Abstract
During the last few years, many progestational steroids were freshly synthesized and widely used for clinical purposes.
From routine biological assays of these steroids, it appears that slight modifications of the structure resulted in marked changes in their biological activities. Not only progestational activity, but some of these steroids have corticosteroid-like activity and some have androgenic or estrogenic activity.
In this experiment, biological characteristics of progestational compounds with corticosteriod-like activities, and effects of corticosteroids on progestational activities of verious synthetic progestins were investigated.
The progestational activities were determined by the McPhail assay and endometrial Carbonic Anhydrase Activity (CAA) in Clauberg rabbit.
CAA was estimated by the Hirashimizu's modification9) of Pincus-Miyake's technique8).
As can be seen in Tab. 1, 17α-acetoxy progesterone derivatives, that is 6α-methyl-17α acetoxy-progesterone (MAP), 6-chloro-6-dehydro-17α-acetoxy-progesterone (Δ6CAP) and 6-methyl-6-dehydro-17α-acetoxy-progesterone (Δ6MAP) were more potent than the other synthetic progestins.
On the other hand, as an indicator of clinical progestational activity, effect of these synthetic progestins on “delay of menses” was tested. The result is shown in Tab. 2, 17α-ethynyL-19-nor-testosterone (ENT) and other estrogenic progestins (i.e. ethynodiol diacetate (EEDDA), norethynodrel (EEO) and Lynestrenol (EEL)) were more effective than 17α-acetoxy-progesterone derivatives. This result markedly differed from that of the above-mentioned animal assays. It is considered that the inherent estrogenic activity in 19-nor-testosterone derivatives impedes the progestational response in Clauberg rabbit, but acts with advantage on delay of menses. 17α-acetoxy-progesterone derivatives have a cortisone-like activity. Some investigators reported that in rats, administration of MAP resulted marked adrenal atrophy and thymus involution. Large doses administration of Δ6 MAP and Δ6 CAP also caused thymus involution.
Therefore, the possibility of potentiating effect with cortisone-like activity on the progestational response in Clauberg rabbit was investigated in the following experiment.
While no endometrial response was found with corticosteroid alone, the administration of corticosteroid in combination with progesterone resulted in a more marked endometrial response in the Clauberg rabbit than that with progesterone alone. The more the corticosteroid was combined, the higher the endometrial response was (Fig. 1). The potentiating effect of prednisolone was significantly higher than that of hydorcortisone acetate. And the potentiating effect of added corticosteroid was observed more markedly on endometrial CAA than on endometrial proliferation in Clauberg rabbit.
As compaired with the assay using progesterone alone, only one thirtieth of progesterone was required in CAA. assay where 25 mg of hydrocortisone acetate was simultaneously administered. These effects of corticosteroids were also observed with some synthetic progestins, while only a very slight effect could be obtained with 17α-ethynyl-4-estrene-38, 17β-diol-diacetate (Table 5).
To potentiate the effect of progesterone, however, simultaneous administration of corticosteroid was not the only method, since corticosteroid administration in the course of estrogen priming or the single injection in progesterone treatment resulted in similar effects as shown in Fig. 2. CAA in the adrenal, kidney, liver and blood were neither influenced by progesterone administration nor by the corticosteroid combination.
Incubation of liver and endometrial tissue with or without cortiscoteroid resulted in no rise in CAA in these tissues.
