Oviduct Motility in the Rhesus Monkey: Spontaneous Activity and Response to Prostaglandins*

Vol. 25, No. 11, November 1974

FERTILITY AND STERILITY

Printed in U.s.A.

Copyright" 1974 The American Fertility Society

OVIDUCT MOTILITY IN THE RHESUS MONKEY: SPONTANEOUS ACTIVITY AND RESPONSE TO PROSTAGLANDINS* CHARLES H. SPILMAN, PH.D.

Fertility Research, The Upjohn Company, Kalamazoo, Michigan 49001

Despite the recognized importance of the mammalian oviduct in regulating the timely entry of the developing embryo into the uterus, little is known about the control of oviduct motility in human and subhuman primates, Several reports 2-4 describe the pattern of oviduct motility in the human at various stages of the menstrual cycle. While these provide some information on changes which occur during the cycle, the results often have been contradictory. Neri et a1 5 have monitored oviducal activity during the menstrual cycle in rhesus monkeys, and have described typical contractile patterns during the follicular, ovulatory, and luteal phases of the cycle. The effect of certain prostaglandins on human tubal motility has been studied extensively in vitro,6 Coutinho and Maia 7 reported that the human oviduct in vivo responds differentially to prostaglandin E2 (PGE 2 ) and prostaglandin F 2 a (PGF 2a) as does the rabbit oviduct in vivo. 6 Possible changes in the response to prostaglandins during the menstrual cycle cannot be determined from their work because it is not clear during which stage of the menstrual cycle their experiments were performed. Information about a nonprimate species8 leads one to expect that the oviduct responds differently during different stages of the menstrual cycle. The following report describes the

changes which occur in spontaneous oviducal activity and in the response to prostaglandins during the rhesus monkey menstrual cycle. These changes are discussed in relation to preliminary measurements of peripheral levels of progesterone and 17,a-estradiol in these animals, and to literature reports of ovarian steroid levels during the menstrual cycle. MATERIALS AND ¥ETHODS

Muscular activity of the oviducal ampulla was monitored in nine monkeys (Macaca mulatta) during 11 menstrual cycles. The first day of menstrual bleeding was designated day 1 of the cycle. The Silicone balloon-tipped catheter method, as previously described, was used to record oviducal motility. 6 On the days recordings were made blood was collected from the femoral vein, placed in tubes containing heparin (10 IU/ml) , and the plasma was harvested. Radioimmunoassays were used to measure progesterone 9 and 17,a-estradiol. 10 Prostaglandins E 1 , E 2 , or F 2 a were dissolved in phosphate buffer (0.2M, pH 7.3) and injected via the saphenous vein. Doses were given as f-tg/kg body weight. The animals were anesthetized with Sernylan (Bio-Ceutic Laboratories, Inc) and placed in a modified Sims' position on an operating table while recordings were made. Recordings were made for as long as 5 hours with additional anesthetic Received December 28, 1973. *A preliminary account of this work has been administered as needed. The exact day of ovulation was not published as an abstract.' 935

November 1974

SPILMAN

936 mmHg

:t~~~~~ 5 0 [.J\"".rLJ'~~~~ [ .y.v....

DAY 10

~~

~

!\

10

5 MINUTES

FIG. 1. Composite of changes in spontaneous ampullary activity throughout the menstrual cycle of the rhesus monkey.

verified by visual observation in these experiments. The menstrual cycle was divided into the following phases based on previous observations of animals in this colony: early follicular, days 3 to 7; late follicular, days 8 to 11; ovulatory, days 12 to 14; early luteal, days 15 to 17; late luteal, days 18 to 24; premenstrual, day 25 to end of cycle. Recordings of motility were made in every animal at least once during each of these phases.

frequency, with the exception of the low frequency contractions recorded during menstruation. The mean progesterone concentration measured at this time, days 12 to 14, was 1.8 ng/ml. Individual measurements of estradiol reflected both the preovulatory increase (183.8 pg/ml) and the nadir (21.8 pg/ml) which follows the preovulatory peak. A true preovulatory peak of estradiol, probably due to infrequent blood sampling, was detected in only one cycle. During the few days following expected ovulation, oviducal activity was characterized by bursts of contractions of fairly high amplitude. Bursts of activity were seldom recorded at any other stage of the cycle. This type of activity was associated with increasing progesterone levels (4.0 ng/ml) and basal estradiol levels (80.1 pg/ml) although there was marked variation among the samples grouped into this phase of the menstrual cycle. Luteal phase progesterone and estradiol concentrations of 4.7 ng/ml and 80.8 pg/ml, respectively, were measured at the time that spontaneous activity in the oviduct was decreasing to its lowest level. PGE 1 and PGE 2 , at intravenous doses of 5 to 20 ILg/kg, had little or no effect on mmHg

RESULTS

Figure 1 is a representative composite of changes in spontaneous activity of the oviducal ampulla throughout the menstrual cycle. The high frequency-low amplitude contractions during the early follicular phase were associated with mean plasma progesterone and estradiol concentrations of 0.5 ng/ml and 81.4 pg/ ml, respectively. A few days before expected ovulation, plasma progesterone and estradiol levels of 0.7 ng/ml and 76.6 pglml, respectively, were associated with a decrease in the frequency of contractions with no change in amplitude. During the ovulatory phase of the cycle, contractions were of the highest amplitude and lowest

POSTOVULATORY

:[

t 10 pg/kg PGEI POST OVULATORY

2.: [

t 10 pg/kg PG E2 20

15 10

5 0

t

20 pg/kg PGE2 5 MINUTES

FIG. 2. Effects of intravenously administered PGE, and PGE 2 on ampullary activity in the rhesus monkey during postovulatory stages of the cycle.

Vol. 25, No. 11 mmHg

OVIDUCT MOTILITY AND PROSTAGLANDINS

937

plitude was still low, PGF2£r caused an increase in the amplitude of contractions and a slight increase in tone. At ovulao tion the oviduct was extremely sensitive to stimulation by PGF2£r (Fig. 3), often 5 pg/kg PGF2a OVULATORY responding to as little as 5 JLglkg. The response was characterized by a large in15 10 crease in tone or a slight increase in tone 5 with contractions of increased amplitude o t and frequency. This latter response, 5 pg/kg PGF2a shown in the lower tracing of Figure 3, is similar to the spontaneous bursts of very 5 MINUTES FIG. 3. Effects of intravenously administered activity recorded during the early luteal PGF2IX on ampullary activity in the rhesus monkey phase of the cycle. during the ovulatory stage of the cycle. The reactivity of the oviduct to PGF2 £r spontaneous activity during preovulatory remained high during the luteal phase of phases of the menstrual cycle. During the cycle (Fig. 4). PGF2£r injected at this postovulatory days when spontaneous time caused a sharp increase in tone and activity was characterized by bursts of an increase in the amplitude and frecontractions, the response to PGEs was quency of contractions. As the next menvariable (Fig. 2). In some cases bursts of strual period approached, the oviduct activity could be interrupted by PGEs, could still be stimulated by PGF2 £r even although there seemed to be great dif- though the level of spontaneous activity ferences in this type of sensitivity among had decreased markedly. However, in animals. During the early luteal phase many cases the required threshold had inof the cycle, spontaneous activity cl)uld be creased and the magnitude of the resuppressed, but a fairly large dose of the sponse had decreased. hormone was required. During the follicular phase of the cycle, DISCUSSION 5 to 20 JLglkg PGF 2£r had no effect on During the ovulatory phase of the spontaneous motility. Just prior to exmenstrual cycle, ampullary activity was pected ovulation, when the frequency of at its highest amplitude and lowest frecontractions was decreasing and the amquency. The very regular, rhythmic conmmHg tractions observed at this time may be essential to allow close association of the fimbria with the ovary at the time of follicular rupture. Low frequency contractions may also be a prerequisite for t 10 pg/kg PGF2a efficient ovum pickup and transport into PREMENSTRur.L the oviduct by ciliary action. l l The bursts 10 of fairly high frequency and amplitude 5 recorded during the few days after ex0 pected ovulation could be important t physiologically in keeping the ova at the 20 pg/kg PGF2a L5 MINUTES ampullary-isthmicjunction without transFIG. 4. Effects of intraveneously administered porting them through the oviduct prePGF2IX on ampullary activity in the rhesus monkey during the luteal and premenstrual stages of the maturely. Bursts of activity in isolated cycle. segments of the ampulla are probably 20 10

f

~

~~~r 15~

OVULATORY

938

November 1974

SPILMAN

responsible for the backward and forward movement of ova that has been observed in other experiments. 12 The response of the monkey oviduct to PGE 1 and PGE2 varied throughout the menstrual cycle, but it was generally very small. This is in contrast to experiments in the rabbit where the same dose ofPGEs caused complete suppression of spontaneous activity. 6 The increased responsiveness to PGEs was associated with increasing plasma levels of progesterone. A similar influence of progesterone on the sensitivity of the rabbit oviduct to PGEs has been noted. 13 Of particular interest is the increased sensitivity of the oviduct to PGF2a stimulation just prior to expected ovulation. This change in sensitivity is associated with dramatic changes in blood hormone levels prior to ovulation. 1us The fact that the oviduct remained responsive to PGF2a during the luteal phase is not easily explained. One possibility is that the increased sensitivity associated with ovulation was maintained for a time and then spontaneously declined. It is al~ possible that continued progesterone mfluence during the luteal phase of the cycle, when estrogen levels are low, decreases the responsiveness to PGF2a. During the late luteal and premenstrual days of the cycle, high doses of PGF2a were required to initiate a response and the magnitude of the response had decreased. The similarity between spontaneous bursts of contractions and those induced by PGF2a is noteworthy. It has been suggested that these bursts are due to local release of norepinephrine. 16 Experiments in the rabbit6 and those reported here suggest that locally acting PGF2a may be the agent causing bursts of tubal contractions. Spilman and Harper 17 have demonstrated the similarity in the response of the rabbit oviduct to norepinephrine and PGF2a. However, the f~ct that norepinephrine and PGF2a can mduce bursts of activity should not be taken

as positive proof that either agent is the factor responsible for spontaneous bursts.

SUMMARY

Muscular activity of the oviducal ampulla was recorded in nine rhesus monkeys during 11 menstrual cycles. Spontaneous activity during the follicular phase of the menstrual cycle was characterized by relatively high frequency-low amplitude contractions. At the time of expected ovulation, there was a decrease in the frequency and a large increase in the amplitUde of contractions. High amplitude bursts of contractions were recorded after expected ovulation during the time corresponding to the tubal transport of the ovum. Motility then decreased and remained low through the duration of the cycle. Intravenous administration of prostaglandins E1 and E2 had little or no effect on spontaneous activity during the follicular phase of the cycle. After ovulation, PGE 1 and PGE 2 suppressed oviducal activity, although the magnitude of the response was variable. During the early follicular phase, PGF2a had no effect. However, immediately prior to expected ovulation, the sensitivity of the oviduct to PGF2a stimulation increased dramatically. The oviduct remained responsive to PGF2a during the luteal phase of the cycle. It is suggested that the low frequency-high amplitude contractions recorded at ovulation are important physiologically in ovum pickup after follicular rupture, and that the intermittent bursts of contractions after ovulation playa role in locating the ova at the ampullary-isthmic junction.

Acknowledgments. I appreciate the assistance of D. C. Beuving, A. D. Forbes, and J. F. Norland, and I am grateful to T. W. Pitts for performing the estradiol radioimmunoassays. Prostaglandins were made available by Experimental Chemistry Research, The Upjohn Company.

Vol. 25, No. 11

OVIDUCT MOTILITY AND PROSTAGLANDINS

REFERENCES 1. Spilman CH, Forbes AD, Norland JF: Oviduct motility during the rhesus monkey menstrual cycle: effect of prostaglandins. BioI Reprod 9: 68, 1973 2. Maia H, Coutinho EM: A new technique for recording human tubal activity in vivo. Am J Obstet Gynecol102:1043, 1968 3. Maia HS, Coutinho EM: Peristalsis and antiperistalsis of the human fallopian tube during the menstrual cycle. BioI Reprod 2:305, 1970 4. Sica-Blanco Y, Cibils LA, Remedio MR, et al: Isthmic and ampullar contractility of the human oviduct in vivo. Am J Obstet Gynecol 111: 91, 1971 5. Neri A, Marcus SL, Fuchs F: Motility of the oviduct in the rhesus monkey. In vivo studies with and without intrauterine contraceptive devices. Obstet Gynecol 39:205, 1972 6. Spilman CH, Harper MJK: Effect of prostaglandins on oviduct motility in estrous rabbits. BioI Reprod 9:36, 1973 7. Coutinho EM, Maia HS: The contractile response of the human uterus, fallopian tubes, and ovary to prostaglandins in vivo. Fertil Steril 22:539, 1971 8. Porter DG, Behrman HR: Prostaglandininduced myometrial activity inhibited by progesterone. Nature (Lond) 232:627,1971 9. deVilla GO, Jr, Roberts K, Wiest WG, et al: A specific radioimmunoassay of plasma progesterone. J Clin Endocrinol Metab 35:458 1972 '

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10. England BG, Niswender GD, Midgley AR: Radioimmunoassay of estradiol-17/3 without chromatography. J Clin Endocrinol Metab 38: 42, 1947 11. Blandau RJ: Gamete transport-comparative aspects. In The Mammalian Oviduct. Edited by ESE Hafez, RJ Blandau. Chicago, The University of Chicago Press, 1969 12. Harper MJK: The mechanisms involved in the movement of newly ovulated eggs through the ampulla of the rabbit fallopian tube. J Reprod Fertil 2:522, 1961 13. Spilman CH: Oviduct response to prostaglandins: influence of estradiol and progesterone. Prostaglandins (In press) 14. Hotchkiss J, Atkinson LE, Knobil E: Time course of serum estrogen and luteinizing hormone (LH) concentrations during the menstrual cycle of the rhesus monkey. Endocrinology 89: 177, 1971 15. Bosu WTK, Holmdahl TH, Johansson EDB, et al: Peripheral plasma levels of oestrogens, progesterone and 17a-hydroxyprogesterone during the menstrual cycle of the rhesus monkey. Acta Endocrinol (Kbh) 71:755, 1972 16. Coutinho EM, Maia H, Filho JA: Response of the human fallopian tube to adrenergic stimulation. Fertil Steril 21:590, 1970 17. Spilman CH, Harper MJK: Comparison of the effects of adrenergic drugs and prostaglandins on rabbit oviduct motility. BioI Reprod 10:549, 1974