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Elevation of rhesus monkey plasma luteinizing hormone levels in response to E series prostaglandins
PROSTAGLANDINS
ELEVATION OF RHESUS MONKEY PLASMA LUTEINIZING HORMONE LEVELS IN RESPONSE TO E SERIES PROSTAGLANDINS
Satish K. Battal, Gordon D. Niswender and Benjamin G. Brackett
Division of Reproductive Biology, Department of Obstetrics and Gynecology, School of Medicine and Section of Reproductive Studies, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
and
Department of Physiology and Biophysics, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado
‘present address:
Department of Physiology, University of Maryland School of Medicine, Baltimore Maryland, 21201
Reprint requests to:
NOVEMBER
Dr. Benjamin G. Brackett University of Pennsylvania School of Veterinary Medicine New Bolton Center Kennett Square, PA 19348
1978 VOL. 16 NO. 5
a35
PROSTAGLANDINS
ABSTRACT Experiments were carried out to assess the influence of prostaglandins (viz. PGE PGE2 and PGF2,) on plasma concentrations of FSH and LH in the fema$' e rhesus monkey. Monkeys were ovariectomised and treated with eatradiol benxoate to suppress endogenous gonadotropin levels prior to these experiments. Femoralvenous blood was taken at intervals following a single carotid arterial injection of the PG in anesthetized monkeys. FSH and LH concentrations, determined by radioimmunoassay,were not significantly altered in 4 control animals receiving saline (2) or ethanol-saline (2), the vehicles for PGF20 and for the E series PGs, respectively. PGEl (Smg) effected dramatic elevations of LH within 5 min in 3 animals and the high plasma concentrations were maintained at least for 60 min. Similarly, 5.0 mg of PGE effected rapid elevation of LH concentrations, from 2- to 7-fold2pre-injectionlevels in 3 animals. In contrast, FSH levels were not so markedly altered by PGEl and PGE2, but in general, appeared to be somewhat decreased by these treatments. had no PGF2e effect on plasma FSH and LH concentrations. These data demonstrate the ability of PGs of the E series to elevate plasma LH concentrations in the rhesus monkey and support studies in other species suggesting a modulating role for PGs on gonadotropin secretion or release.
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Introduction Prostaglandins (PGs) appear to be involved in modulation of gonadotropin secretion (l-8). Host of the work has been done in infra-primate mammals. Recently, we presented preliminary data that PGs also influence the release of gonadotropins in rhesus monkeys (9). The present conrmunicationdescribes the completed studies. Materials and Methods Adult female rhesus monkeys (Macaca mulatab were individually caged and maintained in temperature (22.0 f. 0.5 C) and light controlled rooms (light 12 h/day) at 50% relative humidity. Purina monkey chow and water were given ad libitum. Although in good health for the duration of this study, all of these monkeys had been exposed to tuberculosis. Evidence of some initial lung involvement was found at autopsy but no abdominal lesions were present and none of these animals had reacted positively to intradermal KOT prior to these studies. These animals had been used previously for collection of oviductal fluid or treatment with PGs, estrogens and progesterone. The animals had no experimental treatments in the 6 months preceeding their use in this study. The monkeys were bilaterally ovariectomized 3-5 weeks prior to initiation of these studies and injected (in the 2 days preceeding PG administration) with estradiol benzoate lOOpg/monkey per day. The pretreatment was performed in order to decrease plasma gonadotropin levels which are normally very high following gonadectomy (10). Ovariectomized females were used to avoid the interference of spontaneous variations of plasma gonadotropins due to menstrual cyclicity. PO perform intracarotid injections the animals were anesthetized with pentobarbital sodium (35 mg/kg body weight) and placed in supine position. Skin of the ventral side of the neck was excised and one of the carotid arteries was exposed. A 3-O silk loop was placed around this carotid artery to help stop circulation at the time of injection. Venous blood was collected from the femoral vein, which was exposed and cannulated using a PE 50 polyethylene catheter. After the surgical procedures were completed, heparin 1000 U was injected intravenously. The animals were allowed to rest for one h for homeostasis and biotransformation of endogenously released PGs. PGK and PGE2 were solubilized in a minimal volume of absolute eth8,01, brought to the required concentration in phy@ological saline, and stored under nitrogen in glass tubes at -20 C until use. PGF in the form of tromethamine salt, was dissolved in normal sal2a' ne at the desired concentration and stored similarly. Frozen vials of PGs were thawed and brought to room temperature iznnediately before injection.
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At the time of intracarotid injection the silk loop was retracted stopping the circulation,and injection of the PG was made into the carotid artery on the side of the blockade. After injection the loop of silk was freed to allow normal circulation through the artery. Venous blood samples were collected from the femoral cannula just before the injection of PG was made and at 5 min intervals for one h after the injection. Blood was centrifuged immediately after collecfion for 30 min at 1300 x g. Plasma was separated and stored at -20 C in glass tubes until quantification of LH and FSH by radioimmunoassay. In control experiments, female monkeys were injected intracarotidly with saline or with ethanol-saline. Plasma LH concentrations were determined in duplicate by double antibody radioimmunoassay (10). Values are expressed in terms of LER-M-907-D, a partially purified preparation of monkey pituitaries which has 0.025 U/mg of LH and 0.26 U/mg of FSH as estimated by bioassay (10). FSH was measured by radioimmunoassay also using LER-M-907-D as standard (11). Results Effects of PGEl and PGE2 on release of LH and PSH. Intracarotid injection of the ethanol-saline vehicle into 2 control animals and 1.0 mg of PGEl into each of 3 animals did not elicit any significant stimulatory or inhibitory effect on LH or FSH release. However, when 5 mg of PGE were injected dramatic surges of LH were observed in 2 of 3 animals (Fig. 1). Within 5 min plasma concentrations of IX were increased 3- to 4-fold over basal levels. Plasma levels of LH were also increased significantly in the third monkey (A) although the elevation did not appear as dramatic due to the low levels of LH observed initially in this monkey. The elevated plasma levels of LH were maintained up to 60 min when the experiments were terminated. Plasma levels of FSH did not exhibit any important variation after injection of 1 mg and 5 mg of PGEl. After injection of 5 mg PGE2 the levels of LH in plasma were elevated within S-10 min from 2- to 7-fold (Fig. 2). In 2 animals (436 and 456), the rise was 2-fold, while in the third (450) it was a 7-fold. Plasma FSH measured at the same time intervals after the injection of 5 mg of PGE2 did not show any surge (Fig. 3); instead there
838
NOVEMBER
1978 VOL. 16 NO. 5
PROSTAGLANDINS
Figure 1. Plasma LIIconcentratFone in ovariectomized rhesus monkeys in responee to a single intracarotid injection of 5.0 mg PGE . The asterisk (*> indicates the concentration of LR in femoral venbs plasma immediately prior to the injection of the PG. LR concentrations are expressed in terms of LRR-H-907-D.
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were fluctuations in plasma FSH levels in 2 female monkeys (436 and 456) while in the third monkey (450) the basal values of plasma FSR were below the sensitivity of the standard curve and therefore any change elicited by the injection of PGE2 was not evident.
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1978VOL.16NO.S
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Figure 2. Plasma LH concentrations in ovariectomized rhesus monkeys in response to a single intracarotid injection of 5.0 mg PGE2.
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Figure 3. Plasma FSH concentrations in ovariectomized rhesus monkeys in response to a single intracarotid injection of 5.0 mg PGE2. The asterisk (*) indicates the concentration of FSH in blood plasma collected immediately prior to the injection of the PG. FSH concentrations are expressed in terms of LER-H-907-D. 6 I
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1978 VOL. 16 NO. 5
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Figure 4. Plasma LH concentrations in ovariectomized rhesus monkeys in response to a single intracarotid injection of 5.0 PGF2o. s-
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Effect of PGF2o on release of LH and FSH. The intracarotid injection of 5 mg of PGF2c did not elicit any significant effect upon plasma gonadotropin levels as can be seen in Fig. 4 and Fig. 5 for LH and FSH, respectively. Two control animals injected with saline exhibited no significant alterations in either LH or FSH plasma concentrations. Discussion These results indicate that PGS may influence gonadotropin secretion in the monkey. It is apparent from the data that the effect observed depends on the type and dose of PG injected. In general, PGs of the E series induce release of LH without significantly alterhas no effects on FSH and LH release. ing FSH secretion, whereas PGF PGs are known to be very poten9 and stimulatory to the pituitary hormones (2, 12-16). Batta et al. (l-4) have demonstrated that in castrated female rats and normal male rats, injections of PG would cause substantial release of either LH or FSH depending on the type of PG used. Since then evidence has accumulated not only in rats but in other species as well, that PGs play a role in pituitary gonadotropin secretion
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1978 VOL. 16 NO. 5
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PROSTAGLANDINS
Figure 5. Plasma FSH concentrations in ovariectomized rhesus monkeys in response to a single intracarotid injection of 5.0 mg PGF2c,.
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(17-18). Recently, Carlson, Wong and Perrin (17), have demonstrated to rhesus monkeys during the that administration of PGP.2or PGF late luteal phase resulted in rele&e of LW while the same treatment during mid-cycle failed to induce any LH release. These findings suggest a role for ovarian hormones in the release of gonadotropins by PGs. These workers further demonstrated in rhesus females that large doses of indomethacin could effectively reduce the estradiol induced surge of LH in plasma, confirming the observations that PGs are involved in the ovulatory processes in the monkey (19); that PGs play a physiological role in the process of ovulation is also suggested by the fact that inhibitors of PG synthesis block ovulation (20-25).
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It is premature to draw any conclusion on the site of action of PGs in such a process. However, several hypotheses have been presented including: (a) direct stimulation of the anterior pituitary (6); (b) modulation of the liberation of gonadotropin releasing factors which then pass down the portal vessels to stimulate the pituitary hormones (26-27) and (c) effect on the neurotransmitters acetylcholine, catecholamines, serotonin, etc., in higher nervous centers which are involved in the control of the hypothalamic pituitary complex (4, 28). It is known that all of these neurotransmitters are involved in transferring impulses from the higher nervous centers to the hypothalamus (29). The present data extend to the nonhuman primate the finding that PGs can play a modulatory role in pituitary gonadotropin secretion or release. Taken with other current research cited above (17) insight is provided regarding the role of E series PGs in superovulation induction in the rhesus monkey but the precise mechanism for PG involvement in liberation of gonadotropins remains for further research.
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1978 VOL. 16 NO. 5
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References
1. Batta, S.K., H. Zanisi, and L. Martini, Prostaglandinsand gonadotropinsecretions. Presented at III International Symposiumon "Hormones,the Brain and Behaviour". London, July 18-21, 1972. 2.
Batta, S.K., H. Zanisi, and L. Martini, Prostaglandinsand gonadotropinsecretion,Neuroendocrinology %:224, 1974.
3.
Batta, S.K., M. Zanisi, and L. Martini, Role of prostaglandins in the control of gonadotropinsecretion,Psychoneuroendocrinology 1,:115,1975.
4.
Batta, S.K., R.P. Piorindo,G. Justo, M. Motta, I. Simonovic, M. Zanisi and L. Martini, Role of cholinergicmechanisms and of Prostaglandinsin the control of LH and FSH secretionin NeuroendocrineRegulationof Fertility (T.C. Anandkumar,Ed. Karger, Basel, 1976, p. 155).
5.
Batta, S.K., R.A. Stark, and B.G. Brackett, Ovulation induction by Gonadotropinand Prostaglandintreatmentsof rhesus monkeys and observationsof the ova. Biol. Reprod. -18:264, 1978.
6.
Sato, T., M. Mirono, T. Jyujo, T. Iesaka, K. Taya, and M. Igarashi, Direct action of prostaglandinson the rat pituitary,Endocrinology 96:45, 1975.
7.
Labhsetwar,A.P., and A. Zolovick, Hypothalamicinteraction between orostanlandinsand catecholaminesin uromotiner gonadotropinsecretion for ovulation,Nature INew Biology) 246~55, 1973.
8.
Harms, P.G., S.R. Ojeda, and S.M. McCann, Prostaglandin-induced release of pituitary gonadotropins: Central nervous system and pituitary sites of action, Endocrinology94:1459, 1974.
9.
Batta, S.K., B.G. Brackett, and G.D. Niswender, Effect of prostaglandinsE on pituitary gonadotropinsecretion in rhesun'rnfakzz&caca mulatta). Presented at the InternationalSymposiumon Hypothalamusand Endocrine Functions, Quebec City, Canada, Abs. 4, 11. In: Labrie, F. (ed.), Hypothalamusand EndocrineFunction, 1976.
10.
Niswender,G.D., S.E. Monroe, W.D. Peckam, A.R. Midgley, Jr., E. Knobil, and L.E. Reichert, Jr., Radioimmunoassayfor rhesus monkey luteinizinghormone (TX) with anti-ovineLH serum and ovine LH-1311, Endocrinology88:1327, 1971.
11.
Boorman, G.A., G.D. Niswender,V.L. Gay, L.E. Reichert,Jr., and A.R. Midgley, Jr., Radioimmunoassayfor Follicle-stimulating hormone in the rhesus monkey using an anti-humanFSH serum and rat FSH-1311,Endocrinology-92:618, 1973. -
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12. MacLeod, R.H., and J.E. Lehmeyer, Release of pituitary growth hormone by prostaglandinsand dibutyryl adenosine cyclic 3', 5'-monophosphatein the absence of protein synthesis,Proc Nat Acad Sci -67:1172, 1970. 13. Hertelendy,F., I-I. Todd, K. Ehrhart, and R. Blute, Studies on growth hormone secretion IV: In vivo effects of prostaglandin Prostaglandins2:79, 1972. E1' on Coudert, S.P., and C. Faiman, Effect of prostaglandinF 14. , 1973. anterior pituitary function in man, Prostaglandins3:84* 15. Peng, T.C., K.M. Six, and P.L. Munson, Effects of prostaglandin El on the hypothalamo-hypophysial-adrenocortical axis in rats, Endocrinology=:202, 1970. 16. Vermouth, N.T., and R.P. Deis, Prolactin release induced by prostaglandinF2u in pregnant rats, Nature (New Biology)238: 248, 1972. 17. Carlson, J.C., A.P. Wong, and D.G. Perrin, Prostaglandinand LH release in the rhesus monkey, Proceedingsof the 8th Annual Meeting of Society for the Study of Reproduction,Fort Collins, Colorado,p. 86, July 22-25, 1975. 18. Carlson, J.C., J.W.D. Cole, A.P. Wong, and D.G. Perrin, Effect of Indomethacintreatmenton LH release in the rhesus monkey, Proceedingsof the 9th Annual Meeting of Society for the Study of Reproduction,Philadelphia,Pennsylvania,p. 33, August lo13, 1976. 19. Batta, S.K., and B.G. Brackett, Ovulation induction in rhesus monkeys by treatmentwith gonadotropinsand prostaglandins, Prostaglandins6_:45,1974. by aspirin 20. Orczyk, G.P., and H.R. Behrman, Ovulation'blockade or Indomethacin: In vivo evidence for a role of prostaglandin in gonadotropinsecretion,Prostaglandins1~3, 1972. 21. Armstrong,D.T., and D.L. Grinwich, Blockade of spontaneousand LH-inducedovulationin rats by indomethacin,an inhibitorof prostaglandinbiosynthesis,Prostaglandins1~21, 1972. 22. O'Grady, J.P., B.V. Caldwell,F.J. Auletta, and C. Speroff, The effects of an inhibitorof prostaglandinsynthesis (Indomethacin)on ovulation,pregnancy and pseudopregnancy in the rabbit, Prostaglandins&:97, 1972. 23. Behrman, H.R., G.0. Orczyk, and R.O. Greep, Effect of synthetic gonadotropin-releastng hormone (Gn-RH)on ovulationblocked by aspirin an6 Indomethacin,Prostaglandins1:245, 1972. 24. Tsafriri,A., H.R. Lindner, U. Zor, and S.A. Lamprecht, Physiologicalrole of prostaglandinsin the inductionof ovulation,Prostaglandins2:1, 1972.
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25. Sato, T., K. Taya, T. Jyujo, and N. Igarashi, Ovulationblock by Indomethacin,an inhib or of prostaglandinsynthesis: A study of its site of action in rats, J Reprod Fertil -39:33, 1974. 26. Harms, P.G., S.R. Cjeda, and S.M. McCann, Prostaglandininvolvement in hypothalamiccontrol of gonadotropinand prolactin release,-Science 181:760, 1973. 27. Hedge, G.A., The effect of prostaglandinson ACTH secretion, Endocrinology-91:925, 1972. 28. Perez-Cruet,J., D. Haubrich, and W.E. Reid, ProstaglandinEl (PGEl) induced "paradoxical"sleep and increasedbrain acetylcholine(Ach) levels and serotonin turnover Pharmacologist13~278, 1971. 29. Piva, F., N. Sterescu,H. Zanisi, and L. Martini, Nonsteroidal anti-fertilityagents affectingbrain mechanisms, Bull Wed Health Org -41:275, 1969.
ACKNOWLEDGEMENTS This work was supportedby Grants RR-00340 from the Division of Research Resources,HD 06274, HD 09406 and Career Development Award HD 15861 from National Instituteof Child Health and Human Development,N.I.H., and by a grant from The Ford Foundation.
The authors gratefullyacknowledgethe encouragementof ProfessorLuigi Mastroianni,Jr. Thanks are also due to Dr. John E. Pike of the Upjohn Co., Kalamazoo,Michigan, for the generous gift of prostaglandinsand to Mrs. Joan Trammel,Ms. Carolyn Mathias, and Mr. George Jeitles, Jr., for technicalassistanceand to Mr. Charles Meltzer, Mr. Tom Henry and Mr. Fred Norman for animal care. Received
846
7/l/78 - Accepted
8/28/78
NOVEMBER
1978 VOL. 16 NO. 5
ELEVATION OF RHESUS MONKEY PLASMA LUTEINIZING HORMONE LEVELS IN RESPONSE TO E SERIES PROSTAGLANDINS
Satish K. Battal, Gordon D. Niswender and Benjamin G. Brackett
Division of Reproductive Biology, Department of Obstetrics and Gynecology, School of Medicine and Section of Reproductive Studies, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
and
Department of Physiology and Biophysics, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado
‘present address:
Department of Physiology, University of Maryland School of Medicine, Baltimore Maryland, 21201
Reprint requests to:
NOVEMBER
Dr. Benjamin G. Brackett University of Pennsylvania School of Veterinary Medicine New Bolton Center Kennett Square, PA 19348
1978 VOL. 16 NO. 5
a35
PROSTAGLANDINS
ABSTRACT Experiments were carried out to assess the influence of prostaglandins (viz. PGE PGE2 and PGF2,) on plasma concentrations of FSH and LH in the fema$' e rhesus monkey. Monkeys were ovariectomised and treated with eatradiol benxoate to suppress endogenous gonadotropin levels prior to these experiments. Femoralvenous blood was taken at intervals following a single carotid arterial injection of the PG in anesthetized monkeys. FSH and LH concentrations, determined by radioimmunoassay,were not significantly altered in 4 control animals receiving saline (2) or ethanol-saline (2), the vehicles for PGF20 and for the E series PGs, respectively. PGEl (Smg) effected dramatic elevations of LH within 5 min in 3 animals and the high plasma concentrations were maintained at least for 60 min. Similarly, 5.0 mg of PGE effected rapid elevation of LH concentrations, from 2- to 7-fold2pre-injectionlevels in 3 animals. In contrast, FSH levels were not so markedly altered by PGEl and PGE2, but in general, appeared to be somewhat decreased by these treatments. had no PGF2e effect on plasma FSH and LH concentrations. These data demonstrate the ability of PGs of the E series to elevate plasma LH concentrations in the rhesus monkey and support studies in other species suggesting a modulating role for PGs on gonadotropin secretion or release.
836
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1978VOL.16N0.5
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Introduction Prostaglandins (PGs) appear to be involved in modulation of gonadotropin secretion (l-8). Host of the work has been done in infra-primate mammals. Recently, we presented preliminary data that PGs also influence the release of gonadotropins in rhesus monkeys (9). The present conrmunicationdescribes the completed studies. Materials and Methods Adult female rhesus monkeys (Macaca mulatab were individually caged and maintained in temperature (22.0 f. 0.5 C) and light controlled rooms (light 12 h/day) at 50% relative humidity. Purina monkey chow and water were given ad libitum. Although in good health for the duration of this study, all of these monkeys had been exposed to tuberculosis. Evidence of some initial lung involvement was found at autopsy but no abdominal lesions were present and none of these animals had reacted positively to intradermal KOT prior to these studies. These animals had been used previously for collection of oviductal fluid or treatment with PGs, estrogens and progesterone. The animals had no experimental treatments in the 6 months preceeding their use in this study. The monkeys were bilaterally ovariectomized 3-5 weeks prior to initiation of these studies and injected (in the 2 days preceeding PG administration) with estradiol benzoate lOOpg/monkey per day. The pretreatment was performed in order to decrease plasma gonadotropin levels which are normally very high following gonadectomy (10). Ovariectomized females were used to avoid the interference of spontaneous variations of plasma gonadotropins due to menstrual cyclicity. PO perform intracarotid injections the animals were anesthetized with pentobarbital sodium (35 mg/kg body weight) and placed in supine position. Skin of the ventral side of the neck was excised and one of the carotid arteries was exposed. A 3-O silk loop was placed around this carotid artery to help stop circulation at the time of injection. Venous blood was collected from the femoral vein, which was exposed and cannulated using a PE 50 polyethylene catheter. After the surgical procedures were completed, heparin 1000 U was injected intravenously. The animals were allowed to rest for one h for homeostasis and biotransformation of endogenously released PGs. PGK and PGE2 were solubilized in a minimal volume of absolute eth8,01, brought to the required concentration in phy@ological saline, and stored under nitrogen in glass tubes at -20 C until use. PGF in the form of tromethamine salt, was dissolved in normal sal2a' ne at the desired concentration and stored similarly. Frozen vials of PGs were thawed and brought to room temperature iznnediately before injection.
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1978VOL.16NO.5
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At the time of intracarotid injection the silk loop was retracted stopping the circulation,and injection of the PG was made into the carotid artery on the side of the blockade. After injection the loop of silk was freed to allow normal circulation through the artery. Venous blood samples were collected from the femoral cannula just before the injection of PG was made and at 5 min intervals for one h after the injection. Blood was centrifuged immediately after collecfion for 30 min at 1300 x g. Plasma was separated and stored at -20 C in glass tubes until quantification of LH and FSH by radioimmunoassay. In control experiments, female monkeys were injected intracarotidly with saline or with ethanol-saline. Plasma LH concentrations were determined in duplicate by double antibody radioimmunoassay (10). Values are expressed in terms of LER-M-907-D, a partially purified preparation of monkey pituitaries which has 0.025 U/mg of LH and 0.26 U/mg of FSH as estimated by bioassay (10). FSH was measured by radioimmunoassay also using LER-M-907-D as standard (11). Results Effects of PGEl and PGE2 on release of LH and PSH. Intracarotid injection of the ethanol-saline vehicle into 2 control animals and 1.0 mg of PGEl into each of 3 animals did not elicit any significant stimulatory or inhibitory effect on LH or FSH release. However, when 5 mg of PGE were injected dramatic surges of LH were observed in 2 of 3 animals (Fig. 1). Within 5 min plasma concentrations of IX were increased 3- to 4-fold over basal levels. Plasma levels of LH were also increased significantly in the third monkey (A) although the elevation did not appear as dramatic due to the low levels of LH observed initially in this monkey. The elevated plasma levels of LH were maintained up to 60 min when the experiments were terminated. Plasma levels of FSH did not exhibit any important variation after injection of 1 mg and 5 mg of PGEl. After injection of 5 mg PGE2 the levels of LH in plasma were elevated within S-10 min from 2- to 7-fold (Fig. 2). In 2 animals (436 and 456), the rise was 2-fold, while in the third (450) it was a 7-fold. Plasma FSH measured at the same time intervals after the injection of 5 mg of PGE2 did not show any surge (Fig. 3); instead there
838
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1978 VOL. 16 NO. 5
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Figure 1. Plasma LIIconcentratFone in ovariectomized rhesus monkeys in responee to a single intracarotid injection of 5.0 mg PGE . The asterisk (*> indicates the concentration of LR in femoral venbs plasma immediately prior to the injection of the PG. LR concentrations are expressed in terms of LRR-H-907-D.
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were fluctuations in plasma FSH levels in 2 female monkeys (436 and 456) while in the third monkey (450) the basal values of plasma FSR were below the sensitivity of the standard curve and therefore any change elicited by the injection of PGE2 was not evident.
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1978VOL.16NO.S
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Figure 2. Plasma LH concentrations in ovariectomized rhesus monkeys in response to a single intracarotid injection of 5.0 mg PGE2.
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Figure 3. Plasma FSH concentrations in ovariectomized rhesus monkeys in response to a single intracarotid injection of 5.0 mg PGE2. The asterisk (*) indicates the concentration of FSH in blood plasma collected immediately prior to the injection of the PG. FSH concentrations are expressed in terms of LER-H-907-D. 6 I
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Figure 4. Plasma LH concentrations in ovariectomized rhesus monkeys in response to a single intracarotid injection of 5.0 PGF2o. s-
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Effect of PGF2o on release of LH and FSH. The intracarotid injection of 5 mg of PGF2c did not elicit any significant effect upon plasma gonadotropin levels as can be seen in Fig. 4 and Fig. 5 for LH and FSH, respectively. Two control animals injected with saline exhibited no significant alterations in either LH or FSH plasma concentrations. Discussion These results indicate that PGS may influence gonadotropin secretion in the monkey. It is apparent from the data that the effect observed depends on the type and dose of PG injected. In general, PGs of the E series induce release of LH without significantly alterhas no effects on FSH and LH release. ing FSH secretion, whereas PGF PGs are known to be very poten9 and stimulatory to the pituitary hormones (2, 12-16). Batta et al. (l-4) have demonstrated that in castrated female rats and normal male rats, injections of PG would cause substantial release of either LH or FSH depending on the type of PG used. Since then evidence has accumulated not only in rats but in other species as well, that PGs play a role in pituitary gonadotropin secretion
NOVEMBER
1978 VOL. 16 NO. 5
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PROSTAGLANDINS
Figure 5. Plasma FSH concentrations in ovariectomized rhesus monkeys in response to a single intracarotid injection of 5.0 mg PGF2c,.
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(17-18). Recently, Carlson, Wong and Perrin (17), have demonstrated to rhesus monkeys during the that administration of PGP.2or PGF late luteal phase resulted in rele&e of LW while the same treatment during mid-cycle failed to induce any LH release. These findings suggest a role for ovarian hormones in the release of gonadotropins by PGs. These workers further demonstrated in rhesus females that large doses of indomethacin could effectively reduce the estradiol induced surge of LH in plasma, confirming the observations that PGs are involved in the ovulatory processes in the monkey (19); that PGs play a physiological role in the process of ovulation is also suggested by the fact that inhibitors of PG synthesis block ovulation (20-25).
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It is premature to draw any conclusion on the site of action of PGs in such a process. However, several hypotheses have been presented including: (a) direct stimulation of the anterior pituitary (6); (b) modulation of the liberation of gonadotropin releasing factors which then pass down the portal vessels to stimulate the pituitary hormones (26-27) and (c) effect on the neurotransmitters acetylcholine, catecholamines, serotonin, etc., in higher nervous centers which are involved in the control of the hypothalamic pituitary complex (4, 28). It is known that all of these neurotransmitters are involved in transferring impulses from the higher nervous centers to the hypothalamus (29). The present data extend to the nonhuman primate the finding that PGs can play a modulatory role in pituitary gonadotropin secretion or release. Taken with other current research cited above (17) insight is provided regarding the role of E series PGs in superovulation induction in the rhesus monkey but the precise mechanism for PG involvement in liberation of gonadotropins remains for further research.
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References
1. Batta, S.K., H. Zanisi, and L. Martini, Prostaglandinsand gonadotropinsecretions. Presented at III International Symposiumon "Hormones,the Brain and Behaviour". London, July 18-21, 1972. 2.
Batta, S.K., H. Zanisi, and L. Martini, Prostaglandinsand gonadotropinsecretion,Neuroendocrinology %:224, 1974.
3.
Batta, S.K., M. Zanisi, and L. Martini, Role of prostaglandins in the control of gonadotropinsecretion,Psychoneuroendocrinology 1,:115,1975.
4.
Batta, S.K., R.P. Piorindo,G. Justo, M. Motta, I. Simonovic, M. Zanisi and L. Martini, Role of cholinergicmechanisms and of Prostaglandinsin the control of LH and FSH secretionin NeuroendocrineRegulationof Fertility (T.C. Anandkumar,Ed. Karger, Basel, 1976, p. 155).
5.
Batta, S.K., R.A. Stark, and B.G. Brackett, Ovulation induction by Gonadotropinand Prostaglandintreatmentsof rhesus monkeys and observationsof the ova. Biol. Reprod. -18:264, 1978.
6.
Sato, T., M. Mirono, T. Jyujo, T. Iesaka, K. Taya, and M. Igarashi, Direct action of prostaglandinson the rat pituitary,Endocrinology 96:45, 1975.
7.
Labhsetwar,A.P., and A. Zolovick, Hypothalamicinteraction between orostanlandinsand catecholaminesin uromotiner gonadotropinsecretion for ovulation,Nature INew Biology) 246~55, 1973.
8.
Harms, P.G., S.R. Ojeda, and S.M. McCann, Prostaglandin-induced release of pituitary gonadotropins: Central nervous system and pituitary sites of action, Endocrinology94:1459, 1974.
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Batta, S.K., B.G. Brackett, and G.D. Niswender, Effect of prostaglandinsE on pituitary gonadotropinsecretion in rhesun'rnfakzz&caca mulatta). Presented at the InternationalSymposiumon Hypothalamusand Endocrine Functions, Quebec City, Canada, Abs. 4, 11. In: Labrie, F. (ed.), Hypothalamusand EndocrineFunction, 1976.
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Niswender,G.D., S.E. Monroe, W.D. Peckam, A.R. Midgley, Jr., E. Knobil, and L.E. Reichert, Jr., Radioimmunoassayfor rhesus monkey luteinizinghormone (TX) with anti-ovineLH serum and ovine LH-1311, Endocrinology88:1327, 1971.
11.
Boorman, G.A., G.D. Niswender,V.L. Gay, L.E. Reichert,Jr., and A.R. Midgley, Jr., Radioimmunoassayfor Follicle-stimulating hormone in the rhesus monkey using an anti-humanFSH serum and rat FSH-1311,Endocrinology-92:618, 1973. -
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12. MacLeod, R.H., and J.E. Lehmeyer, Release of pituitary growth hormone by prostaglandinsand dibutyryl adenosine cyclic 3', 5'-monophosphatein the absence of protein synthesis,Proc Nat Acad Sci -67:1172, 1970. 13. Hertelendy,F., I-I. Todd, K. Ehrhart, and R. Blute, Studies on growth hormone secretion IV: In vivo effects of prostaglandin Prostaglandins2:79, 1972. E1' on Coudert, S.P., and C. Faiman, Effect of prostaglandinF 14. , 1973. anterior pituitary function in man, Prostaglandins3:84* 15. Peng, T.C., K.M. Six, and P.L. Munson, Effects of prostaglandin El on the hypothalamo-hypophysial-adrenocortical axis in rats, Endocrinology=:202, 1970. 16. Vermouth, N.T., and R.P. Deis, Prolactin release induced by prostaglandinF2u in pregnant rats, Nature (New Biology)238: 248, 1972. 17. Carlson, J.C., A.P. Wong, and D.G. Perrin, Prostaglandinand LH release in the rhesus monkey, Proceedingsof the 8th Annual Meeting of Society for the Study of Reproduction,Fort Collins, Colorado,p. 86, July 22-25, 1975. 18. Carlson, J.C., J.W.D. Cole, A.P. Wong, and D.G. Perrin, Effect of Indomethacintreatmenton LH release in the rhesus monkey, Proceedingsof the 9th Annual Meeting of Society for the Study of Reproduction,Philadelphia,Pennsylvania,p. 33, August lo13, 1976. 19. Batta, S.K., and B.G. Brackett, Ovulation induction in rhesus monkeys by treatmentwith gonadotropinsand prostaglandins, Prostaglandins6_:45,1974. by aspirin 20. Orczyk, G.P., and H.R. Behrman, Ovulation'blockade or Indomethacin: In vivo evidence for a role of prostaglandin in gonadotropinsecretion,Prostaglandins1~3, 1972. 21. Armstrong,D.T., and D.L. Grinwich, Blockade of spontaneousand LH-inducedovulationin rats by indomethacin,an inhibitorof prostaglandinbiosynthesis,Prostaglandins1~21, 1972. 22. O'Grady, J.P., B.V. Caldwell,F.J. Auletta, and C. Speroff, The effects of an inhibitorof prostaglandinsynthesis (Indomethacin)on ovulation,pregnancy and pseudopregnancy in the rabbit, Prostaglandins&:97, 1972. 23. Behrman, H.R., G.0. Orczyk, and R.O. Greep, Effect of synthetic gonadotropin-releastng hormone (Gn-RH)on ovulationblocked by aspirin an6 Indomethacin,Prostaglandins1:245, 1972. 24. Tsafriri,A., H.R. Lindner, U. Zor, and S.A. Lamprecht, Physiologicalrole of prostaglandinsin the inductionof ovulation,Prostaglandins2:1, 1972.
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25. Sato, T., K. Taya, T. Jyujo, and N. Igarashi, Ovulationblock by Indomethacin,an inhib or of prostaglandinsynthesis: A study of its site of action in rats, J Reprod Fertil -39:33, 1974. 26. Harms, P.G., S.R. Cjeda, and S.M. McCann, Prostaglandininvolvement in hypothalamiccontrol of gonadotropinand prolactin release,-Science 181:760, 1973. 27. Hedge, G.A., The effect of prostaglandinson ACTH secretion, Endocrinology-91:925, 1972. 28. Perez-Cruet,J., D. Haubrich, and W.E. Reid, ProstaglandinEl (PGEl) induced "paradoxical"sleep and increasedbrain acetylcholine(Ach) levels and serotonin turnover Pharmacologist13~278, 1971. 29. Piva, F., N. Sterescu,H. Zanisi, and L. Martini, Nonsteroidal anti-fertilityagents affectingbrain mechanisms, Bull Wed Health Org -41:275, 1969.
ACKNOWLEDGEMENTS This work was supportedby Grants RR-00340 from the Division of Research Resources,HD 06274, HD 09406 and Career Development Award HD 15861 from National Instituteof Child Health and Human Development,N.I.H., and by a grant from The Ford Foundation.
The authors gratefullyacknowledgethe encouragementof ProfessorLuigi Mastroianni,Jr. Thanks are also due to Dr. John E. Pike of the Upjohn Co., Kalamazoo,Michigan, for the generous gift of prostaglandinsand to Mrs. Joan Trammel,Ms. Carolyn Mathias, and Mr. George Jeitles, Jr., for technicalassistanceand to Mr. Charles Meltzer, Mr. Tom Henry and Mr. Fred Norman for animal care. Received
846
7/l/78 - Accepted
8/28/78
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1978 VOL. 16 NO. 5