Abstract
Continuous development of quick parathyroid hormone assays has resulted in a corresponding expansion of their applications in the practical landscape. In-theatre measurement of the parathyroid hormone has long been recognized as a valuable adjunct in parathyroid surgery, with other applications being incorporated in thyroid surgery and out-of-theatre uses. Such widespread utilization of these assays has also brought the concept of point-of-care testing to the endocrine surgical patient. We have herein summarized the established and potential applications of these assays, emphasizing their importance in the point-of-care setting, highlighting the proper selection of the assay type for intraoperative hormone monitoring and spotlighting those applications which should be validated for use in the clinical setting and those which need to be investigated further.
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Sokoll LJ, Wians FH Jr, Remaley AT, 2004 Rapid intraoperative immunoassay of parathyroid hormone and other hormones: a new paradigm for point-of-care testing. Clin Chem 50: 1126–1135.
Point-of-Care Testing Guideline Published by CLSI, 2010 Laboratory Medicine 41: 499–500.
Sadeghi N, Akin E, Lee JY, Roland J, Knoll S, 2008 Targeted parathyroidectomy: effectiveness and intraoperative rapid-parathormone dynamics. Laryngoscope 118: 1997–2002.
Calva-Cerqueira D, Smith BJ, Hostetler ML, et al, 2007 Minimally invasive parathyroidectomy and preoperative MIBI scans: correlation of gland weight and preoperative PTH. J Am Coll Surg 205: Suppl: 38–44.
Jortay AM, Verougstraete G, Wittersheim E, Hooghe L, Bisschop P, Bergmann P, 2004 Intraoperative measurement of parathyroid hormone in minimally invasive surgery for parathyroid adenoma. Acta Otorhinolaryngol Belg 58: 125–128.
Kumar R, Thompson JR, 2011 The regulation of parathyroid hormone secretion and synthesis. J Am Soc Nephrol 22: 216–224.
Bieglmayer C, Prager G, Niederle B, 2002 Kinetic analyses of parathyroid hormone clearance as measured by three rapid immunoassays during parathyroidectomy. Clin Chem 48: 1731–1738.
Barczynski M, Konturek A, Hubalewska-Dydejczyk A, Cichon S, Nowak W, 2009 Evaluation of Halle, Miami, Rome, and Vienna intraoperative iPTH assay criteria in guiding minimally invasive parathyroidectomy. Langenbecks Arch Surg 394: 843–849.
Carneiro DM, Solorzano CC, Nader MC, Ramirez M, Irvin GL3rd, 2003 Comparison of intraoperative iPTH assay (QPTH) criteria in guiding parathyroidectomy: which criterion is the most accurate? Surgery 134: 973–981.
Day KM, Elsayed M, Monchik JM, 2015 No Need to Abandon Focused Unilateral Exploration for Primary Hyperparathyroidism with Intraoperative Monitoring of Intact Parathyroid Hormone. J Am Coll Surg 221: 518–523.
Rajaei MH, Oltmann SC, Adkisson CD, et al, 2014 Is intraoperative parathyroid hormone monitoring necessary with ipsilateral parathyroid gland visualization during anticipated unilateral exploration for primary hyperparathyroidism: a two-institution analysis of more than 2,000 patients. Surgery 156: 760–766.
Rosen D, Pribitkin E A, Sciarrino J, 2012 Minimally-Invasive Parathyroid Surgery, INTECH Open Access Publisher.
Noureldine SI, Lewing N, Tufano RP, Kandil E, 2014 The Role of the Robotic-Assisted Transaxillary Gasless Approach for the Removal of Parathyroid Adenomas. J Otorhinolaryngol Relat Spec 76: 19–24.
Ismail M, Maza S, Swierzy M, et al, 2010 Resection of ectopic mediastinal parathyroid glands with the da Vincirobotic system. Br J Surg 97: 337–343.
Swierzy M, Ismail M, Ruckert JC, 2010 Robotic surgery for ectopic mediastinal parathyroid glands. Innovations (Phila) 5: 203–204.
Van Dessel E, Hendriks J, Lauwers P, Ysebaert D, Van Schil P, 2010 Mediastinal Parathyroidectomy with the da Vinci Robot. Innovations (Phila) 5: 204.
Udelsman R, Donovan PI, 2004 Open minimally invasive parathyroid surgery. World J Surg 28: 1224–1226.
Faiz Z, Baas PC, Kelder W, 2013 Minimally invasive parathyroidectomy seems suitable for day surgery in patients with primary hyperparathyroidism. Eur J Cancer 49: S766–S767.
Lee S, Ryu H, Morris LF, et al, 2014 Operative failure in minimally invasive parathyroidectomy utilizing an intraoperative parathyroid hormone assay. Ann Surg Oncol 21: 1878–1883.
Carneiro DM, Solorzano CC, Irvin GL3rd, 2004 Recurrent disease after limited parathyroidectomy for sporadic primary hyperparathyroidism. J Am Coll Surg 199: 849–853.
Grant CS, Thompson G, Farley D, Van Heerden J, 2005 Primary hyperparathyroidism surgical management since the introduction of minimally invasive parathyroidectomy: Mayo Clinic experience. Arch Surg 140: 472–479.
Komolafe OO, McMinn AG, Doughty JC, Wilson CR, 2009 Parathyroid carcinoma. Mini-series of patients-successfully treated with minimally invasive surgery using intra-operative PTH assays, and literature review. Scott Med J 54: 58.
Udelsman R, Donovan PI, 2006 Remedial parathyroid surgery: changing trends in 130 consecutive cases. Ann Surg 244: 471–479.
Yen TW, Wang TS, Doffek KM, Krzywda EA, Wilson SD, 2008 Reoperative parathyroidectomy: an algorithm for imaging and monitoring of intraoperative parathyroid hormone levels that results in a successful focused approach. Surgery 144: 611–621
Miccoli P, Minuto M, Cetani F, Ambrosini CE, Berti P, 2005 Familial parathyroid hyperplasia: is there a place for minimally invasive surgery? Description of the first treated case. J Endocrinol Invest 28: 942–943.
Rahbari R, Sansano IG, Elaraj DM, Duh QY, Clark OH, Kebebew E, 2010 Prior head and neck radiation exposure is not a contraindication to minimally invasive parathyroidectomy. J Am Coll Surg 210: 942–948.
Sukumar MS, Komanapalli CB, Cohen JI, 2006 Minimally invasive management of the mediastinal parathyroid adenoma. Laryngoscope 116: 482–487.
Chae AW, Perricone A, Brumund KT, Bouvet M, 2008 Outpatient video-assisted thoracoscopic surgery (VATS) for ectopic mediastinal parathyroid adenoma: a case report and review of the literature. J Laparoendosc Adv Surg Tech A 18: 383–390.
Schulte KM, Cupisti K, Dotzenrath C, Schabram J, Roher HD, 2003 The actual role of classic bilateral cervicotomic approach for primary hyperparathyroidism in the era of minimally invasive surgery. Ann Ital Chir 74: 389–393.
Pitt SC, Sippel RS, Chen H, 2009 Secondary and tertiary hyperparathyroidism, state of the art surgical management. Surg Clin North Am 89: 1227–1239.
Özmen T, Manukyan M, Şen S, Kahveci A, Yeğen C, Güllüoğlu BM, 2014 Is three-gland-or-less parathyroidectomy a clinical failure for secondary hyperparathyroidism? Turkish J Surg 30: 201–206.
Muller-Stich BP, Brandie M, Binet I, Warschkow R, Lange J, Clerici T, 2007 To autotransplant simultaneously or not — can intraoperative parathyroid hormone monitoring reliably predict early postoperative parathyroid hormone levels after total parathyroidectomy for hyperplasia? Surgery 142: 47–56.
Moor JW, Roberts S, Atkin SL, England RJ, 2011 Intraoperative parathyroid hormone monitoring to determine long-term success of total parathyroidectomy for secondary hyperparathyroidism. Head Neck 33: 293–296.
Miccoli P, Materazzi G, Berti P, 2009 Minimally invasive video-assisted thyroidectomy and parathyroidectomy. World 1: 27–29.
Alesina PF, Hinrichs J, Kribben A, Walz MK, 2010 Minimally invasive video-assisted parathyroidectomy (MIVAP) for secondary hyperparathyroidism: report of initial experience. Am J Surg 199: 851–855.
Mourad M, Ngongang C, Saab N, et al, 2001 Video-assisted neck exploration for primary and secondary hyperparathyroidism: initial experience. Surg Endosc 15: 1112–1115.
Nawrot I, Chudziński W, Ciąćka T, Barczyński M, Szmidt J, 2014 Reoperations for Persistent or Recurrent Primary Hyperparathyroidism: Results of a Retrospective Cohort Study at a Tertiary Referral Center. Med Sci Monit 20: 1604–1612.
Lew JI, Solorzano CC, Montano RE, Carneiro-Pla DM, Irvin GL, 3rd, 2008 Role of intraoperative parathormone monitoring during parathyroidectomy in patients with discordant localization studies. Surgery 144: 299–306.
Phitayakorn R, Mchenry CR, 2006 Incidence and location of ectopic abnormal parathyroid glands. Am J Surg 191: 418–423.
Mohebati A, Shaha A, 2012 Anatomy of thyroid and parathyroid glands and neurovascular relations. Clinical Anatomy 25: 19–31.
Uludag M, Isgor A, Yetkin G, Atay M, Kebudi A, Akgun I, 2009 Supernumerary ectopic parathyroid glands. Persistent hyperparathyroidism due to mediastinal parathyroid adenoma localized by preoperative single photon emission computed tomography and intraoperative gamma probe application. Hormones (Athens) 8: 144–149.
Henry JF, Defechereux T, Raffaelli M, Lubrano D, Iacobone M, 2000 Supernumerary ectopic hyperfunctioning parathyroid gland: a potential pitfall in surgery for sporadic primary hyperthyroidism. Ann Chir 125: 247–252.
Okada M, Tominaga Y, Yamamoto T, Hiramitsu T, Narumi S, Watarai Y, 2016 Location Frequency of Missed Parathyroid Glands After Parathyroidectomy in Patients with Persistent or Recurrent Secondary Hyperparathyroidism. World J Surg 40: 595–599.
Shen W, Duren M, Morita E, et al, 1996 Reoperation for persistent or recurrent primary hyperparathyroidism. Arch Surg 131: 861–867; discussion 867–869.
Mariette C, Pellissier L, Combemale F, Quievreux JL, Carnaille B, Proye C, 1998 Reoperation for persistent or recurrent primary hyperparathyroidism. Langenbecks Arch Surg 383: 174–179.
Hoda NE, Phillips P, Ahmed N, 2013 Recommendations after non-localizing sestamibi and ultrasound scans in primary hyperparathyroid disease: order more scans or explore surgically? Journal of the Mississippi State Medical Association 54: 36–41.
Elizondo ME, Díaz-Aguirregoitia FJ, Amondarain JA, Vidaur F, 2005 Intraoperative monitoring of intact PTH in surgery for renal hyperparathyroidism as an indicator of complete parathyroid removal. World J Surg 29: 1504–1509.
Alhefdhi A, Schneider DF, Sippel R, Chen H, 2014 Recurrent and persistence primary hyperparathyroidism occurs more frequently in patients with double adenomas. J Surg Res 190: 198–202.
Gauger PG, Mullan MH, Thompson NW, Doherty GM, Matz KA, England BG, 2004 An alternative analysis of intraoperative parathyroid hormone data may improve the ability to detect multiglandular disease. Arch Surg 139: 164–169.
Sugg SL, Krzywda EA, Demeure MJ, Wilson SD, 2004 Detection of multiple gland primary hyperparathyroidism in the era of minimally invasive parathyroidectomy. Surgery 136: 1303–1309.
Solórzano CC, Carneiro-Pla DM, Lew IJ, Rodgers SE, Montano R, Irvin GL, 2007 Intra-operative Parathyroid Hormone Monitoring in Patients with Parathyroid Cancer. Ann Surg Oncol 14: 3216–3222.
Adam MA, Untch BR, Olson JA, Jr, 2010 Parathyroid carcinoma: current understanding and new insights into gene expression and intraoperative parathyroid hormone kinetics. Oncologist 15: 61–72.
Irvin GL, 3rd, Molinari AS, Figueroa C, Carneiro DM, 1999 Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 229: 874–878; discussion 878–879.
Agarwal G, Barakate MS, Robinson B, et al, 2001 Intraoperative quick parathyroid hormone versus same-day parathyroid hormone testing for minimally invasive parathyroidectomy: a cost-effectiveness study. Surgery 130: 963–970.
Irvin GL, 3rd, Solorzano CC, Carneiro DM, 2004 Quick intraoperative parathyroid hormone assay: surgical adjunct to allow limited parathyroidectomy, improve success rate, and predict outcome. World J Surg 28: 1287–1292.
Chen H, Pruhs Z, Starling JR, Mack E, 2005 Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. Surgery 138: 583–587; discussion 587–590.
Barczynski M, Konturek A, Cichon S, Hubalewska-Dydejczyk A, Golkowski F, Huszno B, 2007 Intraoperative parathyroid hormone assay improves outcomes of minimally invasive parathyroidectomy mainly in patients with a presumed solitary parathyroid adenoma and missing concordance of preoperative imaging. Clin Endocrinol (Oxf) 66: 878–885.
Sugino K, Nagahama M, Kitagawa W, et al, 2010 Minimally invasive surgery for primary hyperparathyroidism with or without intraoperative parathyroid hormone monitoring. Endocrine Journal 57: 953–958.
Kim HG, Kim WY, Woo SU, Lee JB, Lee Y-M, 2015 Minimally invasive parathyroidectomy with or without intraoperative parathyroid hormone for primary hyperparathyroidism. Annals of Surgical Treatment and Research 89: 111–116.
Gasparri G, Camandona M, Bertoldo U, et al, 2009 The usefulness of preoperative dual-phase 99mTc MIBI-scintigraphy and IO-PTH assay in the treatment of secondary and tertiary hyperparathyroidism. Ann Surg 250: 868–871.
Taniguchi M, Tanaka M, Hamano T, et al, 2011 Comparison between whole and intact parathyroid hormone assays. Ther Apher Dial 15: Suppl 1: 42–49.
Yamashita H, Gao P, Cantor T, et al, 2004 Comparison of parathyroid hormone levels from the intact and whole parathyroid hormone assays after parathyroidectomy for primary and secondary hyperparathyroidism. Surgery 135: 149–156.
Ikeda Y, Kurihara H, Morita N, Miyabe R, Takami H, 2007 The role of quick bio-intact PTH(1-84) assay during parathyroidectomy for secondary hyperparathyroidism. J Surg Res 141: 306–310.
Kaczirek K, Prager G, Riss P, et al, 2006 Novel parathyroid hormone (1-84) assay as basis for parathyroid hormone monitoring in renal hyperparathyroidism. Arch Surg 141: 129–134.
Yamashita H, Cantor T, Uchino S, et al, 2005 Sequential changes in plasma intact and whole parathyroid hormone levels during parathyroidectomy for secondary hyperparathyroidism. World J Surg 29: 169–173.
Schneider DF, Mazeh H, Chen H, Sippel RS, 2014 Predictors of recurrence in primary hyperparathyroidism: an analysis of 1386 cases. Ann Surg 259: 563–568.
Schneider DF, Ojomo KA, Mazeh H, Oltmann SC, Sippel RS, Chen H, 2013 Significance of rebounding parathyroid hormone levels during parathyroidectomy. J Surg Res 184: 265–268.
Elaraj DM, Remaley AT, Simonds WF, et al, 2002 Utility of rapid intraoperative parathyroid hormone assay to predict severe postoperative hypocalcemia after reoperation for hyperparathyroidism. Surgery 132: 1028–1034.
Shoman N, Melck A, Holmes D, et al, 2008 Utility of intraoperative parathyroid hormone measurement in predicting postparathyroidectomy hypocalcemia. J Otolaryngol Head Neck Surg 37: 16–22.
Stepansky A, Gold-Deutch R, Poluksht N, et al, 2010 Intraoperative parathormone measurements and post-operative hypocalcemia. Isr Med Assoc J 12: 207–210.
Ito F, Sippel R, Lederman J, Chen H, 2007 The utility of intraoperative bilateral internal jugular venous sampling with rapid parathyroid hormone testing. Ann Surg 245: 959–963.
Maceri DR, Kokot N, Green K, Montgomery V, Sharifi J, 2011 Split central venous sampling of parathyroid hormone: An adjunct to surgical exploration. Head Neck 33: 1715–1718.
Lee LS, Canter RJ, Fraker DL, 2006 Intraoperative jugular venous sampling AIDS detection of an undescended parathyroid adenoma. World J Surg 30: 620–623.
Miller P, Kindred A, Kosoy D, et al, 2003 Preoperative sestamibi localization combined with intraoperative parathyroid hormone assay predicts successful focused unilateral neck exploration during surgery for primary hyperparathyroidism. Am Surg 69: 82–85.
Haciyanli M, Lal G, Morita E, Duh QY, Kebebew E, Clark OH, 2003 Accuracy of preoperative localization studies and intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and double adenoma. J Am Coll Surg 197: 739–746.
Barczynski M, Konturek A, Hubalewska-Dydejczyk A, Cichon S, Nowak W, 2009 Utility of intraoperative bilateral internal jugular venous sampling with rapid parathyroid hormone testing in guiding patients with a negative sestamibi scan for minimally invasive parathyroidectomy—a randomized controlled trial. Langenbecks Arch Surg 394: 827–835.
Hanif F, Coffey J C, Romics L Jr, O’sullivan K, Aftab F, Redmond HP, 2006 Rapid intraoperative parathyroid hormone assay—more than just a comfort measure. World J Surg 30: 156–161.
Zawawi F, Mlynarek AM, Cantor A, et al, 2013 Intraoperative parathyroid hormone level in parathyroidectomy: which patients benefit from it? J Otolaryngol Head Neck Surg 42: 56.
Westra WH, Pritchett DD, Udelsman R, 1998 Intraoperative confirmation of parathyroid tissue during parathyroid exploration: a retrospective evaluation of the frozen section. American J Surg Pathol 22: 538–544.
Tampi C, Chavan N, Parikh D, 2014 Intraoperative parathyroid hormone assay-cutting the Gordian knot. Indian J Endocrinol Metab 18: 210–212.
Irvin I ii GL, Carneiro DM, 2000 Management changes in primary hyperparathyroidism. JAMA 284: 934–936.
Farrag T, Weinberger P, Seybt M, Terris DJ, 2011 Point-of-care rapid intraoperative parathyroid hormone assay of needle aspirates from parathyroid tissue: a substitute for frozen sections. Am J Otolaryngol 32: 574–577.
Chen H, Mack E, Starling JR, 2005 A comprehensive evaluation of perioperative adjuncts during minimally invasive parathyroidectomy: which is most reliable? Ann Surg 242: 375–383.
Chan RK, Ibrahim SI, Pil P, Tanasijevic M, Moore FD, 2005 Validation of a method to replace frozen section during parathyroid exploration by using the rapid parathyroid hormone assay on parathyroid aspirates. Arch Surg 140: 371–373.
Guerrero MA, Suh I, Vriens MR, et al, 2010 The number of needle passes affects the accuracy of parathyroid hormone assay with intraoperative parathyroid aspiration. Am J Surg 200: 701–706.
Conrad DN, Olson JE, Hartwig HM, Mack E, Chen H, 2006 A prospective evaluation of novel methods to intraoperatively distinguish parathyroid tissue utilizing a parathyroid hormone assay. J Surg Res 133: 38–41.
Lo CY, Chan WF, Leung P, Luk JM, 2005 Applicability of tissue aspirate for quick parathyroid hormone assay to confirm parathyroid tissue identity during parathyroidectomy for primary hyperparathyroidism. Arch Surg 140: 146–150.
Kiblut NK, Cussac JF, Soudan B, et al, 2004 Fine needle aspiration and intraparathyroid intact parathyroid hormone measurement for reoperative parathyroid surgery. World J Surg 28: 1143–1147.
Baldassarre RL, Chang DC, Brumund KT, Bouvet M, 2012 Predictors of Hypocalcemia after Thyroidectomy: Results from the Nationwide Inpatient Sample. ISRN Surgery 2012: 838614.
Ali S, Yu C, Palmer FL, et al, 2011 Nomogram to aid selection of patients for short-stay thyroidectomy based on risk of postoperative hypocalcemia. Arch Otolaryngol Head Neck Surg 137: 1154–1160.
Lang BH, Yih PC, Ng KK, 2012 A prospective evaluation of quick intraoperative parathyroid hormone assay at the time of skin closure in predicting clinically relevant hypocalcemia after thyroidectomy. World J Surg 36: 1300–1306.
Cavicchi O, Piccin O, Caliceti U, et al, 2008 Accuracy of PTH assay and corrected calcium in early prediction of hypoparathyroidism after thyroid surgery. Otolaryngol Head Neck Surg 138: 594–600.
Noordzij JP, Lee SL, Bernet VJ, et al, 2007 Early prediction of hypocalcemia after thyroidectomy using parathyroid hormone: an analysis of pooled individual patient data from nine observational studies. J Am Coll Surg 205: 748–754.
Bian X-H, Zhang G, Zhang C-H, et al, 2015 Rapid intraoperative parathyroid hormone assay through fine needle aspiration for identification of parathyroid in thyroid surgery. European Surgery Acta Chirurgica Austriaca. Conference: 8th Annual Meeting of Chinese College of Surgeons and 19th Annual Meeting of the European Society of Surgery Beijing China. Conference Start 47.
Pelizzo MR, Losi A, Boschin IM, et al, 2010 Rapid intraoperative parathyroid hormone assay in fine needle aspiration for differential diagnosis in thyroid and parathyroid surgery. Clin Chem Lab Med 48: 1313–1317.
Guerrero MA, Vriens MR, Suh I, Khanafshar E, Clark OH, 2009 Intraoperative diagnostic strategy to distinguish parathyroid adenomas from metastatic thyroid cancer. Endocr Pract 15: 454–457.
James BC, Nagar S, Tracy M, et al, 2014 A novel, ultrarapid parathyroid hormone assay to distinguish parathyroid from nonparathyroid tissue. Surgery 156: 1638–12643.
Mcleod IK, Arciero C, Noordzij JP, et al, 2006 The use of rapid parathyroid hormone assay in predicting postoperative hypocalcemia after total or completion thyroidectomy. Thyroid 16: 259–265.
Sabour S, Manders E, Steward DL, 2009 The role of rapid PACU parathyroid hormone in reducing post-thyroidectomy hypocalcemia. Otolaryngol Head Neck Surg 141: 727–729.
Lebastchi AH, Aruny JE, Donovan PI, et al, 2015 Real-Time Super Selective Venous Sampling in Remedial Parathyroid Surgery. J Am Coll Surg 220: 994–1000.
Udelsman R, Aruny JE, Donovan PI, et al, 2003 Rapid parathyroid hormone analysis during venous localization. Ann Surg 237: 714–721.
Mindel JR, Venbrux AC, Knoll SM, Cohen JL, 2011 Preoperative parathyroid venous sampling in patients with non-localizing primary hyperparathyroidism. Endocr Rev 32 (3 Meeting Abstracts).
Morris LF, Loh C, Ro K, et al, 2012 Non-super-selective venous sampling for persistent hyperparathyroidism using a systemic hypocalcemic challenge. J Vasc Interv Radiol 23: 1191–1199.
Maser C, Donovan P, Santos F, et al, 2006 Sonographically guided fine needle aspiration with rapid parathyroid hormone assay. Ann Surg Oncol 13: 1690–1695.
Graff-Baker A, Roman SA, Boffa D, Aslanian H, Sosa JA, 2009 Diagnosis of Ectopic Middle Mediastinal Parathyroid Adenoma Using Endoscopic Ultrasonography-Guided Fine-Needle Aspiration with Real-Time Rapid Parathyroid Hormone Assay. J Am Coll Surg 209: e1–e4.
Barczynski M, Golkowski F, Konturek A, et al, 2006 Technetium-99m-sestamibi subtraction scintigraphy vs. ultrasonography combined with a rapid parathyroid hormone assay in parathyroid aspirates in preoperative localization of parathyroid adenomas and in directing surgical approach. Clin Endocrinol (Oxf) 65: 106–113.
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Shawky, M.S. Quick parathyroid hormone assays: a comprehensive review of their utility in clinical practice. Hormones 15, 355–367 (2016). https://doi.org/10.14310/horm.2002.1689
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DOI: https://doi.org/10.14310/horm.2002.1689