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Hum. Reprod. Advance Access originally published online on October 23, 2008
Human Reproduction 2009 24(2):398-407; doi:10.1093/humrep/den375
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Peritoneal macrophage depletion by liposomal bisphosphonate attenuates endometriosis in the rat model

E. Haber1, H.D. Danenberg2, N. Koroukhov1, R. Ron-El3, G. Golomb1,4 and M. Schachter3

1 Faculty of Medicine, Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel 2 Department of Cardiology, Hadassah–Hebrew University Hospital, Jerusalem, Israel 3 IVF and Infertility Unit, Assaf Harofeh Medical Center, Zerifin, Israel

4 Correspondence address. Tel: +972-2-6758658; Fax: +972-2-6757126; E-mail: gershong{at}ekmd.huji.ac.il

BACKGROUND: Activation of macrophages is central to the implantation of endometriosis (EM). We examined the hypothesis that macrophage depletion by intraperitoneal (IP) injection of liposomal alendronate (LA) could result in EM attenuation in a rat model, thus supporting the notion of the pivotal role of macrophages in EM pathology.

METHODS: In this study, 90 rats were subjected to an EM model and were divided randomly into seven groups: five groups were treated by 4x once-weekly IP injections of LA (0.02, 0.1, 1, 5 or 10 mg/kg) and the other two groups received saline injections (control) or empty liposomes. Sham-operated rats also received empty liposomes. Depletion of circulating monocytes was determined by flow cytometry analyzes of blood specimens. Four weeks after the initial surgery, the number, size and weight of implants were recorded, adhesions were graded, macrophage infiltration was assessed and the peritoneal fluid was analyzed for monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor alpha (TNF{alpha}).

RESULTS: Monocyte depletion following IP LA administration resulted in an inhibitory effect on the initiation and growth of EM implants, as expressed by implantation rate, adhesion scoring, implants’ size and weight (>0.1 mg/kg LA, P < 0.05). Reduced numbers of infiltrating macrophages were observed in implants of the 1 mg/kg LA group. Peritoneal fluid MCP-1 levels were negatively correlated with LA dose (P < 0.001), whereas no significant correlation could be found for TNF{alpha}.

CONCLUSIONS: Macrophage depletion using IP LA has been shown to effectively inhibit the initiation and growth of EM implants, in a rat EM model. The clear dose–response effect may be viewed as a confirmation of the validity of the concept and encourages further study.

Key words: endometriosis/rat model/liposomal alendronate/macrophages

Submitted on June 17, 2008; resubmitted on September 13, 2008; accepted on September 22, 2008.


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