Hypertrophic osteoarthropathy: estrogens, prostaglandinE2, prostaglandin A2, and the inflammatory reflex

  • Ad Brouwers
  • Pieter G. Dingjan
  • Ben Dujardin
  • Everardus J. van Zoelen
  • Paul Lips
  • Louis J. Gooren
Brief Report


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.


Estrogen Hypertrophic osteoarthropathy Inflammatory reflex Palmar erythema Postaglandin Spider angiomas 



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.


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Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Department of Internal MedicineGelderse Vallei HospitalEdeThe Netherlands
  2. 2.WageningenThe Netherlands
  3. 3.Department of Clinical ChemistryGelderse Vallei HospitalEdeThe Netherlands
  4. 4.EdeThe Netherlands
  5. 5.Department of Cell and Applied Biology Nijmegen, Centre for Molecular Life SciencesRadboud UniversityNijmegenThe Netherlands
  6. 6.OosterbeekThe Netherlands
  7. 7.Endocrine Section, Department of Internal MedicineVU University Medical CenterAmsterdamThe Netherlands
  8. 8.AmsterdamThe Netherlands
  9. 9.Chiang MaiThailand

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