US3816617A - Method for inducing menses - Google Patents

Abstract

THERE IS DISCLOSED HEREIN A METHOD FOR INDUCING MENSES IN PREGNANT PRIMATES WHEREIN CHORIONIC GONADOTROPIN OR PREGNANT MARES'' SERUM GONADOTROPIN, OR MIXTURES THEREOF, ARE ADMINISTERED AS A SINGLE DOSE OR AS CLOSELY SPACED DIVIDED DOSE DURING THE PERIOD OF TIME FROM DAY 14 TO DAY 35 OF GESTATION.

Description

United States Patent 3,816,617 METHOD FOR INDUCING MENSES Upendra K. Banik, Pierrefonds, Quebec, Canada, assignor tls YAmerican Home Products Corporation, New York, No Drawing. Filed July 25, 1972, Ser. No. 274,960 Int. Cl. A61k 17/00, 17/06 US. Cl. 424-100 1 Claim ABSTRACT OF THE DISCLOSURE There is disclosed herein a method for inducing menses in pregnant primates wherein chorionic gonadotropin or pregnant mares serum gonadotropin, or mixtures thereof, are administered as a single dose or as a closely spaced divided dose during the period of time from day 14 to day 35 of gestation.

This invention relates to therapeutic compositions containing gonadotropins and to a method for using such compositions for inducing menstruation or menses.

More specifically, this invention resides in the concept of administering to primates, for example, humans, monkeys or baboons, during the period of time from about day 14 to about day 35 of gestation, an effective dose of a composition to induce menstruation comprising, for example, chorionic gonadotropin or pregnant mares serum gonadotropin.

In another aspect, this invention has relativeness to todays concern for overcoming medical and biosocial problems associated with our increasing population. Today, more and more couples are turning to means for achieving a planned family. For a woman of childbearing age the occurrence of menstruation has always been the most convincing and assuring sign that an unplanned pregnancy has not taken place. This present invention provides means whereby the desired menstruation and accompanying peace of mind may be obtained without the use of mechanical or therapeutic contraceptives, which are so often relied upon today. Furthermore, the method of this invention does not require the administration of prolonged or continuous regimens such as associated with todays therapeutic contraceptives, thereby avoiding the hazards of long-term therapy.

I have found that menstruation may be induced in primates from about 14 to about day 35 of gestation by administering thereto a menses inducing dose of chorionic gonadotropin or pregnant mares serum gonadotropin, or mixtures thereof. For the purpose of this disclosure, day 0 of gestation is defined as the 14th day after the beginning of the last menses for humans, and as the day of mating for other primates.

Chorionic gonadotropin and pregnant mares serum gonadotropin have been found to be suitable to be administered according to the method of this invention. It has been established that these gonadotropins may be administered safely to primates; for example, see I. H. Leathem and A. E. Rakoff, Amer. J. Obstet. GynecoL, 56, 521 (1948) and references therein, and E. B. Astwood in The Pharmacological Basis of Therapeutics, 4th ed., L. S. Goodman and A. Gilman, eds., The Macmillan Co., New York, 1970, pp. 1512-1537. The preparation and characterization of these gonadotropins have been described; see for example, Gonadotropins: Physiochemical and Immunological Properties, Ciba Foundation Study Group No. 22, G. E. W. Wolstenholme and 1. Knight, eds., J. & A. Churchill Ltd., London, 1965. Therapeutically they are used primarily for the treatment of infertility and cryptorchidism. In addition these gonadotropins have been suggested for alleviating a variety of other conditions related to hypogonadal dysfunction, such pr I ICC as hypoovarianism, amenorrhea, functional uterine bleeding, threatened and habitual abortion, as well as for the treatment of testicular hypofunction such as hypogenitalism or hypogonadotropic eunuchoidism.

More specifically, several investigators have established the essential role played by chorionic gonadotropin in primates in maintaining the corpus luteum especially during the first eight to ten weeks of pregnancy; see, I. T. Bradbury er al., Recent Progr. Hormone Res., 5, 151 (1950), C. A. Gemzell et al., J. Clin. Endocrinol. Metab., 18, 133 (1958 and J. D. Neill et al., Endocrinol., 84 45 (1969). Moreover, a similar role has been indicated for pregnant mares serum gonadotropin during pregnancy in the horse, E. B. Astwood, cited above. Accordingly the use of exogenously administered gonadotropins has been studied extensively in women and found in certain cases to stimulate and maintain the integrity of the ovary and corpus luteum; for example, see E. C. Hamblen, Endocrinol., 24, 848 (1939) and R. B. Greenblatt in Ofiice Endocrinology, Charles C. Thomas, Springfield, Ill., 1944, pp. 79-86.

These investigations of the last forty years have definitely established that the gonadotropins, especially Chorionic gonadotropins, are capable of maintaining and prolonging the functional life span of the corpus luteum in non-gravid humans [for example, see F. W. Hanson et al., J. Clin. Endocrinol., 32, 211 (1971)] and nongravid monkeys [F. L. I-Iisaw, Yale J. Biol. Med, 17, 119 (19441945)]. These latter findings concerning the life span of the corpus luteum led several investigators to propose on a seemingly logical basis that chorionic gonadotropin or pregnant mares serum gonadotropin therapy is indicated for the treatment and prevention of threatened abortion; for example, see L. W. Mason, Amer. J. Obstet. Gynec., 35, 559 (1938), W. E. Brown and J. T. Bradbury, Amer. J. Obstet. Gynec., 53, 749 (1947), P. H. Fried and A. E. Rakoff, J. Clin. Endocrinol. Metabol., 12, 321 (1952); see also S. L. Isreal in Menstrual Disorders and Sterility, 5th ed., Harper & Row, New York, 1967, p. 604, who states that, in pregnancy, chorionic gondotropin may be of value as a stimulant to the corpus luteum until the placenta performs its luteal function It is therefore well established in humans and monkeys that the physiological and therapeuticf attribute of chorionic gonadotropin is to be luteotropic and that of pregnant mares serum gonadotropin to be promotion of functional follicles, although a few studies in rodents have shown that these gonadotropins may interfer with pregnancy, see R. M. Coco, Amer. J. Physiol, 137, 143 (1942) and W. H. Yang and M. C. Chang, Endocrinol., 83, 217 (1968).

It is well known, however, that because of the unpredictable nature of applying the findings respecting the corpus luteum of one species to another and because of the fundamental physiologic differences in the reproductive processes of rodents and primates, these later findings in rats, rabbits and hamsters have not lead any one to expect that gonadotropins could be used as menses inducers in primates". This unpredictability respecting species has been expressed by several authorities in this field, see e.g. Greenblatt or Brown and Bradbury, both cited above. B. V. Caldwell et al., J. Reprod. Fert., Suppl. 8, 59 (1969) has expressed it in the following way: Throughout the class Mammalia there is a wide variation in corpora lutea life-span and function, and the effects of operations such as hysterectomy and hypophysectomy in various species are by no means uniform.

It will readily be seen from the foregoing review of the literature that it was the consensus of scientific opinion that gonadotropins were useful in re-establishing normal gonadal function in primates in cases of gonadal hypofunction, and that gonadotropins played an important role in maintaining a normally functioning corpus luteun which is essential to protect and preserve the integrity of the fetus during early pregnancy.

In marked contradistinction to those opinions I have now found that the administration of gonadotropins to primates during early pregnancy, i.e., from about day 14 to about day 35 of gestation, induces menses within 3-7 days after administration. In the light of the foregoing it will be readily understood, therefore, that my discovery of the herein disclosed menses inducing properties of gonadotropins in primates was indeed paradoxical, unexpected and surprising.

When used in accordance with this invention, the gonadotropins are administered intramuscularly, intravenously, subcutaneously, or intravaginally to the pregnant primate, preferably with a pharmaceutical carrier in dosage units.

For intramuscular, intravenous or subcutaneous, administration, commercial preparations of these gonadotropins, for example, see Remingtons Pharmaceutical Sciences, 14th ed., Mack Publishing Co., Easton, P'a., pp. 956-957, are injected into the primate. More specifically, in accordance with the method of this invention, doses ranging from 200-1200 i.u./kg, of chorionic gonadotropin or -120 i.u./kg. of pregnant mares serum gonadotropin, or appropriately proportioned mixtures thereof, are administered intramuscularly or subcutaneously either as a single dose or in divided doses over a closely spaced period of time, for example, one to three days, to primates within the period of time of from about day 14 to about day 35 of gestation. For convenience, it is preferred to administer this dosage as a single dose. Thereafter, menses commence usually within three to seven days. When the gonadotropins of this invention are administered intravenously, the same dosages for the gonadotropins are used, administered preferably at a continuous rate over a period of 30 minutes to three hours.

For vaginal applications similar doses of the gonadotropins of this invention are prepared with suitable carriers to form tablets, capsules, creams or the like suitable for insertion into the vagina. For example, a suitable tablet or capsule may be prepared using lactose, starch or sucrose as the carrier. Other suitable carriers and methods for compounding them into tablets, capsules, creams and the like are described in Remingtons Pharmaceutical Sciences, cited above.

The effects of administering the gonadotropins according to the method of this invention was specifically demonstrated in the following manner.

Female rhesus monkeys weighing from 2.5 to 6.0 kg. and having a regular menstrual cycle of between 25 to 30 days were housed (one per cage) during the 11th to 15th day of their cycle with a male rhesus monkey of proven fertility. The female monkeys were observed for mating signs, i.e., the presence of spermatozoa in the vagina. When mating signs were observed the female monkey was placed in a separate cage.

Thereafter pregnancy was established in the female monkey by gestational bleeding occurring approximately 22 to 30 days after the last menses and by the detection of serum or urinary chorionic gonadotropin by a method using the bioassay of H. O. Burdick et al., EndocrinoL, 33, 1 (1943). As in this particular method, a 24 hour collection of urine was treated with twice its volume of acetone. The resulting precipitate was dried under reduced pressure and dissolved in distilled water. The solution was injected intraperitoneally into adult diestrus mice at 3 pm. With respect to the serum, a sample of it was diluted two times with distilled water and injected into the test animals as before. The animals were sacrificed on the following morning. The observation that freshly shed ova were present in the fallopian tubes of the mice indicated that chorionic gonadotropin was present in the original urine or serum sample, thereby indicating pregnancy. [Other pregnancy tests may also be used; see for example, B. M. Hibbard, -Brit. Med. 1., 1, 593 (1971).] When pregnancy was diagnosed, the day on which mating signs were observed was assigned day 0 of gestation. The diagnosis of pregnancy was verified further by rectal palpation during the second and third week of gestation. The pregnant monkeys were then divided into two groups of six monkeys. The first group of monkeys were given a single dose of either 5000 i.u. of human chorionic gonadotropin or 1,000 i.u. of pregnant mares serum gonadotropin reconstituted with a sterile diluent. This dose was administered between day 20 and day 35 of gestation. The second group served as control and received only an injection of the sterile diluent.

Within seven days after the injection, a menstrual type of bleeding occurred in more than 50% of the monkeys in the first or treated group; whereas bleeding was found to occur in less than 10% of the second or control group. Practically every monkey in which bleeding or menses had thereby been induced in the first group returned subsequently to a regular cycling period.

I claim:

1. A method for inducing menses in pregnant primates selected from the class consisting of monkeys and humans which comprises administering to said primates a menses inducing dose of a material, selected from the group consisting of chorionic gonadotropin in doses of from 200- 1200 i.u./kg, pregnant mares serum gonadotropin in doses of from 10-120 i.u./kg, and a mixture thereof, within the period of time of from about day 14 to day 35 of gestation to produce menstruation and a return to the normal menstrual cycle.

References Cited Greenwald et al.: Chem. Abst., vol. 71 (1969), p. 19231p.

Moor et al.: Chem. Abst., vol. 71 (1969), p. 5720*5r.

SAM ROSEN, Primary Examiner US. Cl. X.R. 42410l, 108