Radiotherapy in acromegaly: the argument against

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73294/1/j.1365-2265.2003.01704.x.pd

Acromegalic Arthropathy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47506/1/11102_2004_Article_5093754.pd

Acromegaly

In the majority of cases, acromegaly is due to GH hypersecretion by a somatotroph pituitary tumor. The etiology of acromegaly is not known, and may be related to GHRH hypersecretion, intrinsic pituitary defect, or a combination thereof. Recent physiologic data and molecular biology techniques provide insights into the pathophysiology of this condition. Treatment options include surgery, radiation, and judicious administration of pharmacologic compounds inhibiting GH secretion and tumor growth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29921/1/0000278.pd

Gene Expression Signature in Adipose Tissue of Acromegaly Patients.

To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly

Medical Management of Growth Hormone-Secreting Pituitary Adenomas

The primary treatment of acromegaly remains transsphenoidal adenomectomy, yet the tissue overgrowth of acromegaly often progresses following surgery, and responds to radiotherapy only after significant delay. Persistently elevated serum growth hormone (GH) and insulin-like growth factor-I (IGF-I) concentrations can be normalized in about half of post-surgery acromegalics using the pharmacologic alternatives presently available, the dopamine agonists (DA) and somatostatin (SST) analogs. Cabergoline, the most efficacious DA, normalizes IGF-I in approximately 37% of patients, whereas the long-acting SST analogs, Octreotide LAR and Lanreotide SR, do so in 66%. Significant tumor shrinkage may be attained with SST analogs in particular, and when necessary, the primary medical treatment of acromegaly may be successfully addressed with this class of drugs. Greatly enhanced efficacy is expected from the GH receptor antagonist pegvisomant, which is nearing market availability and will enable the normalization of serum IGF-I in virtually all patients treated. We review here the pharmacologic treatments of excessive GH secretion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47513/1/11102_2004_Article_5115783.pd

Pergolide As Primary Therapy for Macroprolactinomas

The objective of this study is to determine whether pergolide therapy is an effective modality for the de novo treatment of patients with macroprolactinomas. Twenty-two consecutive patients with macroprolactinomas were included in the study and followed prospectively. These included 16 men and 6 women in whom pregnancy was not of concern. Pergolide was administered once or twice a day depending on the patient's preference. Ten patients received 0.1 mg daily as a maintenance regimen and in the others the daily dose ranged from 0.05 to 0.5 mg. Eight patients reported minor but tolerable side effects. One patient had to be switched to cabergoline because of intolerable nausea. After a mean of 12 months (range, 3–36), mean PRL levels declined from 3,135 ng/ml (range, 126–31,513) to 50 ng/ml (3–573), representing a mean PRL suppression of 88% (range, 0–99). PRL levels became normal in 15 patients and decreased to 25–40 ng/ml in 3 others. The mean tumor volume shrinkage was 25% or greater in 19 patients (86%), 50% or greater in 17 patients (77%), and 75% or greater in 10 patients (45%). Visual abnormalities were reversible after pergolide therapy in all but 1 of 12 patients with initially abnormal formal visual testing. Two out of 4 premenopausal women did not normalize PRL levels and had persistent oligomenorrhea. Testosterone was low in 14 men at presentation and normalized in 3 with pergolide therapy. We conclude that pergolide is a safe, inexpensive, and generally well-tolerated dopamine agonist for the treatment of macroprolactinomas in men and women in whom pregnancy is not of concern. In these specific populations, pergolide may become the first-line therapy for treatment of macroprolactinomas.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47496/1/11102_2004_Article_382165.pd

Rapid Re-expansion of a Macroprolactinoma After Early Discontinuation of Bromocriptine

Prolactin (PRL)-secreting pituitary adenomas are the most common functioning pituitary tumors. Medical treatment with dopamine agonists is the therapy of choice for macroprolactinomas (≥10 mm). Withdrawal of bromocriptine after weeks or months of uninterrupted therapy has been associated with rapid tumor re-expansion as evidenced by x-ray and CT scanning of the pituitary region. We report a patient with a giant macroprolactinoma who had a dramatic response to bromocriptine (tumor volume shrinkage of 53% within a month) but rapid re-expansion to its original dimensions one week after discontinuation of bromocriptine. To our knowledge, this is the first time that the rapid shrinkage/re-expansion of a macroprolactinoma has been documented with serial MRI scans.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47493/1/11102_2004_Article_324060.pd

Growth Hormone (GH) Secretion in Primary Adrenal Insufficiency: Effects of Cortisol Withdrawal and Patterned Replacement on GH Pulsatility and Circadian Rhythmicity

We studied the effects of cortisol withdrawal and patterned replacement upon spontaneous GH secretion and circadian rhythmicity in 7 patients with Addison's disease. Hydrocortisone was administered in physiological daily total dosages, and all resulting plasma cortisol values were 2–15 μg/dl. It was given in 3 pulsatile modes: simulating “physiological” rhythm, “reverse” diurnal rhythmicity and “continuous” pulsatility. All modes of cortisol administration increased mean 24h, GH pulse amplitude and interpulse GH levels. During saline infusions circadian GH rhythmicity was preserved, with GH being at its highest between 2400–0400 h. Administration of hydrocortisone in any mode did not modify circadian GH rhythmicity. We conclude: Cortisol replacement in physiological daily doses increases GH output in patients with Addison's disease by augmenting GH pulse amplitude and interpulse levels. This is likely due to the attenuation of hypothalamic somatostatin (SRIF) secretion by physiologic levels of cortisol. By inference, it implies that cortisol deficiency leads to diminution of GH output with low GH pulse amplitude, likely as a result of an augmented hypothalamic somatostatin secretion. However, circadian rhythmicity of GH secretion is glucocorticoid-independent.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47487/1/11102_2004_Article_324056.pd

Effect of chronic octreotide treatment on intestinal absorption in patients with acromegaly

The adverse gastrointestinal effects of octreotide, a synthetic analog of somatostatin, have not been fully elucidated. Low-dose octreotide frequently causes adverse gastrointestinal symptoms in normal individuals. We investigated the adverse gastrointestinal effects of high-dose octreotide, which is required for the normalization of growth hormone hypersecretion in some patients with acromegaly. Patients with acromegaly ( N =8) were treated with octreotide, 450 μg/day, then 1500 μg/day for two months at each dosage. Carbohydrate absorption was assessed using the d -xylose test, and fat absorption using fecal fat excretion and serum carotene concentrations, at baseline, at each dosage of octreotide, and after one month of washout. Ultrasonography was used to monitor for cholelithiasis. Growth hormone and insulin-like growth factor-I concentrations were significantly suppressed at both dosages. Adverse gastrointestinal symptoms were mild and transient. d -Xylose absorption remained normal at each dosage and after one month of washout. Fecal fat excretion increased from 7±2 to 12±2 g/24 hr ( P <0.05) after the higher dosage and resumed baseline levels after the washout. Mean fasting serum carotene levels remained normal, and carotene loading test (15,000 units three times a day for three days) was unreliable in identifying patients with high fecal fat. No new cholelithiasis was detected by ultrasonography. One of two patients with preexisting cholelithiasis developed biliary colic several days after the treatment period. Although steatorrhea was common, small intestinal absorptive capacity was otherwise unchanged by four months of high-dose octreotide treatment, which significantly suppressed growth hormone secretion in acromegalic patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44417/1/10620_2005_Article_BF01307549.pd

Somatotropinoma Infarction During Octreotide Therapy Leading to Bilateral Cavernous Sinus Syndrome

The cyclic somatostatin analog, octreotide, forms the mainstay of medical treatment for acromegaly. In addition to lowering circulating growth hormone levels and shrinking tumor size, octreotide may provide symptomatic relief of headaches associated with growth hormone secreting tumors. The majority of reported complications of octreotide therapy are gastrointestinal and metabolic. The present case illustrates the development of acute bilateral cavernous sinus syndrome with loss of eye movement bilaterally during octreotide therapy. Serial MRI examination suggest tumor infarction as the etiology. The symptoms resolved over 2 months as the tumor shrunk in size and growth hormone was dramatically reduced.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47491/1/11102_2004_Article_324058.pd