Protective Effect Of Progesterone Research Articles

HRT and cancer risks

Experimental experience points to the natural hormone 17β-estradiol as a carcinogen in animals. The administration of estradiol to mice and rats will, among others, increase the incidence of mammary and pituitary tumors [ 1 International Agency for Research on Cancer, In: Monographs on the evaluation of carcinogenic risks to humans, Lyon, France: IARC, Suppl 7, 1987. pp. 280–85. Google Scholar , 2 Inoh A. Kamiya K. Fujii Y. Yokoro K. Protective effects of progesterone and tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/Fu rats. Jpn. J. Cancer Res. 1985; 76: 699-704 PubMed Google Scholar ]. Such tumor models have been developed using pharmacological doses of estradiol such as to examine the tumorigenic activity of this hormone in a relatively short period of time. However, no animal models have been developed in which tumors are induced by very low doses of estradiol, presumably because of difficulties in long-term maintenance and dosing in view of the varying endogenous levels in cycling females. Therefore, the predictive value of carcinogenicity testing at high doses has been questioned [ [3] Gold L.S. Slone T.H. Stern B.R. Manley N.B. Ames B.N. Rodent carcinogens: setting priorities. Cience. 1982; 258: 261-265 Google Scholar ].

Effects of progesterone on postovariectomy bone loss in aged rats

The effects of progesterone on oophorectomy-induced bone loss in aged rats were evaluated. Female rats aged 12 months were divided into three groups: (1) sham-operated controls (SHAM); (2) oophorectomized (OVX); (3) OVX rats treated with progesterone (OVX + PROG). After 20 weeks the dry weight, bone ash, and calcium content of femur, tibia, and fourth lumbar vertebra were significantly lower in OVX than in sham rats. These reductions did not occur in OVX rats treated with PROG. There was no difference in the bone composition between the control and progesterone-treated rats. Vertebral bone histomorphometry showed increased bone resorption as well as increased bone formation parameters in OVX rats. Progesterone treatment inhibited the increased resorption indices, but the bone formation remained elevated. The results indicate that progesterone therapy prevents the postovariectomy bone loss in aged rats. The protective effect of progesterone is mediated by inhibition of bone resorption while maintaining the increased bone formation. These findings suggest that progesterone alone may be a valuable agent for management of postmenopausal osteoporosis.

Inhibitory effect of progesterone on cell death of mouse uterine epithelium.

The protective effect of progesterone against cell death of mouse uterine epithelium was evaluated by examining the retention of 5'-[125I]iodo-2'-deoxyuridine [( 125I]IdUrd) incorporated into the whole uterus and the apoptotic index (percentage of apoptotic cells in total cells), which is a good index of physiological cell death. Castrated adult female mice were given a daily injection of oestradiol-17 beta for 3 days, and then an injection of [125I]IdUrd. They were then divided into 4 groups, which received a daily injection of vehicle only, oestradiol-17 beta (E), progesterone (P), or both oestradiol-17 beta and progesterone (EP), and were killed at intervals during these treatments for determination of 125I radioactivity retained in the whole uterus. On treatment with vehicle only, the 125I radioactivity retained in the uterus decreased rapidly, but treatment with E, P or EP reduced the loss of 125I radioactivity significantly. Progesterone did not antagonize the effect of oestradiol-17 beta on the 125I radioactivity retained in the uterus. The apoptotic index of uterine cells was examined by a similar experimental protocol, but without injection of [125I]IdUrd. In the group treated with vehicle only, the apoptotic indices of both luminal and glandular epithelia increased markedly, but the injection of E, P or EP suppressed these increases significantly. Progesterone did not antagonize the effect of oestradiol-17 beta on the apoptotic index. The apoptotic index of stroma was not affected by the injection of E, P or EP. On the other hand, progesterone completely inhibited the increase in the mitotic index of uterine epithelia induced by oestradiol-17 beta. These results show that progesterone alone or in combination with oestrogen reduced cell death in mouse uterine epithelium and that the effects of oestrogen and progesterone on uterine cell death were independent of their actions on cell division.

Chemoprotective Effect of Progesterone on Carcinoma Formation in Mice and Rats<xref ref-type="fn" rid="FN2">2</xref>

The protective effect of progesterone on the development of chemically induced carcinomas (squamous cell carcinomas in mice and basal cell carcinomas in rats) by 3-methylcholanthrene [(MCA) CAS: 56-49-5] was studied. Progesterone administration decreased the average number, size, and weight of carcinomas by 45-50% as compared to those of tumors treated with MCA alone at any time interval. DNA radioactivity and autoradiographic studies with the use of [3H]thymidine showed an inhibition of DNA synthesis in the neoplastic cell nuclei following a concomitant administration of progesterone and MCA (18.4%) as compared to the DNA synthesis following administration of MCA alone (35.0%). Electron microscopic and cytologic observations revealed salient ultrastructural findings following progesterone administration, with advanced cytolysis, tumefied mitochondria, large populations of secondary lysosomes, and autophagic formations; also, cell differentiation tended to be of a glandular-adenomatoid type following progesterone and MCA administration as compared to the characteristic squamous cell and basal cell carcinomas after treatment with MCA alone. In addition, scanning electron microscopic observations revealed advanced cytolytic areas with several disintegrated neoplastic cells and cell debris intermingled with red blood cells, following progesterone and MCA administration. The present findings demonstrate that progesterone in pharmacologic doses exerts important chemoprotective effects on carcinoma formation, possibly by interfering with MCA metabolism and inhibiting DNA synthesis in the epidermal neoplastic cells, and thus plays an important role in tumorigenesis.

Protective effects of progesterone and tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/Fu rats.

The protective effect of progesterone or tamoxifen, an antiestrogenic agent, was investigated in estrogen-induced mammary carcinogenesis. Multiple mammary tumors (MT) of tubular or medullary carcinoma type developed at a high rate following prolonged treatment of ovariectomized W/Fu rats with diethylstilbestrol or 17 beta-estradiol. All MTs were located adjacent to the nipple and were slow-growing. The induction rate, multiplicity and size of estrogen-induced MTs were reduced by the simultaneous administration of either progesterone or tamoxifen. The estrogen-induced pituitary tumorigenesis was effectively inhibited by tamoxifen treatment, but it was not affected by progesterone. The results indicated that the inhibitory effect of progesterone or tamoxifen in estrogen-induced carcinogenesis is attributable to interference with the binding of estrogen to the estrogen receptors on the target cells.