How to use progestin in hormone replacement therapy: an animal experiment

To determine whether continuous or cyclic hormone replacement therapy (estrogen and progestogen) is better.

One hundred and forty Sprague-Dawley rats were randomly divided into seven groups. The 1st and 2nd groups were normal estrous and ovariectomy (OVX) controls. Treatment of the other groups imitated the clinical regimen (continuous and cyclic) with estradiol valerate (E2V) and medroxy progesterone (MPA) in different ratios of combination. The rats were sacrificed and sections of uterus were stained with HE and histochemical methods to detect mitosis and proliferating cell nuclear antigen (PCNA), respectively. The mitotic index (MI) and PCNA index were calculated.

The MI and PCNA index were similar in luminal and glandular cells. Both markers were low in the two control groups. When E2V was given for 1 to 6 days, both the MI and PCNA index increased with duration of treatment. When MPA was added, both markers were reduced to a very low level. In the continuous regimen, both markers decreased as the MPA dosage increased. The ratio of E2V: MPA = 1:0.5 was enough to suppress markers to a low level similar to that of normal estrous rats. A further increase in the ratio to 1:1.0 showed no further decrease in PCNA index. In the cyclic regimen, MPA was added for the last 5 days. The mitotic index reached a significantly low level near 0 in all ratios, but the PCNA index in each subgroup was still as high as the positive control, even though the dosage of MPA was increased several times to 1:8.0. When MPA was added for the last 10 days, the PCNA index at a ratio of 1:4.0 could be reduced to a low level.

The results of this study suggest that the continuous regimen was better than the cyclic regimen in postmenopausal hormone replacement therapy (HRT). Progestin should be given for at least 10 days in the cyclic regimen.