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) rat were implanted with E2 pellets (5 micrograms/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 less than 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 less than 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 +/- 0.02; 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 (micrograms/pit) to INT levels and were lower (P less than 0.05) than OVX levels. Mean BMC of E2, CC-1- or CC-5-treated rats was greater (P less than 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.
Chakraborty
P K
PK
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
Brown
J L
JL
Ruff
C B
CB
Nelson
M F
MF
Mitchell
A S
AS
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000502:physiology*; D002996:Clomiphene / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage*; D005260:Female; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D010902:Pituitary Gland / Q000033:anatomy & histology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014599:Uterus / Q000033:anatomy & histology
D002996:Clomiphene; D004958:Estradiol