Original Paper Gynecol Obstet Invest 1992;33:161-164

Department of Obstetrics and Gynecology B, Sapir Medical Center, Kfar Saba, Israel, affiliated to the Sackler Medical School, Tel Aviv University

Conservative T reatment of Ectopic Pregnancy and Its Effect on Corpus luteum Activity

Key Words


Corpus luteum Ectopic pregnancy Methotrexate therapy

Corpus luteum activity was monitored in 15 women undergoing nonsurgical management of ectopic pregnancy with local methotrexate injection followed by alternating oral methotrexate and citrovorum factor (group A, n = 8) or local methotrexate injection alone (group B, n = 7). All patients initially dem­ onstrated a viable corpus luteum (plasma progersterone ranged from 1.4 to 19 ng/ml). The treatment was successful in 14, with the exception of one whose tube ruptured 11 days after local administration of methotrexate, despite a continuous decrease in |3 human chorionic gonadotropin, 17p-estradiol and plasma progesterone levels. There seems to be no correlation between the suc­ cess of the treatment and the behavior of P human chorionic gonadotropin, 17p-estradiol and plasma progesterone. Three patients from group A and two from group B displayed an initial rise in p human chorionic gonadotropin following the initiation of the therapy, but the corpus luteum response dif­ fered. In group B patients, 17P-estradiol and plasma progesterone levels increased in parallel with P human chorionic gonadotropin. Group A patients displayed a continuous decrease in 17P-estradiol and plasma progesterone lev­ els despite the elevation of p human chorionic gonadotropin, suggesting a pos­ sible effect of the systemic methotrexate on corpus luteum activity.

Introduction The corpus luteum is essential for maintaining normal pregnancy during the first 6 weeks of gestation [1]. It is believed to be a major source for plasma progesterone (PP) and 17P-estradiol (Ei) production in early pregnan­ cy. Little is known about the corpus luteum activity in ectopic pregnancies. The nonsurgical management of ec­ topic pregnancy provides a unique opportunity to observe the activity of the associated corpus luteum. Medical ther­

Received: June 13, 1991 Accepted: October 9, 1991

apy consists mainly of methotrexate (MTX) or prosta­ glandins administered locally, systemically or combined [2-4]. This study addressed the following questions examin­ ing the effect of MTX administration on the corpus luteum and trophoblastic activity: (1) Can the corpus luteum activity and/or the trophoblastic activity predict the response to nonsurgical therapy?, and (2) Does the systemic administration of MTX have a toxic effect on corpus luteum activity?

Adrian Shulman, MD Department of Obstetrics and Gynecology ‘B' Sapir Medical Center Kfar Saba. 44281 (Israel)

© 1992 S. Karger AG, Basel 0378-7346/92/0333-0161 S2.75/0

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Adrian Shutman Ron Maymon Nissim Zmira Michael Lotan Michael Holtzinger Charles Bahary

Table 1. Clinical data for 15 patients Case

Age years




GestaSize of tionalage pregnancy cm days

Serum hCG mIU/ml

Serum PP ng/ml

1.6 7.5 4

Group 1 2 3 4 5 6 7 8

A (local and systemic MTX) 2 1 right 25 7 left 33 3 2 right 28 3 4 3 left 38 34 left 5 3 1 left 18 0 26 3 2 left 1 29 0 right

44 51 57 48 59 60 55 48

2X3 2X 2 2X2 3X3 4X 4 4X 4 3X3 3X3

320 2,000 216 980 1,060 3,160 1,620 1,400

Group 9 10 11 12 13 14 15

B (local MTX only) 29 2 3 27 1 2 4 30 5 21 1 0 4 25 3 2 1 33 1 28 3

52 63 45 59 65 48 53

3X2 2X2 2X3 2X3 3X3 2X2 4X 4

119 183 720 274 119 712 1,250

right left left right right left right

Serum e2 pg/ml

140 107 1,960





Success Days/hCG Hospitalresolution ization of treatment days

+ + + +


19.0 5.5 3.5

240 180 172


6.0 4.6 1.4

90 140 30

+ +



6.0 4.5 4.0

95 112 155

16 21 14 31 23 20

12 14 8 12 10 16 11 11

17 14 16 10 22 25 23

8 7 17 7 10 9 12

20 -

+ +


+ + + +

Table 2. Hormonal profile at day of laparotomy (0), 2,4, and 6 days later for 5 patients displaying initial hCG level increases Case No.

2a 6a 7a 9 llb

e2 hCG MIU/ml pg/ml

2,000 3,160 1,620 119 720

107 240 180 90 30

D ay+ 6

Day +4

PP ng/ml

hCG e2 MIU/ml pg/ml

7.5 19.0 5.5 6.0 1.4

2,560 3,840 1.900 215 820

72 240 165 130 37

PP ng/ml

hCG e2 MIU/ml pg/ml

6.7 19.0 4.0 8.0 2.2

2,380 2,800 1,700 155 480

84 230 150 71 36

PP ng/ml

hCG e2 MIU/ml pg/ml

PP ng/ml

4.9 16.0 3.5 4.8 1.2

1,720 3,100 1,400 100 448

4.3 8.5 2.3 3.1 1.3

43 120 120 79 26

Days of hCG resolution

_ 23 23 18 16

Cases 2, 6, 7 received additional systemic MTX. Case 11 ruptured her tube 11 days following the initial laparoscopy and had a salpingectomy.

Materials and Methods During an 18-month period, 35 tubal pregnancies were diag­ nosed. The diagnosis was based on the relevant medical history, symptoms, human chorionic gonadotropin (hCG) levels in serum, vaginal ultrasonography and laparoscopy. The criterion to attempt primary conservative management was an unruptured tubal preg­ nancy of up to 4 cm in diameter. Patients with larger tubal pregnan­ cies, arterial bleeding or signs of hemorrhagic shock were excluded. The final sample comprised 15 patients (mean age 28.3 years, ranging between 18 and 38 years), who gave their informed consent. They had a mean gestational age of 53.8 ± 6.5 days. We randomly


divided the patients into two groups: group A: 8 patients, who received both local and systemic therapy; Group B: 7 patients, who received only local therapy. The patients first underwent laparoscopic inspection of the pel­ vis, where any free blood was suctioned away. Local treatment, 12.5 mg of MTX diluted in 7 ml of physiologic solution, was injected into the swollen tube of each of the patients through a 15-gauge, 40-cm needle using a suprapubic approach. Oral MTX (0.5 mg/kg of body weight) was administered on alternate days with citrovorum factor (0.1 mg/kg body weight) for 10 consecutive days (5 doses of each). Serum (3 subunit hCG (P-hCG; Immunoradiometric assay, Magnetic Solid Phase-Maia Clone, Serono), 17pE2 (Diagnostic Products Corp..

Shulman/Maymon/Zmira/Lotan/ Holtzinger/Bahary

Methotrexate and Corpus luteum Activity

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a b

Day +2

Day 0

Coat A-Count Method: l25I-labelled RIA) and progesterone (Diag­ nostic Products Corp., Coat A-Count Method; l25I-labcllcd RIA) lev­ els were measured at least once preoperatively and every other day postoperatively until the patient was discharged. Thereafter, they were measured every 5 days until the disappearance of (3-hCG. Dur­ ing hospitalization, blood was sampled every other day for blood cell count, liver enzymes and kidney function.


Discussion With modern diagnostic techniques, many tubal preg­ nancies can now be recognized at stages when conserva­ tive treatment is still feasible. The nonsurgical manage­ ment of ectopic pregnancy provides a unique opportunity to observe the activity of the associated corpus luteum from the time of diagnosis through resolution. During

Days since MTX injection

Fig. 1. The serum (1-hCG and plasma progesterone behavior in patient No. 11.

laparoscopic examination, our 15 ectopic gestations ap­ peared comparable; all were unruptured, 2-4 cm in size and ampullar in location. We believe that some ectopic pregnancies consist of viable, growing trophoblastic masses that produce (3-hCG that is both bioreactive and immunoreactive. This is associated with an active steroid producing corpus luteum. The functional integrity of the corpus luteum in ectopic pregnancy appears to be related to immunoreactive (3-hCG, but not dependent upon it. There was no high correlation between the (3-hCG ra­ dioimmunoassay behavior and the steroid hormones pro­ duced by the corpus luteum. Measurement of the corpus luteum activity and immunoreactive P-hCG could not predict the response to nonsurgical therapy. All of our patients initially demonstrated an active cor­ pus luteum. The (3-hCG, E2 and PP course after the lapa­ roscopy was unpredictable and we could not draw a corre­ lation between the gestational age, size of the pregnancy and levels of these hormones. A continuous decrease in hormonal levels did not necessarily ensure successful treatment, just as an inadvertent increase in [3-hCG and steroid hormone levels was not followed by a detrimental result. (3-hCG is produced primarily in the mitosing cytotrophoblasts and to a lesser degree in syncytiotrophoblasts. Falling (3-hCG could reflect a decrease in mitosing cytotrophoblasts directly resulting from chemotherapy, but not necessarily a resorption of syncytiotrophoblastic mass. Even though the cytotrophoblastic mitosis may be halted, syncytiotrophoblastic mass may increase, thus ac­ counting for the unpredictable behavior of the P-hCG.


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All the patients in the study had ampullary tubal preg­ nancies. Table 1 shows the clinical data of the patients treated locally and systemically (group A) or only locally (group B). There were no intraoperative complications, and no systemic side effects were noted in any of the patients. The patients reported no postoperative com­ plaints and preoperative, lower abdominal pain had abated. The initial hCG levels were 1,344.5 ± 951.8 mlU/ml in group A and 482.4 ± 427.3 mlU/ml in group B, with comparable gestational age between the two groups; 52.7 ± 5.8 days in group A and 55.0 ± 6.5 days in group B. The hCG disappeared from the blood after 20.6 ± 5.0 days in group A and after 19.5 ± 4.4 days in group B. One patient (No. 11) from group B ruptured her tube 11 days after laparoscopy despite a continuous decrease in (3hCG, Et and PP levels. Figure 1 shows the P-hCG, Et and PP levels of these patients. Five patients, 3 from group A and 2 patients from group B display an initial transient rise in p-hCG levels for a few days consecutive to the beginning of the treatment, then followed by a continuous drop in P-hCG levels. The increase in p-hCG serum levels for the patients treated only with a local injection of MTX was paralleled by an increase in E2 and PP levels as well. In the patients receiving systemic MTX, this initial rise in p-hCG was associated with a decrease in E2 and PP levels (table 2). The clearance rate of the E2 and PP was higher for those patients treated with systemic MTX independent of the P-hCG behavior.

References 2



gested by Sauer et al. [5], that there is a direct toxic effect by the systemic MTX administration on the corpus luteum activity. This observation is further enhanced by the different E2 and PP clearing rates in the two groups, despite comparable clearance rates of radioimmunoassay p-hCG. Alternatively, the hCG produced during MTX treatment might be biologically less active. We conclude that in patients diagnosed with ectopic pregnancies and conservatively treated, serial measure­ ments of P-hCG and of the steroid hormones produced by corpus luteum must be accompanied by hospital surveil­ lance until the complete resolution of the clinical findings and cessation of trophoblastic activity. Locally adminis­ tered MTX is effective against the trophoblastic tissue, but the systemic administration may exert an additional effect on the corpus luteum.

Henzl ML, Segre ER: Physiology of human menstrual cycle and early pregnancy. A review of recent investigations. Contraception 1970; 1: 315-320. Pansky M, Bukovsky J, Golan A: Local metho­ trexate injection. A nonsurgical treatment of ectopic pregnancy. Am J Obstet Gynecol 1989; 161:313-316. Ory SJ, Villanueva AL, Sand PK, Tamura RK: Conservative treatment of ectopic pregnancy with methotrexate. Am J Obstet Gynecol 1986; 154:1299-1306.

Shulman/Maymon/Zmira/Lotan/ Holtzinger/Bahary



Lindbolm B, Kallfelt B, Hahlin M, Hamberger L: Local prostaglandin F2a injection for termi­ nation of ectopic pregnancy. Lancet 1987;i: 776-777. Sauer MV, GorrillJ, Rodi 1A, YekoTR, Buster JE: Corpus luteum activity in tubal pregnancy. Obstet Gynecol 1988;71:667-670.

Methotrexate and Corpus luteum Activity

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In spite of a continuous decrease in p-hCG, Eo and PP levels, patient No. 11 ruptured her tube 11 days after the initial laparoscopy. At the time of the rupture, her (3-hCG levels were 132 mlU/ml (less than 20% of the initial val­ ues measured at the time of diagnosis), and no corpus luteum activity was present (PP = 0.4 ng/ml). As the trophoblast stopped secreting hCG, concurrent events in the tube may have included separation of the trophoblast from the tubal wall, intratubal bleeding, a pressure necro­ sis from an intraluminal clot and other intratubal me­ chanical events that may have promoted the rupture. Thus the measurement of P-hCG and corpus luteum activity did not prove to be of absolute value in assessing the success of the treatment. The initial increase in the P-hCG levels in some of the patients and a discordant response in the corpus luteum activity between the two treatment groups supported a previous speculation, sug­

Conservative treatment of ectopic pregnancy and its effect on corpus luteum activity.

Corpus luteum activity was monitored in 15 women undergoing nonsurgical management of ectopic pregnancy with local methotrexate injection followed by ...
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