human hyperplastic parathyroid gland could remain in solution for transportation, without showing ultrastructural damages. METHODS: This prospective study included 11 patients, who underwent total parathyroidectomy with heterotopic autotransplantation and cryopreservation of parathyroid tissue fragments. Part of the tissue intended for pathological examination was selected for storage at solution for transportation. Five periods were defined, related to the storage time of parathyroid fragments at solution for transportation. At time 1, the material was fixed at the time of surgical resection, without contact with the solution for transport, this time was used as control. At time 2, the fragments of tissue remained stored at the solution for transportation for 2 hours, at time 3, this period was 6 hours, and Times 4 and 5, corresponded to the parathyroid fragments stored in the transport solution for 12 and 24 hours, respectively. At the end of each period the fragments were removed from the transport solution and fixed with 2% glutaraldehyde, followed by preparation of material for ultrathin sections. The analysis by electron microscopy was used to evaluate cell adhesion and integrity of plasma membranes, nuclei and mitochondria, and the presence of edema and cell vacuoles. RESULTS: Of the 11 cases studied, 10 showed ultrastructural findings consistent with the normal tissue fragments that remained in the solution to transport up to 12 hours. In only one of these cases, there was preservation of the morphological characteristics of the tissue for 24 hours, at the solution for transportation. In one case, there were findings of marked signs of irreversible cell damage in all periods, including the initial time in which the tissue was fixed at the time of surgical resection, without contact with the solution for transportation. Changes of mitochondria represented the ultrastructural damage more constant in the cases studied. CONCLUSION: The analysis of the ultrastructure of human hyperplastic parathyroid gland tissue shows that, in most cases, ultrastructural integrity is properly maintained in fragments stored up to 12 hours in a solution of cell culture, at 4° C.

INTRODUÇÃO: Hiperparatireoidismo primário (HPT) é uma doença endócrina relativamente comum, caracterizada por hipercalcemia associada a concentrações de PTH elevadas ou inapropriadamente normais. A maioria dos pacientes (90%-95%) apresenta a forma esporádica da doença, enquanto a forma familiar pode ocorrer associada à neoplasia endócrina múltipla tipo 1 (NEM1) e tipo 2, HPT-tumor de mandíbula, HPT neonatal severo e HPT isolada familiar. HPT associado com NEM1 (HPT/NEM1) difere da forma esporádica em vários aspectos, entre eles: acometimento multiglandular das paratireóides (hiperplasia x adenoma); início da doença mais precoce (20 x 40 anos); afeta homens e mulheres em proporção semelhante (1:1), em contraste a 1:3 no HPT esporádico; diferentes tratamentos cirúrgicos (paratireoidectomia total ou subtotal x adenomectomia); maior taxa de recorrência após paratireoidectomia (PTx); e tende a ser menos agressivo que o HPT esporádico. No HPT esporádico, o perfil da perda mineral óssea e o impacto do tratamento cirúrgico na densidade mineral óssea (DMO) estão bem definidos. Por outro lado, dados sobre perda óssea no HPT/NEM1 e sua potencial recuperação após PTx são escassamente relatados. O objetivo deste estudo é avaliar o perfil densitométrico e o impacto do tratamento cirúrgico na DMO em pacientes com HPT/NEM1. MÉTODOS: Neste estudo, avaliamos inicialmente 36 pacientes (18 homens e 18 mulheres) com diagnóstico de HPT/NEM1 (média de idade ao diagnóstico de HPT de 38,99 ± 14.46 anos, 20-74 anos). Estes pacientes pertenciam a oito famílias não relacionadas previamente caracterizadas clinicamente e portadoras de mutações germinativas MEN1. Avaliamos a DMO no terço proximal do rádio distal (1/3 RD), fêmur (colo do fêmur e fêmur total) e coluna lombar (L1-L4) destes 36 pacientes. A DMO foi medida pela densitometria óssea de dupla emissão com fonte de raios X (DXA) e os valores expressos em índice T, índice Z e em valores absolutos (g/cm2). Após esta avaliação da DMO, vinte e quatro pacientes foram submetidos à paratireoidectomia total seguida por auto-implante em antebraço não dominante. Em um grupo selecionado de 16 pacientes foi avaliada a densidade mineral óssea antes e após (período médio de 15 meses) o tratamento cirúrgico. RESULTADOS: Desmineralização óssea (osteoporose/osteopenia) foi observada no 1/3 RD (28/34, 79,4%); colo do fêmur (26/36, 72,7%) e na coluna lombar (25/36, 69,4%). Osteopenia foi principalmente observada no colo do fêmur (19/36, 52,8%), seguida pelo 1/3 RD (14/34, 41,2%) e coluna lombar (11/36, 30,5%). Osteoporose foi observada principalmente na coluna lombar (14/36, 38,9%) e 1/3 RD (14/34, 41,2%); enquanto no colo do fêmur (7/36, 19,4%) a prevalência foi menor . Valores médios de índice T estavam severamente reduzidos no 1/3 RD (- 2,46±1,436 DP), seguido pela coluna lombar (-2,05±1,539 DP). O colo do fêmur foi o menos afetado (-1,60±1,138 DP). Nos 16 pacientes submetidos ao tratamento cirúrgico, no período médio de 15 meses após PTx, a DMO (g/cm2) aumentou significativamente na coluna lombar de 0,843 para 0,909 g/cm2 (+ 8,4%; p=0,001). A DMO (g/cm2) no colo do fêmur também aumentou significativamente de 0,745 para 0,798 g/cm2 (+ 7,7%; p=0.0001). No 1/3 RD não houve modificação estatisticamente significante da DMO (0,627 ± 0,089 para 0,622 ± 0,075; p=0,76). CONCLUSÃO: Nossos dados demonstraram que o rádio distal é o sítio ósseo preferencial para desmineralização óssea e que a coluna lombar pode não estar relativamente protegida na HPT/MEN1, como descrito no HPT esporádico. Um aumento significante foi observado na coluna lombar e no colo do fêmur em pacientes com HPT/NEM1, em um período médio de 15 meses após paratireoidectomia; enquanto no terço proximal do radio distal, não houve melhora significativa durante este estudo / INTRODUTION: Primary hyperparathyroidism (HPT) is a relatively common endocrine disorder, which is characterized by hypercalcemia and elevated or inappropriately normal levels of PTH. Most patients (90-95%) present with the sporadic form of the disease, whereas familial cases may occur associated with multiple endocrine neoplasias type 1 (MEN1) and type 2, jaw tumours, as well as severe neonatal form and familial isolated HPT. HPT associated with MEN1 (HPT/MEN1) differs from sporadic primary HPT (s- HPT) in the following aspects: it presents as a multiglandular parathyroid neoplasia (hyperplasia vs adenoma); it has an earlier disease onset (20 vs. 40 years of age); there is a sex ratio of 1:1 in contrast to the 1:3 ratio for s- HPT; different surgical treatment (total or subtotal parathyroidectomy x adenomectomy); there are higher recurrence rates after a parathyroidectomy (PTx); and it frequently tends to be less aggressive than s-HPT. In s-HPT, the bone loss profile and the impact of parathyroid surgery are well defined. In contrast, data on bone losses in HPT/MEN1 and the potential bone recovery after PTx have been scarcely reported. The aim of this study is to evaluate the bone mineral status and the impact of surgical treatment on bone mineral density (BMD) in HPT/MEN1 patients. METHODS: We studied 36 cases (18 males and 18 females) diagnosed with HPT/MEN1 (average age at the HPT diagnosis of 38.9 ± 14.46 years; range, 20-74 years). These patients belonged to eight unrelated MEN1 families previously clinically characterized and harboring germline MEN1 mutations. We have assessed the values of BMD in the proximal one third distal radius (1/3 distal radius), femoral (femoral neck and total) and lumbar spine (L1-L4) of these 36 HPT/MEN1 cases. BMD values were measured by dual-energy X-ray absorptiometry and the values expressed in T, Z-score and in absolute values. After BMD analyses, twenty four out of them were submitted to total parathyroidectomy followed by autoimplant in the non-dominant forearm. BMD measurements were evaluated before and in a mean period of 15 months after surgery, in a subset of 16 patients. RESULTS: Bone demineralization (osteoporosis/osteopenia) was seen at the proximal third of distal radius (28/34, 79.4%); femoral neck (26/36, 72.7%) and in the lumbar spine (25/36, 69.4%). Osteopenia was mostly found in femoral neck (19/36, 52.8%), whereas 1/3 distal radius (14/34, 41.2%) and lumbar spine (11/36, 30.5%) were also represented. Osteoporosis was mostly marked at lumbar spine (14/36, 38.9%) and 1/3 DR (14/34, 41.2%), but femoral neck (7/36, 19.4%) was also affected. Mean T score values at the 1/3 DR were severely reduced (-2.46±1.436 SD), followed by lumbar spine (-2.05 ± 1.539 SD). The femoral neck was the least affected site (-1. 60 ± 1.138 SD). In the 16 cases submitted to surgical treatment, in a mean period of 15 months after PTX, BMD (g/cm2) significantly increased at the lumbar spine from 0.843 to 0.909 g/cm2 (+ 8.4%; p=0.001). Femoral neck BMD (g/cm2) also increased significantly from 0.745 to 0.798 g/cm2 (+ 7.7%; p=0.0001). In the proximal one third of distal radius, BMD (g/cm2) remained unchanged (baseline, 0.627 ± 0.089 to 0.622 ± 0.075; p=0.76). CONCLUSION: Our data confirmed distal radius as the preferential site of bone demineralization and that lumbar spine may not be relatively protected in HPT/MEN1, as related in the s-HPT. A significant increase in the BMD has been verified in the lumbar spine and femoral neck BMD in 16 patients with HPT/MEN1, in a mean period of 15 months after parathyroidectomy. However, the proximal one third of distal radius BMD did not present significant improvement during this study

INTRODUÇÃO: A criopreservação de tecido paratireóideo é empregada no tratamento cirúrgico do hiperparatireoidismo secundário nos pacientes com doença renal crônica. Entre a captação do tecido e a criopreservação, realizada em laboratório especializado, o tecido é preservado em solução para cultura de células a 4°C (solução para transporte). Não há dados que demonstrem por quanto tempo o tecido paratireóideo humano pode permanecer viável nesta solução, antes de ser criopreservado. Este estudo objetiva avaliar o período de tempo que o tecido da glândula paratireóide hiperplásica de humanos pode permanecer na solução para transporte, sem apresentar danos ultra-estruturais. MÉTODOS: Estudo prospectivo que incluiu 11 pacientes submetidos a paratireoidectomia total com autoimplante heterotópico e criopreservação de fragmentos de tecido paratireóideo. Parte do tecido destinado para exame anatomopatológico foi selecionado para preservação em solução para transporte. Foram definidos 5 períodos relacionados ao tempo de permanência dos fragmentos de paratireóide na solução para transporte. No tempo 1, o material foi fixado a fresco, sem contato com a solução para transporte, este tempo serviu para controle. No tempo 2, os fragmentos de tecido permaneceram imersos na solução para transporte por 2 horas, no tempo 3, este período foi de 6 horas, e os tempos 4 e 5, corresponderam a preservação dos fragmento de paratireóide na solução para transporte por 12 e 24 horas respectivamente. Ao final de cada período os fragmentos foram removidos da solução de transporte e fixados com glutaraldeído a 2%, seguido por preparo do material para cortes ultrafinos. A análise por microscopia eletrônica avaliou a adesão celular e a integridade das membranas plasmáticas, dos núcleos e das mitocôndrias, além da presença de edema celular e de vacúolos. RESULTADOS: Dos 11 casos estudados, 10 apresentaram achados ultraestruturais compatíveis com a normalidade nos fragmentos de tecido que permaneceram na solução para transporte por até 12 horas. Em apenas um destes casos, houve preservação das características morfológicas do tecido por 24 horas, na solução para transporte. Em um caso os achados caracterizaram sinais de dano celular irreversível em todos os períodos, inclusive no tempo inicial, em que o tecido foi fixado a fresco, sem contato com a solução para transporte. As alterações das mitocôndrias representaram os danos ultra-estruturais mais constantes nos casos estudados. CONCLUSÃO: A análise da ultra-estrutura do tecido da glândula paratireoide hiperplásica de humanos permite concluir que ocorre manutenção adequada da integridade estrutural do tecido que permanece na solução com meio de cultura de células a 4°C.até cerca de 12 horas após sua retirada do organismo, na maioria dos casos. / BACKGROUND: The cryopreservation of parathyroid tissue is employed in the surgical treatment of secondary hyperparathyroidism in patients with chronic kidney disease. During the period between surgical resection and cryopreservation of tissue, which requires a specialized laboratory, the tissue is stored in a cell culture solution, at 4 °C (solution for transport from the operating room to the laboratory). There is no data showing for how long the human parathyroid tissue can remain viable in this solution, before being cryopreserved. The present study evaluates the time that the tissue of human hyperplastic parathyroid gland could remain in solution for transportation, without showing ultrastructural damages. METHODS: This prospective study included 11 patients, who underwent total parathyroidectomy with heterotopic autotransplantation and cryopreservation of parathyroid tissue fragments. Part of the tissue intended for pathological examination was selected for storage at solution for transportation. Five periods were defined, related to the storage time of parathyroid fragments at solution for transportation. At time 1, the material was fixed at the time of surgical resection, without contact with the solution for transport, this time was used as control. At time 2, the fragments of tissue remained stored at the solution for transportation for 2 hours, at time 3, this period was 6 hours, and Times 4 and 5, corresponded to the parathyroid fragments stored in the transport solution for 12 and 24 hours, respectively. At the end of each period the fragments were removed from the transport solution and fixed with 2% glutaraldehyde, followed by preparation of material for ultrathin sections. The analysis by electron microscopy was used to evaluate cell adhesion and integrity of plasma membranes, nuclei and mitochondria, and the presence of edema and cell vacuoles. RESULTS: Of the 11 cases studied, 10 showed ultrastructural findings consistent with the normal tissue fragments that remained in the solution to transport up to 12 hours. In only one of these cases, there was preservation of the morphological characteristics of the tissue for 24 hours, at the solution for transportation. In one case, there were findings of marked signs of irreversible cell damage in all periods, including the initial time in which the tissue was fixed at the time of surgical resection, without contact with the solution for transportation. Changes of mitochondria represented the ultrastructural damage more constant in the cases studied. CONCLUSION: The analysis of the ultrastructure of human hyperplastic parathyroid gland tissue shows that, in most cases, ultrastructural integrity is properly maintained in fragments stored up to 12 hours in a solution of cell culture, at 4° C.

<p>Cardiovascular risk in primary hyperparathyroidism (HPT) is controversial, and studies mainly from Europe associate HPT with increased cardiovascular morbidity and mortality. Cardiovascular morphology and function were evaluated prospectively in 31 consecutive HPT patients (mean serum calcium 2.97±0.04) and randomly enrolled controls matched for age and sex. Patients were re-examined at normocalcemia about one year after parathyroidectomy. </p><p>HPT patients showed an operatively reversible disturbance in endothelial vasodilatory function that seemed unrelated to an early sign of atherosclerosis, i.e. thickness of carotid artery intima-media complex. Acute hypercalcemia in healthy subjects induced a similar impairment in endothelial function, which suggests a dependence on biochemical rather than structural vascular changes in HPT. Echocardiography showed left ventricular diastolic dysfunction and supernormal systolic performance being reversed after operation. Left ventricular mass tended to be irreversibly increased. During exercise HPT patients exhibited greater rise in systolic blood pressure compared to controls and an increased number of premature ventricular beats. This indicated increased work load and a propensity for fatal cardiac events. Following surgery, an improvement with less pronounced ST-segment depression was seen. 24-hour ambulatory blood pressure monitoring showed irreversibly increased levels despite maintained diurnal rhythm, while 24-hour heart rate variability analysis displayed blunted nocturnal increase of low and very low frequency bands that was corrected postoperatively. </p><p>Parathyroidectomy seems to alleviate most of the cardiovascular disturbances in HPT, except for hypertension. This is consistent with the normalised longevity in HPT treated with parathyroidectomy and supports active treatment of HPT. </p>

<p>In hyperparathyroidism (HPT) raised serum concentrations of ionized calcium is caused by increased secretion of parathyroid hormone (PTH) by parathyroid tumors. Active vitamin D, 1α,25-dihydroxyvitamin D₃, is known to suppress PTH secretion and to reduce proliferation of parathyroid tumor cells.</p><p>The aim of this thesis was to examine expression of vitamin D hydroxylating enzymes, regulating the activation and inactivation of vitamin D and to study effects of vitamin D analogues, in parathyroid tumors and breast cancer.</p><p>The vitamin D activating enzyme, CYP27B1/25-hydroxyvitamin D₃ 1α-hydroxylase (1α-hydroxylase) and the vitamin D inactivating enzyme CYP24A1/25-hydroxyvitamin D₃ 24-hydroxylase (24-hydroxylase) were expressed in parathyroid tumors and breast cancer. </p><p>The parathyroid tumors had raised expression levels of 1α-hydroxylase and reduced levels of 24-hydroxylase in comparison to normal parathyroid glands, indicating ability for endogenous activation of vitamin D. The expression of 1α-hydroxylase may be of therapeutic advantage for local activation of non-1α-hydroxylated vitamin D analogues in tumor cells, thereby reducing unwanted hypercalcemic effects. </p><p>Three of five selected low calcemic vitamin D analogues had as efficient PTH suppressing effect, in bovine parathyroid cells, as three vitamin D analogues used clinically for treatment of secondary HPT.</p><p>The non-1α-hydroxylated vitamin D analogue EB1285 showed antiproliferative and PTH suppressive effects as well as transcriptional activity in parathyroid and breast tumor cells, respectively.</p><p>Ketoconazole, an inhibitor of vitamin D hydroxylating enzymes, suppressed PTH secretion and potentiated the effect of vitamin D analogues. Combined treatment with vitamin D analogues and specific 24-hydroxylase inhibitors may be important for future therapy. </p>

Cardiovascular risk in primary hyperparathyroidism (HPT) is controversial, and studies mainly from Europe associate HPT with increased cardiovascular morbidity and mortality. Cardiovascular morphology and function were evaluated prospectively in 31 consecutive HPT patients (mean serum calcium 2.97±0.04) and randomly enrolled controls matched for age and sex. Patients were re-examined at normocalcemia about one year after parathyroidectomy. HPT patients showed an operatively reversible disturbance in endothelial vasodilatory function that seemed unrelated to an early sign of atherosclerosis, i.e. thickness of carotid artery intima-media complex. Acute hypercalcemia in healthy subjects induced a similar impairment in endothelial function, which suggests a dependence on biochemical rather than structural vascular changes in HPT. Echocardiography showed left ventricular diastolic dysfunction and supernormal systolic performance being reversed after operation. Left ventricular mass tended to be irreversibly increased. During exercise HPT patients exhibited greater rise in systolic blood pressure compared to controls and an increased number of premature ventricular beats. This indicated increased work load and a propensity for fatal cardiac events. Following surgery, an improvement with less pronounced ST-segment depression was seen. 24-hour ambulatory blood pressure monitoring showed irreversibly increased levels despite maintained diurnal rhythm, while 24-hour heart rate variability analysis displayed blunted nocturnal increase of low and very low frequency bands that was corrected postoperatively. Parathyroidectomy seems to alleviate most of the cardiovascular disturbances in HPT, except for hypertension. This is consistent with the normalised longevity in HPT treated with parathyroidectomy and supports active treatment of HPT.

In hyperparathyroidism (HPT) raised serum concentrations of ionized calcium is caused by increased secretion of parathyroid hormone (PTH) by parathyroid tumors. Active vitamin D, 1α,25-dihydroxyvitamin D3, is known to suppress PTH secretion and to reduce proliferation of parathyroid tumor cells. The aim of this thesis was to examine expression of vitamin D hydroxylating enzymes, regulating the activation and inactivation of vitamin D and to study effects of vitamin D analogues, in parathyroid tumors and breast cancer. The vitamin D activating enzyme, CYP27B1/25-hydroxyvitamin D3 1α-hydroxylase (1α-hydroxylase) and the vitamin D inactivating enzyme CYP24A1/25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) were expressed in parathyroid tumors and breast cancer. The parathyroid tumors had raised expression levels of 1α-hydroxylase and reduced levels of 24-hydroxylase in comparison to normal parathyroid glands, indicating ability for endogenous activation of vitamin D. The expression of 1α-hydroxylase may be of therapeutic advantage for local activation of non-1α-hydroxylated vitamin D analogues in tumor cells, thereby reducing unwanted hypercalcemic effects. Three of five selected low calcemic vitamin D analogues had as efficient PTH suppressing effect, in bovine parathyroid cells, as three vitamin D analogues used clinically for treatment of secondary HPT. The non-1α-hydroxylated vitamin D analogue EB1285 showed antiproliferative and PTH suppressive effects as well as transcriptional activity in parathyroid and breast tumor cells, respectively. Ketoconazole, an inhibitor of vitamin D hydroxylating enzymes, suppressed PTH secretion and potentiated the effect of vitamin D analogues. Combined treatment with vitamin D analogues and specific 24-hydroxylase inhibitors may be important for future therapy.