Progestogen-Related Gross and Microscopic Changes in Female Beagles

Abstract

Absrruct.Long-term studies of megestrol acetate and chlormadinone acetate in 100 female dogs are in progress. Doses of zero, one, 10 and 25 times the expected human dose of megestrol acetate and 25 times the expected human dose of chlormadinone acetate (on a milligram per kilogram body weight basis) are being given daily. During the first 4 years, eight dogs from each of the five groups were killed. The principal gross findings included enlarged uteri with mucoid material in the lumina, mammary development in dogs given middle and high doses of megestrol acetate and chlormadinone acetate, and thickened gallbladder walls in dogs given high doses of each. Histologic evaluation showed inhibition of ovulation for progestogen-treated dogs and suppression of ovarian follicular development with the high doses. Cystic endometrial hyperplasia was slight in the low-dose dogs and moderate to severe in most of the high-dose dogs; a few also had ulcerative endometritis and pyometra. The mammary glands of dogs given the middle and high doses produced lobules, acini, and secretion exceeding natural metestrus. Slight to marked cystic mucinous hyperplasia occurred in the gallbladders of most dogs given the high doses. Two high-dose megestrol dogs had clinical signs and microscopic pancreatic, renal, and ocular changes indicative of diabetes mellitus.Uterine cystic glandular hyperplasia and pyometra have been known to be related to endocrine imbalances in female dogs for many years [5,6,23]. Similar changes have been produced in the female dog by using naturally occurring hormone progesterone [3,7,8, 201. The causal relationship of cystic glandular hyperplasia to the synthetic progestogen, medroxyprogesterone acetate, is well documented [l, 21. Clinical descriptions of mammary development and secretion are occasionally included in these reports [3,4], but most are for the uterus with no reference to the histologic changes in the other genital organs.

Comparison of the histological changes in the dog after treatment with the progestins medroxyprogesterone acetate and proligestone

“…In the mammary glands of all progestin-treated dogs there were well developed lobules and proliferation of ductular epithelium as in normal dogs in the luteal phase of the oestrus cycle (22). Treatment with progesterone of young beagle dogs results in maximal mammary gland development, with hyperplasia of secretory and myoepithelial elements (1).…”

“…The role of progestins in mammary cell proliferation is well recognized (10,22) but its contribution to mammary tumour induction is still debated (24,29,32). The dog has been rejected as a model for studies on the role of progestins in the formation of mammary tumours because of the progestin-induced growth hormone excess (11).…”

“…Whereas the effects of progestins on their primary target organs have been studied extensively (10,22), far less is known about the effects on other tissues. The intrinsic glucocorticoid actions of progestins can affect the hypothalamic-pituitary-adrenocortical axis.…”

Chronic Effects of the Novel Glucocorticosteroid RPR 106541 Administered to Beagle Dogs by Inhalation

“…The antiovulatory effect of glucocorticosteroids is likely exerted at the level of the hypothalamus, although an effect at the level of the pituitary gland might be postulated. However, few published reports of progestin-induced abnormalities in dogs describe progestin-related effects in specific detail for the canine ovary (11,30,40 (20,27). Eight weeks of treatment of young intact beagle bitches (first anestrus) with progesterone, levonorgestrel, or cyproterone acetate (CPA) induced stimulation of GH cells in the pituitary gland in parallel to dose-dependent lobuloalveolar development of the mammary gland (7,16).…”

Spontaneous Diabetes Mellitus in Animals

“…Long term administration of synthetic progestagenes (medroxyprogesterone and megestrol acetate) initiates diabetes by vacuolization of -cells [62].…”