Effects of long-term treatment with estradiol or clomiphene citrate on bone maintenance, and pituitary and uterine weights in ovariectomized rats

Long-term estrogen replacement therapy in postmenopausal women can bring relief to hot flushes and reduce loss of bone mass due to osteoporosis, however, such treatment often can cause uterine hyperplasia and other undesirable effects. This study compared changes in bone mineral content (BMC), uterine weight, pituitary weight and pituitary gonadotropin content in the ovariectomized rat model following treatment with estradiol (E₂) or two levels of clomiphene citrate (CC), an estrogen agonist/antagonist. Groups (n = 8-12) of adult ovariectomized (OVX) rats were implanted with E₂ pellets (5 μg/day) or injected subcutaneously with CC at 1 mg/kg body wt (CC-1) or 5 mg/kg body wt (CC-5) twice weekly for 12 months. Placebo implanted OVX and intact (INT) female rats served as negative and positive controls, respectively. Following treatment, the uterus, pituitary gland and right femur were collected from each animal. E₂ treatment increased (P<0.05) uterine weight compared to all other treatment groups, while both CC doses increased uterine weight over the OVX group only (E₂, 0.24±0.03; INT, 0.14±0.01; CC-1, 0.06±0.01; CC-5, 0.07±0.01; and OVX, 0.02±0.01 g per 100 g body wt). Pituitary weight was increased 15-fold (P<0.05) by E₂ treatment over all other treatment groups (E₂, 65.7±13.9; INT, 4.0±0.5; CC-1, 3.3±0.03; CC-5, 2.7±0.2; and OVX, 2.9±0.02 mg per 100 g body wt). Both E₂ and CC treatments reduced pituitary luteinizing hormone and follicle stimulating hormone content (μg/pit) to INT levels and were lower (P<0.05) than OVX levels. Mean BMC of E₂, CC-1- or CC-5-treated rats was greater (P<0.05) than that of either the INT or OVX groups, while INT animals had a higher BMC compared to OVX animals (E₂, 0.027±0.003; CC-1, 0.026±0.001; CC-5, 0.028±0.001; INT, 0.021±0.001; and OVX, 0.017±0.001 g/cm per 100 g body wt). These data indicate that CC has the potential to reduce bone mineral loss without causing other undesirable effects, including uterine hyperstimulation, and thus needs to be further investigated.