acromegaly

Acromegaly

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A 34-year-old man who had been admitted to the hospital with diabetic ketoacidosis was noted to have coarse facial features. He had no known medical history but had noted an increase in shoe size by three full sizes over the past 10 years and blurry vision for the past 3 years. Physical examination showed a widened nose, frontal bossing, prominent lower jaw, and malocclusion of the upper incisors (Panel A), findings not seen in a photograph taken 15 years earlier (Panel B). Visual-field testing showed bitemporal hemianopsia. Laboratory studies showed a glycated hemoglobin level of 12.3% (reference range, 5 to 14), an insulin-like growth factor 1 (IGF-1) level of 478 ng per milliliter (reference range, 53 to 331), and a growth hormone level of more than 65 ng per milliliter (reference value, ≤7.1). A diagnosis of acromegaly was made. Magnetic resonance imaging of the head revealed a pituitary macroadenoma measuring 6.0 cm by 3.4 cm by 2.8 cm (Panel C, asterisk) and macroglossia. Transsphenoidal partial tumor resection was performed. Histopathological testing showed a somatotroph adenoma (Panel D, hematoxylin and eosin staining) that also stained positive for growth hormone. The patient was discharged with instructions to receive monthly octreotide to treat residual tumor and with medications for diabetes and hypertension. At 1 month of follow-up, the patient’s IGF-1 level had reduced, but the mass gradually reexpanded, which led to a second resection 8 months after the initial surgery.

SOURCE: NEJM

Acromegaly associated with late-onset diabetes

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Uncontrolled, persistent acromegaly is a strong predictor of incident type 2 diabetes, whereas disease diagnosis at an older age, and not disease activity, was associated with hypertension and major adverse cardiac events, according to a recent analysis.

“These findings suggest that the lack of a tight control of acromegaly activity plays a central role in the development of metabolic complications, whereas older age at diagnosis of disease influences the development of cardiovascular complications and events,” Fausto Bogazzi, MD, PhD, associate professor of endocrinology at University of Pisa, Italy, and colleagues wrote. “In addition, being overweight or obese and [a] smoking habit increased the [CV] risk in acromegalic patients as in the general population.”

Fausto Bogazzi

Fausto Bogazzi

In a retrospective study, Sardella and colleagues analyzed medical records from 200 patients with acromegaly referred to the endocrinology section of the department of clinical and experimental medicine at University of Pisa between 1974 and 2014 (58.5% women). Using Cox regression analysis, researchers evaluated incidents of diabetes, hypertension and major adverse cardiac events. Each patient was included in the analysis of a specific outcome, unless they were affected when acromegaly was diagnosed. Patients were further classified as being in remission after pituitary adenomectomy, controlled by somatostatin analogue therapy or not controlled by somatostatin analogue therapy.

At diagnosis, 64 patients (32%) had diabetes 93 patients (46.5%) had hypertension and 17 patients (8.5%) already experienced a CV event.

After a diagnosis of acromegaly, diabetes occurred in 40.8% of patients. Researchers found that patients not controlled by somatostatin analogue therapy had a higher risk for diabetes vs. those who underwent adenomectomy (HR = 3.32; P = .006), whereas those well controlled with somatostatin analogue therapy had a 1.4-fold higher risk (P = .38) for diabetes vs. the adenomectomy group.

“It has been reported that [somatostatin analogue therapy] can worsen glucose metabolism by inhibiting insulin secretion and may be less effective than pituitary surgery in reducing the risk for death in patients affected by diabetes,” the researchers wrote. “However, it is possible that the relatively small number of patients included in the study affected the power of the analysis.”

Researchers found that age (HR = 1.06, P = .01) and BMI (HR = 1.05; P = .01) were predictors of hypertension, which occurred in 35.5% of patients after acromegaly diagnosis. Age (HR = 1.09; 95% CI, 1.02-1.17) and smoking (HR = 5.95; 95% CI, 1.52-25.26) were predictors of major adverse CV events, which occurred in 11.8% of patients after diagnosis. Therapy for acromegaly did not influence hypertension or major adverse CV events, according to researchers.

“Our study pointed out that the control of acromegaly activity is necessary but is not the only target in the whole management of patients with this rare syndrome,” Bogazzi told Endocrine Today. “The cure (and prevention) of systemic complications of acromegaly is the mainstay of the therapeutic strategy and should include prevention of hypertension, diabetes, cessation of smoking and a weight loss program. All those objectives did not differ from those advocated for non-acromegalic patients.” – by Regina Schaffer

GH therapy increases fracture risk in patients previously treated for acromegaly

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Adult patients with severe growth hormone deficiency previously treated for acromegaly saw an increased fracture risk after 6 years of growth hormone replacement therapy, whereas those previously treated for Cushing’s disease did not experience the same risk, according to a recent observational study.

Nadege C. van Varsseveld, MD, of the department of internal medicine at VU University Medical Center in Amsterdam, and colleagues analyzed data from 1,028 patients with previous nonfunctioning pituitary adenoma (NFPA; n = 783), acromegaly (n = 65) and Cushing’s disease (n = 180), identified through the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide, long-term surveillance study in patients with severe GH deficiency. Data were collected biannually from medical records through 2009. Baseline DXA measurements were available for 414 patients; 71 (17.1%) had osteoporosis at one or more of the measured sites; 147 (35.5%) had osteopenia.

During a mean follow-up of 5.2 years, researchers found that 166 of patients with previous NFPA were prescribed osteoporosis medications (21.3%), as were 69 patients with previous Cushing’s disease (38.5%) and 22 patients with previous acromegaly (33.4%). During follow-up, 39 patients experienced fractures (3.8%; 32 experiencing one fracture), including 26 patients in the previous NFPA group, eight patients in the previous Cushing’s disease group and five patients in the previous acromegaly group. The median time between baseline and first fracture was 2.4 years (mean age, 59 years).

Researchers found that fracture risk did not differ between groups before 6 years’ follow-up. Fracture risk increased in patients with previous acromegaly after 6 years’ follow-up, but not for those with previous Cushing’s disease vs. patients with NFPA. Results persisted after adjustment for multiple factors, including sex, age, fracture history and the extent of pituitary insufficiency.

The researchers noted that patients with previous Cushing’s disease were younger and more often women and had a greater history of osteopenia or osteoporosis, whereas patients with acromegaly had a longer duration between tumor treatment and the start of GH therapy and were treated more often with radiotherapy.

“During active acromegaly, increased bone turnover has been observed, but reported effects on [bone mineral density] are heterogeneous,” the researchers wrote. “It is postulated that cortical BMD increases, whereas trabecular BMD decreases or remains unaffected.

“The increased fracture risk in the present study may be a long-term effect of impaired skeletal health due to previous GH excess, even though this was not reflected by an increased occurrence of osteopenia or osteoporosis in the medical history,” the researchers wrote. – by Regina Schaffer

Ghrelin paralleled adiposity increase after acromegaly surgery

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The rise in total ghrelin found to accompany some remaining cardiovascular risk markers and adiposity increase in patients with acromegaly remission after surgery could be interrelated, according to research published in The Journal of Clinical Endocrinology & Metabolism.

“Our prospective study found increases in weight and central adiposity after surgery for acromegaly along with reductions in many, but not all, markers of cardiovascular risk,” the researchers wrote. “Ghrelin levels rose in parallel with the less favorable anthropometric profile, novel evidence of a possible relationship of ghrelin to the increase in adiposity that follows surgical treatment of acromegaly mechanisms and long-term implications of changes with acromegaly treatment.”

At tertiary referral centers for pituitary tumors, Carlos Reyes-Vidal, MD, of the Columbia University College of Physicians and Surgeons, New York, and colleagues looked at 42 adults who had untreated active acromegaly before surgery.

The researchers evaluated changes in outcome measures from before to after surgery in 26 patients who achieved remission, or normal insulin-like growth factor I and 16 patients whose active acromegaly, or elevated IGF-I, persisted.

By 6 months, patients with remission had increases in total ghrelin, body weight, waist circumference, C-reactive protein, homocysteine, HDL and leptin, and decreases in systolic blood pressure, homeostasis model assessment, triglycerides and lipoprotein(a); the changes remained for 32 ± 4 months after surgery. Higher ghrelin correlated with the reduced levels of growth hormone, IGF-I and insulin and insulin resistance.

Patients with persistent active acromegaly did not demonstrate significant increases in weight, waist circumference and ghrelin. In 15 patients with remission, total body fat, trunk fat and percentage total body fat increased by 1 year after surgery: Increase in body fat correlated with increase in total ghrelin.
“It is unknown whether the changes represent a readjustment to the anthropometric and cardiovascular risk profile they would have were they not to have acromegaly,” the researchers wrote. “Further investigation into the mechanisms of these changes and their long-term implications is warranted.”

Stereotactic radiosurgery yielded favorable remission of acromegaly.

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Stereotactic radiosurgery may yield favorable remission response rates in patients with acromegaly with a low rate of adverse events, according to data published in the Journal of Clinical Endocrinology and Metabolism.

  • Surgical resection is currently the primary treatment for patients with acromegaly, according to researchers. The rates of endocrine remission relate to tumor size, degree of invasiveness and surgical expertise, the researchers wrote.

They conducted a retrospective review of 136 patients (mean age, 44 years) withacromegaly treated with stereotactic radiosurgery at the University of Virginia. Gamma Knife radiosurgery data were collected from 1989 to 2012.

Follow-up data at 61.5 months indicated that 65.4% of the patients reached remission of acromegaly, with a mean time to remission of 27.5 months.

Specifically, there was a 31.7% remission rate at 2 years, 64.5% at 4 years, 73.4% at 6 years and 82.6% at 8 years after radiosurgery, according to data.

After the withdrawal of growth hormone or insulin-like growth factor I medications, patients with an oral glucose tolerance test GH level <1 ng/mL or normal IGF-I were considered to be in remission, researchers wrote.

Favorable prognostic factors for remission included higher radiation combined with maximum dose and lower initial IGF-I levels, according to data.

“Hypothalamic-pituitary dysfunction is the most common intermediate to late complication of [stereotactic radiosurgery] of pituitary adenomas. In our series, 31.6% patients developed new hormone deficiency at a median of 50.5 months following radiosurgery,” researchers wrote.

Two patients (1.5%) developed panhypopituitarism. Other risk factors for pituitary hormone deficiencies included a margin dose >25 G and tumor volume >2.5 mL. An adverse radiation effect was observed in one patient, visual deterioration in four, and new oculomotor nerve palsy in one. Seven patients who reached remission after surgery developed a recurrence of the disease at 42 months.

 

 
 

PERSPECTIVE

John D. Carmichael

  • Acromegaly is a difficult disease to treat in many cases. The patients’ clinical experiences range from those which are mild and straight-forward to those with aggressive tumors, very challenging biochemistry, and disease attributes that require multimodal therapy. It’s good to see a large study like this reporting on radiotherapy outcomes and safety, which is one part of our treatment armamentarium.

    The response rates that they report are encouraging in terms of the biochemistry because there are patients who do require more aggressive treatment than just surgery or medication.

    I think the difficulties of such a study are that long-term follow-up is challenged with treatment performed through a tertiary referral center, and as they acknowledge in their paper, they rely on other endocrinologists’ data in some cases and are unable to obtain complete data sets. This might be one of the shortcomings of the study: that sometimes, the tests that you want to complete don’t always get done in terms of both safety assessments and assessments of recurrence.

    In general, they compare their findings to both prior radiosurgery techniques and to prior conventional radiotherapy. I think that many people are hoping that the gamma knife radiosurgery will have significantly improved response rates and a better safety profile in terms of hypopituitarism and damage to adjacent structures.

    The authors have shown that their response rates are satisfactory enough to consider radiosurgery as a viable treatment. Unfortunately, the hypopituitarism demonstrated in these patients is comparable to prior reports of radiotherapy-induced hypopituitarism and practitioners are concerned about this adverse effect. These data are not going to make gamma knife radiosurgery more appealing to those who are concerned about the effects of hypopituitarism. The use of radiotherapy is a divisive topic in the treatment of patients with acromegaly and physicians have very strong opinions about the use and the timing of this mode of therapy. Some may utilize it earlier on in the care of patients, so that a patient will directly be treated with radiosurgery after failed transsphenoidal surgery, as many of the patients were in this study. Alternatively, one may use radiosurgery only in those resistant to medical therapy and unable to gain biochemical or tumor control.

    The follow-up for patients treated with radiosurgery does require longer duration of observation and while this group has some of the longest follow-up compared to other studies, nevertheless more time is required for safety assessments such as development of secondary tumors and hypopituitarism.

    • John D. Carmichael, MD
    • Assistant Professor of Medicine in the Division of Endocrinology, Diabetes and Metabolism at the David Geffen School of Medicine at the University of California, Los Angeles; and
      Staff Physician of Endocrinology/Metabolism at Cedars-Sinai Medical Center

Comparative effectiveness review of treatment options for pituitary microadenomas in acromegaly.

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Acromegaly, a syndrome of excess growth hormone (GH) secretion typically caused by a GH-secreting pituitary adenoma, reduces life expectancy by approximately 10 years when left untreated. Treatment of acromegaly involves combinations of one or more discrete therapeutic modalities to achieve biochemical control. Unfortunately, data capable of informing decisions among alternate management strategies are presently lacking.

Methods

The authors performed a comparative effectiveness research (CER) review integrating efficacy, cost, and quality of life (QOL) analysis for treatment strategies comprising various combinations of surgery, radiotherapy, stereotactic radiosurgery, and pharmacotherapy in patients with acromegaly caused by a pituitary microadenoma. A management decision tree was used to identify 5 treatment strategies, each with up to 4 potential treatment steps. Efficacy was assessed using recent literature reports of biochemical control rates for each modality. Cost estimations were derived from wholesale drug prices and from the Healthcare Cost and Utility Project. Quality of life data were obtained from studies utilizing the Acromegaly Quality of Life Questionnaire.

Results

Individual treatment modalities were analyzed and ranked in each of 3 domains: highest rate of success, lowest cost, and highest QOL, and these scores were combined to facilitate comparison of overall effectiveness of each of the management strategies. These aggregate effectiveness scores were used to compare the 5 strategies from the decision tree, and a novel strategy was also proposed.

Conclusions

The choice of management strategy must be individualized for each patient with acromegaly. This CER analysis provides a comprehensive framework to inform clinical decisions among alternate management strategies in patients with GH-secreting pituitary microadenomas.

Source: Journal of neurosurgery.