Long-term mifepristone associated with endometrial thickening, bleeding

SAN FRANCISCO – Long-term mifepristone therapy for Cushing’s syndrome was associated with endometrial thickening, with some women showing histologic changes consistent with progesterone receptor modulator–associated endometrial changes, in two studies of a total of 35 patients.

The women received 300-1,200 mg/day of mifepristone in the 24-week open-label Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome (SEISMIC) and in an extension of the study in 18 patients who continued for a median of 27 months (range, 14-43 months).

Mifeprex is used, with misoprostol, to end an early pregnancy (within 49 days of the start of a woman’s last menstrual period), according to the Food and Drug Administration’s website. The treatment of Cushing’s syndrome is an off-label use.

Transvaginal ultrasounds in 26 women at baseline and 27 women after the start of the study showed that mifepristone use was associated with endometrial thickening, especially in premenopausal women. The endometrium thickened by more than 5 mm in 8 of 26 premenopausal women (31%) and in two of nine postmenopausal women (22%), with thickening of more than 10 mm in 4 premenopausal women (15%) and one postmenopausal woman (11%), Dr. Ty Carroll reported.

Four (22%) of the 18 women in the extension study who’d been on mifepristone for 14 or more weeks and who had endometrial thickening greater than 20 mm developed clinically relevant endometrial bleeding and underwent hysterectomy (three patients) or dilation and curettage. The endometrial thickening ranged from 25 to 55 mm in these women, who remained on mifepristone therapy throughout the studies, Dr. Carroll and his associates reported in a featured poster presentation at the annual meeting of the Endocrine Society.

“Gynecologic consultation may be required in patients with persistent endometrial bleeding,” said Dr. Carroll of the Medical College of Wisconsin, Milwaukee.

Vaginal bleeding of any kind occurred in 10 premenopausal women (38.5%) and two postmenopausal patients (7%). Three premenopausal women reported minor bleeding upon starting mifepristone, and one premenopausal woman reported minor bleeding after stopping mifepristone. Two premenopausal and two postmenopausal women reported intermittent, self-limited spotting or bleeding during treatment.

Bleeding did not always occur following endometrial thickening. Three patients with endometrial thickening greater than 20 mm after 6 months reported no bleeding.

Mifepristone use was not associated with precancerous endometrial lesions. In 33 endometrial biopsies obtained from 15 patients (11 premenopausal and 4 postmenopausal women), 31 biopsies (94%) had benign histology with variable findings of inactive, atrophic, disordered, or mixed-pattern endometrium, and 18 biopsies (56%) showed findings of progesterone receptor modulator–associated endometrial changes. Simple hyperplasia in one patient could not be confirmed on a repeat biopsy, and complex atypical endometrial hyperplasia in a second patient was thought to have existed prior to the study, Dr. Carroll reported. No patients showed evidence of endometrial carcinoma.

Previous studies have reported progesterone receptor modulator–associated endometrial changes from the use of mifepristone, a competitive progesterone receptor antagonist, in doses of 5-200 mg/day that are not associated with glucocorticoid receptor antagonism.

In the current study, median endometrial thickness for the premenopausal women was 5 mm at baseline and 11 mm at 6 months, and for postmenopausal women, was 3 mm at baseline and 6.4 mm at 6 months. The gain was statistically significant for premenopausal but not postmenopausal women. Endometrial thickness continued to increase in the extension study.

The SEISMIC study included adult females with endogenous Cushing’s syndrome and type 2 diabetes or impaired glucose function and/or hypertension. It excluded premenopausal women with an endometrial thickness greater than 20 mm, postmenopausal women with an endometrial thickness greater than 5 mm, patients with ovarian cysts with diameters measuring greater than 5 cm (premenopausal) or 2 cm (postmenopausal), or women with free fluid pockets greater than 4 cm. Premenopausal participants had a mean age of 39 years, and postmenopausal participants had a mean age of 57 years.

Dr. Carroll has been a speaker and researcher for Corcept Therapeutics, which markets mifepristone. His coinvestigators were employees, contractors, or consultants for Corcept, which provided some funding for the study.

By: SHERRY BOSCHERT, Clinical Endocrinology News Digital Network

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

From Clinical Endocrinology News

When to think Cushing’s syndrome in type 2 diabetes

ESTES PARK, COLO. – Diabetes mellitus, osteoporosis, and hypertension are conditions that should boost the index of suspicion that a patient with some cushingoid features may in fact have endogenous Cushing’s syndrome, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

An estimated 1 in 20 patients with type 2 diabetes has endogenous Cushing’s syndrome. The prevalence of this form of hypercortisolism is even greater – estimated at up to 11% – among individuals with osteoporosis. In hypertensive patients, the figure is 1%. And among patients with an incidentally detected adrenal mass, it’s 6%-9%, according to Dr. McDermott, professor of medicine and director of endocrinology and diabetes at the University of Colorado.

“Endogenous Cushing’s syndrome is not rare. I suspect I’ve seen more cases than I’ve diagnosed,” he observed. “I’ve probably missed a lot because I failed to screen people, not recognizing that they had cushingoid features. Not everyone looks classic.”

There are three screening tests for endogenous Cushing’s syndrome that all primary care physicians ought to be familiar with: the 24-hour urine cortisol test, the bedtime salivary cortisol test, and the overnight 1-mg dexamethasone suppression test.

“I think if you have moderate or mild suspicion, you should use one of these tests. If you have more than moderate suspicion – if a patient really looks like he or she has Cushing’s syndrome – then I would use at least two screening tests to rule out endogenous Cushing’s syndrome,” the endocrinologist continued.

The patient performs the bedtime salivary cortisol test at home, obtaining samples two nights in a row and mailing them to an outside laboratory. The overnight dexamethasone suppression test entails taking 1 mg of dexamethasone at bedtime, then measuring serum cortisol the next morning. A value greater than 1.8 mcg/dL is a positive result.

Pregnant women constitute a special population for whom the screening method recommended in Endocrine Society clinical practice guidelines (J. Clin. Endocrinol. Metab. 2008;93:1526-40) is the 24-hour urine cortisol test. That’s because pregnancy is a state featuring high levels of cortisol-binding globulins, which invalidates the other tests. In patients with renal failure, the recommended screening test is the 1-mg dexamethasone suppression test. In patients on antiepileptic drugs, the 24-hour urine cortisol or bedtime salivary cortisol test is advised, because antiseizure medications enhance the metabolism of dexamethasone.

Dr. McDermott said that “by far” the most discriminatory clinical features of endogenous Cushing’s syndrome are easy bruising, violaceous striae on the trunk, facial plethora, and proximal muscle weakness.

“They’re by no means specific. You’ll see these features in people who don’t have Cushing’s syndrome. But those are the four things that should make you really consider Cushing’s syndrome in your differential diagnosis,” he stressed.

More widely recognized yet actually less discriminatory clinical features include facial fullness and the “buffalo hump,” supraclavicular fullness, central obesity, hirsutism, reduced libido, edema, and thin or poorly healing skin.

Endogenous Cushing’s syndrome can have three causes. An adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma accounts for 80% of cases. A cortisol-secreting adrenal tumor is the cause of 10%. And another 10% are due to an ectopic ACTH-secreting tumor, most commonly a bronchial carcinoid tumor.

Once the primary care physician has a positive screening test in hand, it’s typical to refer the affected patient to an endocrinologist in order to differentiate which of the three causes is present. This is accomplished based upon the results of a large, 8-mg dexamethasone suppression test coupled with measurement of plasma ACTH levels.

Dr. McDermott recommended as a good read on the topic of evaluating a patient with endogenous Cushing’s syndrome a recent review article that included a useful algorithm (N. Engl. J. Med. 2013;368:2126-36).

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

From http://www.clinicalendocrinologynews.com

A cellular and molecular basis for the selective desmopressin-induced ACTH release in Cushing’s disease patients: key role of AVPR1b receptor and potential therapeutic implications

Journal of Clinical Endocrinology and Metabolism, 07/25/2013  Review Article

Luque RM et al. – The study aims to determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release, and to elucidate the cellular and molecular mechanisms involved in desmopressin–induced ACTH increase in Cushing’s disease (CD).

The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and post–surgery prognosis of CD.

Furthermore, the data indicates that AVPR1b is responsible of the direct/exclusive desmopressin–stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b–antagonists as potential therapeutic tools for CD treatment.

~~~~~~~~

Abstract

  1. RM Luque1,#,
  2. A Ibáñez-Costa1,#,
  3. LM López-Sánchez1,
  4. L Jiménez-Reina2,
  5. E Venegas-Moreno3,
  6. MA Gálvez4,
  7. A Villa-Osaba1,
  8. AM Madrazo-Atutxa3,
  9. MA Japón5,
  10. A de la Riva6,
  11. DA Cano3,
  12. P Benito-López4,
  13. A Soto-Moreno3,
  14. MD Gahete1,
  15. A Leal-Cerro3,*and
  16. JP Castaño1,*

Author Affiliations


  1. 1Department of Cell Biology, Physiology and Immunology University of Córdoba, Reina Sofía University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC); CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn); 14014, Córdoba, Spain.

  2. 2Department of Morphological Sciences, University of Córdoba. Córdoba, Spain.

  3. 3Instituto de Biomedicina de Sevilla (IBiS), University Hospital Virgen del Rocío/Consejo Superior de Investigaciones Científicas/University of Seville and Endocrinology, Metabolism and Nutrition Unit, Virgen del Rocío University Hospital, Seville, Spain.

  4. 4Service of Endocrinology and Nutrition, Reina Sofía University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC). Córdoba, Spain.

  5. 5Department of Pathology, Virgen del Rocio University Hospital, Seville, Spain.

  6. 6Service of Neurosurgery, Reina Sofía University Hospital Córdoba, Spain.
  1. Address all correspondence and requests for reprints to: Raúl M. Luque and Justo P. Castaño.Department of Cell Biology, Physiology and Immunology; Campus Universitario de Rabanales, Edificio Severo Ochoa (C6), Planta 3; University of Córdoba, E-14014 Córdoba, Spain. Phone:(34)-957218594. Fax: (34)-957218634. E-mails: raul.luque@uco.esjusto@uco.es.
  1. # These authors have codirected this study.

Abstract

Context: Desmopressin is a synthetic agonist of vasopressin-receptors (AVPRs). Desmopressin stimulation test is employed in the diagnosis and post-surgery prognosis of Cushing’s disease (CD). However, the cellular and molecular mechanisms underlying the desmopressin-induced ACTH increase in CD patients are poorly understood.

Objective: 1) To determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release, and 2) to elucidate the cellular and molecular mechanisms involved in desmopressin-induced ACTH increase in CD.

Design: 8 normal-pituitaries (NPs), 23 corticotropinomas, 14 nonfunctioning-pituitary adenomas (NFPA), 17 somatotropinomas and 3 prolactinomas were analyzed for AVPRs-expression by qrtPCR. Primary cultures derived from corticotropinomas, NFPAs, somatotropinomas, prolactinomas and NPs were treated with desmopressin and ACTH-secretion/expression, [Ca2+]i-kinetics, AVPRs-expression and/or proliferative-response were evaluated. The relationship between AVPRs-expression and plasma adrenocorticotropin/cortisol levels obtained from desmopressin-tests was assessed.

Results: Desmopressin affects all functional parameters evaluated in corticotropinoma-cells but not in NPs or other pituitary-adenomas cells. These effects might be due to the dramatic elevation of AVPR1b expression levels found in corticotropinomas. In line with this notion, the use of an AVPR1b-antagonist completely blocked desmopressin-stimulatory effects. Remarkably, only AVPR1b-expression was positively correlated with elevated plasma adrenocorticotropin levels in corticotropinomas.

The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and post-surgery prognosis of CD. Furthermore, our data indicates that AVPR1b is responsible of the direct/exclusive desmopressin-stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b-antagonists as potential therapeutic tools for CD treatment.

Footnotes

  • * These authors have codirected this study.

Full Text (PDF)

Quality of Life and Other Outcomes in Children Treated for Cushing Syndrome

Abstract

Journal of Clinical Endocrinology and Metabolism, 05/16/2013  Review Article  Clinical Article

Keil MF – Cushing syndrome (CS) in children is associated with residual impairment in measures of health–related quality of life, even after successful resolution of hypercortisolemia, highlighting the need for early identification of morbidities and improvements in long–term management of these patients.

A review of the literature identifies significant morbidities associated with CS of pediatric onset, which must not be treated in isolation. CS affects children and adolescents in many ways that are different than adults.

Post–treatment challenges for the child or adolescent treated for CS include: optimize growth and pubertal development, normalize body composition, and promote psychological health and cognitive maturation. All these factors impact health–related quality of life, which is an important outcome measure to assess the burden of disease as well as the effect of treatment.

Get this article here

Research on Cushing’s Disease Presented at ENDO 2013

endo-chart

Researchers at PHAR, in conjunction with experts from Novartis Pharmaceuticals Corporation, presented the results of several studies on Cushing’s disease at the Endocrine Society’s 95th Annual Meeting on June 19th, 2013.

Cushing’s disease, a pituitary disorder, is poorly studied because of its rarity. The PHAR research team reported on the incidence, treatment patterns, and annual economic burden associated with the disease–topics on which very little was previously known.

The three posters presented at ENDO can be viewed by clicking the links below:

Incidence of Cushing’s Disease in the United States

Real-World Treatment Patterns in Cushing’s Disease Patients in Two Large US Nationwide Databases: Application of a Novel, Graphical Methodology

Annual Economic Burden Associated with Cushing’s Disease in the United States

%d bloggers like this: