Prostaglandins in reproductive physiology

(

CURRENT DEVELOPMENTS

Prostaglandins in reproductive physiology LEON

SPEROFF,

PETER New

W. Haven,

M.D.

RAMWELL,

Connecticut,

PH.D. and Palo

Alto,

California

is the generic name for a family of biologically active lipids. The first clue to the existence of these compounds appeared in the literature in 1930 when two New York gynecologists (Kurzrok and Lieb4g) reported that fresh human seminal fluid could produce both relaxation and strong contractions when applied to isolated strips of the human uterus. In 1933 and 1934, Goldblatt34 in England and von Euler? in Sweden independently discovered and studied smooth muscle-stimulating and vasodepressor activity in extracts of the seminal vesicle. Subsequently von Euler,77 in 1935, reported that this biologic activity was due to an acidic lipid which he named prostaglandin. Little more was accomplished until the late 1950’s when isotopic, mass spectrometric, and chromatographic techniques were becoming available, and at this time BergStrom3 organized a widespread program for collecting sheep vesicular glands. In 1962, Bergstrom and associates4 reported the chem-

ical structures of 3 of the primary prostaglandins. Since then, the prostaglandin literature has burgeoned to the point where the Upjohn Company (Kalamazoo, Michigan) distributes a comprehensive bibliography which is revised periodically and supplemented annually. Nevertheless, the physiologic role of the prostaglandins remains to be elucidated. Extensive biologic studies have been reported, however, and it is the purpose of this review to survey and evaluate the present status of prostaglandins as they are related to reproductive physiology. For further reading, the review by Horton41 and the monograph by von Euler and Eliasson7s are recommended.

PROSTAGLANDIN

Nomenclature

In human sementhere are at least 13 different prostaglandins. As in steroid chemistry, there is a basic configuration and an accepted systemof naming. Prostaglandins may be abbreviated as PG, and the chemical names of the various PG’s are based on a hypothetical molecule, prostanoic acid.5 Thus prostaglandins are C-20 fatty acids containing a cyclopentane ring, numbered as shown in Fig. 1. Substituents on the same side of the ring as the carboxyl group are in the alpha position,

From the Department of Obstetrics and Gynecology, Yale University School of Medicine, and the Department of Physiology, Stanford University School of Medicine.

1111

1112

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and

Ramwell

Amer.

August J. Obstet.

1, I970 Gynec.

0

10@gg$$;F3 1719 Fig.

1. Prostanoic

E (k OH

acid. OH

and those on the same side as the alkyl group are in the beta position i.e., below the plane of the ring is alpha and above is beta. There are 4 major groups of prostaglandins identified by the letters E, F, A, and B. Each letter corresponds to a particular ring structure (Fig. 2). The adjective “primary” refers to the 6 naturally occurring compounds in the PGE and PGF groups. All 6 are designated as primary because none is a precursor of the others (Fig. 3). The numeral in the subscript position after the letter indicates the degree of unsaturation in the alkyl and carboxylic side chains. Thus, the numeral 1 indicates the presence of a trans double bond at C-13,14 (e.g., PGE,) . The numeral 2 denotes the presence of a cis double bond in the C-5,6 position in addition to the one at C-13,14 (e.g., PGEz), and the numeral 3 indicates the presence of a third double bond in the C-l 7,18 position (e.g., PGE,) . All naturally occurring prostaglandins contain an alpha hydroxyl group at the C-15 position and a trans double bond in the C-13,14 position (see Table I). The PGFp isomers have not been found in nature. In addition, there are prostaglandins with a hydroxyl group in the C-19 position, the 19-OH prostaglandins. Metabolism is known to occur by ( 1) beta-oxidation which gives rise to the dinor and tetranor prostaglandins containing 2 and 4 less carbon atoms, respectively, (2) by dehydrogenation at the C-15 hydroxyl group, and (3) by reduction of the double bond at C-13,14. Biosynthesis,

separation,

and

analysis

Prostaglandins are biosynthesized from the C-20 essential fatty acids by cyclization and introduction of molecular oxygen; the enzyme system is associated with the microsome frac-

0

F Fig. 2. The ring structures characteristic taglandins of the E, F, A, and B groups, tively.

of prosrespec-

tion. The primary precursors are: dihomo-ylinolenic acid (all-cis-eicosa-8,11,14-trienoic acid), arachidonic acid (all-cis-eicosa-5,8,11, 14-tetraenoic acid), and all-cis-eicosa-5,8,11, 14,17-pentaenoic acid (Fig. 3) .6 Extraction of prostaglandins from tissues and body fluids is usually accomplished with ethanol or ethyl acetate, followed by partition into a polar solvent, ethyl acetate or diethyl ether, from an acidified solution. Thin-layer chromatography in one solvent system is sufficient to separate the E, F, and A groups. Chromatography in a second system, using silver nitrate-impregnated silica gel, will isolate the primary compounds by their degree of unsaturation. The standard method of detecting and measuring prostaglandins is by bioassay with smooth muscle preparations since chemical methods are thus far insufficiently sensitive. The bioassay methods vary according to the prostaglandin to be assayed and the amount expected to be present. Rat uterus, rat stomach fundus, rabbit jejunum, guinea pig ileum, hamster and gerbil colon, and rat blood pressure preparations have all been used.= Care must be taken in choosing the appropriate preparation. There is no single standard method, and experience must be gained in the method used in order to achieve reliability. Changes in sensitivity, incomplete extraction, and a scarcity of pure compounds for use as standards remain as chief obstacles. The tissue content of prostaglandins is measured in the range of nano-

Volume ?Iumber

107 7

Prostaglandins

1113

/* -OH

\

OH

PGE,

OH

8, II, I4-EICOSATRIENOIC

A,wCOOH

ACID

PGFIa

aoH

5,8,

II, I4-EICOSATETRAENOIC

ACID

PGF;! a

0 A-

-COOH

-

5, 8, II, 14,17-

, -

COOH

PGE,

EICOSAPENTAENOIC

ACID

f’GF3a

Fig.

3. The

primary

prostaglandins

and the 3 primary

grams ( lob9 grams) per gram of tissue, and changes occur rapidly with variations in pH, temperature, and oxidative conditions. For an introduction to the pharmacology of prostaglandins, see the review by Bergstrijm, Carlson, and Weeks.6 Shaw and Ramwe1173 have published a definitive survey of the procedures used for the separation, identification, and estimation of prostaglandins.

precursors.

Studies

with

seminal

ptostaglandins

Prostaglandins have been demonstrated to be present in menstrual fluid, umbilical cord, amniotic fluid, decidua, proliferative and secretory endometrium, semen, and vesicular glands, but the greatest number of different prostaglandins and the highest concentration are found in human seminal plasma (Table II). Prostaglandins are also found in the

1.114 Speroff and Ramwell

August 1, 1970 Amer.

J. Obstet.

Gynec.

Table I. Structure and nomenclature of the naturally occurring prostaglandins and their derivatives (after Ramwell and DanielP) -Name

eo” bH

H

OH

Prostaglandin E1: 1 la,15 (S) -dihydroxy9-0x0-13-tram-prostenoic acid

“OH

Older abbreviation

Present abbreviation

PGE

PGE,

Prostaglandin Ez: lla,l5 ( S ) -dihydroxy9-0x0-5-&-1 3&ansprostadienoic acid

PGE?

Prostaglandin Ea : 1 la,15 (S) -dithydroxy9-0x0-5-cir-134rans17-cis-prostatrienoic acid

PGE,

0 Prostaglandin FI, : 90(,1 la,l5(S)-trihydroxy13-tram-prostenoic

PGFI-1; PGF,

PGE,

Prostaglandin F,,: 9a,lla,l5(S)-trihydroxy5-cir-134ransprostatrienoic acid

PGK-2

PGF,,

Prostaglandin Faa: 9a,lla,l5(S)-trihydroxy-

PGK-,

PGF,,

Prostaglandin F,B: 9a, 11 (Y, 15 ( S ) -trihydroxy13-tram-prostenoic acid

PGFw

PGF,s

Prostaglandin 9P,l la,l5’(S) 5-cis-134mnsprostadienoic

PGFz.2

PGFzs

acid

5-cis-13-tram-17&sprostatrienoic

+&OH AH

”

&-A?+ dH

acid

H

F?B: -trihydroxyacid

Vc.lume Number

Prostaglandins

107 7

1115

Table I-Cont’d Older abbreviation

Present abbreviation

Prostaglandin F38: 9P,lla,15(S)-trihydroxy5-cis-13-tram-17-&rprostatrienoic acid

PGFz-3

PGF,o

Prostaglandin Al: ,I5 (S) -hydroxy-9-oxo10,134raw prostadienoic acid

PGEI-220; PC&-218; PGE,-217; Al”-PGEl

PGA,

Prostaglandin AZ: 715 (S) -hydroxy-9-oxo5-cis-10,13-transprostatrienoic acid

PGEz-2 17 ; W’-PGEz

PGA?

Prostaglandin BI: 15 (S) -hydroxy-9-oxo8(12),13-trans prostadienoic acid

PGE,-278

PC&

Prostaglandin B?: ‘15 (S) -hydroxy-9-oxo5-h-8 ( 12)) 134ransprostatrienoic acid

PGE,-278

PGBz

Name

& &I$ OH

A"

H

kg

'OH

H

0 lClOH &

8

H

&

C,

OH

H

t C

‘OH

+ Ii

0 'OH *

0

0

8,” “OHOH

&

&

& ‘OH

H

19-Hydroxyprostaglandin 15 (S) ,19-dihydroxy-9-oxo10,13-tram-prostadienoic acid

A,:

19-HydroxyPGEI-217

19-HydroxyPGAl

19-Hydroxyprostaglandin 15 (S) ,19-dihydroxy-9-oxo5-cis-10,13-tramprostatrianoic acid

AZ : 19-HydroxyPGE,-217

19-HydroxyPGA,

19-Hydroxyprostaglandin 15 (S) ,19-dihydroxy-9-oxo8(12),134ransprostadienoic acid

B1:

19-HydroqPGBl

19-Hydroxyprostaglandin 15 ( S) ,19-dihydroxy-9-oxo5-cis-8( 12) ,13-transprostatrienoic acid

Bz :

1 9;1Liy7;I

1 9-HydroxyPGEz-278

19-HydroxyPGBz

1116

Speroff and Ramwell Amer.

Table

August J. Obstet.

1, 1970 Gynec.

ILCont’d Older abbreviation

Name

--c\

OH

Present abbreviation

11 a, 15 (S) -Dihydroxy-9-oxoprostanoic acid

15 (S)-Hydroxy-9-oxo8 ( 12) -prostanoic

DihydroPGE,

DihydroPGB,

PGE,-237 acid

9a, 15 ( S ) -Dihydroxy13-tram-prostenoic

ll-oxoacid

1 l-DehydroPGF,,

1 la-Hydroxy-9,15-diketoprost-13-enoic

acid

15-KetoPGE,

2,3-Dinorprostaglandin

F,,:

DinorPGFm

2,3-Dinor-9a,lla,15(S) trihydroxy-1 J-transprostenoic acid

semen of sheep and goats, and in sheep vesicular glands. The seminal fluid from the horse, boar, ox, and dog is reported to contain no detectable prostaglandin activity,20 but much of this work requires reinvestigation. Semen, vesicular glands, and the prostate gland from the rhesus monkey contain a vasodepressor substance (named vesiglandin) probably related but not identical to prostaglandin.77 Although “prostaglandin” is firmly established as a name, it is misleading, for prostatic fluid does not contain significant amounts of prostaglandin-like activity. Studies of split ejaculate specimens in men demonstrated that prostaglandins and fructose have the same origin, i.e., the seminal vesicles

Table II. plasmal

Prostaglandins 37

in human

seminal

Cbncentration (e/ml.)

PG El E?, E,

25 23 5.5

I

53.5

F Ia F 2a

3.6 4.4

J

8

A1

I

AZ BI B* 19-OH 19-OH 19-OH 19-OH

A1 AZ B, B?

50

200

Volume Number

107 7

Prostaglandins

to the number and motility of sperms present, or to the frequency of abnormal forms.lq Hawkins,38 on the other hand, in a series of 50 subfertile patients, suggested that there was a correlation between oligospermia and prostaglandin activity. In men with normal sperm counts, there was no relation between prostaglandin activity and conception rate, but in a group of men with oligospermia, there did appear to be a correlation between prostaglandin content and conception. In semen specimens obtained from 5 subfertile oligospermic men with normal wives, there was a proportionate reduction in content of all the prostaglandins estimated. SamuelssonG in the discussion following Hawkins’ report,3s presented a series of 76 infertile couples in which 17 per cent of the males had PGE values below 20 per cent of normal. Studies of this nature are complicated by the fact that variation in prostaglandin activity is sometimes found in semen samples from the same individuaLzO It would be of interest to measure the prostaglandin con-

(Fig. 4) .21 However the prostaglandin content of semen was found to be independent of the fructose content (which is proportional to androgen activity) and of the various products of the prostate gland.2j While the mere presence of a substance does not necessarily denote a physiological role, the ubiquitous nature of prostaglandins (Table III) and their remarkable potency suggest that they have a physiologic function, especially in human reproduction in view of the high concentration in semen. In semen from normal men, the biologic activity is predominantly due to the presence of the PGE compounds and two PGF compounds (Table II). 14p37 Attempts have been made to relate these prostaglandins to male fertility. Pooled semen from men with suspect fertility had a lower concentration of prostaglandins than pooled semen from men with normal fertility. I4 Analysis of 10 individual samples of semen indicated, however, that the concentration of prostaglandins in men with suspect fertility was not related

Table III.

Distribution

of the six primary

1117

prostaglandins

Source Reproductive

tract Seminal plasma, human Seminal plasma, sheep Vesicular gland, sheep Menstrual fluid, human Amniotic fluid, human Endometrium, human Umbilical cord, human Placental vessels, human Decidua, human

Central nervous system Brain, bovine Spinal cord, frog CNS, cat CNS, fowl Other tissues Adrenal, rat Renal medulla, rabbit and pig Pancreas, bovine Thymus, calf Intestine, frog Fat, rat Iris, sheep Lungs, sheep Lungs, bovine Lungs, pig, guinea pig, monkey, human

+ + + + + + +

+ + t + + t + t +

+ + +

t t t + + + +

t t + t t f + + +

+

+ + t

+

+

+ + +

+ + +

+

+ + +

+

+

+ t + -6

+

1118

August

Speroff and Ramwell

Amer.

8ooo-

4cQ-

-fom--

350-z

zoo-

Es--

z e

% 6c!oo--~m-~

IOOO--

50--

J. Ohstet.

1, 1970 Gynec.

ao-

ro--

%

7 Acid

I 150--

a--

25--

IO--

phorphotose

\

-o--d I

2 Fraction

Fig. 4. Characterization and fructose, i.e., the 1963.21 Fig. j, p. 407.)

of a split ejaculation seminal vesicles. (From

tent in repeated ejaculations. It would be worthwhile to study the effects of prostaglandins on cervical mucus. Prostaglandins are absorbed from semen deposited in the vagina. This was first demonstrated with human semen in rabbits by Asplund’ in 1947. An indirect indication of vaginal absorption was reported by Eliasson and PossepG when they found a change in resistance to tubal insufflation (Rubin’s test) following intravaginal deposition of a purified prostaglandin extract in amounts corresponding to a normal ejaculate. At midcycle, 3 out of 7 women with known patent tubes showed an increase in pressure. That absorption is via the vagina was confirmed by the use of a cervical cap and tritiumlabeled prostaglandin. Approximately 10 to 25 per cent of the radioactivity from 5,6-3HPGE, deposited in the posterior fornix in 7 women was excreted in the urine over 24 to 32 hours, regardless of phase of menstrual cycle or whether the external OS had been covered with a cervical cap or not (Fig. 5) .‘I? Since elimination via the kidney was slow, little could be concluded as to the significance of vaginal absorption in relation to fertility (the amount of prostaglandin absorbed in

indicating Eliasson,

3 number

4

5

a common origin for prostaglandin R.: Biochem. Pharmacol. 12: 405,

the first few minutes could not be measured). The increase in resistance to insufflation found by Eliasson and Posse,26 however, occurred within 25 to 40 minutes, indicating an initial rapid absorption of prostaglandins from the vagina. Prostaglandins are rapidly metabolized by liver, lungs, and the alimentary canal, and, therefore, it would be of interest to determine if any metabolism occures in the vagina. Sperm are rich in adenyl cyclase and there is good evidence indicating that some of the effects of prostaglandins are mediated via this enzyme. I1 However there is no evidence that PGE, influences the metabolism of human spermatozoa, as measured by oxygen uptake and production of radioactive carbon dioxide from labeled fructose.Z7 Interpretation of these studies is hampered by a small number of experiments, a lack of full knowledge of the substances concerned, and imprecise methods. Clearly far more definitive studies are required before generalizations can be made, but one certainly cannot preclude roles for prostaglandins in sperm transport, sperm capacitation, tubal retention of the ovum, and fertilization.

Volume Number

107 7

Effects

Prostaglandins

on

the

uterus

There have been extensive studies on the motility and reactive pattern of myometrium in response to the prostaglandins, both in vitro and in vivo, with a variety of species, including human. It is difficult to present a precise summary because results are not totally uniform. In general, however, it can be said that the majority of prostaglandins, in varying doses, inhibit the spontaneous motility of isolated nonpregnant human myometrium. In contrast, PGF,, and PGF,, (and PGE, in low doses) have the opposite effect, stimulating both the tone and amplitude of contractions. In nonpregnant myometrium then, the PGE compounds, which predominate in semen, inhibit contractions, while the PGF compounds, which predominate in menstrual fluid, stimulate contractions.12, 13, 15 The two main muscle-stimulating

components lipids in

percent crcretion

of the smooth human endo-

with

metrium and menstrual fluid are PGE, and with the latter being the principal PGF,,, The total prostaglandin recompound.‘g covery (composed mainly of PGF compounds) from endometrial curettings during the proliferative phase was approximately 35 ng. per gram wet tissue, while in the secretory phase it was 50 ng. per gram wet tissueaG2 Pickles and associates +Z feel that these figures represent a minimum estimation. Since the average amount of PGF,, recovered from a single menstrual collection was about 450 ng. and that of PGE, about 12 ng., a conservative estimate is given of about 1 pg total prostaglandins per gram of endometrial tissue and approximately 56 ng. per milliliter of menstrual fluid. Menstrual fluid contains about 10 times more PGF,, than is found in secretory endometrial curettings; this may be due to formation shortly before or during menstruation,Fz or to decreased metabolism. In our laboratory,

cervical

cup secretory

proliferative

PGE, from A., RydCn,

urinary excretion the vagina with G., and Joelsson,

phase

phase

proliferative

Fig. 5. The

1119

phase

of radioactivity in 3 women due to absorption of tritium-labeled a cervical cap in place. (From Sandberg, F., Ingelman-Sundberg, I.: Acta Obstet. Gynec. Stand. 47: 22, 1968.T2)

1120

Speroff

and

Ramwell

Amer.

Function

August J. Obstet.

1, 1970 Gynec.

of

Dysmenorrhea

Porturition

b

*---

Anti

Delayed

Ovum

Transport

- Fertility

Ovorion

Steroidogenesis

Effects

Ef feet

Luteolysis

ImploOnntotion Site

Fig.

6. Possible

physioIogic

and

pharmacoIogic

we have been able to show that in most tissues, including the adrenal gland and the brain, more prostaglandin is released into tissue perfusate than can be extracted from the tissue, indicating that biosynthesis occurs very readily. The average total prostaglandin content of menstrual fluid from 7 patients with primary dysmenorrhea did not significantly differ from normal, but the results suggested that dysmenorrheic patients produce a higher proportion of PGF compounds, which, therefore, would be more spasmogenic.62 This is supported by the finding of a greater amount of PGF,, in menstrual fluid collected from ovulatory cycles than in fluid from anovulatory cycles.61 It is suggested that PGF,, may play a significant part in the physiology of primary dysmenorrhea (Fig. 6). Studies with nonpregnant human myometrium have shown no qualitative or quantitative differences between the effects of semen and/or equivalent amounts of purified PGE compounds. 2o All 19-hydroxy derivatives, the PGA compounds, and the PGB compounds have an inhibitory activity similar to the of the PGE compounds. I5 The sensitivity myometrium to prostagIandins, however, changes during the menstrual cycle. Isolated human myometrial strips are 3 to 5 times more sensitive to inhibition by PGE, at midcycle near ovulation time,12* 21 and they are

roIes

for

PGF?,

in

reproductive

biology.

more sensitive to PGF,a stimulation just before menstruationfi2 and during pregnancy.121 28 One can then infer that the hormonal state of the uterus influences its response to the various prostaglandins. The addition of progesterone in vitro to guinea pig and rat uterus reduced the sensitivity to PGE, and PGF,,.75 An attempt was made by Hawkins, Jessup, and Ramwe to clarify this response of the rat uterus to prostaglandins. Using adrenalectomized-ovariectomized rats, they were able to show that all prostaglandins tested contracted the isolated uterus but that pretreatment of the rats with estrogen, and to a lesser extent, progesterone, reduced the responsiveness of the tissue. Ovarian hormones added directly to the organ bath either inhibit or have no effect on oxytocic substances; prostaglandins do not appear to be exceptions to this general rule.3g The sensitivity of human myometrium is likewise affected by the ovarian steroid hormones in vitro.” Progesterone and estradiol (separately and together) decreased the response to PGE, at midcycle. However the in vitro effects of ovarian hormones on the responsiveness of human myometrium should be regarded with caution, since the concentrations of hormone in bath fluid do not represent physiologic conditions. Nevertheless, the responsiveness of the human uterus

Volume Number

107 7

does seem to reflect endogenous hormone concentrations; for example, the effect of prostaglandins on human myometrial strips is reduced in specimens obtained from postmenopausal women.12p I3 Whether the changes in responsiveness of human myometrial strips can be ascribed to the estrogen progesterone ratio remains to be determined. The increased sensitivity of human myometrium at ovulation may be related to a physiologic role for prostaglandins at coitus; Bickers and Main,’ in 1941, reported the inhibition of uterine motility by coitus. The inhibitory effects of the PGE compounds in semen on human myometrium at the time of ovulation may facilitate sperm migration and/or play a role in capacitation and fertilization. Support for this is found in the early work of Kurzrok and Lieb4g who found that the small number of in vitro myometrial strips which responded to semen with an increase in tone rather than a decrease in tone were obtained from patients with a history of infertility. Bickers7 reported similar findings in vivo; hypertonic dyskinetic contractions associated with abnormal sperm migration were recorded in 8 of 23 patients with unexplained infertility. Eliasson and Possez5 tested these findings in vivo. Prostaglandins were introduced into the posterior fornix of 8 normal fertile women volunteers, in amounts corresponding to those usually found in ejaculates. During menstruation and in the proliferative and secretory phases, prostaglandins had little effect. But at the time of ovulation, prostaglandins increased uterine activity in 5 of 7 women. This initial stimulation was followed in 3 cases by inhibition, attributed to a gradual increase in blood or tissue concentration, producing stimulation at low dosage and inhibition at high dosage as with in vitro experiments.“O In an attempt to mimic conditions during coitus, a slow continuous infusion of oxytocin was carried out, and simultaneously, prostaglandins were administered intravaginally at midcycle in 2 of the 3 subjects showing later irihibition. The initial stimulation did not occur, but a marked inhibition was recorded, and it was suggested

Prostaglandins

1121

that prostaglandins may play a role in facilitating sperm migration. An attempt was made to duplicate this experiment with in vitro preparations. In none of the in vitro experiments was the effect of PGE, on myometrium changed by vasopressin or oxytocin.‘” The reason for this difference between in vivo and in vitro effects is not apparent. The action of prostaglandin on isolated nonpregnant human myometrium does not seem to be mediated by adrenergic receptors. The addition of beta-blocking agents had no effect on the response to PGE, or to a total prostaglandin extract from human semen.*” Similar results were obtained in a few experiments with alpha-adrenergic blocking agents. The action of PGE, on the rat uterine horn was not abolished by cholinergic, adrenergic, or serotonin antagonists.“6 Therefore PGE, does not appear to produce contractions in the rat uterus by releasing known neurotransmitters. PGE, contractions do seem to be Ca++ dependent and to require an oxidative mechanism.“” The effects of prostaglandins on isolated human myometrium at midcycle can be altered by changes in the extracellular (bath fluid) potassium and calcium concentration.” At low extracellular levels of potassium the inhibitory effect of PGE, was enhanced, while at high extracellular potassium concentration the sensitivity to the stimulatory effect of PGF,, was increased. This suggests a relationship between prostaglandin and membrane potential. The effect of calcium concentration was not as marked; a decrease in Ca+* increased the inhibitory effect of PGE, at midcycle. Studies

related

to

pregnancy

The response of the pregnant human uterus is different from that of the nonpregnant uterus. Embrey and Morrisonz8 studied muscle strips obtained at cesarean section both from the upper segment of the uterus and the lower segment. Both PGE, and PGF,, were spasmogenic on upper segment myometrium but were relatively inactive on lower segment strips. This stimulatory activ-

1122

Speroff

and Ramwell

Amer.

-PPGEz

50

w

OL

lpglminp

PGE,

2pg/minw

I

1, 1970 Cynec.

4pg/min+

6 pg/min

4pg/min

August J. Obstet.

-

I 5 MIN

Fig. 7. The uterine dose-response to intravenous infusion of PGE? in a term pregnant patient. The bottom curve is a continuation of the top curve. (From Bygdeman, M., Kwon, S. U., Mukherjee, T., and Wiqvist, N.: AMER. J. OBSTET. GYNEC. 102: 317, 1968.16) ity by PGE, contrasts with the usual inhibition of myometrium by PGE compounds in the nonpregnant uterus. Clinical investigations have been carried out in Stockholm with PGE, and PGE, by Bygdeman and associatesl’j and Wiqvist and associates.*” The studies were performed on women in the second trimester admitted for therapeutic abortion and women in the third trimester undergoing amniocentesis for erythroblastosis. The potency and effects of PGE, and PGE, were found to be about the same. A single intravenous injection during midpregnancy caused a rapid increase in uterine tone with some minor small contractions. There was a gradual increase in response with an increase in dose (Fig. 7). A dose greater than 50 pg resulted in nausea and an increase in pulse rate. There were no consistent effects on blood pressure. Large doses of PGE, (75 pg or more) given intravenously caused an almost immediate uterine contracture which lasted 30 minutes with a tone of 40 to 50 mm. Hg. (The halflife of radioactivity in blood after intravenous injection of tritium-labeled PGE, in man is 10 to 15 minutes.35) The response to intramuscular injections was similar to that of the intravenous injections, only latent in effect and duration as might be expected because of the time required for absorption. There was no response in 3 patients in whom 75 pug of PGE, was administered intra-amniotically. In addition, there were no effects in 6

women who had the intravaginal administration of large doses (200 to 1,000 pg PGE,) followed in 3 cases by 5 to 6 ml. of fresh seminal fluid. This suggests either a difference in vaginal absorption during pregnancy and/or a difference in responsiveness. In term and near-term patients, it seemed as if amplitude increased more than tone (as with oxytocin). The important finding, however, was that the difference in dose that stimulated intensity and frequency of contractions in comparison to the dose that increased tone was very small. Therefore the PGE compounds are not suitable for induction of labor, although they might have a pharmacologic use similar to the ergot group of drugs.16p 8o In contrast to the findings with the PGE group of compounds, the work of Karim and associates45, 47 in Uganda suggests that the PGF compounds have oxytocic properties which may be useful. PicklesGo first described the smooth muscle-stimulating properties of human menstrual fluid, and later it was reported that the most potent stimulant of myometrium was PGF,,, the predominant prostaglandin in secretory endometrium and menstrual fluid.19p 62 Karim and Devlir+ 46 then identified four prostaglandins in human amniotic fluid obtained during normal labor and during spontaneous abortion, with a predominance of PGF compounds: PGE,, 1 ng. per milliliter; PGE,, 0.5 ng. per milli-

Volume Number

107 7

PGF,,, liter; PGF la, 140 ng. per milliliter; 30 ng. per milliliter. The prostaglandin content of amniotic fluid seemed to show a relationship to labor.46 In 8 of 16 specimens taken from patients not in labor and prior to term, there were no detectable prostaglandins, while the remaining 8 contained only PGE, in a concentration range of 0.06 to 3.1 ng. per milliliter. In all 11 patients at term, but not in labor, specimens contained PGE, (0.11 to 4.1 ng. per milliliter) , and 3 contained some PGE,. Amniotic fluid extracts obtained from patients not in labor (containing predominantly PGE compounds) caused isolated strips of pregnant myometrium to relax.46 Specimens from all 10 term patients in labor contained relatively large amounts of PGF,, (5.5 to 57 ng. per milliliter) in addition to a mixture of PGE,, PGE,, and PGF,,. One specimen obtained during spontaneous abortion at 16 weeks contained some PGE, and PGE2, but significant amounts of PGF,, (20 ng. per milliliter) and PGF,, (36 ng. per milliliter). The PGF compounds, therefore, were present only in specimens obtained from patients who were in labor. With these findings in mind, it was thought that prostaglandins might conceivably play a role in the physiology of labor. Karim4j collected blood samples from over 70 pregnant women. Individual samples of venous blood from 38 women not in labor, between the twelfth week of pregnancy and term, were found to contain no detectable amounts of prostaglandin. Four women who were 4 to 5 weeks postmature and 7 women at term, all were delivered by cesarean section before the onset of labor, also did not have any detectable prostaglandins in their venous blood. Prostaglandin was found in the venous blood obtained only from patients in labor, and only one prostaglandin, PGF,,, was identified. Furthermore, the presence of PGF,, in human blood during labor showed a consistent pattern. Uterine contractions were recorded by means of an external tocodynamometer, and periodic samples of blood revealed that the highest concentra-

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1123

tion of PGF,, was reached during contractions (an average of 6.34 ng. per milliliter of plasma). Samples taken during the minute preceding a contraction contained almost as much PGF,, as was present during a contraction. Significantly, samples taken during the period between contractions contained no detectable prostaglandins. Although there was some variation, in general, there was more PGF,, present during the second stage of labor than in the first or third stage. Only 2 of 10 samples taken 3 hours post partum contained detectable amounts of prostaglandin. These findings suggest a physiological role for PGFZa, but KarimlS recognizes that it is still impossible to state whether the presence of PGF2, in blood during labor is a consequence of labor or whether there is a causal relationship. Decidua has been suggested as the source of the prostaglandins in amniotic fluid,16 and likewise this could be the source of PGF,, in the blood during labor. It is known that human decidua in vitro can biosynthe54 Decidua obtained prior size prostaglandins. to term from patients not in labor contains only PGE,, but in a concentration 10 to 30 times higher than that found in amniotic fluid. Decidua from patients in labor contains PGE,, PGE,, PGF,,, and PGF,,.46 Karim4” suggests that the prostaglandins in maternal blood could be of neural origin since it is known that prostaglandin release from tissues can be correlated with increased neural activity.6” In a careful study, Karim and associates4’ proceeded to demonstrate in 7 women the successful induction of labor and delivery with infusion of PGF?,. First the safety of PGF,, infusion at a rate up to 2 pg per kilogram per minute (40 to 80 times higher than the dose used for induction of labor) was ascertained in 1 nonpregnant female and 5 male volunteers. There were no significant effects on heart rate, blood pressure, respiration rate, or the electrocardiogram. Next the effect of PGF,, infusion in the pregnant human uterus in vivo was tested in 2 women with intrauterine fetal death.

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Finally, successful induction of labor and delivery was carried out in 7 of 8 women, the eighth woman, who was the only primigravida in the group, was delivered by cesarean section for cephalopelvic disproportion after 12 hours of labor. In all cases, uterine contractions started 20 minutes after the onset of infusion, and the average induction to delivery interval was 6 hours, 46 minutes. The pattern of uterine contractility as measured by recording changes in amniotic fluid pressure was similar in all cases to that of normal labor. There were no increases in resting tone, and in no case was a sustained contraction encountered. Maternal blood pressure was not affected. Monitoring of the fetal heart failed to detect any irregularities, and all babies were born in good condition. The third stage was normal in all cases. The infusion rate ranged from 25 ng. per kilogram per minute to 50 ng. per kilogram per minute. There clearly seems to be a role for prostaglandins in uterine function, both from a physiologic. and a pharmacologic point of view (Fig. 6). The duplication of normal and oxytocin-induced labor patterns has many implications, including the practical application of a new oxytocic agent. More clinical studies will obviously be forthcoming. The blood vessels of the human umbilical cord obtained at term contained PGF,,, PGE,, and PGE,. 44 Extracts of plaPGFm, cental vessels were found to contain the same 4 prostaglandins, while placental tissue itself contained no detectable prostaglandin activity. The absence of these prostaglandins from maternal and fetal blood suggested that the origin of these substances is within the pregnant uterus. 44 PGE,, PGFla, and PGF,, each caused contraction of the isoIated umbilical artery at term, but PGE, caused relaxation.40 Contraction was caused by a mixture of all 4 prostaglandins in the same proportion in which they were present in the cord. Specimens obtained early in gestation, however, generally did not respond. Prostaglandin release is associated with neural stimulation in many unrelated tis-

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August J. Obstet.

1, 1970 Gym.

sues, and prostaglandins may also affect neural activity. 63 With the recent demonstration of neural fibers in the human umbilical cord which give off branches to form a plexus in the walls of the umbilical vesselsJ3” it is tempting (albeit highly speculative) to postulate a relationship between prostaglandins, neural activity in the umbilical cord, and the important changes which occur in the umbilical vessels at birth. Prosfaglandins Fallopian

and

the

tube

A prominent feature in speculation on prostaglandins and Fallopian tubes is a possible role of prostaglandins in sperm and own1 transport. Accordingly attention has been focused on the effect of prostaglandins on tube motility. Spontaneous contractions of the oviduct in the rabbit were inhibited by intravenous administration of PGE,.4’ The results were similar after intravaginal administration (with isoIation of the oviduct by ligatures) except for a latent period due to time required for absorption. Since similar effects were obtained in pithed and with in vitro preparations, the response probably represented a direct effect of prostaglandins on the tube. It is unlikely, however, that this is a physiologic mechanism in the rabbit since the prostaglandin content of semen in this species is barely detectable. In a species in which the semen is rich in prostaglandins (sheep), variable effects were noted.s2 Also of significance, the intravaginal threshold dose for an effect in the ewe oviduct was 4 times the total prostaglandin content present in a singIe ram ejaculate, and invariably it induced a fall in blood pressure. As mentioned previously, 3 out of 7 women showed an increase in pressure during tubal insufflation after the intravaginal administration of prostaglandins.?‘j Hawkins38 could not confirm this finding, and in fact recorded a fall in pressure in 2 patients. These reports are limited by the small number of patients. Further work needs to be done and should include the effects of all prostaglandins.

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Fig. 8. The effect of PGEl (1 pg) on 4 segments of the longitudinal muscle of the human Fallopian tube: contraction of the proximal segment (top curve) and relaxation of the distal 3 segments. Bath volume 20 ml. Wash indicated by 0. (From Sandberg, F., Ingleman-Sundberg, A., and Rydkn, G.: Acta Obstet. Gynec. Sand. 42: 269, 1963.69) The effects of various prostaglandins on the human Fallopian tube in vitro have been studied. In a series of papers, Sandberg and co-workersGS-71 used preparations in which the longitudinal muscle of the human tube was divided into 4 equal segments. In specimens from 33 patients, PGE, had a stimulatory effect on the proximal segment and an inhibitory effect on the distal 3 segments, regardless of phase of cycle (Fig. 8) .6g In preparations from 41 women, PGE, increased the tone and maximum amplitude of the proximal segment and inhibited the remaining segments, the stimulatory effect being more pronounced in the secretory phase; PGE, inhibited all 4 segments in both proliferative and secretory phases.?O PGF2, had a strong stimulatory effect on all segments of tubes from 73 patients, even greater than its effect on uterine muscle.71 PGF,, also stimulated all 4 segments, but had a greater effect on the proximal segment; PGF,s had a weak stimulatory effect, and PGF,b had a weak inhibitory effect.71 The PGE compounds were generally less effective than the PGF compounds, but since the former predominate in semen, their effects of contracting the proximal segment and relaxing the rest of the tube may have

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physiological significance. Sandberg and his associates”8-71 speculate that this leads itself to the suction theory for attraction and retention of the ovum. There is doubt, however, that suction is important in the mechanism of egg pickup,36 and a more likely role would be in a tubal blocking action for retention of the ovum, and perhaps for sperm capacitation. However, one must keep in mind that these experiments were in vitro and measured only the effect on longitudinal muscle, therefore their physiologic importance is questionable. Nutting and Cammarata55 have preliminary evidence in vivo that prostaglandins in pharmacologic doses may delay transportation of the fertilized ovum through the rat oviduct, thus producing an antifertility effeet (Fig. 6). In 3 of 5 rats, prostaglandins given subcutaneously delayed nidation. This was demonstrated by obtaining blastocysts from oviductal and uterine washings on day 7 of pregnancy. It would be of interest to study the effect of prostaglandins on tubal ciliary activity and the coordinated in vivo tubal muscular activity (peristalsis and segmenting contractions). Such studies would need to be correlated with phase of cycle and sex steroid levels. Further work in the rabbit again raised the possibility of a relationship between prostaglandins and neural activity. Electrical stimulation of the hypogastric nerve caused constriction in the uterine part of the oviduct. Brundinl” found that the intravenous administration of PGE, caused an inhibition of this response. After administration of PGE, there was a decreased response to norepinephrine, suggesting that the PGE, is involved in inhibition of adrenergic neural activity. There are no data concerning the presence or absence of prostaglandins in the tube itself. With the recent interest in tubal fluid, it would be worthwhile to examine tubal fluid for prostaglandin content and release. The

ovary

and

prostaglandins

Very little has been done with the ovary and prostaglandins, since the presence of

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small amounts of prostaglandin-like material in the ovaries of cows and sheep was reported in 1937 by von Euler.78 Interest has been rekindled only recently, mainly because of the possible role of prostaglandins as a luteolytic agent. The search for a luteolysin has been stimulated by the observation of an apparent luteolytic effect of the uterus in many mammals other than primates and marsupials.23 Hysterectomy during pseudopregnancy results in a prolonged life-span of the corpus luteum in the rat, hamster, and rabbit. In the guinea pig, sheep, pig, and cow, hysterectomy extends the normal estrus cycle to apparently that of gestation. There is doubt, however, as to whether a similar mechanism exists in primates. A recent paper showed that hysterectomy in rhesus monkeys did not lengthen ovulatory cycles.53 Nevertheless, the pharmacologic importance of a luteolytic agent as a method of fertility control can be appreciated. Pharriss, Wyngarden, and Gutknecht58y 5g have proposed that the life-span of the corpus luteum is critically regulated by local blood flow. Since all animals which exhibit a local influence of the uterus on the corpus luteum also have a common venous pathway shared by the ovary and the nearby uterine horn, a substance which exerted a local venoconstrictive effect could regulate ovarian blood flow. PGF,, fits the requirements for this agent. It increases venous tone,‘* and it is present in endometrium in significant concentrations which seem to correlate with the activity of the corpus luteum, i.e., it is present in secretory endometrium in greater concentrations than in proliferative endometrium.F’, 62 In pseudopregnant rats given PGF,, by subcutaneous injections, the mean length of pseudopregnancy was 9 days less than that of the control group.5Q PGA, or PGF,o (by subcutaneous injection) and PGE, up to toxic levels (by infusion) were all without effect on the life-span of the corpus luteum. PGF,a, therefore, is apparently luteolytic in the rat in vivo. This effect was further examined by study-

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August J. Obstet.

1, 1970 Gynec.

ing the progestin levels in ovaries treated in vivo with PGF,,. The pseudopregnant rat ovary produces primarily two steroids, progesterone and 20a-hydroxy-pregn-4-en-3-one (20a(-OHP), and a shift from progesterone production to 20cu-OHP production has been reported to be one of the earliest signs of corpus luteum degeneration.“@ 51 Pharriss, Wyngarden, and Gutknecht5* found a significant decrease in progesterone production and an increase in ~OCX-OHP production after in vivo treatment with PGF,,. This may be the mechanism by which PGF,, terminates pseudopregnancy in rats. Pituitary LH content was not altered by PGF,, at 4 mg. per day for 5 days; presumably the effect is not mediated via the pituitary.js To rule out the possibility of a direct toxic effect of PGF,, on pseudopregnant rat ovaries, the rat ovaries were incubated with Increasing concentrations of PGF,, PGF,,. were found to proportionately stimulate steroidogenesis5* Thus in the rat, PGF,, is steroidogenic in vitro and luteolytic in vivo. Blatchley and Donovan9 have presented evidence that PGF,, is also luteolytic in the guinea pig, and that this effect does not require the presence of the uterus. Six hysterectomized guinea pigs were administered PGF,,, 0.5 mg. intraperitoneally twice a day for 7 days, and the ovaries were removed, serially sectioned, and examined histologically. In 5 of the 6 animals the corpora lutea were in an advanced state of regression, and in the sixth animal the corpora lutea were smaller than in the control group. There were no histologic signs of any adverse effects on follicular development, and therefore, Blatchley and Donovan” feel that there was no critical reduction in ovarian blood flow. However the precise sensitivity of the follicle and the corpus luteum to a reduction in ovarian blood flow is not known, As mentioned in the discussion of the Fallopian tube, an antifertility effect has been demonstrated in pregnant rats.55 Prostaglandin mixtures (predominantly either PGE, or PGF,,) were injected subcutaneously on each of the first 6 to 7 days of preg-

Volume Number

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nancy at a dose of approximately 0.5 mg. twice a day. Significantly fewer than normal implantation sites were found, and those implantations which were present were beginning to resorb. In 3 of 5 rats, evidence was found for delayed nidation, namely, oviductal and uterine washings on day 7 of pregnancy contained blastocysts, a finding which is abnormal in the strain of rats used. Prostaglandins, therefore, seemed to exert an antifertility action, possibly by delaying nidation and/or an indirect or direct effect on the implantation site. Of note is the fact that the mixture containing predominantly PGEz exerted the same effect as the mixture containing predominantly PGF,,, in contrast to the lack of luteolytic effect of PGE, in vivo in the pseudopregnant rat.“9 In view of the relatively large doses involved, of concern and possibly of physiologic significance is the fact that defecation and signs of central nervous system disturbance were noted in the animals, developing 5 minutes after injection and lasting 3 to 4 hours. Kirton. Pharriss, and Forbes4s have carried this work to primates. In 3 rhesus monkeys, 30 mg. PGF,, per day (again a very large dose), given subcutaneously for 5 days starting on day 11 after ovulation, almost completely reduced circulating progestin levels. This was a rapid effect with onset of menses on the second, third, and fourth day of PGF,, administration. One animal became pregnant despite a temporary drop in progestin levels and onset of menses (normal control fertility rate was 75 to 80 per cent). In a fourth animal, PGF,, administration was begun earlier in the luteal phase (on day 7 after ovulation), and there was no effect. This work has been extended to include more animals, and similar luteolytic cffccts have been observed along with a decrease in fertility.57 Obviously these results are preliminary, and the mechanism of action remains to be explained. One other study on ovarian steroidogenesis has been reported. Bedwani and Horton? incubated rabbit ovaries with PGE, and PGE,. There were no consistent results, ex-

Prostaglandins

1127

cept for a substantial potentiation of the production of ~OCY-OHP in incubations with PGE, and gonadotropins in 5 out of 6 experiments. In view of past similarities between ovarian and adrenal biochemistry, findings in the adrenal gland are of interest. Flack, Jessup, and Ramwell”’ have shown that prostaglandins are present in the rat adrenal gland, and that small doses of PGE,, PGE,, and in suPGF,, increase corticosteroidogenesis perfused rat adrenal glands.31 Precise examination of ovaries for prostaglandin content has not been reported, but results in our laboratory indicate that PGE and PGF compounds are present in the bovine ovary, but only PGF activity was detectable in the bovine corpus luteurn.‘” Prostaglandins are apparently absent from human, rabbit, and bovine follicular fluid. In demonstrating that the smooth muscle-stimulating substances in follicular fluid of various species was follicular kinin, Ramwell, Shaw, and Jessup”” showed that prostaglandins were not detectable in follicular washings. Other results from our laboratory indicate that all prostaglandins thus far tested (PGE,, PGE?, PGF,,, and PGA,) stimulate steroidogenesis in bovine corpus luteum slices in vitro.‘” The relationship, if any, between gonadotropins, adenosine 3’,5’-monophosphate (cyclic AMP), and prostaglandins needs to be investigated. The levels of cyclic AMP in tissues which have been examined are affected by prostaglandins,ll and the effect of luteinizing hormone on steroidogenesis in vitro is apparently mediated by cyclic AMP.5Z Prostaglandins may well be a part of this possible mechanism. Furthermore, prostaglandins and cyclic AMP may be associated with the uterine enzyme activities that occur at implantation. The most singular comment which can be made in summary of prostaglandins and the ovary is that there seemingly exists a paradox, stimulatory effects in vitro and inhibitory effects in vivo. The in vivo luteolytic response may represent a chronic action of pharmacologic doses on local hemodynamics. On the other hand, the in vitro steroidogenic

1128

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effect may reflect an acute cellular action. The mechanism for these effects remains to be determined. Final

comment

This review which contains as much speculation as fact hopefully will stimulate new ideas and studies. In addition, much of the work reviewed herein requires reinvestigation since it was done with impure compounds or small amounts of authentic prostaglandins. The past years have seen a rapid accumulation of knowledge in the chemistry of prosta,$andins, but the study of the biologic role is just beginning. The need for work in primates is self-evident. Perhaps most exciting is the work which suggests possible roles in luteolysis, ovum transport, and implantation. Effort must be directed to the development of any agent which with full safety may alleviate the pressures of overpopulation. Presently this aspect of prostaglandin research carries with it a very real possibility of practical application. Before long clinical studies should be underway, and perhaps prostaglandins will prove to be as important as speculation would have them. Addendum-recent publications Pharmacology. The general rule is that any structural alteration in a prostaglandin results in loss of biologic activity. However an unexpected biologic potency of certain unnatural synthetic stereoisomers has been reported. Ramwell, Shaw, Corey, and Anderson (Nature 221: 1251, 1969) found the mirror image compounds of the I5-epi derivatives of PGE, and PGA, to be more active than the naturally occurring isomer. Eakins, Karim, and Miller (Life Sciences 9: 1, 1970; Fed. Proc. 29: 745, 1970; and Brit. J. Pharmacol. In press) have shown that polyphloretin phosphate selectively antagonizes the smooth muscle stimulating action of PGF,, and PGE,, apparently by competitive inhibition. In vivo, the effect of PGF,, on the blood pressure of the anesthetized rabbit was blocked. The 7-0~0 derivatives of prostaglandins have also been found to be antagonists (Ramwell and Shaw, Recent Progr. Hormone Res. 1969). Studies with seminal prostaglandins. Carpenter and Wiseman (Fed. Proc. 29: 248, 1970) have shown the incorporation of radioactivity from

.41ncr.

August J. Obstet.

1, 1970 Gyncc.

*4C-linoleic acid into PGE,, PGE,, PGF,,, and when the radioactive fatty acid was inPGF,, jected into rat testis, indicating active synthesis of these prostaglandins by rat testicular tissue. Bygdeman (Int. J. Fertil. 14: 228, 1969) found a significant decrease in the PGE prostaglandins in semen from men with infertile marriages when compared to semen from marriages of normal fertility. Studies related to pregnancy. Experience with PGF,, in pregnancy has been extended with the report of the successful induction of labor in 33 women (Karim and associates, J. Obstct. Gynaec. Brit. Comm. 76: ‘769, 1969). In addition, Karim (personal communication) has detected PGE, in the maternal blood during labor in a concentration which is l/5 of that found for PGF,,. \‘ery recently, t\vo groups have reported the successful induction of labor with PGE,. Karim and associates, in Uganda (J. Obstct. Gpnaec. Brit. Comm. 77: 200, 1970) described their cxperirncc with 50 PGE, inductions at 34 to 44 weeks’ grstation, and Beazley, Dewhurst, and Gillespie in London (J. Obst. Gynaec. Brit. Comm. 77: 193. 1970) successfully induced labor in 37 of 40 patients at 29 to 42 weeks’ gestation. There have been no gastrointestinal or cardiovascular side effects. A similar experience with PGEz was rcported in a preliminary study by Emhrey (J. Ohstet. Gynaec. Brit. Comm. 76: 783, 1969), and Emhrey later reported the induction of labor with both PGE, and PGE, (Brit. Med. J. 2: 256, 1970). Even more exciting is the application of prostaglandin’s oxytocic properties to the induction of therapeutic abortions. Roth-Brandel and associates (Lancet 1: 190, 1970) and Karim and Filshie (Lancet 1: 157, 1970) have aborted women in the first and second trimesters using PGE,, PGE,, and PGF,, infusions in concentrations 10 to 15 times greater than that required for the induction of labor at term. The only significant side effect was vomiting and diarrhea in about half of the cases in which PGF,, was used. Karim (Brit. Med. J. In press) has reported on the use of PGE, (5 pg per min ute) for therapeutic abortion in 52 consecutive cases of 9 to 22 weeks’ gestation. There were 2 failures, 7 patients required completion curettage, 10 patients had nausea and vomiting, 4 had diarrhea, and the average infusion period was 14 hours 50 minutes. Karim (Brit. Med. J. In press) has also successfully used PGE, infusions to terminate pregnancy in 6 patients with missed abortions, 1 patient with a hydatidiform mole, and 14 of 15 patients with intrauterine

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Prostaglandins

death in the third trimester. Embrey has used both PGE, and PGE, for therapeutic abortion in 11 patients (Brit. Med. J. 2: 258, 1970). Wiqvist and Bygdeman (Lancet 1: 889, 1970) have emphasized the contrast between oxytocin and prostaglandins in that the early pregnant uterus (sixth to eighhth weeks of pregnancy) is very sensitive to the stimulating effect of prostaglandins. The ovary and prostaglandins. Gutknecht, Cornette, and Pharriss (Biol. Reprod. 1: 367, 1969) reported that medroxyprogesterone acetate (Provera) was very effective in reversing the antinidatory effects of PGF,,. The same authors (J. Reprod. Fertil. In press) have directly measured a rfiduction in the venous outflow in the uteroovarian vein in rats and rabbits following PGF,, treatment, lending support to their theory that PGF,, is luteolytic by reducing the blood flow through the ovary. Against this theory is the report by McCracken, Glew, and Scaramuzzi (J. Clin. Endocr. 30: 544, 1970) showing that the infusion of PGF,, (50 pg per hour) during the luteal phase reduced progester-

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one secretion without a significant change in blood flow in the sheep ovary autotransplanted to the neck. Using a similar sheep preparation, Aldridge and associates (J. Reprod. Fertil. 21: 369, 1970) found that PGE, produced only a small decrease in the rate of progesterone secretion because of an increase in blood flow, while PGF,, significantly decreased progesterone secretion in 3 of -k sheep with no consistent changes in blood flow. Wiqvist and Bygdeman (Lancet 1: 889, 1970) have shown in humans that PGF,, infusion in the late luteal phase produces menstrual-like bleeding. Marsh (Fed. Proc. 29: 387, 1970) has presented evidence that the in vitro steroidogenic effect of prostaglandins involves cyclic AMP. He has shown that PGE, stimulates adenyl cyclase activity in bovine corpora lutea homogenates, and the extent of adenyl cyclase stimulation correlates w-ith the degree of steroidogenesis. Peng, Six, and Munson (Endocrinology 86: 202, 1970) have reported PGE, stimulates the adrenal cortex of the rat in vivo by indirect means, perhaps at the hypothalamic level.

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