The annual meeting of The Endocrine Society, held in San Francisco, June 15th –18th, drew the largest number of attendees in the history of the meeting with over 7,000 attendees. Since 1995, the CSRF has had an exhibit to increase awareness of Cushing’s among endocrinologists and to encourage physicians to mention patient support. While booth traffic was sporadic, a great deal of literature was handed out and a good number of contacts made.
In the technical sessions, which again, were excellent, there was a substantial amount of information relating to Cushing’s. Of primary importance was the presentation of the Endocrine Society Clinical Guidelines for the Diagnosis of Cushing’s Syndrome. These important guidelines were generated by a Cushing’s Task Force sponsored by The Endocrine Society and the European Society for Endocrinology. The task force was chaired by Dr. Lynnette Nieman (NIH, Bethesda, MD) and included Dr. Beverley Biller (Mass Gen Hosp, Boston, MA), Dr. James Findling (Medical College of Wisconsin, Milwaukee, WI), Dr. John Newell-Price (Univ of Sheffield, Sheffield, UK), Dr. Martin Savage (Univ of London, London, UK), Dr. Paul Stewart (University of Birmingham, Birmingham, UK) and Dr. Victor Montori (Mayo Clinic, Rochester, NY). For more information on the guidelines, which are meant to assist all clinical practitioners in diagnosing Cushing’s, see the article that appears in this newsletter. While it is impossible to summarize all the excellent presentations and posters, a few deserve additional mention. In the area of testing, an interesting poster (Thomson SG, et al, Univ of Western Ontario, Canada) demonstrated the measurement of cortisol in 1cm, hair segments that approximate 1 month of hair growth. In one case, increased hair cortisol levels were found 5 mo before the patient reported experiencing symptoms. While further work is ongoing, in the future, such an analysis might be helpful for determining on-set of Cushing’s and evaluating patients suspected of having cyclic Cushing’s. A number of other presentations focused on the usefulness of night-time salivary cortisol to diagnose or rule out Cushing’s, but the long and short of the current status of testing is that there is still no one single test that can diagnose or rule out Cushing’s.
In the area of pituitary tumors, there were a number of presentations dealing with pituitary tumor recurrences and post surgical evaluation. For a number of years, a low post surgical cortisol level has been used to assess whether surgery was successful and the probability of recurrence. While it is generally agreed that a low post surgical cortisol level is indicative of cure, a low cortisol level does not necessarily mean that the tumor will not recur. Likewise, it is generally accepted that a normal cortisol reading following surgery indicates an increased likelihood of recurrence, however this doesn’t necessarily mean that the tumor will recur. One study assessed the use of post-surgical ACTH measurements to indicate likelihood of recurrence (Abdelmannan D, et al, Case Western Reserve, Cleveland, OH). In this study, ACTH measurements during a 48hr period after surgery, clearly separated those patients who recurred versus those that did not; all patients who recurred in 38-66 months had ACTH levels greater than 20ng/L post surgery. Thus, while many further studies are needed, assessment of post-surgical ACTH levels may be a better indicator of the likelihood of recurrence.
Recently, it has become apparent that in a minority of patients, 11% in one series, (Batista DL, Mass Gen Hosp., Boston, MA) there can be a delay in the drop of cortisol following surgery from 8 to 42 days after surgery. In another study, 9.4% of patients showed slow drops in cortisol following surgery (Machado MC, et al, Univ of Sao Paulo, Brazil). Another case study of a delayed drop in cortisol was discussed by Dr. Lewis Blevins (UCSF, San Francisco, CA) in a Meet the Professor session, who suggested waiting 6 weeks before determining further treatment.
It is well accepted that experienced pituitary neurosurgeons achieve cure of Cushing’s in 80-90% of patients, with the cure rate being somewhat lower for macroadenomas. Several studies reported cure rates for second pituitary surgeries. Machado (Univ of Sao Paulo, Brazil) et al reported a cure rate of 38.4% for pituitary tumor recurrences, Vegt-Wagenmakers (Radboud Univ, Netherlands) reported a 61% cure rate and Batista (Mass General Hosp, Boston) reported a 52% cure rate, thus available data does suggest that the likelihood of cure is lower with a second pituitary surgery.
It is well known that following pituitary surgery and/or radiation, patients need to be evaluated for pituitary hormone deficiencies. One very interesting presentation (Ausiello JC, et al, Columbia Univ, NY, NY) presented information that appropriate testing for GH deficiency following pituitary surgery is severely lacking. In completed surveys from 179 people who had pituitary surgery, only 3.4% are taking growth hormone, only 17% were aware that they are at risk of GH deficiency and only 20% report being tested for GH deficiency. The risk for GH deficiency is estimated to increase with the presence of other hormone deficiencies; 46-61% with 1 other deficiency, 70-83% with 2 other deficiencies and > 90% with 3 or more deficiencies. In this study only 6.3% of those with 1 hormone deficiency reported taking GH. This indicates that GH testing and treatment is lacking.
In the area of GH replacement, Behan LA, et al, (Beaumont Hosp, Dublin, Ireland) reported significant short and long term improvements in quality of life with GH replacement in GH deficient patients, with the best improvement demonstrated in those with the lowest quality of life prior to starting GH replacement. Madrazo-Atutxa A, et al (Univ Hosp, Sevilla, Spain) demonstrated improvement in cognitive function and quality of life following GH replacement in GH deficient patients.
From the patient’s perspective, one report (Kennedy, L et al, Univ of Florida, Gainesville, FL) emphasized the need to listen to the patient. In this case, very little supporting biochemical testing supported a recurrence, however the patient insisted that she was recurring. Surgery was performed and was successful.
The subject of Cyclic Cushing’s Disease was discussed by Alexandraki KI, et al (St. Bartholomew’s Hosp, London, UK) and indicated that pre-diagnosis, 9% of 201 patients displayed evidence of cyclic Cushing’s. Cyclical Cushing’s was more prevalent in women (16.8%) as compared to men (8.7%). Ludlum et al (Swedish Med Center, Seattle, WA) reported on differences in pathology findings for cyclical Cushing’s versus primarily adenoma tumors that sustained excess ACTH production and therefore high cortisol levels. Physicians and patients need to be aware that cyclical Cushing’s, while relatively rare, can be important in obtaining a correct diagnosis since testing needs to be done during active hormone production cycles.
Medical therapy for recurrent Cushing’s Disease was discussed in a number of presentations. In one study (Godbout A, et al, CHUM, Montreal, Canada) cabergoline was shown to have long term effectiveness in controlling cortisol levels in 27.5% of 29 patients over an average time of 22 months. A partial response was seen in an additional 17% of cases. Another study (Romanholi DJPC, et al, Hosp das Clins-FMUSP, San Paulo, Brazil) indicated that greater drops in cortisol may be observed with a combination of cabergoline and octreotide than with either medication by itself. A study of 72 patients along with pathology and molecular biology studies of removed tumor tissue (Pivonello R, et al, Federic II Univ, Naples, Italy) showed that the molecular biology of the tumor greatly influences the short and long term response to cabergoline.
Nelson’s Syndrome was discussed by Dr. Xavier Bertagna (Cochin Hosp, Paris, France). Patients with a pituitary tumor who have a bilateral adrenalectomy should be closely followed by MRI and ACTH to provide an early diagnosis of tumor growth. Another study on 1 patient (Bramswig JH, et al, Univ Children’s Hosp, Munster, Germany) reported successful use of Temozolomide to drop ACTH levels and sustain tumor size, as did Nethaji C, et al (Univ Coll Hosp, London, UK), however, further studies are needed. Thus far, retinoic acid has been shown to be effective in animal studies and DeMarco V, et al (Sao Paulo, Brazil) described the effectiveness of retinoic acid treatment of a dog with Nelson’s. ACTH levels were seen to decrease and tumor size decreased.
In the area of Pediatrics, Verma S, et al (NIH, Bethesda, MD) reported that in children, almost all cured patients recovered normal adrenal function within 12 months following pituitary surgery. Lodish MB (NIH, Bethesda, MD) showed that while high blood pressure is reduced in children immediately following cure of Cushing’s Disease, further improvements are seen 1 year post surgery. Prior to surgery, 48% of females and 50% of males were hypertensive. At one year follow up, hypertension was present in 12% of females and 18% of males.
The area of subclinical Cushing’s (lack of typical Cushing’s symptoms) and accidentally discovered adrenal tumors was discussed in numerous presentations. Giordano, et al (Univ of Turin, Italy) studied 73 patients with accidentally discovered adrenal tumors and found a prevalence of 25% of subclinical Cushing’s. However, in 4 patients that had an adrenalectomy, no clinical improvements were noted and in the other patients, no progression of Cushing’s was observed. In a similar study of 386 patients with accidentally discovered adrenal tumors, Ichijo, et al (Toho Univ, Ohashi Hosp., Tokyo, Japan) reported a prevalence of subclinical Cushing’s of 23%. In a Meet the Professor session, Dr. Terzolo (Univ. of Turin, Italy) discussed testing for subclinical Cushing’s, which has not been well defined. The theory is that some patients with subclinical Cushing’s may have detrimental medical conditions related to elevated cortisol, however there is a lack of solid evidence that surgical removal of the adrenal mass improves patient outcomes, thus additional studies are needed. In this session, the suggestion was that tumors over 4 cm should be surgically removed.
Cushing’s caused by medications was highlighted in several presentations. Molimard et al (Univ of Bordeaux, France) reported that adrenal insufficiency can occur in patients treated with inhaled steroids primarily when used in doses exceeding 550 ug/day beclomethasone-equivalents in children and 1000ug/day in adults. Cushing’s symptoms can also occur. Another case report (Patel, et al, Beth Israel Med Center, NY) described a case of adrenal insufficiency caused by multiple epidural injections. Another study (Daniell et al, UC Davis, California) reported DHEA deficiency in adults using inhaled steroids, which could be important for bone and skin health. Cushing’s was also reported in a patient using a steroid containing skin cream in very high doses (Seebus, et al, VU Med Center, Amsterdam).
In the area of adrenalcortical carcinoma, Dr. Allolio (Med Univ Klinik, Wuerzberg, Germany) reported in a symposium that mitotane given after complete removal of the tumor for 2 years and within closely monitored therapeutic ranges can “significantly improve disease free survival”. Results of a clinical trial combining mitotane and chemotherapy agents for severe cases will be available in 2011, however, it is still clear that additional agents are needed. Work towards identifying compounds capable of inhibiting the growth of adrenal cancer cells in culture continues. Barlasker et al (Univ of Michigan, Ann Arbor, MI) discussed the fact IGF II is present in high quantities in a large percentage of adrenalcortical cancers, making the receptor through which it exerts its cellular effects an appealing pharmacological target. An IGF receptor blocker has been studied in mice with good results. Clinical trials in humans are suggested.
Editor’s note: You can read the abstracts yourself at: www.endo-society.org/endo.
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