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Elevated estradiol with prolonged mifepristone to treat progesterone-receptor positive meningioma

Aharon, Devora A., MDa,; Carpinello, Olivia J., MDb; Bishop, Lauren A., MDb; DeCherney, Alan H., MDb

doi: 10.1097/GRH.0000000000000019
Brief Reports

Objective: To report a finding of persistently elevated estradiol (E2) after prolonged mifepristone use for treatment of progesterone-receptor positive meningioma, an association which has not previously been reported.

Design: This is a case report.

Setting: Outpatient Reproductive Endocrine clinic at a tertiary referral center.

Case Report: A 48-year-old gravida 1 para 0-0-1-0 with progesterone-receptor positive meningioma, recurrent after multiple debulking surgeries. Patient was treated with mifepristone for 11 years with symptomatic improvement and tumor shrinkage. Levels of follicle-stimulating hormone, luteinizing hormone, and estradiol (E2) were followed throughout the patient’s course of mifepristone therapy. E2 levels were found to be persistently elevated to 500–700 pg/mL.

Materials and Methods: Enhanced E2 assay, a liquid-chromatography tandem mass spectrometry (LC-MS/MS) based assay, was measured simultaneously with the routinely used immunoassay for 5 years in attempt to obtain a more accurate assessment.

Results: E2 levels using the standard immunoassay were found to be persistently elevated while the patient was taking mifepristone. Using the enhanced LC-MS/MS assay, E2 was initially elevated, however was subsequently low. After the patient discontinued the medication, E2 levels as measured by the immunoassay normalized.

Conclusions: Prolonged mifepristone use was found to be associated with markedly elevated E2 levels in our patient. If this is a true elevation, it may help explain the incidence of endometrial hyperplasia and endometrial polyps with prolonged mifepristone use. However, this was likely a false elevation, potentially due to cross-reactivity of mifepristone with the immunoassay, given the normal values obtained with the enhanced LC-MS/MS E2 assay. Whether prolonged mifepristone use may cause true or falsely elevated E2 in a wider population, and the mechanism through which it does so, should be further investigated.

aDepartment of Obstetrics, Gynecology, and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY

bEunice Kennedy Shriver National Institute of Child Health and Human Development, Program in Reproductive and Adult Endocrinology, Bethesda, MD

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 8 August 2018

Corresponding author. Address: Department of Obstetrics, Gynecology, and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, 1176 5th Avenue, P.O. Box 1170, New York, NY 10029. Tel/fax: +917-613-0512. E-mail address: devora.aharon@mountsinai.org (D.A. Aharon).

Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.

Received January 11, 2018

Accepted July 12, 2018

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Introduction

Mifepristone is a progesterone antagonist that may be used for emergency contraception and induced termination of pregnancy1. Prolonged mifepristone use has been investigated for treatment of uterine fibroids, endometriosis, and Cushing syndrome2–4. Nongynecologic uses of prolonged mifepristone include treatment of progesterone-receptor positive meningioma5–9. Up to 70% of meningiomas have progesterone receptors10. Prolonged mifepristone use has been associated with increased risk of endometrial hyperplasia and endometrial polyps, which is generally thought to be due to the effect of unopposed estrogen on endometrial tissue secondary to progesterone antagonism7,8. The effect of prolonged mifepristone use on serum estrogen levels has not been reported.

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Case report

A 48-year-old gravida 1 para 0-0-1-0 with a history of right-sided petroclival progesterone-receptor positive meningioma as well as uterine fibroids was referred to our clinic in 2008. The patient was status-post two debulking surgeries in 2000 and 2005 as well as a ventriculoperitoneal shunt placement in 2004 with removal in 2008. Her second surgery had been complicated by partial third nerve injury with hearing loss in the right ear, as well as tracheostomy and percutaneous gastrostomy tube placement which were subsequently removed. She had been started on mifepristone 200 mg daily in 2006 for treatment of the meningioma as well as uterine fibroids. Her neurological symptoms had improved and her tumor had decreased slightly in size since starting the mifepristone. At the time of referral, she had 2 fibroids each measuring ∼3 cm each. Medical history was also significant for hypothyroidism.

Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were drawn to evaluate ovarian function and menopausal status and were initially within normal limits. FSH, LH, and E2 were followed through the course of her treatment (Table 1). Mifepristone was held for 6 months starting in March 2009 due to the development of breakthrough bleeding, with a finding of endometrial hyperplasia without atypia on endometrial biopsy. In September 2009 the patient had had regular menses for 6 months and endometrial stripe was thin, so mifepristone was restarted. Mifepristone therapy was continued for a total of eleven years with occasional breaks to allow for menses. The dose was titrated up to 300 mg daily, and the patient reported self-administering additional medication up to 800 mg when her neurological symptoms were more severe. Hormone levels continued to be followed, and serum E2 levels were markedly elevated from 2012 to 2014, up to 632.6 pg/mL (Table 1). Follow-up transvaginal ultrasound in 2014 revealed no uterine fibroids and endometrial stripe was 0.47 cm. In March of 2017 a second ventriculoperitoneal shunt was placed, after which the patient lost insurance coverage and stopped taking mifepristone. She reported worsening of neurological symptoms after stopping mifepristone and was found to have slight growth in the tumor. Surgery followed by radiation was recommended, however the patient declined. Mifepristone was not restarted due to persistent insurance issues. She has been followed with expectant management since that time with spontaneous improvement in her symptoms. Her FSH, LH, and E2 were repeated at her follow-up visit after discontinuing the mifepristone, and serum E2 had normalized.

Table 1

Table 1

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Materials and methods

In addition to the estrogen immunoassay used routinely in our facility, estrogen was measured via enhanced liquid-chromatography tandem mass spectrometry (LC-MS/MS) based assay starting in November 2012 in attempt to detect a more accurate E2 level. E2 was followed through December 2017 using the standard immunoassay as well as the enhanced LC-MS/MS assay.

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Results

E2 was initially elevated to 319 pg/mL using the enhanced assay. From 2013 to 2014, E2 ranged from 521 to 719 pg/mL using the standard assay but was <5 pg/mL using the enhanced assay. Lupron was given in August 2014 in attempt to suppress E2; however, 3 weeks later, E2 was persistently elevated to 633.9 pg/mL but was <5 pg/mL with the enhanced assay. In December 2017, after the patient had stopped mifepristone 9 months earlier, E2 using the standard assay was <5 pg/mL.

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Discussion

Prolonged mifepristone use was found to be associated with persistently elevated serum E2 levels in this case, which has not previously been reported. Long-term mifepristone has been associated with increased risk of endometrial hyperplasia and endometrial polyps7,8. The mechanism for this risk is thought to be progesterone antagonism allowing for unopposed estrogen to stimulate the endometrium7,8. Treatment with mifepristone for 12 weeks was found to be associated with a decline in the expression of HAND2, a gene which is suppressed in endometrial hyperplasia and endometrial cancer11.

In addition to the lack of progesterone counteracting the effect of normal circulating estrogen, however, it is possible that an elevation in E2 level occurs during prolonged mifepristone use. Prior studies did not report elevated E2 levels during administration of mifepristone. However, side effects that may be related to elevated serum estrogen have been reported with prolonged mifepristone use, including gynecomastia and decreased libido in men, and pedal edema, nausea, and partial alopecia in women7–9. In our case, a marked increase in E2 was seen after the patient had been taking the medication for 6 years and her dose had been increased to 300 mg daily, with occasional self-administration of excess doses. Mifepristone could potentially cause elevated estrogen via peripheral aromatization of elevated adrenal androgens due to the antiglucocorticoid effect of mifepristone, which generates an increase in ACTH and cortisol8. Our patient’s cortisol level, however, was within normal limits in July 2010 and August 2014.

However, this patient’s markedly elevated E2 is likely a false elevation. Interference in immunoassays is known to occur as a result of antianimal antibodies12. Laboratory interference in estrogen immunoassays has been reported due to heterophilic antibodies from monoclonal gammopathies13, or due to conjugated steroid cross-reactivity14. This patient’s temporary elevation in E2 may have been a result of steroid cross-reactivity generated by high levels of mifepristone administration. Mass spectrometry has been found to have a higher sensitivity and specificity to detect E2 than immunoassays which have greater inter-assay variability. Mass spectrometry is particularly useful in men, children, and postmenopausal women to quantify low levels of E2 <5 pg/mL15,16. Our patient’s E2 levels as measured by LC-MS/MS are likely more accurate than those measured by immunoassay. However, in November 2012 E2 measured by mass spectrometry was elevated to 319 pg/mL, indicating that the elevated E2 seen in our patient may not be entirely false. Whether our patient’s elevated E2 was a true or false elevation is not entirely clear.

In conclusion, prolonged mifepristone use was found to be associated with markedly elevated E2 levels in our patient, which has not previously been reported. Further investigation is warranted into whether this association occurs with prolonged mifepristone use in a wider population. Whether this is a false elevation due to cross-reactivity with the assay, or a true elevation that may help explain the incidence of endometrial hyperplasia and endometrial polyps with prolonged mifepristone use, requires further evaluation.

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Sources of funding

None.

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Conflicts of interest disclosures

The authors declare that they have no financial conflict of interest with regard to the content of this report.

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References

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Keywords:

Estrogen; Mifepristone; Immunoassay; Mass spectrometry

Copyright © 2018 The Authors. Published by Wolters Kluwer on behalf of the International Federation of Fertility Societies. All rights reserved.