Clinical effectiveness of metyrapone monotherapy in 195 patients with Cushing’s syndrome

From Day 1 of the 16th International Congress of Endocrinology and the Endocrine Society’s 96th Annual Meeting and Expo »

Chicago, IL – June 21, 2014

E Daniel, SJB Aylwin, SG Ball, K Boelaert, D Cuthbertson, C Daousi, JR Davis, W Drake, AB Grossman, M Gurnell, N Karavitaki, T Kearney, K Meeran, A Rees, PJ Trainer, JDC Newell-Price

Summary: Metyrapone is widely used in the UK for the control of cortisol excess in Cushing’s syndrome, but its use is not standardised. The few published reports on metyrapone use pertain to limited patient numbers. In this report, the largest report on metyrapone use, metyrapone was effective in achieving eucortisolemia in over 70% of patients without any other cortisol-lowering intervention, with a satisfactory safety profile. A variety of monitoring regimens were used, but greater standardisation of practice and more active dose titration is needed.

Methods:

  • A retrospective survey was conducted across 13 tertiary centres in England and Wales.
  • Using a standardised proforma, extensive data including monitoring and safety information were collected for patients with Cushing’s syndrome on metyrapone therapy between 1997 and 2013.
  • Eucortisolemia was defined according to the monitoring test used as a mean cortisol ‘day curve’ value ≤300 nmol/l, a urinary free cortisol bellow the upper limit of normal (ULN) or a 9am serum cortisol

Results:

  • A total of 195 patients received metyrapone (160 as monotherapy). Average age was 49.6 +/-15.7 years: 87.2% had metyrapone in conjunction with other interventions (surgery, radiotherapy or chemotherapy) while 12.8% had cortisol-lowering treatment alone.
  • Dose-titration was used in 81% of patients, whereas 19% had a block-and-replace regimen.
  • A total of 138 patients received metyrapone monotherapy for a mean duration of 162 days before any other intervention took place.
  • The etiology of Cushing’s syndrome in this subgroup was: pituitary-dependent disease [CD, 59% (macroadenoma 32% of CD)], ectopic ACTH syndrome (EAS, 17%), adrenocortical carcinoma (ACC, 4%), adrenal adenoma (AA, 17%) and other benign adrenal disease (3%).
  • Hypokalemia was actively managed with potassium levels increasing during metyrapone therapy (3.90 mmol/L vs 3.68 mmol/L, P=0.0026).
  • In this subgroup, 74% achieved eucortisolemia on varying doses: CD 1370 mg, EAS 2080 mg, AA 1170 mg, ACC 750 mg daily in divided doses.
  • The preferred monitoring method was by cortisol ‘day-curves’, followed by 9am cortisol and urinary free cortisol.
  • Overall, 25.3% of patients developed side effects, most commonly gastrointestinal upset and hypoadrenalism.
  • 88% of adverse events were managed as outpatients; 36% of patients treated for more than one month had ≤2 monitoring assessments and insufficient dose titration.

From MDLinx

Utility of measurement of dexamethasone levels in the diagnostic testing for Cushing’s syndrome

From Day 1 of the 16th International Congress of Endocrinology and the Endocrine Society’s 96th Annual Meeting and Expo »

Chicago, IL – June 21, 2014

ST Sharma, JA Yanovski, SB Abraham, LK Nieman

Summary: Dexamethasone (dex) suppression tests (DST) are used for screening and differential diagnosis of Cushing’s syndrome (CS). The 1 mg overnight (LD) DST is used to diagnose CS, the dex-suppressed CRH stimulation (Dex-CRH) test to differentiate CS from pseudocushings (PCS) while the 8 mg overnight (HD) DST is used to differentiate Cushing’s disease (CD) from ectopic ACTH syndrome (EAS). Researchers assessed the utility of dex levels in improving the diagnostic accuracy of these tests and they found that low dex and high CBG levels can account for false positive (FP) DST and Dex-CRH test results. Use of a higher dex dose in pts with low dex levels can help decrease FP results.

Methods:

  • This is a retrospective study of patients (pts) with CS, PCS and normal volunteers (NV) who had a dex level measured as part of LDDST, HDDST or Dex-CRH test.
  • A post-dex cortisol (F) level ≥1.8 mcg/dl in the LDDST and a 15 min post-CRH F level ≥1.4 mcg/dl in the Dex-CRH test suggested CS.
  • A ≥69% suppression of F levels in HDDST indicated CD.
  • Dex levels

Results:

  • LDDST (n=77): Post-dex F was abnormal in 44 pts, 37 of these did not have CS on follow-up.
  • Proportion of pts with low dex levels was similar in those with incorrect or correct LDDST results (P=0.7).
  • Three of 5 pts with an abnormal result and low dex levels (44-117 ng/dl) had suppressed post-dex F levels after a 2 mg overnight DST. HDDST (N=56): Results were not consistent with the final diagnosis (CD or EAS) in 13 (23%) pts.
  • Of these, 5 had low dex levels (400-1220 ng/dl).
  • Proportion of pts with low dex levels was similar between those with correct and incorrect HDDST results (P=0.5).
  • HDDST in 1 pt with ACTH-dependent CS suggested EAS (28% suppression) with low dex level.
  • IPSS indicated CD.
  • After a doubled dex dose (16 mg), F levels suppressed by 76%, changing the HDDST result to CD.
  • Dex-CRH (n=139): Results were consistent with the final diagnosis in 133 pts (74 CS, 20 NV, 39 PCS).
  • Six pts with an abnormal result had dex levels
  • Of these, repeat testing with doubled dex dose (1 mg every 6 hours) in 2 pts led to higher dex levels (610, 757 ng/dl) and normal F level in one.
  • Two pts with abnormal result were on OCPs, 1 with a known high cortisol binding globulin (CBG) level.
  • None had CS on follow-up.
  • There was no correlation between dex and post-dex F levels in LDDST, 15 min post-CRH F levels in Dex-CRH test and % suppression of F post-dex in HDDST (P=NS).

Diagnosing and Treating Cortisol Excess and Deficiency

From Day 1 of the 16th International Congress of Endocrinology and the Endocrine Society’s 96th Annual Meeting and Expo »

Chicago, IL – June 21, 2014

A phase 2 study of Chronocort®, a modified release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia

A Mallappa, L-A Daley, N Sinaii, C Van Ryzin, H Huatan, D Digweed, D Eckland, M Whitaker, LK Nieman, RJ Ross, DP Merke

Summary: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and aldosterone deficiency and androgen excess. Current conventional glucocorticoid therapy is suboptimal as it cannot replace the normal cortisol circadian rhythm and inadequate or inappropriate suppression of adrenal androgens are common. In the preliminary results of a phase 2 study of Chronocort®, a modified release hydrocortisone capsule formulation, researchers found that Chronocort®, a novel modified release hydrocortisone capsule formulation, approximates physiological cortisol secretion, and improves biochemical control of CAH. Further analyses are underway.

Methods:

  • The study objectives were to characterize pharmacokinetics and examine disease control following 6 months dose titration.
  • Serial profiling was obtained at baseline (conventional glucocorticoid) and every 2 months.
  • Twice-daily Chronocort® was initiated: 20 mg at 2300 h, 10 mg at 0700 h.
  • Dose titration was based on clinical status and optimal hormonal ranges (17OHP 300-1200 ng/dL, normal androstenedione (males: 40-150, females: 30-200 ng/dL), with androstenedione prioritized.
  • Chronocort® cortisol pharmacokinetic profile was the primary endpoint.
  • Secondary endpoints included biomarkers of disease control.

Results:

  • A total of 16 adults (8 females; age 29 ±13 years) with classic CAH (12 salt-wasting, 4 simple virilizing) participated.
  • Conventional therapy varied (5 dexamethasone, 7 prednisone, 4 hydrocortisone).
  • Chronocort® cortisol pharmacokinetic profile approximated physiological cortisol secretion.
  • Ten patients required Chronocort® dose adjustments (decrease in 8, increase in 2; mean hydrocortisone equivalent dose conventional vs 6 months: 16.1 ± 6.4 vs 14.7 ± 6.4 mg/m2).
  • Serial androstenedione levels were in the normal range in 8 (50%) of patients on conventional therapy compared with 12 (75%) on Chronocort® at 6 months.
  • The majority of patients on Chronocort® achieved 17O HP levels within the normal range, rather than within the mildly elevated range currently used for management.
  • At 6 months, Chronocort® resulted in lower 24-hr (P=0.02), morning (0700-1500; P=0.008), and afternoon (1500-2300; P=0.03) area-under-the-curve androstenedione compared with conventional therapy.
  • No serious adverse events occurred.
  • Common adverse events were headache, fatigue, early awakening, and anemia.
  • Three patients had unexpected carpal tunnel syndrome, which resolved with wrist splints.

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ5BA369FDE9DE4CED82CB6A7CD5BFD1BE/16521/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ICE/EN2014&nonus=0#

Long-term remission and recurrence rate in a cohort of Cushing’s disease: the need for long-term follow-up

Pituitary. 2014 Apr 19. [Epub ahead of print]

Author information

 Abstract

OBJECTIVE:

Transsphenoidal surgery is the procedure of choice in Cushing disease (CD), with immediate post-operative remission rates ranging between 59 and 94 % and recurrence rates between 3 and 46 %, both depending upon the definition criteria and the duration of the follow-up. Our aim was to assess the rate of remission, recurrence and persistence of the disease after the first treatment and to identify predictors of remission in the CD population of our center.

METHODS:

Retrospective cohort study of the patients diagnosed of CD and with follow-up in our center between 1974 and 2011. We analyzed 41 patients (35 women and 6 men) with a mean age at diagnosis of 34 ± 13 years. The mean follow-up was 14 ± 10 years (range 1-37 years) and the median of follow-up period was 6.68 years.

RESULTS:

Thirty-five (85.4 %) patients underwent transsphenoidal surgery as first treatment option. Histopathological evidence of a pituitary adenoma was registered in 17 (48.5 %) patients. Thirty-two (78 %) patients achieved disease remission after the first treatment, 21 (65.6 %) of them presented disease recurrence. Persistent disease was observed in 9 (22 %) patients. Twelve (29.3 %) subjects developed post-surgical adrenal insufficiency, 7 of which (70 %) achieved stable remission. Two parameters were found to be significant predictors of remission after the first treatment: age at disease diagnosis and the development of adrenal insufficiency (cortisol ❤ μg/dl) in the immediate post-operative state.

CONCLUSIONS:

We report a high recurrence rate, at least partially attributable to the long follow-up time. Early post-surgery adrenal insufficiency predicts remission. Hypopituitarism was also very prevalent, and strongly associated with radiotherapy. These results lead us to the conclusion that CD needs a life-long strict follow-up.

PMID:

 

24748528

 

[PubMed – as supplied by publisher]

Interview with Stacy, Mom to Possible Cushing’s Patient

Stacy writes in her bio

MacKenna is my daughter.  I am in desperate need of assistance regarding her weight.

She is 6 years old and weighs about 95 pounds.  At four, she was normal to underweight.

First clue – she gained 10 pounds in three months.  Of course doctor’s wanted a food log …. however, as her parent, I knew something was wrong.

So much to say, I NEED to help my baby and am hoping someone on this board can point me to a good pedi endo (I am currently on my second).  I have pictures to show the progression of her changes.  Her growth pattern is abnormal as she does not gain height while she gains weight and vice versa.

I believe it is cyclical cushings.  And if it isn’t, I still need help as this is going to kill her – her little frame cannot hold much more.

 

McKenna’s mom will be interviewed June 11 at 6:00 pm eastern in BlogTalkRadio.  Archives will be available later in the Cushing’s Podcast.

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