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Rowlands & Williams [1943] recently reported that the consecutive injection of mare-serum gonadotrophin and chorionic gonadotrophin would cause ovulation in hypophysectomized rats. Serum gonadotrophin was given to stimulate the growth of the atrophic follicles and, subsequently, chorionic and other gonadotrophins containing an excess of the luteinizing hormone were used as a means of causing their rupture. Ova were found in the Fallopian tubes 1–2 hr. after their discharge from the ovaries. Similar experiments have been carried out in the intact immature rat to study, in greater quantitative detail, the optimal conditions necessary for ovulation. A comparative study of the hormonal control of ovulation in different species seemed desirable, particularly on account of the disappointing results that have been frequently reported on the use of mare-serum gonadotrophin in causing ovulation in women.

Studies on the metabolism of progesterone in rabbit plasma and tissues during constant infusion of [³H]progesterone revealed a gradual increase in the concentration of progesterone in plasma until a state of equilibrium was attained about 2 h after the start of infusion. The metabolic clearance rate of progesterone was 0·116 l/min and the turn-over time was 0·006 min/ml plasma. Under conditions of equilibrium, the concentration of radioactivity as well as that of labelled progesterone was higher in the tissues than in plasma. On a unit–weight basis, myometrium localized 6·6 nCi, Fallopian tube 5·5 nCi and vagina 6·1 nCi [³H]progesterone/g tissue. A higher concentration of progesterone, 16·5 nCi, was localized in the mammary gland tissue. Skin localized only 0·9 nCi progesterone and the lowest amount (0·34 nCi/ml) was found in plasma.

The metabolism of progesterone in tissues differed from that in plasma. In plasma only 5·6% of the infused steroid was recovered as unconverted progesterone and the major amount was metabolized to polar compounds with smaller amounts of 5α-pregnane-3,20-dione, 5α-pregnan-3β-ol-20-one and 20α-hydroxypregn-4-en-3-one. In the myometrium and Fallopian tubes the major metabolites were 5α-pregnan-3β-ol-20-one and 5α-pregnane-3,20-dione respectively. In the vagina, like the myometrium, 5α-pregnan-3β-ol,20-one was the major metabolite. 20α-Hydroxypregn-4-en-3-one was the major identified metabolite of mammary gland tissue.

The 'positive feedback' effect of exogenous oestradiol-17β in advancing ovulation induced by pregnant mare serum gonadotrophin (PMSG) has been used in the present study as a model in which to test the possible oestrogenic or antioestrogenic effects of the catechol oestrogens, 2-hydroxyoestradiol (2-OHE₂) and 4-OHE₂. Sprague–Dawley rats of 26 days of age were injected with 20 i.u. PMSG together with either vehicle alone or test steroids. The animals were killed 72 h later and the Fallopian tubes were examined for the presence of ova. Advancement of induced ovulation by treatment with oestradiol was confirmed; 2-OHE₂, in doses of up to 100 pg, influenced neither the time of ovulation nor the number of ova present but 4-OHE₂ was equipotent with oestradiol in doses varying from 0·5 pg (the minimum effective dose for both steroids) to 10 μg. The possible antioestrogenic effect of 2-OHE₂ was tested by giving a 100 pg dose either at the same time or 2 h before PMSG plus 2 pg oestradiol or 4-OHE₂. The effects of oestradiol and 4-OHE₂ were not altered by this treatment. These data show that, in this model of'positive feedback', 2-OHE₂ has neither an oestrogenic nor an antioestrogenic action but that 4-OHE₂ has a potent oestrogenic action, thus raising the question of a physiological role for 4-OHE₂ in the regulation of ovulation.

In the giant fruit-bat of India, Burma and Ceylon, both ovaries and uterine horns are functional, but only one ovum is released each year after copulation. As the corpus luteum becomes active (but while the fertilized ovum is still in the Fallopian tube), a progestational reaction occurs in the horn adjacent to the ovary which contains the ruptured follicle, whereas the opposite horn retains its oestrous appearance. The site of this asymmetric reaction (at which implantation subsequently takes place) is confined to the extreme distal end of the horn, where uterine and ovarian tissues lie in close proximity. Blood vessels, some of them of an apparently sinusoidal nature, traverse the short intervening isthmus, and the corpus luteum is often formed at a distance of less than 2 mm from the endometrium. In view of this unusual anatomical arrangement, it is suggested that progesterone may pass directly from the ovulatory pole of the ovary to the uterine horn, either through the vessels described, or by way of the lymphatics and tissue spaces.

Follicles in relatively large numbers (average 26) have been consistently produced by the injection of 3600 and 4500 i.u. of whole pregnant mares' serum, and to a slightly lesser degree (average 14), by the injection of similar amounts of commercial processed pregnant mares' serum.

Ovulation after this treatment has been spontaneous, but to a lesser degree when using the processed material (5·4% ovulations) than when using the whole plasma (24% ovulations).

The percentage of ovulations after this treatment has been increased by the intravenous injection of chorionic gonadotrophin at a dosage of 2000 i.u. (22% for processed material and 42% for whole serum). Where a large corpus luteum was present in the ovary during the time of treatment, the percentage ovulations was 52 as compared with only 14 in those cases in which no corpus luteum was present.

Injections of 20 mg. progesterone daily for 4 days after removal of the corpus luteum, and after the p.m.s. injections, had the same effect on the ovulation rate (55% ovulations) as the presence of a large corpus luteum.

Ova produced by either processed or whole serum can be fertilized fairly readily in the absence of a corpus luteum, but in its presence or after daily injections of progesterone, no fertilization takes place.

In the presence of a corpus luteum or after injections of progesterone, the ova travel down the Fallopian tube at a greatly increased rate, but were in some cases slowed up by the injection of oestrogens.

SUMMARY

In an attempt to characterize the endocrine profile of prostaglandin F_2α (PGF_2α) in relation to the female reproductive system, the compound (racemic form) was administered to hamsters and rats in various reproductive states. The prostaglandin terminated pregnancy when given once a day either subcutaneously (50 μg/hamster) or orally (1·5–2 mg/hamster) from Days 4 to 6 of pregnancy inclusive, or as a single subcutaneous injection (50 μg/animal) on Day 4. In the rat, higher (500 μg/injection) and more frequent (twice daily) s.c. injections were required to get even foetal resorption. Concomitant administration of progesterone (4 mg/animal) in either species protected pregnancy. Prostaglandin F_2α terminated pregnancy without interfering with the Pontamine blue reaction, suggesting that its antifertility effects were not mediated by inhibition of implantation. In both hamsters and rats the prostaglandin markedly reduced the size of deciduomata which could be restored to normal by administration of progesterone. Prostaglandin F_2α delayed passage of zygotes through the Fallopian tubes in a proportion of rats but failed to accelerate egg transport in rats and hamsters. Furthermore, it caused a marked histological degeneration of the corpora lutea and induced formation of a fresh set of corpora lutea in pseudopregnant, pregnant and pseudopregnant—hysterectomized hamsters. These deleterious effects of prostaglandin were accompanied, in hamsters, by the appearance of freshly ovulated tubal ova. Most of the endocrine effects of PGF_2α observed in this study can be accounted for by its luteolytic property.