It has been claimed that hyperestrogenism occurs in hypertrophic osteoarthropathy (HOA), but not in simple clubbing. However, one of our patients had simple clubbing and hyperestrogenism. We therefore measured estrogens, androgens, sex hormone-binding globulin (SHBG), and gonadotropins in five patients with HOA and in 18 patients with simple clubbing. Of the patients with HOA, 80% had a high urinary estriol concentration. In their serum, 80% had high estrone, 0% high estradiol, and 40% high SHBG. Of the patients with simple clubbing, 89% had a high urinary estriol concentration. In their serum, 76% had high estrone, 6% high estradiol, and 31% high SHBG. In all patients, urinary estriol concentration correlated positively with the degree of clubbing. Serum concentration of androstenedione, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was mostly normal, but androstenedione concentration correlated positively with the degree of clubbing. Spider angiomas were present in 74%, palmar erythema in 39%, and gynecomastia in 9%. Urinary creatinine concentration was low in 48% and correlated positively with the degree of clubbing. We reject the claim that hyperestrogenism occurs in HOA, but not in simple clubbing. Hyperestrogenism occurs both in HOA and in simple clubbing. Our results also support earlier reports that clubbing and HOA are associated with spider angiomas, palmar erythema, gynecomastia, adrenal cortical hyperfunction, muscle atrophy, and water retention. These results led to a new hypothesis on the pathogenesis of HOA, involving estrogens, prostaglandin E2, prostaglandin A2, and the inflammatory reflex.
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The authors are indebted to Henk Teurlings and Twan Peeters for their technical and analytical support regarding laboratory techniques, to Maarten de Waard, Ph.D., and Adje Brouwers-de Werd, for reading the manuscript and providing us with important feedback.
Compliance with ethical standards
The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments at the time of data collection. All persons gave their informed consent prior to their inclusion in the study. Details that might disclose the identity of the subjects under study have been omitted.
Conflict of interest
PL has received honorarium from Friesland Campina dairy industry for advice. The other authors have no potential conflict of interests to declare.
Waring WW, Wilkinson RW, Wiebe RA, Faul BC, Hilman BC (1971) Quantitation of digital clubbing in children. Measurements of casts of the index finger. Am Rev Respir Dis 104:166–174PubMedGoogle Scholar
Gebhardt DO, Soederhuizen W, Moolenaar AJ (1985) Use of octadecyl (C18) columns for the estimation of oestrogens in the urine of non-pregnant women. Ann Clin Biochem 22:541–543CrossRefPubMedGoogle Scholar
Uppal S, Diggle CP, Carr IM, Fishwick CW, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bieleńska A, Phillips SE, Markham AF, Bennett CP, Bonthron DT (2008) Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet 40:789–793CrossRefPubMedGoogle Scholar
Murphey LJ, Williams MK, Sanchez SC, Byrne LM, Csiki I, Oates JA, Johnson DH, Morrow JD (2004) Quantification of the major urinary metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay: determination of cyclooxygenase-specific PGE2 synthesis in healthy humans and those with lung cancer. Anal Biochem 334:266–275CrossRefPubMedGoogle Scholar
Cattral MS, Altraif I, Greig PD, Blendis L, Levy GA (1994) Toxic effects of intravenous and oral prostaglandin E therapy in patients with liver disease. Am J Med 97:369–373CrossRefPubMedGoogle Scholar
Lund J, Brown WP, Tregerman L (1982) The toxicology of PGE1 and PGI2. In: Wu K, Rossi EC (eds) Prostaglandins in clinical medicine and thrombotic disorders. Year Book Medical Publishers, Inc, Chicago, pp 93–109Google Scholar
High WB (1987) Effects of orally administered prostaglandin E-2 on cortical bone turnover in adult dogs: a histomorphometric study. Bone 8:363–373CrossRefPubMedGoogle Scholar
Zimna A, Kurpisz M (2015) Hypoxia-inducible Factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. Biomed Res Int 549412Google Scholar
Atkinson S, Fox SB (2004) Vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing. J Pathol 203:721–728CrossRefPubMedGoogle Scholar
Samarajeewa NU, Yang F, Docanto MM, Sakurai M, McNamara KM, Sasano H, Fox SB, Simpson ER, Brown KA (2013) HIF-1alpha stimulates aromatase expression driven by prostaglandin E2 in breast adipose stroma. Breast Cancer Res 15:R30CrossRefPubMedPubMedCentralGoogle Scholar
Thorsen K, Kristoffersson AO, Lerner UH, Lorentzon RP (1996) In situ microdialysis in bone tissue. Stimulation of prostaglandin E2 release by weight-bearing mechanical loading. J Clin Invest 98:2446–2449CrossRefPubMedPubMedCentralGoogle Scholar
Still K, Grabowski P, Mackie I, Perry M, Bishop N (2008) The peroxisome proliferator activator receptor alpha/delta agonists linoleic acid and bezafibrate upregulate osteoblast differentiation and induce periosteal bone formation in vivo. Calcif Tissue Int 83:285–292CrossRefPubMedGoogle Scholar
Straus DS, Glass CK (2001) Cyclopentenone prostaglandins: new insights on biological activities and cellular targets. Med Res Rev 21:185–210CrossRefPubMedGoogle Scholar
Takahashi HK, Iwagaki H, Hamano R, Yoshino T, Tanaka N, Nishibori M (2006) Effect of nicotine on IL-18-initiated immune response in human monocytes. J Leukoc Biol 80:1388–1394CrossRefPubMedGoogle Scholar
Ek M, Kurosawa M, Lundeberg T, Ericsson A (1998) Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci 18:9471–9479PubMedGoogle Scholar
Dam WH, Hagelsten JO (1964) Blocking of the vagus nerve relieving osteoarthropathy in lung diseases. Dan Med Bull 11:131–133PubMedGoogle Scholar
Huckstep RL, Bodkin PE (1958) Vagotomy in hypertrophic pulmonary osteoarthropathy associated with bronchial carcinoma. Lancet 2:343–345CrossRefPubMedGoogle Scholar
Lopez-Enriquez E, Morales AR, Robert F (1980) Effect of atropine sulfate in pulmonary hypertrophic osteoarthropathy. Arthritis Rheum 1980;23(7):822–824Google Scholar
Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, Gallowitsch-Puerta M, Ashok M, Czura CJ, Foxwell B, Tracey KJ, Ulloa L (2006) Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med 203:1623–1628CrossRefPubMedPubMedCentralGoogle Scholar
Critchley HO, Osei J, Henderson TA, Boswell L, Sales KJ, Jabbour HN, Hirani N (2006) Hypoxia-inducible factor-1alpha expression in human endometrium and its regulation by prostaglandin E-series prostanoid receptor 2 (EP2). Endocrinology 147:744–753CrossRefPubMedGoogle Scholar
Jozkowicz A, Nigisch A, Wegrzyn J, Weigel G, Huk I, Dulak J (2004) Opposite effects of prostaglandin-J2 on VEGF in normoxia and hypoxia: role of HIF-1. Biochem Biophys Res Commun 314:31–38CrossRefPubMedGoogle Scholar
Shan ZZ, Masuko-Hongo K, Dai SM, Nakamura H, Kato T, Nishioka K (2004) A potential role of 15-deoxy-delta(12,14)-prostaglandin J2 for induction of human articular chondrocyte apoptosis in arthritis. J Biol Chem 279:37939–37950CrossRefPubMedGoogle Scholar
Jao JY, Barlow JJ, Krant MJ (1969) Pulmonary hypertrophic osteoarthropathy, spider angiomata, and estrogen hyperexcretion in neoplasia. Ann Intern Med 70:581–584CrossRefPubMedGoogle Scholar
Martini GA (1975) Extrahepatic manifestations of cirrhosis. Clin Gastroenterol 4:439–460PubMedGoogle Scholar
Hedge GA (1977) Roles for the prostaglandins in the regulation of anterior pituitary secretion. Life Sci 20:17–33CrossRefPubMedGoogle Scholar
Nguyen M, Camenisch T, Snouwaert JN, Hicks E, Coffman TM, Anderson PA, Malouf NN, Koller BH (1997) The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth. Nature 390:78–81CrossRefPubMedGoogle Scholar
Hoevels-Guerich H, Haferkorn L, Persigehl M, Hofstetter R, von Bernuth G (1984) Widening of cranial sutures after long-term prostaglandin E2 therapy in two newborn infants. J Pediatr 105:72–74CrossRefPubMedGoogle Scholar
Iwata C, Akimoto N, Sato T, Morokuma Y, Ito A (2005) Augmentation of lipogenesis by 15-deoxy-Delta12,14-prostaglandin J2 in hamster sebaceous glands: identification of cytochrome P-450-mediated 15-deoxy-Delta12,14-prostaglandin J2 production. J Invest Dermatol 125:865–872CrossRefPubMedGoogle Scholar
Boyd EJ, Hulks G, Thomas JS, McColl KE (1988) Hypertrophic gastritis associated with increased gastric mucosal prostaglandin E2 concentrations in a patient with the carcinoid syndrome. Gut 29:1270–1276CrossRefPubMedPubMedCentralGoogle Scholar
Fontenay-Roupie M, Dupuy E, Berrou E, Tobelem G, Bryckaert M (1995) Increased proliferation of bone marrow-derived fibroblasts in primitive hypertrophic osteoarthropathy with severe myelofibrosis. Blood 85:3229–3238PubMedGoogle Scholar
Erl W, Weber C, Zernecke A, Neuzil J, Vosseler CA, Kim HJ, Weber PC (2004) Cyclopentenone prostaglandins induce endothelial cell apoptosis independent of the peroxisome proliferator-activated receptor-gamma. Eur J Immunol 34:241–250CrossRefPubMedGoogle Scholar
Materazzi S, Nassini R, Andrè E, Campi B, Amadesi S, Trevisani M, Bunnett NW, Patacchini R, Geppetti P (2008) Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A 105:12045–12050CrossRefPubMedPubMedCentralGoogle Scholar
Andersson DA, Gentry C, Alenmyr L, et al. TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Delta(9)-tetrahydrocannabiorcol. Nat Commun 2:551Google Scholar