Estrogen metabolites in human corpus luteum physiology: differential effects on angiogenic activity

The human corpus luteum produces estrogens metabolites: methoxyestrogen, chatecolestrogens, and ketoestrogens. However, their biological activity has not been studied in the human ovary.


Soledad Henríquez, Ph.D., Paulina Kohen, B.S., Xia Xu, Ph.D., Timothy D. Veenstra, Ph.D., Alex Muñoz, B.Sc., Wilder A. Palomino, M.D., Jerome F. Strauss III, M.D., Ph.D., Luigi Devoto, M.D.



To determine tissue concentrations of E2, estrone, P, and estrogens metabolites (EMs) 2-methoxyestradiol, 2-methoxyestrone, 4-hydroxyestrone, and 16-ketoestradiol in corpus luteum (CL) of different ages, and after hCG administration; and to examine the effects of EMs on vascular endothelial growth factor (VEGF) secretion and angiogenic activity released by cultured luteinizing granulosa cells in the presence and absence of hCG.


Experimental study.




Thirty-two healthy women of reproductive age.


Corpus luteum was collected at the time of minilaparotomy for tubal sterilization, at varying stages of the luteal phase (LP). Late-LP CL was collected 24 hours after IM administration of 10,000 IU hCG. Granulosa cells were isolated from follicular aspirates obtained from healthy women participating in our IVF program for male factor infertility.

Main Outcomes Measure(s):

Estrogen metabolite concentrations were determined in CL tissue, and VEGF was assessed in conditioned medium. The angiogenic activity was analyzed by bioassay.


Concentrations of EMs with proangiogenic activity (16-ketoestradiol and 4-hydroxyestrone) were higher in early and mid-LP CL vs. late-LP CL. These EMs and hCG increased VEGF production and angiogenic activity. Conversely, late-LP CL had significantly higher levels of 2-methoxyestrone and 2-methoxyestradiol, which have antiangiogenic activity. Administration of hCG reduced the production of these EMs.


Our findings suggest that the EMs are important paracrine modulators of CL function. Administration of hCG increases the production of EMs with proangiogenic activity and reduces the secretion of those EMs with antiangiogenic action, suggesting a novel mechanism by which the late-LP CL is rescued in conception cycles.

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