Immediate Effect of Prostaglandin F2α During the Luteal Phase of the Menstrual Cycle*

Vol. 26, No.7, July 1975 Printed in U.S.A.

FERTILITY AND STERILITY Copyright " 1975 The American Fertility Society

IMMEDIATE EFFECT OF PROSTAGLANDIN F2a DURING THE LUTEAL PHASE OF THE MENSTRUAL CYCLE* R. NURAN TURKSOY, M.D.,

AND

HOMA S. SAFAII, M.D.

Department of Obstetrics and Gynecology and Department of Pathology, Tufts Universtiy School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts 02111

The luteolytic effect of prostaglandin F 2a (PGF~) in non primate species has been well documented. 1 Intravenous administration of PGF~ has been shown to cause a dramatic fall in progesterone levels in sheep2· 3 and monkeys. 4 However, there are conflicting reports on the luteolytic action of PGF 2a in the human. Some studies have failed to show a shortening of the luteal phase and have failed to show a decline of progesterone in normally ovulating women. 5 • 6 However, others have reported a transient luteolytic effect of PGF~ in the human. 7• 8 The present investigation was undertaken to determine the effect of PGF2a on corpus luteum function during the luteal phase in normally ovulating women who were not pregnant. A 25-~A-glml solution of PGF2a was infused at a rate of 1 ml/minute for 48 hours, beginning on the 4th day of the luteal phase. This dose rate is known to be clinically effective in inducing uterine contractions and is considered to be an active dose pharmacologically and physiologically. MATERIALS AND METHODS

Five healthy, ovulating women of reproductive age, who were practicing mechanical means of contraception, volunteered for the study. Informed consent Received August 16, 1974. *Supported in part by National Institutes of Health Grant NIH FR 0054, through the General Clinic Research Services, and by The Upjohn Company, Kalamazoo, Mich.

was obtained in a manner approved by the Human Investigation Committee of the New England Medical Center Hospitals. All had shown biphasic basal body temperature curves on two or more occasions. They had normal medical and gynecologic histories, normal pelvic examinations, and negative Papanicolaou smears. The day of ovulation was arbitrarily assigned on the basis of an increase in basal body temperature of 0.5 to 1.00 F above the base line value. The mean control luteal phase serum progesterone levels were above 6 ng/ml on the 4th day of the luteal phase in the cycle preceding the infusion cycle. The study subjects were admitted to the Clinical Study Unit at the New England Medical Center Hospitals. A physician monitored all infusions. Special charts were kept during each infusion, and temperature, pulse, blood pressure, and respiration rate were recorded every half-hour. Side effects were recorded at the time of occurrence. PGF~was supplied by The Upjohn Company in sterile vials containing 25 mg of THAM salt (Tris buffer). The contents of one vial were added to 1000 ml of normal saline; the solution, 25 #Lg of PGF2a/ml, was infused for 48 hours, at a rate of 1 ml/minute, with an Ivac infusion pump. A total of 75 mg of PGF~ was infused. The infusion was begun on the 4th day of the luteal phase. Control levels of serum progesterone, 17-hydroxy-

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635

EFFECT OF PROSTAGLANDIN F,a ON THE MENSTRUAL CYCLE

TABLE 1. Serum Progesterone Levels Days after ovulation +1

Hours after PGFzct infusion

Hours of PGF2 a infusion

Patient +2

0

8

16

24

32

40

48

8

24

nglml

Patient 1 Mean ± SE Patient 2 Mean ± SE Patient 3 Mean ± SE Patient 4 Mean ± SE Patient 5 Mean ± SE

13.2 1.2

14.6 0.9

14.5 1.1

13.05 0.55

14.2 1.1

10.05 0.15

10.7 1.0

8.4 1.2

7.8 0.6

11.65 1.01

13.3 0.9

17.7 1.3

19.5 1.2

21.15 1.02

18.45 1.05

15.85 1.24

20.85 0.65

14.55 1.45

10.35 1.15

10.0 0.4

16.4 1.1

19.3 1.1

15.3 0.9

17.6 1.2

20.1 1.4

18.6 1.1

19.95 1.32

19.5 1.1

18.4 0.9

16.85 1.25

19.6 1.3

18.4 1.1

18.9 0.3

19.5 1.3

19.0 1.2

17.85 1.45

15.65 0.75

15.05 0.35

14.1 0.3

10.5 1.1

18.3 1.1

17.9 0.5

9.0 0.6

9.4 0.8

5.45 1.15

5.85 0.95

4.5 0.7

6.6 1.2

7.0 0.2

8.85 1.10

7.5 0.9

progesterone, estradiol, and luteinizing RESULTS hormone were determined the first 2 days Tables 1 and 2 summarize the changes after ovulation. Blood samples were obtained at the beginning of the infusion in the mean values for serum progesterone (0 hour), every 8 hours during the period and 17 -hydroxyprogesterone for each subof infusion, and after termination of the ject. Peripheral mean serum progesterone infusion. Hormone assays were per- and 17 -hydroxyprogesterone levels deformed in duplicate on each specimen. dined in each subject when control 0-hour Blood samples were assayed for progester- hormone concentrations were compared one, 17 -hydroxyprogesterone, estradiol, with the hormone concentration at the end and luteinizing hormone levels, utilizing of the infusion. The greatest depression a minor modification of previously re- in mean serum progesterone and 17ported radioimmunoassay techniques. 9- 12 hydroxyprogesterone levels occurred at Endometrial biopsies were obtained the end of the infusion. However, an increase, to control levels, was observed at the termination of the infusion. TABLE 2. Serum 17-Hydroxyprogesterone Levels Patient

Days after ovulation +1

+2

Hours after PGFzct infusion

Hours of PGF2a infusion 0

8

16

24

32

40

48

8

24

nglml

Patient 1 Mean ± SE Patient 2 Mean ± SE Patient 3 Mean ± SE Patient 4 Mean ± SE Patient 5 Mean ± SE

2.5 0.1

2.4 0.2

2.4 0.2

2.1 0.1

1.7 0.1

1.5 0.1

1.35 0.05

1.3 0.1

1.05 0.05

1.9 0.3

1.5 0.1

2.1 0.1

2.2 0.2

2.15 0.15

1.55 0.05

1.35 0.05

1.2 0.1

1.1 0.1

1.3 0.1

1.25 0.15

1.55 0.35

1.55 0.35

2.3 0.1

2.6 0.2

2.8 0.2

2.5 0.3

2.3 0.1

2.6 0.2

2.5 0.1

1.95 0.05

2.7 0.3

2.0 0.2

1.7 0.1

3.4 0.4

2.85 0.05

2.8 0.2

2.8 0.2

2.65 0.25

2.6 0.1

2.5 0.1

2.15 0.15

1.65 0.15

2.7 0.3

2.4 0.1

1.45 0.45

1.1 0.1

1.15 0.25

0.7 0.1

0.7 0.1

0.35 0.25

0.45 0.35

1.0 0.2

0.8 0.2

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July 1975

TURKSOY AND SAFAII

24 hours after the termination of the infusion. Serum luteinizing hormone and estradiol levels in each subject revealed considerable fluctuation but no definite pattern. The changes in the serum luteinizing hormone and estradiol values varied independently between themselves, and there was no correlation with the changes in progesterone level. Transient bleeding was observed in each patient during infusion. Menstruation occurred within 24 te 72 hours following the prostaglandin F 2a infusion in each subject. Bleeding was not excessive, and it was not associated with severe menstrual cramps. The duration of bleeding did not exceed 4 or 5 days. In all five cases, endometrial curettage for histologic evaluation was carried out. The changes were mainly those involving the stroma and consisted of focal breakdown and necrosis, with focal and diffuse infiltration of polymorphonuclear leukocytes, occasional sinus thrombi, and moderate to marked stromal edema. These focal changes were similar to the stromal breakdown in a normal menstrual endometrium. The endometrial glands were scant for an adequate study in one case (patient 2); in the remaining four patients, they were consistent with early endometrium (17 to 18 days) in patient 1, 21- to 22-day secretory endometrium in patient 3, 18- to 19-day secretory endometrium in patient 4, and 22- to 23-day secretory endometrium in patient 5. None of the patients showed predecidual formation. Stromal breakdown and necrosis were the most significant histologic changes; the glands did not seem to be affected to any recognizable extent. However, in patients 1 and 4, the possibility of some degree of delayed secretory change could not be totally excluded. Menstruation in each patient occurred at least 3 to 4 days earlier than expected from the control ovulatory menstrual cycle. Basal body temperature graphs

A.H

99.0

a:

::!;

~

98.0

0

PGF

DAYS

2a

+

FIG. 1. Basal body temperature during control and PGF2" treatment cycles. o, PGF2a treatment cycle; e, control cycle.

and control and prostaglandin infusion cycles are illustrated for one of the patients studied (Fig. 1). All patients experienced gastrointestinal symptoms. The intensity and severity of the symptoms varied from one patient to another. Profuse vomiting, diarrhea, or respiratory difficulties were not noted in any patient, but a mild to moderate degree of uterine cramping and a local tissue reaction at the site of the intravenous infusion were observed in all patients. In one patient, infusion was terminated after 32 hours because of a 10-second episode of syncope upon standing. This patient had had rare episodes of syncope as a child and also had a family history of seizures (her identical twin and nephew). An electroencephalogram the following day revealed borderline, nonspecific changes; a repeat electroencephalogram 1 week later was within the normal range. In all patients, subsequent menstrual cycles were normal. One patient conceived and delivered a full-term normal infant. DISCUSSION

Our observation indicated that the histologic integrity of the normal secretory endometrium could be interrupted by the possible local action of PGF2a. Histologic examination of endometrial tissue revealed focal menstrual changes in the presence of a normally developed secretory endometrium. Uterine contractions were associated with episodes of transient vaginal bleeding during the PGF2a infu-

Vol. 26, No.7

EFFECT OF PROSTAGLANDIN F.,. ON THE MENSTRUAL CYCLE

sion period. This might likely ensue from vascular insufficiency secondary to the contractions. More likely, the bleeding was a result of a direct vasoconstrictive effect within the endometrium, causing blockade of arterial flow and ischemia of the endometrium. Menstrual flow began while serum progesterone and 17hydroxyprogesterone levels were still elevated, indicating a steroidogenic mechanism of the corpus luteum. Transient decreases in serum progesterone and 17-hydroxyprogesterone levels may suggest a direct effect of PGF2a on granulosa cells or on the blood supply of the corpus luteum, as postulated by Wentz and Jones. 8 However, on the basis of the present study, no definite conclusions can be reached concerning the luteolytic effect of PGF2a on human corpus luteum at the dose schedule used in this study. SUMMARY

Serum luteinizing hormone, estradiol, 17 -hydroxyprogesterone, and progesterone determinations were performed in five normally ovulating women prior to, during, and after prostaglandin F 2 a (PGF 2a) infusion. A total of 75 mg of PGF2a was infused over 48 hours, beginning on the 4th day of the luteal phase. Endometrial biopsies were obtained at the completion of the infusion. In all patients, transient decreases in serum progesterone and 17-hydroxyprogesterone levels were observed during PGF2a infusion. Subsequent rises in the serum progesterone and 17-hydroxyprogesterone levels were observed 24 hours after completion of the infusion. There was no significant change in serum luteinizing hormone levels. Premature menstrual bleeding occurred within 24 to 72 hours after the termination of the infusion, while progesterone and 17hydroxyprogesterone levels were still

637

elevated. Endometrial histology revealed focal stromal necrosis in the presence of the normal secretory endometrium. It is concluded that, in the human, PGF2a at this dose and time schedule is not luteolytic. REFERENCES 1. Blatchley FR, Donovan BT: The effect of prostaglandin F 2a and prostaglandin E 2 upon luteal function and ovulation in the guinea pig. J Endocrinol 53:493, 1972 2. McCrak.en J, Glew ME, Scaramuzzi RJ: Corpus luteum regression induced by prostaglandin F 2a. J Clin Endocrinol Metab 30:544, 1970 3. Barrett S, Blockey MA deB, Brown JM, Cumming IA, Goding JR, Mole BJ, Obst JM: Initiation of the oestrous cycle in the ewe by infusions ofPGF.,. to the autotransplanted ovary. J Reprod Fertil 24:136, 1971 4. Kirton KT, PharriBB BB, Forbes AD: Luteolytic effects of prostaglandin F 2a in primates. Proc Soc Exp Bioi Med 133:314, 1970 5. Jewelewicz R, Cantor B, Dyrenfurth I, Warren MP, Vande Wiele R: Intravenous infusion of prostaglandin F.,. in the midluteal phase of the normal human menstrual cycle. Prostaglandins 1:443,1972 6. LeMaire WJ, Shapiro AG: Prostaglandin F.,.: its effect on the corpus luteum of the menstrual cycle. Prostaglandins 1:259, 1972 7. Lehmann F, Peters F, Breckwoldt M, Bettendorf G: Plasma progesterone levels during infusion of prostaglandin F 2a in the human. Prostaglandins 1:269, 1972 8. Wentz AC, Jones GS: Transient luteolytic effect of prostaglandin F 2a in the human. Obstet Gynecol 42:172, 1973 9. Abraham GE, Swerdloff R, Tulchinsky D, Odell W: RadioimmunoaBBay of plasma progesterone. J Clin Endocrinol Metab 32:619, 1971 10. Abraham GE, Swerdloff R, Tulchinsky D, Odell W: RadioimmunoaBSay of plasma 17-hydroxyprogesterone. J Clin Endocrinol Metab 33:42, 1971 11. Second Karolinska Symposium on Research Methods in Reproductive Endocrinologysteroid assay by protein binding. Acta Endocrinol [Suppl] (Kbh) 147:320, 1970 12. Odell WD, Rayford PL, Ross GT: Simplified, partially automated method for radioimmunoaBSay of human thyroid-stimulating, growth, luteinizing and follicle-stimulating hormones. J Lab Clin Med 70:973, 1967