Medroxy-progesterone acetate(MPA)가 생쥐의 교미 및 배란에 미치는 영향
고도의 영장류를 제외한 대부분의 포유동물에서 암컷은 배란이 일어나는 발정기가 있어 이때에만 성적반응을 나타내거나 교미를 허용한다. 즉 이 기간에 암컷은 특이한 성적행동을 나타내고 수컷은 암컷의 이러한 행동에서 교미의 기회를 포착하여 교미를 하게 된다(Nalb-andov, 1958).
포유동물들중에서 쥐와 생쥐를 예로 든다면 발정기의 성적행동에는 대체로 3가지를 들 수 있다. 첫째, 교미허용, 둘째, 암컷의 척추전만(lordosis)과 수컷과의 합착(mounting), 셋째로 달리는 행위등인데(Young, 1961) 이러한 성적반응을 나타내는 시기는 반드시 이 동물의 발정기에 한하여 나타내며 또 이 때에 한해서 수컷과의 교미를 허용한다. 이미 성숙기에 들어 있는 쥐의 난소를 제거해 버리면 이와 같은 성적반응이 일어나지 않는 것으로 미루어 발정기에서의 성적반응은 난소와 직접적인 관계를 가지고 있음이 초기의 생식생리학분야의 연구과정에서 밟혀졌다(Ball, 1936: Robson, 1938: Young과 Orbison, 1944). 이 이후 다시 여러 학자들의 연구로 쥐(Boling과 Blandau, 1939; Beach, 1942), 생쥐(Ring, 1944), 햄스터(Frank와 Fraps, 1945; Kent와 Lieberman, 1947)와 소(Melampy등, 1957)등의 동물에서 이러한 성적행동을 나타내는 데는 에스트로겐과 프로게스테론의 적절한 복합으로 가능함을 발견하게 되었다. Zeilmaker(1966)는 프로게스테론이 쥐에서 발정주기와 주사시기와의 관계에 따라 성선자극홀몬(gonadotrophic hormone)의 분비를 촉진시키거나 지연시키는 효과가 있음을 알았고 Zucker(1966)는 프로게스테론이 성적행동에 대해 이중효과를 가지고 있다고 했으며 Kawakami와 Sawyer(1959)는 프로게스테론이 성선자극홀몬분비를 차단 혹은 억제하는 기전으로는 성선자극홀몬분비기전에서 신경활동의 한계치를 변경시키므로서 일어난다고 하였다.
근래에 와서 스테로이드(steroid)홀몬의 합성이 가능해졌고 프로게스테론보다 몇배나 생물학적 효과가 강한 medroxy progesterone (17α-hydroxy-6α-methylpregn-4-ene-3,20-dione)도 이미 인간에서 피임약으로 등장되고 있다(Zanartu, 1968; Soichet, 1969). Medroxy-progesterone acetate(MPA)는 인간에서 주로 배란을 억제하고(Mishell, 1967; Zanartu등 1970) 또 자궁경부점막과 자궁내막에 영향을 주므로써(Mishell등, 1968; Zanartu등, 1970) 피임효과를 나타낸다고 알려져 있다.
그리고 MPA가 저에서는 배란, 자궁수액저류 및 질상피각화를 억제한다고 했으며(Banik와 Herr, 1969) 또한 배아착상을 지연시키거나 억제한다고 하였다(Barnes와 Meyer, 1964; Yoshinaga와 Greep,1971). 그러나 생쥐에서는 배아착상을 지연시키지 않는다고 하였다(Chung, 1977).
이에 본 저자는 생쥐에서 성선자극홀몬주사로 배란을 유발시켰을 때 MPA가 교미 및 배란에 미치는 영향과 또 이와 병행해서 성선자극홀몬의 증량이 MPA의 효과에 미치는 영향에 대하이 실험한 바 다음과 같은 결론을 얻었다.
1. MPA (2mg/ml)를 발정일을 제외한 발정주기의 어떠한 날에도 교미전에 주사하면 교미를 억제한다.
2. MPA (2mg/ml)는 Pregnant Mare's Serum(PMS) 2 international unit(iu)와 Human Chorionic Gonadotrophin(HCG) 2iu로 유도된 인공배란에는 영향을 미치지 않았다.
3. MPA는 자궁상태에 심한 이상을 나타내었다.
4. 이와 같은 MPA의 작용과 PMS나 HCG의 증량과는 상호 상관관계를 관찰할 수 없었다.
Females of most mammals, except for higher primates, show specific sexual behavior and permit copulation only during estrus when ovulation occurs. During this period females reveal peculiar sexual behavior while males, seizing opportunities for copulation from such behavior, usually carry out copulation (Nalbandov, 1958).
Among the mammals, rats and mice, for instance, reveal the following three signs of sexual behavior during estrus: first, permission of copulation; second, lordosis and male like mounting: and third, running activity (Young, 1961). However these signs of sexual behavior come always during estrus, and females allow copulation with males only during that period. In the early stage of reproductive physiology, it was confirmed through research that sexual behavior during estrus directly
linked with ovaries, in view of the fact that rats do net reveal such behavior when ovaries are removed (Ball, 1936; Robson, 1938; Young and Orbison, 1944). Later research by many investigators led to discovery of the fact that an appropriate combination of estrogen and progesterone is required to induce sexual behavior in the rat (Boling and Blandau, 1939; Beach, 1942), mouse (Ring, 1944), hamster (Frank and Fraps, 1945; Kent and Lieberman, 1947) and cow (Melampy et al., 1957).
Zeilmaker (1966) observed that progesterone had the effect or advance or delay in the release of gonadotrophic hormones under the influence of time of injection and estrous cycle of the rat. Progesterone had also been described to have a biphasic effect on estrous behavior (Zucker, 1966) and it had been postulated that
progesterone effects on estrous behavior and pituitary stimulation are mediated by means of altered thresholds of neural activity (Kawakami and Sawyer, 1959).
The synthesis of steroid hormones has become possible, while medroxy-progesterone acetate(MPA), which has a far stronger biological effect than progesterone, has emerged as a contraceptive drug (Zanartu, 1968; Soichet, 1969). MPA is believed to have contraceptive effects by inhibition of ovulation (Mishell, 1967; Zanartu et al., 1970) and by influencing the uterine cervical mucus and endometrium (Mishell et al., 1968: Zanartu et al., 1970). In rats, MPA is known to inhibit ovulation, uterine water retention and vaginal epithelial cornification (Banik and Herr, 1969). MPA is also believed to delay or suppress implantation in rats(Barnes and Meyer, 1964; Yoshinaga and Greep, 1971), but not in mice (Chung, 1977).
It was therefore the aim of this study to research the effect of MPA on the sexual behavior of mice and to ascertain the relation between ovulation and sexual behavior after ovulation has been induced with gonadotrophin injection.
Mammals used for the experiment were mice weighing about 25 to 30 grams, while the mammal subjects were adapted to an environment where illumination was controlled in order to keep the estrous cycle constant. Bright and dark conditions were maintained to last 14 and 10 hours, respectively, while the indoor temperature was kept at 17 to 25 degrees C.
The progesterone used for this experiment was MPA (2 mg/ml) manufactured by Upjohn Pharmaceutical Co. In order to ensure synchronization with the estrous cycle. 2 international unit (iu) of pregnant mare's serum (PMS) was injected into the intraperitoneal cavity, and after the elapse of 48 hours, 2 iu of human chorionic gonadotrophin (HCG) was also injected into the intraperitoneal cavity, and then the female mouse was put into a cage along with mature male. The next morning copulation was confirmed by using vaginal plugs.
In addition, in order to observe ovulation, the number of ovulated eggs and the state of uterine condition, the mice were slaughtered through cervical dislocation, and the fallopian tube was removed by opening the abdominal cavity. Then the number of eggs collected by washing the fallopian tube from the upper part known with 0.85% physiological salt water was counted under a dissection microscope.
The first experiment was to determine the effect of the MPA on mating behavior during the estrous cycle. The experimental group was divided into four subgroups, each of fifteen mice.
The second experiment was to see whether or not there was any difference in the MPA effect according to vehicles, Fer this the experimental group was divided into four, each of fifteen mice.
The third experiment was to determine, on the basis of the results of the first and second experiments, what change the MPA brought about when the amount of PMS was increased.
The experimental group was divided into four, each of fifteen mice.
The fourth experiment was to determine, on the basis of the first through the third experiments, what change the MPA brought about when the amount of HCG was increased. The experimental group was divided into six, each of fifteen mice.
The results are as follows:
1. The injection of medroxy-progesterone acetate (MPA, 2mg/ml) into mice before mating during any day of the estrous cycle, except for the day of estrus, restricts mating.
2. MPA foils to have any influence on artificial ovulation induced through the injection of Pregnant Mare's serum (PMS) 2 iu and Human Chorionic Gonadotrophin (HCG) 2 iu.
3. MPA is believed to have a strong disturbing effect on uterine condition.
4. No sign of interrelation between such functions of MPA and the amount of PMS or HCG can be observed.