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Toward gene therapy of premature ovarian failure: intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(−/−) FORKO mice

  1. M. Ghadami1,2,3,
  2. E. El-Demerdash4,5,
  3. S.A. Salama5,
  4. A.A. Binhazim6,
  5. A.E. Archibong1,
  6. X. Chen7,
  7. B.R. Ballard6,
  8. M.R. Sairam7 and
  9. A. Al-Hendy1,*
  1. 1Department of Obstetric and Gynecology, Center for Women's Health Research, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA
  2. 2Department of Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
  3. 3Iranian Academic Center for Education, Culture and Research, Tehran University of Medical Science Branch, Tehran, Islamic Republic of Iran
  4. 4Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
  5. 5Department of Obstetric and Gynecology, UTMB, Galveston, TX, USA
  6. 6Department of Pathology, School of Medicine, Meharry Medical College, Nashville, TN, USA
  7. 7Clinical Research Institute of Montreal, Univerisité de Montréal, Montreal, QC, Canada
  1. *Correspondence address. Tel: +1-615-963-3107; Fax: +1-615-327-9682; E-mail: ahendy{at}mmc.edu
  • Received October 15, 2009.
  • Revision received December 15, 2009.
  • Accepted January 8, 2010.

Abstract

A homozygous missense mutation, C566T, in the follicle stimulation hormone receptor (FSHR) gene has been linked to premature ovarian failure. The disease leads to infertility in a normal karyotype female with an elevated follicle stimulating hormone (FSH) and decreased serum estrogen level. Female mice carrying mutated FSHR gene, called follitropin receptor knockout (FORKO), display similar phenotype and are sterile because of a folliculogenesis block at a primary stage. We investigated the effects of bilateral intra-ovarian injection of an adenovirus expressing a normal copy of human FSHR on the reproductive system of 6–10 weeks female FORKO mice. Ad-LacZ was injected directly into each ovary of the control group. Animals were sacrificed at 2, 4, 8 and 12 weeks post-injection and tissues collected for evaluation. Treated mice showed estrogenic changes in daily vaginal smear whereas control animals remained fixated in the diestrus stage. Histological evaluation showed on average 26 ± 4 follicles/ovary in treated group with 8 ± 2 follicles at the antral stage compared with only 5 ± 2 with zero follicles at antral stage in Ad-LacZ control mice. There was no significant change in serum level of progesterone, however, estrogen level increased 2–3-fold (P < 0.02) and FSH decreased by up to 50% (P < 0.04) in treated animals. FSHR mRNA was detected in the ovaries of the treated group. In conclusion, intra-ovarian injection of an adenovirus expressing human FSHR gene is able to restore FSH responsiveness and reinitiate ovarian folliculogenesis as well as resume estrogen production in female FORKO mice. Ad-LacZ injections indicate the absence of systemic viral dissemination or germ line transmission of adenovirus DNA to offspring.

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    1. Mol. Hum. Reprod. (2010) 16 (4): 241-250. doi: 10.1093/molehr/gaq003 First published online: January 19, 2010
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