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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 323-326
Copyright © 2003 by The Endocrine Society

Original Article

Termination of Pregnancy with Mifepristone and Prostaglandin Suppresses Transiently Circulating Glucocorticoid Bioactivity

Oskari Heikinheimo, Taneli Raivio, Helena Honkanen, Sirpa Ranta and Olli A. Jänne

Department of Obstetrics and Gynecology (O.H., H.H.), Institute of Biomedicine (O.H., T.R., S.R., O.A.J.), and Department of Clinical Chemistry (O.A.J.), University of Helsinki and Helsinki University Central Hospital, FIN-00014 Helsinki, Finland

Address all correspondence and requests for reprints to: Dr. Olli A. Jänne, Biomedicum Helsinki, Institute of Biomedicine (Physiology), P.O. Box 63, Haartmaninkatu 8, University of Helsinki, FIN-00014 Helsinki, Finland. E-mail: olli.janne{at}helsinki.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Mifepristone is a potent antiglucocorticoid, the administration of which results in a dose-dependent activation of the hypothalamic-pituitary-adrenal axis. However, the net effect of this compound on circulating glucocorticoid activity is not known. We have used a recombinant cell bioassay to study glucocorticoid bioactivity (GBA), measured directly from serum, in 18 women undergoing medical termination of an early pregnancy with 200 mg mifepristone, followed by 0.8 mg misoprostol, a prostaglandin. Increased serum mifepristone was accompanied by an increase in serum cortisol that was insufficient to maintain circulating GBA within the normal (pre-mifepristone) range (34.7–93.8 nM cortisol equivalents); after approximately 43, 46, and 68 h of mifepristone ingestion, the mean serum GBA levels were much lower than the mean pre-mifepristone level (P < 0.0001). At the corresponding times, 16, 13, and 12 women displayed subnormal serum GBA levels (ranges, <15.6–23, <15.6–25.6, and <15.6–32.5 nM cortisol equivalents, respectively). Altogether 11 subjects displayed subnormal serum GBA (range, <15.6–32.5 nM cortisol equivalents) continuously in the presence of high concentrations of mifepristone. Two weeks after mifepristone administration, circulating GBA had returned to normal levels in all subjects. We conclude that 200 mg mifepristone elicits a significant suppression of serum GBA, to one third of the pretreatment value, despite the compensatory increase in the serum cortisol concentration.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MEDICAL TERMINATION OF an early pregnancy using a combination of mifepristone followed by synthetic prostaglandin is effective and safe (1). Mifepristone is used in several European countries, China, and the United States. Various doses of mifepristone and different prostaglandin derivatives and regimens are in use. In addition to the antiprogestational action of mifepristone, the antiglucocorticoid nature of this compound is well characterized. Mifepristone binds to the glucocorticoid receptor (GR), and oral administration of the drug results in a compensatory, dose-dependent activation of the hypothalamic-pituitary-adrenal (HPA) axis (2, 3). In the initial studies a significant increase in serum ACTH and cortisol was evident only after oral doses of mifepristone of 200 mg and above (2, 3). However, continuous administration of 50 mg/d (4), but not 10 mg/d (5), mifepristone increased the serum cortisol concentration. Ingestion of high doses (6 mg/kg) of mifepristone also prevented the vasoconstrictive effects of topically administered glucocorticoids (6). However, daily administration of 10 mg/kg mifepristone to healthy male volunteers for 1–2 wk was not associated with alterations in several laboratory parameters of immune function (7). Because of the antiglucocorticoid nature of this drug, hypocortisolemia or dependence on exogenous glucocorticoids is a contraindication for the use of mifepristone (8, 9).

Activation of the HPA axis during medical termination of pregnancy in healthy pregnant women has been considered sufficient to compensate for the antiglucocorticoid action of mifepristone (7). However, it is not known whether the increase in serum cortisol is indeed sufficient to maintain circulating glucocorticoid bioactivity within the normal range. In the present study we investigated by using a recombinant cell bioassay (10) whether administration of single dose of 200 mg mifepristone as part of medical termination of pregnancy results in functional glucocorticoid deprivation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Eighteen healthy women, aged 18–41 yr, requesting medical termination of an unwanted pregnancy of less than 9-wk duration (or <=63 d of amenorrhea) were enrolled. The women took part in a WHO multicenter trial evaluating the effect of the route and duration of misoprostol administration on the efficacy of medical termination of pregnancy (WHO, manuscript submitted). The study was approved by the institutional review board of the Department of Obstetrics and Gynecology, University of Helsinki. The subjects gave their informed consent before participation in the study. The eligibility criteria used were the same as those employed and described in a previous WHO study (9). All patients received a single 200-mg dose of mifepristone orally on d 0. On d 2 the patients received 0.8 mg misoprostol (a prostaglandin) either orally or vaginally. Starting on d 3, 7 patients received oral placebo, and 11 were given 0.4 mg oral misoprostol twice daily for 7 d. The patients returned to the hospital for an additional blood sample on d 3 and for a clinical control sample on d 14. The final outcome of the treatment was assessed 6 wk after the treatment. All patients included in this study had complete abortion, and no surgical measures were needed.

Consecutive serum samples were drawn in five instances. The first sample (d 0) was collected at 1525 h (median; range, 0940–1750 h) before the administration of mifepristone. The second blood sample (d 2) was drawn at 0905 h (0800–0945 h), on the average 43 h after mifepristone ingestion, and immediately before administration of misoprostol. The third blood sample (d 2) was obtained 3 h later (46 h after mifepristone ingestion) at 1215 h (1130–1245 h). The fourth blood sample was obtained on d 3 at 1000 h (0800–1315 h; 68 h after mifepristone ingestion). The fifth and last sample was drawn on d 14 at 1605 h (0905–1750 h).

Hormone assays

The concentration of serum cortisol was measured in duplicate samples by time-resolved fluoroimmunoassay, using a DELFIA-based system manufactured by Perkin-Elmer Life Sciences, Wallac, Inc. (Turku, Finland). Serum mifepristone was quantified by a specific RIA after Chromosorb (W-NAW-60-80 Mesh, Sigma-Aldrich, St. Louis, MO) column chromatography, as described previously (11). The specific tracer, [6,7-3H]RU 486, was provided by Roussel-UCLAF (Romainville, France), and the monoclonal antimifepristone antibody was a gift from Dr. Fortune Kohen (Weizmann Institute, Rehovot, Israel). Glucocorticoid bioactivity (GBA) was measured directly from 10-µl serum samples using a recombinant cell bioassay in which COS-1 cells are transfected with expression vectors encoding human GR and a nuclear receptor coregulator, ARIP3, together with an appropriate reporter gene (10). The assay parameters have been published previously (10); the within-assay coefficient of variation determined from pooled sera of the present study subjects (d 0) was 8%. In the current work serum GBA values less than 15.6 nM cortisol equivalents were considered undetectable.

Statistical analyses

Paired t test was used to compare the mean serum GBA measured before mifepristone administration (d 0) to serum GBA levels measured on d 2 or d 3. Linear correlation was employed to investigate the relationship between serum GBA and cortisol, and Spearman rank correlation was used in other correlation analyses. In all analyses undetectably low serum GBA was considered to be equal to 15.6 nM cortisol equivalents. P < 0.05 was accepted as indicating statistical significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
We measured serum GBA using a recombinant cell bioassay (10) in 18 women undergoing medical termination of pregnancy with a regimen containing 200 mg mifepristone, followed 36–48 h later by 0.8 mg oral or vaginal prostaglandin (misoprostol). Serum cortisol, mifepristone, and GBA levels before and at different time intervals after mifepristone ingestion are summarized in Fig. 1Go. An increased mifepristone concentration in serum was accompanied by an increase in serum cortisol (Fig. 1Go) that was, however, insufficient to maintain the circulating GBA within the normal (pre-mifepristone) range (34.7–93.8 nM cortisol equivalents). After 2 and 3 d (43, 46, and 68 h) of mifepristone ingestion, the mean serum GBA levels were much lower than those measured before the administration of mifepristone (P < 0.0001). At the corresponding times, 16, 13, and 12 of the 18 women studied displayed subnormal serum GBA levels; the respective ranges of serum GBA in these women were less than 15.6–23, less than 15.6–25.6, and less than 15.6–32.5 nM cortisol equivalents. Eleven of the 18 subjects had subnormal serum GBA (range, <15.6–32.5 nM cortisol equivalents) continuously from d 2–3 (from 43–68 h after mifepristone ingestion). There were 4, 3, and 4 women with undetectable serum GBA at 43, 46, and 68 h after mifepristone ingestion, respectively. Four of them had 2 undetectable GBA values each, and the 3 remaining women each displayed a single undetectable serum GBA value during the study. Only 2 subjects had their circulating GBA within the normal reference range throughout the study. After 2 wk of mifepristone administration, each study participant exhibited normal serum GBA (Fig. 1Go).



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  		Figure 1. Serum mifepristone (upper panel) and cortisol (middle panel) concentrations and GBA (lower panel) in 18 healthy women undergoing medical termination of early pregnancy with a mifepristone (200 mg, orally), followed by misoprostol (0.8 mg, orally or vaginally) given on d 2. The assays were performed and described in Subjects and Methods. Horizontal lines at each time point indicate 10th, 25th, 50th, 75th, and 90th percentiles; extreme values are depicted separately.

 
Serum GBA and cortisol levels correlated before (r = 0.68; P < 0.005; n = 18) and after 2 wk of mifepristone ingestion (r = 0.80; P < 0.0001; n = 18). Serum GBA values on d 2 and 3 correlated negatively with serum mifepristone (r = -0.38; P < 0.01; n = 54) and positively with serum cortisol (r = 0.40; P < 0.01; n = 54). A strong negative correlation was found between serum GBA and mifepristone to cortisol ratio (r = -0.66; P < 0.0001; n = 54; Fig. 2Go). Finally, we verified that the administration of prostaglandin (misoprostol) did not influence the relationship between serum GBA and the mifepristone to cortisol ratio; correlations between these variables were similar immediately before (r = -0.57; n = 18; P < 0.05) and 3 h after misoprostol administration (r = -0.55; n = 18; P < 0.05).



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  		Figure 2. The relationship between serum glucocorticoid bioactivity (x-axis) and serum mifepristone to cortisol ratio in 18 women undergoing medical termination of an early pregnancy with mifepristone (200 mg, orally), followed by misoprostol (0.8 mg, orally or vaginally). The levels were measured 2 and 3 d after the administration of mifepristone. Three values are shown for each subject. Undetectably low serum GBA values were set as equal to 15.6 nM cortisol equivalents.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this work we have examined the effect of mifepristone on circulating GBA in women undergoing medical termination of pregnancy. Our results show that in response to mifepristone, the majority of women display markedly suppressed GBA despite the compensatory increase in serum cortisol. Providing that serum GBA measured on d 0 represents the normal reference range, serum GBA was continuously within this reference range in only two women after mifepristone administration.

The most profound suppression of serum GBA was observed on d 2, i.e. before the administration of prostaglandin and thus before eventual abortion process (8). This excludes the potential effect of the expulsion of fetal and trophoblast tissue as a cause of reduced circulating GBA. Moreover, on the basis of similar correlations between the mifepristone to cortisol ratio and GBA before and after misoprostol administration on d 2, prostaglandin is concluded not to influence serum GBA.

In agreement with previous observations (2), administration of 200 mg mifepristone resulted in a compensatory increase in serum cortisol concentration. The most profound increase was evident in the samples collected 1.5–2 d after mifepristone ingestion, and by d 14 serum cortisol values had returned to pretreatment levels. The pretreatment samples were collected after 1200 h, whereas the samples on d 2 and d 3 were obtained before 1200 h. This difference in timing may have affected serum cortisol levels, as circadian variation in serum cortisol is known to persist both during pregnancy (12) and after mifepristone administration (2, 3). On the other hand, on d 2 and 3 the sera were collected around the peak of cortisol secretion, but the majority of women still displayed unequivocally suppressed serum GBA. This suggests that the actual suppression of serum GBA at night (when cortisol levels are low) may have been even more pronounced if measured earlier than in the current study. This idea is supported by the rapid absorption and sustained micromolar levels of mifepristone in serum after the ingestion of 100 mg or more of the drug (13).

Similar to our previous results, high levels of mifepristone were measured in serum on d 2 and 3 of treatment, and practically none was found at the follow-up 2 wk later (13). Serum cortisol and mifepristone concentrations were almost equimolar on d 2 and 3 of treatment. Given the high affinity of mifepristone to the human GR (14) and the possible additional antiglucocorticoid effect of the demethylated and hydroxylated metabolites of mifepristone (13, 14), it is not surprising that serum GBA was significantly suppressed after mifepristone administration. On the other hand, serum GBA and cortisol levels correlated positively. This is in agreement with our previous observation in children (10). As could have been expected, the serum mifepristone to cortisol ratio was a better indicator of circulating GBA than either hormone level alone. Serum ACTH concentrations increase concomitantly with cortisol after mifepristone administration (2, 3, 7), indicating that functional hypocortisolemia occurs after the intake of mifepristone. It should be noted, however, that the serum ACTH concentration can only be considered as an indirect indicator of the net effect of GR agonists and antagonists in the circulation, whereas serum GBA measurement provides direct information about it. A potential caveat in the current GBA measurement is that serum samples are diluted 10-fold in cell culture medium, which may result in dissimilar dissociation rates for mifepristone from {alpha}1-acid glycoprotein (11, 13) and cortisol from cortisol-binding globulin. As a consequence, we cannot not formally rule out the possibility that in this instance the bioassay does not faithfully reflect the situation in the patient’s circulation.

The clinical implications of the reduced GBA are uncertain. Given the safety of mifepristone-induced termination of pregnancy, alterations in the currently used mifepristone regimens appear unnecessary. However, in view of the dose-dependent activation of the HPA axis after mifepristone administration (2, 3), the present study encourages the use of the lowest effective dose of mifepristone for pregnancy termination in healthy subjects. The common side-effects of mifepristone/misoprostol-induced termination of pregnancy (nausea, vomiting, diarrhea, and pain) (8) are those often associated with the abortion process and the use of synthetic prostaglandins (15). However, vomiting and nausea are also typical symptoms of hypocortisolemia (16) and of pregnancy itself. It may well be that coadministration of glucocorticoids with mifepristone would reduce the incidence of some of the side-effects associated with mifepristone-induced termination of pregnancy. Further studies are warranted to confirm this hypothesis. Finally, mifepristone is used in the treatment of Cushing’s syndrome in both children and adults (17, 18, 19). The results of the present study imply that the current bioassay should be suitable for monitoring the treatment of such patients.

We conclude that administration of a single 200-mg dose of mifepristone results in a profound, but transient, suppression of circulating GBA in patients undergoing medical termination of a first trimester pregnancy. Recognition of suppressed GBA is important when choosing mifepristone doses for clinical practice and especially if mifepristone is administered to patients with suboptimal function of the HPA axis.


   Acknowledgments
 
We thank Ms. Johanna Iso-Oja and Ms. Marjatta Tevilin for their expert laboratory work.


   Footnotes
 
This work was supported by The Population Council (New York, NY), Biocentrum Helsinki, Academy of Finland, Helsinki University Central Hospital Research Funds, and a Finnish Medical Foundation clinical fellowship grant (to O.H.). The content of the this report does not necessarily reflect the policy of any of the funding sources.

O.H. and T.R. contributed equally to this work.

Abbreviations: GBA, Glucocorticoid bioactivity; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal.

Received May 23, 2002.

Accepted October 10, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  4. Murphy A, Kettel LM, Morales A, Roberts V, Yen S 1993 Regression of uterine leiomyomata in response to the antiprogesterone RU486. J Clin Endocrinol Metab 76:513–517[Abstract]
  5. Croxatto H, Salvatierra A, Croxatto H, Fuentealba B 1993 Effect of continuous treatment with low dose mifepristone throughout one menstrual cycle. Hum Reprod 8:201–207[Abstract/Free Full Text]
  6. Gaillard R, Poffet D, Riondel A, Saurat J-H 1985 RU 486 inhibits peripheral effects of glucocorticoids in humans. J Clin Endocrinol Metab 61:1009–1011[Abstract/Free Full Text]
  7. Laue L, Lotze M, Chrousos G, Barnes K, Loriaux DL, Fleisher T 1990 Effect of chronic treatment with glucocorticoid antagonist RU 486 in man: toxicity, immunological, and hormonal aspects. J Clin Endocrinol Metab 71:1474–1480[Abstract/Free Full Text]
  8. Spitz I, Bardin CW, Benton L, Robbins A 1998 Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med 338:1241–1247[Abstract/Free Full Text]
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  10. Raivio T, Palvimo JJ, Kannisto S, Voutilainen R, Jänne OA 2002 Transactivation assay for determination of glucocorticoid bioactivity in human serum. J Clin Endocrinol Metab 87:3740–3744[Abstract/Free Full Text]
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