post-conceptional induction of menses with a single vaginal suppository of (15s)-15-methyl...

PROSTAGLANDINS

POST-CONCEPTIONAL. INDUCTION OF MENSES WITH A SINGLE VAGINAL SUPPOSITORY OF (15S)-15-MZTZYL PROSTAGDANDIN

F2a MZTZYL ESTER

by Jonathan Scher, M.D., Dai-Yun Jeng, Ph.D., M.D. and

Thomas D. Kerenyi, M.D.

Department of Obstetrics and Gynecology, Division of Perinatology, Mount Sinai Medical Center, New York,

N.Y. 10029.

ABSTRACT

The induction of post-conceptional menses needs a technically simple method which would avoid avoid instrumentation of the uterus. One possible method investigated in this study is the abortifacient effect of a single dose long-acting vaginal suppository containing 3.0 mg of (15S)-15-methyl prostaglandin F2a methyl ester. Preg- nancy was terminated successfully in 13 of the 14 subjects. Two successful patients required curettage for prolonged bleeding and retained products of conception. Prolonged vaginal bleeding and the uncertainty ocendpoints with particular reference to human chorionic gonadotropin (HCG) constitute the major problem with this non-invasive method, and are discussed in the light of the data obtained.

INTRODUCTION

In the U.S.A. there are an increasing number of early thera- peutic abortions. At present the method used is vacuum aspiration of the uterus which is effective and has a continuing pregnancy rate of less than one percent. However, it is an invasive technique and requires trained personnel to maintain this efficiency. A pharmacological method would offer the advantages of non-invasion, self-administration and privacy. Further, the early application could result in menstrual-like bleeding which women may find preferable.

The naturally occurring prostaglandin F2a and Z2 have been extensively used by many investigators by different routes of administration for the termination of human pregnancy at many stages of gestation (1,2).

Prostaglandin F2a is used extensively either alone or in com- bination with hypertonic saline for second trimester pregnancy

SEPTEMBER 1980VOL.20N0.3 469

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termination. Csapo, et al. (1973) showed that this substance was highly efficient in the first trimester also, when given by the intrauterine route (3).

To avoid entering the uterus prostaglandin F2a (PGF2a) was administered vaginally but the naturally occurring prostaglandins are rapidly metabolized to less active metabolites by dehydrogenation at C-15 by the enzyme prostaglandin-15-dehydrogenase. The introduction of a methyl group in the 15 position of PGF2a results in a slower inactivation and increases the smooth muscle stimulating properties.

Bygdeman, et al. (1977) (4) reported a series of 25 patients undergoing midt=er pregnancy termination using a long-acting vaginal suppository containing 3.0 mg of (15S)-lz-methyl PGF2a methyl ester with a 92 percent success rate. Green, et al. (1978) used single vaginal suppositories containing 2, 2.5 or 3 mg of (15S)-methyl PGF2a methyl ester for termination of early pregnancy with a 94.5 percent success rate in the 3 mg group (5).

The present study was undertaken to evaluate the clinical characteristics and applicability of vaginal administration of a single suppository of (15S)-15-methyl PGF2a methyl ester in post- conceptional induction of menses.

PATIENTS AND METHODS

Fourteen healthy women desiring early pregnancy interruption who were no more than 49 days (7 weeks) pregnant, as calculated from the first day of the last regular menstrual period &PMP), were accepted for study.

A positive pregnancy test for human chorionic gonadotropin activity (beta-subunit HCG) was obtained in all cases. The patients had normal clinical examinations, medical histories and laboratory screening tests before entry into the study. Those with any signs, symptoms, or history of threatened abortion, clinical cervical incompetence, attempted interference with the current pregnancy or or gynecological disease were excluded.

The procedure was performed on an outpatient basis utilizing the Clinical Research Center of the Mount Sinai Medical Center. There was a 10 hour observation time and control at one and two weeks thereafter.

Each vaginal suppository contained 3.0 mg of (15S)-15-methyl

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PGF2a methyl ester in a 2.2 gm base of Witepsol E-76-A. The suppositories were stored at -200 C. until used. A gynecological examination was performed without the use of any lubricant or cleansing agent. One suppository was inserted high into the vagina in the region of the posterior fomix. No further vaginal examinations were done during therapy. The patients remained in bed for one hour and were then allowed to ambulate freely for the rest of the observation time. Recumbent blood pressure, radial pulse, respiration and temperature were recorded hourly and side effects noted. If diarrhea, or nausea and vomiting occurred, Kaopectate, 30 ml by mouth and pershlorperazine (Compazine) were used, respectively. Painful uterine contractions were treated with either oral acetcmino- phen (Tylenol) or intramuscular meperidine AC1 (Demerol).

Blood samples for serum chorionic gonadotropin (HCG) levels and serum progesterone levels were drawn at zero, 4, 8, and 10 hours and again at the 14th day follow-up visit.

HCG levels were determined by the f3-subunit radioimmunoassay using the method of Vaitukaitis, et al. (6). Blood progesterone levels were determined by the method of Eirton, et al. (7) using radioimmunoassay. Blood prostaglandin levels were measured in the first 11 patients and samples were drawn into heparinized tubes at zero, 4, 8, and 10 hours following administration of the suppository. Radioimmunoassay was the technique used incorporating the method of Comette, et al. (8). This assay measures both the free acid of the 15-methyl PGF2a methyl ester as well as the C-l methyl ester.

Serial analyses were also made for the following parameters at zero, 10 hours and 14 days: bilirubin (direct and total), SGGT, SGPT, alkaline phosphatase, serum creatinine, BUN, serum aldehydes, blood glucose, hemoglobin, hematocrit, white cell count, differential and platelet, and urine analysis,

The amount of bleeding was not measured quantitatively but judged by the patient in comparison with her usual menstru- ation.

RESULTS

Table 1 shows the clinical details of the patients.

The menses delay averaged 44.9 days in nulliparous and 45.8 days in parous patients (range: 40-49).

HCG and progesterone levels and the estimation of the blood prostaglandin levels mentioned above were carried out through the kindness of the Upjohn Clinical Research Laboratory, Kalamazoo, Michigan.


Table 1: Clinical Details

z

Pt. Age Menses Parity

Induc-

Induc-

Length

Diarrhea Nausea Vomiting

Analgesia

D & C

6

Delay

tion to tion to

of

Contrac- Bleed-

Bleed-

%

(days)

tion

ing

ing

(min.)

bin.

) bi

n.)

(episodes)

(episodes)

M.G. 40

40

C.R. 25 48

L.J. 32 45

B.B. 23

48

J.K. 35 42

S.J. 40

40

D.A. 21

44

A.W. 25 46

M.O'C. 30 48

A.L. 26

40

L.C. 24 47

R.K. 20 42

L.A. 26 49

T.Q. 19 49

l Tylenol = Acetaminophen

**Demerol = Meperidine BC1 75

185

60

300

15

60

55

90

120

285

97

378

FAILED

120

720

75

390

75

240

90

315

125

373

120

60

300

300

14

4

6

14

2

14

2

14

3

14

5

14

3

14

3

4

4

8

1

a

7

14

8

3

present

present

present

present

present

present

present

present

present

present

present

present

present

TY

l.2~O

lf

Tylenol*

Yes

Demerol**

Tylenol*

Demerol**

none

Yes

1

TYleno1*

4

Tylenol*

Yes

1

TYlen01*

1

Tylenol*

none

Tylenol*

2

Tylenol*

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Success Pate

The termination, in terms of continuing pregnancy, was successful in all but one patient. In eight cases vaginal bleeding persisted for at least 14 days. Two of these patients underwent curettage at four weeks and nine weeks after the procedure.

The failure (mentioned above) was an obese woman who exper- ienced mild vaginal bleeding 30 minutes after insertion of the suppository and mild suprapubic cramps after one hour. Twenty- four hours later these symptoma disappeared. Her pregnancy test remained positive, basal body temperature did not decline, and pregnancy symptoms continued. Serum HCG and plasma progesterone levels did not decline. Uterine growth was obvious.

Serum HCG and Plasma Progesterone Pattern

Before administration, the HCG levels in the serum ranged from 3.3 I.U./ml to 0.6 I.U./ml (see Figure 1). These levels had dropped below the arbitrary limit of 1 I.U./ml within two weeks after therapy in 36 percent of the cases.

IU

0 2 4 6 Hours Days

TIME AFTER INSERTION

Fig. 1: Serum HCG levels following insertion of prostaglandin F3o suppository.


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Plasma progesterone levels ranged from 32 to 50 ng/ml. Proges- terone concentration had declined below the baseline level of 5 ny/ml within two weeks (see Figure 2).

0 2 4 6 8 IO 14 Hours Days

TIME AFTER INSERTION

Fig. 2: Plasma progesterone levels following insertion of prostaglandin F2a suppository.

Serum HCG and prpgesterone in patients with prolonged bleeding showed a significantly slower decline than in patients with an un- eventful abortion.

Plasma 15-Methyl Prostaglandin F2a (pg/ml)

From Figure 3 one can see the wide range of prostaglandin values at 4 and 8 hours. The non-uniformity of these levels is marked.


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2500 ’ ’ ’ ! ’ 2000 1500 PROSTAGLANDIN

15 Me F2, 1000

n=ll

Poll

0 0 2 4 6 8 IO

Hours TIME AFTER INSERTION

Fig. 3: Blood prostaglandin levels following insertion of prostaglandin F2u suppository.

The one failure in the series had an initial value of 72 pg/m.l at 4 and 8 hours. Another patient with a low 4 hour value (below 100 pg/ ml) did, however, have a very elevated 8 hour level. All the cases with undetectable levels at 8 hours had initial values over 138 pg/ml.


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Histologic Findings

Curettage was not performed routinely. It was indicated in three patients. In the case which failed, grossly recognizable frond-like placental tissue and fragments of fetal parts were found. In the second, friable, hemorrhagic tissue without fetal parts was seen. In the third case, curettage was carried out at nine weeks after the prostaglandin insertion as continuous vaginal bleeding occurred. Products of conception with fetal parts were obtained with a diagnosis of a missed abortion.

Analgesia

The subjective pain ratings of the patients were assessed. However, all patients required analgesics (see Table 1). In two instances meperidine I-Xl (Demerol) was required by remaining cases had oral analgesics [acetaminophen which were adequate.

injection. The (Tylenol) 1

Side Effects

Diarrhea was noted in 86 percent and vomiting in 36 percent of the patients. The mean frequency of episodes of diarrhea and vomiting was 3.3 and 1.8 percent, respectively. In only two patients did nausea accompany the vomiting. These results are seen in Table . I.

No post-therapy infection occurred in these cases.

DISCUSSION

The ability to self-induce early abortion or delayed menses using a vaginal suppository by a woman privately and at home, has real advantages. It eliminates the risk of a surgical procedure, relieves the strain on hospital staff and provides confidentiality. The technique could encourage earlier medical advice to be sought pre- venting the complications which become more common with advancing pregnancy terminations.

The mechanism by which prostaglandins cause abortion is uncertain. Numerous articles have appeared discussion the effect of prostaglandins on the pregnant human uterus (9, 10, 11). It appears that this effect is not luteolytic (12, 13) but causes the abortion by mechan- ical separation of the pregnancy by uterine muscle contraction. It seems that the initial impact is important and not the prolonged stimulation of the uterus by prostaglandin (Csapo, 1979, personal communication). The fact that the drug could not be detected at 8 hours in 30 percent of the successful cases in this study suggests


PROSTAGLANDINS

that the uterine activity induced initially by the drug caused mech- anical trauma to the intrauterine tissues and precipitated an ongoing process. G&en and Svanborg (13) demonstrated an increased endogenous synthesis of prostaglandin F2a and prostaglandin Ep using this technique in second trimester abortions.

The concept of the importance of the initial impact of prostaglandin on the uterus and conceptus may be important in overcoming a major problem illustrated in the study, i.e. the prolonged bleeding. This latter event is supported by the slow decline of HCG and is un- acceptable to the patient and the physician. In the case of the latter it causes confusion as to the endpoint of the abortion. This po$t needs to be defined not only clinically but by HCG levels. Green, et al. (1978) (5) performed exeresis on their patients if two weeks following single suppository administration HCG levels were above 1,000 I.U./or if significant bleeding persisted or for any other indication. Though the success rate was high (93 percent) in tenrs of continuing pregnancy, with only one failure, prolonged bleeding and to a lesser degree gastrointestinal symptoms, are the major drawbacks (14). Recent studies have shown that repeated administration of 16, 16-dimethyl prostaglandin E2 vaginal suppositories have promising results and are equally effective when compared with vacuum aspiration. Mowever, the latter is superior regarding completeness of abortion, duration of bleeding and frequency of gastrointestinal side effects (15).

The considerable variation in the plasma levels of 15-methyl prostaglandin F2a shown in Figure 3 are unexplained. It is uncertain whether this may be due to a local factor in the vagina or possibly to the delivery system used. Even though there is considerable variation, the trend seems to show a gradual incre?se towards a max- imum at 8 hours after placing the suppository. Green, et al. (1976) (16) used a more specific detection system, namely gas chromatography coupled with mass spectroscopy and showed a two hour peak in two patients using a similar vaginal suppository. This study confirms that administration of.one vaginal suppository containing 3.0 mq of (15S)-15-methyl PGF3a methyl ester is efficient in terminating early first trimester pregnancies (5) and its potential widespread use depends on attention being given to shortening of bleeding time and diminishing of gastrointestinal side effects. The patients were interviewed at the follow-up visit on day 14 and overall they felt that the method was very acceptable, but the prolonged bleeding was very trying especially as they were under emotional strain. However, they felt that they had more control over what was happening to them, including the avoidance of general or local anesthesia.

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ACKNOWLEDGEMENT

The authors wish to thank Dr. E.M. Southern and Mr. Glenn Gutknecht of the Upjohn Company, Kalamazoo, Michigan for their advice and help.

This study has been supported in part by N.I.H. Grant No. RR-71, Division of Research Resources, General Clinical Research Centers Branch.

We are grateful to Ina N. Solomon for the preparation of the manuscipt.

REFERENCES

1. Karim, S.M. (editor), Prostaglandins and Reproduction: Ad- vances in Prostaglandin Research. Medical and Technical Publi- cations, New York, 1975.

2. Southern, E.M. (editor), The Prostaglandins: Clinical Appli- cations in Human Reproduction. Futura Publishing Co., Inc., New York, 1972.

3. Csapo, A.I., P. Mocsary, T. Nagy and H.L. Kaihola: The ef- ficacy and acceptability of the "prostaglandin impact" in inducing complete abortion during the second week after the missed menstrual period. Contraception 3:125, 1973. -

4. Bygdeman, M., A. Ganguli, K. Kinoshita, V. Lundstrtim, K. Green and S. Bergstrom: Development of a vaginal suppository suit- able for a single administration for interruption of second trimester pregnancy. Contraception 15: 219, 1977. -

5. Grden, K., M. Bygdeman and K. Brenime: Interruption of early first trimester pregnancy by single vaginal administration of 15- methyl PGF2a methyl ester. Contraception 18: 551, 197%. -

6. Vaitukaitis, J., G. Braunstein and J. Gover: A radioimmunoassay which specifically measured human chorionic gonadotropin in the presence of human luteinizing hormone. Am. J. Obstet. Gynecol. 113: 751, 1972.

7. Kirton, K-T.: Serum luteinising hormone and progesterone concentration during the menstrual cycle of the Rhesus monkey. J. Clin. Endocrinol. Metabol. 30: 105, 1970. -

a. Comette, J.C., D.C. Beuving, and K.T. Kirton: Measurement of (15S)-15-methyl prostaglandin F2a by radioimmunoassay. Pros- taglandins 12 (Suppl.): 53, 1976.

9. Csapo, A.I. and M.O. Pulkkinen: The mechanism of prostaglandin action on the pregnant human uterus. Prostaglandins 17: 277, 1979. -


10. Csapo, A.I.: "Prostaglandin Impact" for menstrual induction. Population Reports, Series G, No. 4, 1974, p. 33.

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11. Csapo, A.I. and M.O. Pulkkinen: The mechanism of prostaglandin action on the early pregnant human uterus. Prostaglandins 18: 479, - 1979.

12. Bygdeman, El., J.N. Martin, A. Leader, V. Lundstrtim, M. Ramaden, P. Eneroth, and K. G&en: Early pregnancy interruption by (15S)-15- methyl prostaglandin F2a methyl ester. Obstet. Gynecol. 48: 221, 1976. -

13. Gr6en, K. and K. Svanborg: On the mechanism of action of 15- methyl PGF2a as an abortifacient. Prostaglandins 17: 277, 1979. -

14. Mandelin, M.: Termination of early pregnancy by a single dose 3.0 mg 15-methyl PGF2a methyl ester vaginal suppositories. Prostaglandins 16: 143, 1978. -

15. Lundstrtim, V., M. Bygdeman, S. Foteon, K. Grrien and K. Kino- shita: Abortion in early pregnancy by vaginal administration of 16, 16-dimethyl PGE2 in comparison with vacuum aspiration. Con- traception 16: 167, 1977. -

16. G&en, K., M. Bygdeman, A. Leader and J.N. Martin: Pharmaco- kinetic studies on 15 methyl PGF2a methyl ester after administration to the human via various routes for induction of abortion. In: Advances in Prostaglandin and Thromboxane Research, (B. Samuel- sson and K. Paoletti, eds.). Raven Press, New York, Vol. 2, 1976, p. 719.

Editor: Marc Bygdeman Received: l-11-80 Accepted: 7-7-80


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