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Emergence of Uterine Pathology during Accelerated Biological Aging in FSH Receptor-Haploinsufficient Mice

Molecular Reproduction Research Laboratory (N.D., M.R.S.), Clinical Research Institute of Montréal, Montréal, Québec H2W 1R7, Canada; Department of Medicine (N.D., M.R.S.), Division of Experimental Medicine, McGill University, and Department of Pathology (I.R.), St. Mary’s Hospital of McGill University, Montréal, Canada H3T 1M5; and Department of Medicine (M.R.S.), Université de Montréal, Montréal, Canada H3T 1J4

Address all correspondence and requests for reprints to: M. Ram Sairam, Ph.D., Director, Molecular Reproduction Research Laboratory, Clinical Research Institute of Montréal, 110 Pine Avenue West, Montréal, Québec, Canada H2W 1R7. E-mail: sairamm{at}ircm.qc.ca.

A fully functional FSH receptor (Fshr) is required for ovarian follicular development and fertility. Fshr null females are sterile because of failure of follicular maturation, ovulation, and estrogen deficiency. Because Fshr-haploinsufficient females also begin to show age-dependent reproductive deficits that mimic biological aging, we have investigated the changes that occur in the uterus of these mice. The uterine weight in 12-month-old Fshr +/- mice increased 2-fold, and most retired breeders (those that stopped breeding earlier than our wild-type females) developed unilateral uterine masses that appeared similar to several abnormalities that also occur in women and associated with infertility. Curiously, there was a tendency for most of the abnormality to occur in the right horn. Up to 25% of the virgin Fshr-haploinsufficient mice also developed pathology. These transformations were not present in either wild-type mice or the estrogen-deficient Fshr null females at any age. In haploinsufficient females, estrogen and progesterone were reduced and testosterone was elevated in circulation by 1 yr. Fshr-haploinsufficient mice developed an imbalance of progesterone receptor isoforms A and B in the uterus. This alteration of progesterone receptors along with an increase in LH receptors in the uterus may contribute to the induction of high frequency of uterine pathology. Angiogenesis, vascular abnormality, and adenomyosis appeared to be increased in the uterine horn bearing pathological mass. The Fshr-haploinsufficient mice might help in understanding the molecular basis of induction of uterine pathology and tissue patterning.

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