Uterine Bleeding Induced by Progesterone**Some of the work referred to was done by B. Zondek and M. Vesell in the Beth Israel Hospital in New York.

In 1941, Hartman & Speert showed that crystalline progesterone can produce uterine withdrawal bleeding in spayed monkeys not pre-treated with oestrogen.The investigation recorded below confirms and establishes a quantitative basis for this observation. MATERIAL AND METHODSFour rhesus monkeys (Macaca mulatta) were studied. Three were adult females (418, 435, 461) which had been bilaterally ovariectomized before puberty, and were subsequently used in experimental work on the action of oestrogens for periods of between 7 and 9 years. No hormones had been given to them for 3-6 months before the start of the present investigation. Vaginal lavages taken during this period indicated that their accessory reproductive organs were in a state of complete castration atrophy. The fourth monkey (584) was an intact animal 8 months old which had never been injected before. Since menarche in M. mulatta is attained between 2\ m=1/ 2\ and 3 years [Hartman, 1932;Eckstein, 1948], it may be assumed that in this specimen endogenous hormone production had not yet reached a sufficiently high level to cause proliferative changes in the uterus.Crystalline progesterone (10mg./ml. arachis oil) was given by intramuscular injection. For amounts of less than 1 mg. suitable dilutions of the stock solution were used.

Section: Resultssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

The Induction of Progesterone Withdrawal Bleeding in Spayed Rhesus Monkeys

Eckstein¹

1950

“…For the most efficient use of these extracts in the production of ovulation the interval elapsing between their injections is of the utmost importance. It must be remembered that serum gonadotrophin is long-acting since it is equally effective if given as one single injection or as five daily injections; chorionic gonadotrophin on the other hand is quickly destroyed or excreted-50 % disappears in the first hour after its injection into intact rats [Zondek, 1940; Zondek, * An unpublished experiment.…”

Section: Discussionmentioning

confidence: 99%

Production of Ovulation in Hypophysectomized Rats

Rowlands¹,

Williams²

1942

In the intact rat the intrinsic action of gonadotrophic substances is often complicated by the action of the endogenous gonadotrophins of the test animal. Evidence of such complications is provided by histological differences between the condition of the ovaries of intact and hypophysectomized immature rats when subjected to stimulation by each of a variety of different gonadotrophic substances [Noble, Rowlands, Warwick & Williams, 1939], and by the ability of mare serum gonadotrophin to cause ovulation in intact rats but not in hypophysectomized rats [Rowlands & Williams, 1941]. The ineffectiveness of the serum gonadotrophin in causing ovulation in the absence of the pituitary gland of the test animal may be partly explained by its relative lack of luteinizing activity, but it is also certainly caused, in part, by the atrophic condition of the ovaries when the injection is made [Williams, 1943]. Leonard & Smith [1933] observed that in hypophysectomized rats an extract prepared from the urine of post-menopausal women caused only follicular stimula¬ tion ; its action thus resembled that of mare serum gonadotrophin. Ovulation did not occur unless the rats were subsequently treated with chorionic gonadotrophin. This latter substance, by itself, does not cause ovulation in the hypophysectomized rat. Foster and his colleagues [Foster & Fevold, 1935;Foster, Foster & Hisaw, 1937] have shown that ovulation may also be produced in hypophysectomized rabbits if folliclestimulating and luteinizing extracts are both given, but not if either of them is given alone.Guided by these results we have produced ovulation and even superovulation in hypophysectomized rats by overcoming the ovarian atrophy with a single injection of mare serum gonadotrophin and subsequently injecting chorionic or other gonadotrophins. We have worked out in some detail the optimal conditions for producing ovulation by these means, so that the results so far obtained may act as a basis for similar investigations in other species.MATERIAL AND METHODS Hypophysectomy. Immature, or in some cases mature, female rats were hypophy¬ sectomized by the retro-pharyngeal approach under ether anaesthesia. Body-weight changes and inspection of the sella turcica at autopsy served as checks on the com¬ pleteness of the operation.Extracts. The following gonadotrophic preparations were used and were made up in aqueous solution before injection.(a) Mare serum gonadotrophin : PMS 26-a sample of dried serum which was re¬ constituted by the addition of water before injection. The resulting solution contained 200 international units (i.u.) per ml. * Beit Memorial Research Fellow.

“…First, if the injected rat is ovariectomized before the 26th hour, oestrus is inhibited, but if the ovaries are only removed 27 hr. after the gonadotrophin injection oestrus occurs normally [Zondek, 1940]. The time involved has been confirmed by experiments [Zondek, 1940; Zondek, Sulman & Sklow, 1941] in which antigonadotrophin has been injected into immature female rats at various times after injecting chorionic gonadotrophin.…”

mentioning

confidence: 83%

Further Investigations on the Mechanism of Oestrone Production in the Ovary

Zondek¹,

Sklow²

1942

Following the injection of chorionic gonadotrophin into immature female rats, oestrogen is produced in the ovary and passes into the circulation between the 26th and 27th hour after the injection. This has been shown in two experiments. First, if the injected rat is ovariectomized before the 26th hour, oestrus is inhibited, but if the ovaries are only removed 27 hr. after the gonadotrophin injection oestrus occurs normally [Zondek, 1940]. The time involved has been confirmed by experiments [Zondek, 1940; Zondek, Sulman & Sklow, 1941] in which antigonadotrophin has been injected into immature female rats at various times after injecting chorionic gonadotrophin. If the antihormone is given up to 26 hr. after the chorionic gonadotrophin the normal reactions of the rats (oestrus and the appearance of`b lood-points' and corpora lutea in the ovaries) are partially or completely inhibited, while if the antihormone is given 27 hr. after the gonadotrophin there is no inhibition.It is possible that the oestrogen is produced in the ovary solely in the 26th hour after the injection but it is also possible that the interval between the gonadotrophin injection and the passage of the oestrogen into the circulation is occupied by the formation of an oestrogenically inactive precursor ('pro-oestrogen') in the ovaries. The experiment recorded below has been devised to test these points.An injection of chorionic gonadotrophin into immature female rats has been followed 18 hr. later by the injection of sufficient antigonadotrophin to neutralize the response of the rats. This antihormone has been followed in its turn by a second gonadotrophin injection, 20 hr. after the first. If the oestrogen produced is formed in the ovaries only in the single hour 26 hr. after the injection of gonadotrophin, the oestrous response of the rats should occur 20 hr. later than it would after the single gonadotrophin injection. If, however, pro-oestrogen is already present in the ovary when the antihormone is injected this may be transformed into oestrogen under the influence of the second gonadotrophin injection so that the oestrous response should not be delayed. This is actually what happens.