Study Examines Therapy Options for Post-adrenalectomy Low Glucocorticoid Levels

Hydrocortisone and prednisone have comparable safety and effectiveness when used as glucocorticoid replacement therapy in patients with adrenal adenoma or Cushing’s disease who underwent adrenalectomy, a new study shows.

The study, “Comparison of hydrocortisone and prednisone in the glucocorticoid replacement therapy post-adrenalectomy of Cushing’s Syndrome,” was published in the journal Oncotarget.

The symptoms of Cushing’s syndrome are related to excessive levels of glucocorticoids in our body. Glucocorticoids are a type of steroid hormones produced by the adrenal gland. Consequently, a procedure called adrenalectomy – removal of the adrenal glands – is usually conducted in patients with Cushing’s syndrome.

Unfortunately, adrenalectomy leads to a sharp drop in hormones that are necessary for our bodies. So, post-adrenalectomy glucocorticoid replacement therapy is required for patients.

Hydrocortisone and prednisone are synthetic glucocorticoids that most often are used for glucocorticoid replacement therapy.

Treatment with either hydrocortisone or prednisone has proven effective in patients with Cushing’s syndrome. However, few studies have compared the two treatments directly to determine if there are significant advantages of one therapy over another.

Chinese researchers set out to compare the effectiveness and safety of hydrocortisone and prednisone treatments in patients with Cushing’s syndrome, up to six months after undergoing adrenalectomy.

Patients were treated with either hydrocortisone or prednisone starting at day two post-adrenalectomy. The withdrawal schedule varied by individual patients.

At baseline, both groups had similar responses to the adrenalectomy, including the correction of hypertension (high blood pressure), hyperglycemia (high blood glucose levels), and hypokalemia (low potassium levels). Furthermore, most patients in both groups lost weight and showed significant improvement, as judged by a subjective evaluation questionnaire.

Hydrocortisone did show a significant advantage over prednisone in the improvement of liver function, but its use also was associated with significant swelling of the lower extremities, as compared to prednisone.

Patients in both groups went on to develop adrenal insufficiency (AI) during glucocorticoid withdrawal. However, there were no significant differences in the AI incidence rate – 35 percent in the hydrocortisone group versus 45 percent in the prednisone group. The severity of A also was not significantly different between the groups.

Furthermore, most of the AI symptoms were relieved by going back to the initial doses of the glucocorticoid replacement.

As there were no significant differences between the two treatments, the findings support “the use of both hydrocortisone and prednisone in the glucocorticoid replacement therapy post-adrenalectomy for patients of adrenal adenoma or Cushing’s disease,” researchers concluded.

From https://cushingsdiseasenews.com/2018/01/11/post-adrenalectomy-glucocorticoid-replacement-therapy/

Intraoperative MRI improves complete resection of pituitary macroadenoma

A 63-year-old man was referred to the Massachusetts General Hospital Neuroendocrine & Pituitary Tumor Clinical Center for management of a pituitary macroadenoma. He experienced increasingly severe retro-orbital headaches in the past year. He reported no double vision, fatigue, orthostatic dizziness, change in beard growth or reduction in libido. An outside head CT scan showed an enlarged pituitary gland.

Imaging and laboratory tests

A pituitary MRI with magnified pituitary slices and gadolinium contrast was ordered. A well-circumscribed “snowman-shaped” sellar mass was identified, measuring 2.6 cm x 2 cm x 1.8 cm (anteroposterior x transverse x craniocaudal) with suprasellar extension (Figure 1). The lesion was heterogeneous on T1-weighted scans after enhancement with IV gadolinium contrast. An area of hypointensity in the superior margin was consistent with a small area of cystic or hemorrhagic degeneration.

Although the mass did not extend laterally into the cavernous sinus, the sellar mass extended upward into the suprasellar cistern through a hole in the dural, the diaphragma sellae, to compress the optic chiasm. The restriction of adenoma growth by the diaphragma sellae results in the snowman shape of the macroadenoma. The optic chiasm and infundibulum (pituitary stalk) could not be identified on coronal or sagittal images (Figure 1). Visual field on confrontation suggested lateral field deficits (bilateral lateral hemianopsia) that were confirmed on formal Goldmann kinetic perimetry visual fields.

Figure 1. Preoperative MRI scan. A large “snowman-shaped” pituitary adenoma (green arrow) has heterogeneous enhancement after gadolinium contrast administration. A small hypodense area in the adenoma likely represented hemorrhage/cystic degeneration (yellow arrow). The tumor does not surround the carotid siphon, an S-shaped portion of the internal carotid artery (red arrows) within the cavernous sinus located laterally from the sella turcica where the pituitary gland resides. (A) Coronal image. (B) Sagittal image. Abbreviation: SS = spenoid sinus.

Source: Stephanie L. Lee, MD, PhD, ECNU. Reprinted with permission.

Initial hormonal evaluation was normal and included morning adrenocorticotropic hormone 18 pg/mL, cortisol 13.64 µg/dL, thyroid-stimulating hormone 2.14 uIU/mL, free thyroxine 1.2 ng/dL and prolactin 12.6 ng/mL. The patient’s morning testosterone level was normal at 324 ng/dL, with follicle-stimulating hormone 2.4 mIU/mL and luteinizing hormone 1.6 mIU/mL. His insulin-like growth factor I level was normal at 124 ng/mL.

Tumor resection

The patient was treated preoperatively with stress-dose hydrocortisone 50 mg. He then underwent transsphenoidal pituitary tumor resection. After the surgeon believed there was an adequate excision of the tumor, the extent of tumor resection was confirmed by an intraoperative MRI (Figure 2 on page 8).

Figure 2. Intraoperative MRI scan. The large macroadenoma is not seen after transsphenoidal surgery. The optic chiasm (yellow arrow) can be seen after removal of the tumor. (A) Coronal image. (B) Sagittal image. Abbreviation: SS = spenoid sinus.

The operation was concluded after the imaging confirmed the complete resection of the pituitary adenoma. The patient’s postoperative course was uneventful. Imaging 4 weeks after the resection confirmed complete resection of the suprasellar mass with residual enhancement of the resection bed and sphenoid sinuses (Figure 3 on page 8). The postoperative MRI revealed a normal optical chiasm and a downward tending of the infundibulum to the residual pituitary gland located inferiorly along the sella turcica (pituitary fossa) of the sphenoid bone. Pathology confirmed a pituitary adenoma. His anterior and posterior pituitary function were normal 6 weeks postoperatively, and his visual field deficit improved.

Intraoperative MRI

Imaging like that used in this case occurs in a specially designed operating room that allows MRI scans during surgery without moving the patient from the surgical table. The MRI is kept in a shielded enclosure during the procedure and then moved along a track into the operating room for imaging. Clinical indications for the use of intraoperative MRI in neurosurgery include resection of pituitary macroadenomas. In the past, these tumors underwent transsphenoidal resection, and the postoperative MRI was performed after 1 or more days after the procedure to check for complete removal. If residual tumor was found, the patients underwent watchful waiting, external radiation or repeat surgery.

The strategic advantage of an intraoperative MRI is that the imaging is performed during the operative procedure, and if there is any residual tumor, surgery can be resumed after the MRI is moved back into the shielded enclosure.

Figure 3. Four-week postoperative MRI scan. The large macroadenoma is not seen after the transsphenoidal survey. The optic chiasm and infundibulum (pituitary stalk) can be seen after resection of the tumor. The pituitary stalk is deviated to the left of the sella where the residual normal thyroid is locate along the sella turcica. The floor of the sella enhances with gadolinium infusion after surgery due to postoperative inflammation. (A) Coronal image. (B) Sagittal image. Abbreviation: SS = spenoid sinus.

It has been reported that the use of intraoperative MRI does not increase complication rates compared with conventional transsphenoidal surgery. Reports on the improvement of gross tumor resection using intraoperative MRI are variable, perhaps due to the expertise of the surgeon. Several reports suggest the use of intraoperative MRI allowed additional resection of noninvasive macroadenomas in 67% to 83% of the patients with a gross tumor resection. These results suggest that a substantial volume reduction and increased gross tumor resection of pituitary macroadenomas occurs with the use of intraoperative MRI compared with standard surgery. One study demonstrated that the gross tumor resection rates of invasive tumors was also improved with the use of intraoperative MRI compared with usual preoperative imaging and surgery (25% vs. 7%).

The use of intraoperative MRI, especially with transsphenoidal reoperations for invasive and noninvasive pituitary macroadenomas, leads to significantly higher “gross tumor resection” rates. This method prevents additional operations or treatment, such as radiation, because it reduces the number of patients with residual adenoma after surgery. This technology is usually found in specialized tertiary care hospitals but should be considered for reoperation for large pituitary macroadenomas or initial operation for large invasive pituitary macroadenomas.

Disclosures: Lee and Swearingen report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/print/endocrine-today/%7B23183444-4d29-477b-844f-6eb995ac74f4%7D/intraoperative-mri-improves-complete-resection-of-pituitary-macroadenoma

Health Care Expenditure Burden High in Adrenal Insufficiency

Patients with adrenal insufficiency may accrue substantial health care costs and have more hospital stays and outpatient visits compared with healthy controls, according to findings published in the Journal of the Endocrine Society.

Candace Gunnarsson, PhD, vice president of health economics and outcomes research at CTI Clinical Trial and Consulting in Cincinnati, and colleagues evaluated data from a U.S.-based payer database on 10,383 patients with adrenal insufficiency to determine the estimated annual health care burden among them.

Participants were divided into groups based on their type of adrenal insufficiency: primary adrenal insufficiency (n = 1,014), adrenal insufficiency secondary to pituitary disease (n = 8,818) or congenital adrenal hyperplasia (n = 551). A group of matched controls was also evaluated for comparison.

Total annual health care expenditures were significantly higher in the primary adrenal insufficiency group ($18,624 vs. $4,320), adrenal insufficiency secondary to pituitary disease group ($32,218 vs. $6,956) and the congenital adrenal hyperplasia group ($7,677 vs. $4,203) compared with controls. The adrenal insufficiency secondary to pituitary disease group had the highest health care expenditure estimated with an incremental health care burden of $25,262, followed by the primary adrenal insufficiency group ($14,304) and the congenital adrenal hyperplasia group ($3,474).

Compared with controls, participants with adrenal insufficiency spent eight to 10 times more days in the hospital and had up to twice as many outpatient visits per year.

“When comparing [adrenal insufficiency] patients within each cohort based on their drug regimen, patients receiving prednisone therapy vs. hydrocortisone therapy had significantly higher total annual expenditures in the [primary adrenal insufficiency] and [congenital adrenal hyperplasia] and significantly lower total expenditures in the [pituitary disease] cohort,” the researchers wrote. “Patients taking only hydrocortisone and meeting the threshold of 50% adherence were found to have lower expenditures when medication adherence was 75% or higher.” – by Amber Cox

Disclosure: Gunnarsson reports being an employee of CTI Clinical Trial and Consulting. Please see the full study for a list of all other authors’ relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B8f92bd0c-0c72-4902-beb5-663c356a61cb%7D/health-care-expenditure-burden-high-in-adrenal-insufficiency

Exogenous Cushing’s syndrome due to a Chinese herbalist’s prescription of ointment containing dexamethasone

BMJ Case Reports 2017; doi:10.1136/bcr-2016-218721

Summary

Eczema in children is a chronic disabling condition. The impact of this condition on the lives of families is often underestimated by conventional physicians. As a consequence parents may investigate complementary treatment options. Close monitoring by a paediatrician is essential, considering that a variety of adverse effects can occur during the use of complementary treatment.

We present a 5-year-old girl with eczema. She visited a Chinese herbalist who prescribed an ointment. The parents noticed that the eczema resolved fast, itching decreased and she was finally sleeping well. However, her behaviour changed and appetite increased. Undetectable levels of serum cortisol were found, which was indicative of exogenous Cushing’s syndrome. Analysis of the ointment revealed the presence of dexamethasone.

Hydrocortisone substitution and subsequently a reduction schedule were implemented, after which endogenous cortisol production recovered after 4 months. Physicians should be aware that unregistered herbal medicine can contain potent drugs such as glucocorticoids.

Read more at http://casereports.bmj.com/content/2017/bcr-2016-218721.short?rss=1

 

Prednisolone May Raise Cholesterol in Adrenal Insufficiency

Prednisolone treatment of patients with adrenal insufficiency is associated with significantly elevated total-and low-density-lipoprotein (LDL) cholesterol levels compared with use of an alternative glucocorticoid, hydrocortisone, new data suggest.

Real-world data from the European Adrenal Insufficiency Registry (EU-AIR) were presented on April 2 here at ENDO 2017: The Endocrine Society Annual Meeting by Robert D Murray, MBBS, consultant endocrinologist and honorary associate professor at Leeds Teaching Hospitals NHS Trust, United Kingdom.

In an interview, Dr Murray told Medscape Medical News, “In addition to previous data showing that prednisolone can cause lower bone mass, we’ve now shown that it may raise cholesterol to a higher degree than hydrocortisone.”

Asked to comment, session moderator Constantine A Stratakis, MD, chief medical officer of the National Institute of Child Health & Human Development, Bethesda, Maryland, said: “These are significant findings. I think that the difference he’s seeing may be mostly due to the differences in how glucocorticoids are metabolized locally in the liver and fat tissues.”

Regarding clinical implications, Dr Stratakis said, “These data point to the need for using hydrocortisone. Clearly, at these doses anyway, you have increases in LDL and cholesterol with prednisolone.”

Indeed, the new findings support recent recommendations from the Endocrine Society to use hydrocortisone as first-line glucocorticoid replacement therapy for primary adrenal insufficiency.

But the huge cost difference between the two generic medications has led some to suggest otherwise. In 2014, the BMJ published editorials arguing both for and against the preferred use of prednisolone.

During his presentation, Dr Murray reported that in the United Kingdom, an annual supply of 5-mg prednisolone (one tablet a day) costs about £16 and 3 mg (three 1-mg tablets a day) about £48, compared with £1910 for a year’s supply of twice-daily 10-mg hydrocortisone.

(Hydrocortisone is also considerably more expensive than prednisolone in the United States, although the differential isn’t quite as dramatic.)

Dr Murray pointed out that about 75% of the patients in the database were taking 5 mg/day of prednisolone and that although that’s within the recommended range (3–5 mg/day), it might be too much. “I suspect this isn’t related to the steroid use, but that we may actually have gotten the doses wrong, and we may need a smaller dose of prednisolone. I think probably in reality the ideal dose is probably nearer to 3.5 to 4 mg. Therefore, I think we may be slightly overtreating these people and both the bone mass and the cholesterol may be a reflection of that.

“I think for now we have to stay with hydrocortisone as our mainstay of treating adrenal insufficiency, but I think more studies need to be done in patients taking 3.5 to 4.0 mg to then look at the effects on cholesterol, bone mass, and other markers….It would be quite a significant saving if we were able to move patients to prednisolone,” he added.

Dr Stratakis commented, “I have to say the price difference to me is amazing.” Asked about Dr Murray’s dose hypothesis, he responded, “It is possible we may be giving more prednisolone than we should. Also, there might be important differences in the handling of glucocorticoids at the tissue level, in fat and liver, specifically, that we don’t account for.”

Hydrocortisone vs Prednisolone

Beginning his presentation, Dr Murray noted that data on risk factors for cardiovascular disease in patients with adrenal insufficiency treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality, and so in this analysis he and his colleagues aimed to address this gap in the literature.

EU-AIR is a prospective, observational study, initiated in August 2012 to monitor the long-term safety of glucocorticoids in patients with adrenal insufficiency, and of 946 enrolled — in Germany, the Netherlands, Sweden, and the United Kingdom — 91.8% were using hydrocortisone for glucocorticoid replacement therapy compared to just 6.8% using prednisone, with marked heterogeneity in doses and frequency and timing of dosing (Endocrine Abstracts. 2015: DOI:10.1530/endoabs.37.EP39).

Other previous studies have found lower bone mass at the hip and spine with prednisolone compared with hydrocortisone-treated patients, but no quality-of-life difference between the two treatments, Dr Murray said.

The current study is the first patient-matched analysis of cardiovascular-risk-factor differences for the two glucocorticoid therapies. Patients were excluded if they were receiving more than one glucocorticoid, had congenital adrenal hyperplasia, were receiving modified-release hydrocortisone, or were receiving prednisolone or hydrocortisone doses outside the Endocrine Society’s recommended ranges.

Prior to matching, the 909 hydrocortisone patients were significantly more likely to be female, to have primary adrenal insufficiency, to be older, and to have longer disease duration. After matching three hydrocortisone patients for every one taking prednisolone, the 141 hydrocortisone and 47 prednisolone patients were similar for those factors: 62% were female, 40% had primary adrenal insufficiency, average age was around 59 years, and disease duration 23 years.

Both total cholesterol and LDL levels were significantly higher, at 6.3 and 3.9 mmol/L, respectively, in the prednisolone group compared with 5.4 and 3.2 mmol/L for hydrocortisone (both P < .05). However, there were no significant differences in rates of hypertension, diabetes (of either type), blood pressure, triglycerides, or HDL cholesterol.

In subgroup analysis, both total and LDL cholesterol were elevated among patients with primary adrenal insufficiency taking prednisolone, but among those with only secondary adrenal insufficiency, just total cholesterol was elevated with prednisolone.

Dr Stratakis told Medscape Medical News, “It is peculiar for me to see that the only difference he found from all the parameters he measured were in lipids, and specifically total cholesterol and LDL. I think the difference is tissue-specific.”

Dr Murray said it’s certainly plausible that the current prednisolone dosing is too high for two reasons: First, in the United Kingdom prednisolone comes in 1-mg and 5-mg tablets, so taking 5 mg/day is simpler than taking the lower end of the recommended range.

Second, “hydrocortisone is cortisol, so you know what the body produces and about what your levels should be, but you can’t do that with prednisone because it’s an analog. So, we’re guessing, and I think we’ve guessed too high.”

Dr Murray is a speaker and consultant to Shire. Disclosures for the coauthors are listed in the abstract. Dr Stratakis has no relevant financial relationships.   

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ENDO 2017. April 2, 2017; Orlando, Florida. Abstract OR03-5

 

From http://www.medscape.com/viewarticle/878097

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