Multiple facets in the control of acromegaly

Aims

The current article provides a brief overview of the criteria for defining disease control in acromegaly.

Methods

This was a retrospective, narrative review of previously published evidence chosen at the author’s discretion along with an illustrative case study from Latin America.

Findings and Conclusions

In the strictest sense, “cure” in acromegaly is defined as complete restoration of normal pulsatile growth hormone secretion, although this is rarely achieved. Rather than “cure”, as such, it is more appropriate to refer to disease control and remission, which is defined mainly in terms of specific biochemical targets (for growth hormone and insulin-like growth factor-1) that predict or correlate with symptoms, comorbidities and mortality. However, optimal management of acromegaly goes beyond biochemical control to include control of tumour growth (which may be independent of biochemical control) and comprehensive management of the symptoms and comorbidities typically associated with the disease, as these may not be adequately managed with acromegaly-specific therapy alone.

     

Multiple facets of follicle-stimulating hormone receptor function

Follicle-stimulating hormone (FSH) is a glycoprotein hormone produced by the anterior pituitary gland. This gonadotropin plays an essential role in reproduction. Its receptor (FSHR) belongs to the superfamily of G protein-coupled receptors (GPCR), specifically the family of rhodopsin-like receptors. Agonist binding to the FSHR triggers the rapid activation of multiple signaling cascades, mainly the cAMP–adenylyl cyclase–protein kinase A cascade, that impact diverse biological effects of FSH in the gonads. As in other G protein-coupled receptors, the several cytoplasmic domains of the FSHR are involved in signal transduction and termination of the FSH signal. Here we summarize some recent information on the signaling cascades activated by FSH as well as on the role of the intracytoplasmic domains of the FSHR in coupling to membrane and cytosolic proteins linked to key biological functions regulated by the FSH–FSHR system.     

Tamoxifen enhances the control of acromegaly treated with somatostatin analog lanreotide

We present the case of a 51-year old female patient with acromegaly that was resistant to somatostatin analogs and dopamine agonists. The patient was diagnosed with breast cancer requiring treatment with the anti-estrogen tamoxifen. Prior to initiating the treatment with tamoxifen, the IGF-I level was very high at 415% of the upper limit of normal for the patient's age and sex. During the tamoxifen treatment, the level of IGF-I dropped spectacularly down to normal levels. This observation highlights the effect of an anti-estrogen treatment in certain female patients with acromegaly.     

Quality of life after long-term biochemical control of acromegaly

Pituitary - To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to...     

Tamoxifen enhances the control of acromegaly treated with somatostatin analog lanreotide

We present the case of a 51-year old female patient with acromegaly that was resistant to somatostatin analogs and dopamine agonists. The patient was diagnosed with breast cancer requiring treatment with the anti-estrogen tamoxifen. Prior to initiating the treatment with tamoxifen, the IGF-I level was very high at 415% of the upper limit of normal for the patient’s age and sex. During the tamoxifen treatment, the level of IGF-I dropped spectacularly down to normal levels. This observation highlights the effect of an anti-estrogen treatment in certain female patients with acromegaly.     

Tamoxifen enhances the control of acromegaly treated with somatostatin analog lanreotide

Incidence estimates for pituitary adenomas vary widely, suggesting the effects of numerous risk factors or varying levels of tumor surveillance. We studied the epidemiology of pituitary adenomas using 2004–2007 data collected by 17 Surveillance, Epidemiology, and End Results Programs in the United States (N = 8,276). We observed that incidence rates generally increased with age and were higher in females in early life and higher in males in later life. Males are diagnosed with larger tumors on average than females. Diagnosis may be delayed for males, giving tumors a chance to grow larger before clinical detection. We also observed that American Blacks have higher incidence rates for pituitary adenomas compared with other ethnic groups. There are several potential explanations for this finding with some evidence that at least part of the effect may be due to differential diagnosis between races.     

Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly

Context

The somatostatin analogues octreotide LAR and lanreotide Autogel have been evaluated for the treatment of acromegaly in numerous clinical trials, with considerable heterogeneity in reported biochemical response rates. This review examines and attempts to account for these differences in response rates reported in the literature.

Evidence acquisition

PubMed was searched for English-language studies of a minimum duration of 24 weeks that evaluated ≥10 patients with acromegaly treated with octreotide LAR or lanreotide Autogel from 1990 to March 2015 and reported GH and/or IGF-1 data as the primary objective of the study.

Evidence synthesis

Of the 190 clinical trials found, 18 octreotide LAR and 15 lanreotide Autogel studies fulfilled the criteria for analysis. It is evident from the protocols of these studies that multiple factors are capable of impacting on reported response rates. Prospective studies reporting an intention-to-treat analysis that evaluated medically naïve patients and used the composite endpoint of both GH and IGF-1 control were associated with lower response rates. The use of non-composite biochemical control endpoints, heterogeneous patient populations, analyses that exclude treatment non-responders, assay variability and prior responsiveness to medical therapy are just a few of the factors identified that likely contribute to higher success rates.

Conclusions

The wide range of reported response rates with somatostatin analogues may be confusing and could lead to misinterpretation by both the patient and the physician in certain situations. Understanding the factors that potentially drive the variation in response rates should allow clinicians to better gauge treatment expectations in specific patients.

     

Amelioration of cardiovascular risk factors with partial biochemical control of acromegaly

Objective Complete remission of acromegaly is associated with favourable changes in cardiovascular risk parameters. We evaluated the effects of suboptimal therapy on haemodynamic, metabolic, inflammatory and coagulation cardiovascular risk indices. Design and methods Eighteen acromegalic patients on somatostatin analogues, with incomplete biochemical control, were evaluated at diagnosis and 6 months after treatment and compared to 15 healthy age‐ and body mass index (BMI)‐matched controls. Measurements of blood pressure, GH, IGF‐I, glucose, insulin, glycated haemoglobin (HbA1c), lipids, apolipoprotein A1 (apoA1), apoB, high‐sensitivity C‐reactive protein (hs‐CRP), fibrinogen, plasminogen activator inhibitor 1 (PAI‐1), tissue plasminogen activator (tPA) and circulating thrombomodulin were performed in all study participants, followed by an oral glucose tolerance test (OGTT). Insulin sensitivity (IS) was expressed by the Matsuda index (OGTT_ISI). Results Partial control of acromegaly resulted in a significant reduction in systolic and diastolic blood pressure, glucose, insulin, HbA1c, total (T‐C) and low density lipoprotein cholesterol (LDL‐C) and triglyceride levels, and a significant increase in apoA1, high density lipoprotein cholesterol (HDL‐C) and OGTT_ISI compared to pretreatment levels. Plasma fibrinogen and PAI‐1 levels fell significantly [respectively (mean ± SEM), 11·04 ± 0·41 vs. 10·12 ± 0·34 µmol/l, P = 0·003 and 9·6 ± 1·97 vs. 6·55 ± 1·89 µg/l, P < 0·001]. However, a marked reduction in tPA [median (IQR) 5·1 (2·5–15) vs. 3·4 (2·4–8·6) µg/l, P = 0·031] and an increase in hs‐CRP [median (IQR) 0·05 (0·03–0·11) vs. 0·1 (0·06–0·23) mg/l, P < 0·001] were also noted. On treatment, acromegalic patients were comparable to controls, except for OGTT_ISI, lipoprotein(a) [Lp(a)], fibrinogen and tPA and HDL‐C levels. Thrombomodulin and apoB levels were not affected by treatment. Conclusions Partial control in disease activity following somatostatin analogues results in significant improvement in a considerable number of cardiovascular risk markers in acromegaly.     

Aldosterone in acromegaly

Ten patients with acromegaly, six with active acromegaly and four with inactive acromegaly were studied with regard to the possible relationship between aldosterone metabolism and hypertension. It was noted that tetrahydroaldosterone-3-glucuronide levels were highest in those cases which exhibited the highest prolactin levels. It was in these cases that hypertension was present and they were active as judged by clinical and biochemical parameters. On administration of bromocryptine there was a reduction of tetrahydroaldosterone-3-glucuronide, prolactin and also a significant reduction of blood pressure. The significance of these results is discussed.     

Surgical debulking of pituitary macroadenomas causing acromegaly improves control by lanreotide

Background Macroadenomas causing acromegaly are cured surgically in only around 50% of patients. Primary medical treatment with somatostatin analogues has been suggested to be a means of treating patients with a potentially poor surgical outcome. Previous retrospective studies have also suggested that surgical debulking of pituitary tumours causing acromegaly improves control by somatostatin analogues. No prospective study using lanreotide has been carried out thus far to assess whether this is the case. Objective We carried out a prospective study to assess whether surgical debulking of pituitary macroadenomas causing acromegaly improved the subsequent control of acromegaly by the somatostatin analogue lanreotide. Patients and methods We treated 26 consecutive patients [10 males and 16 females – median age 53·5 years (range 22–70)] with macroadenoma causing acromegaly unselected for somatostatin response for 16 weeks with lanreotide, maximizing GH and IGF‐I suppression, if necessary, by incremental dosing. Surgical resection was carried out and the patients were re‐assessed off medical treatment at 16 weeks following surgery. Those with nadir GH > 2 mU/l in the oral glucose tolerance test (OGTT) and a mean GH in the GH day curve (GHDC) > 5 mU/l were subsequently restarted on lanreotide and the responses were assessed at the same time points as during the preoperative lanreotide treatment. Results GH values fell on lanreotide treatment and prior to surgery they were considered ‘safe’ (mean GH in GHDC < 5 mU/l) in eight patients (30·7%). After surgery, they were ‘safe’ in 18 patients (69·2%). The figures for normal IGF‐I were 11 (42·3%) before surgery and 23 (88·5%) after surgery. After surgery, six patients had nadir GH > 2 mU/l in the OGTT and ‘unsafe’ GH levels (mean GH in GHDC > 5 mU/l); on re‐exposure to lanreotide, GH levels fell in all patients and at the end of 16 weeks postsurgery, they were ‘safe’ in three of them (50%) (P < 0·05). Pituitary tumour volume was also assessed prospectively, preoperatively on lanreotide and showed a mean fall of 33·1%. Eighty‐three percent of patients had > 20% shrinkage. Conclusions In this first prospective study using lanreotide, surgical debulking of pituitary tumours causing acromegaly improved subsequent postoperative control by the somatostatin analogue lanreotide. Surgery should, therefore, be considered in patients with macroadenoma causing acromegaly, even if there is little prospect of surgical cure. Lanreotide causes significant pituitary tumour shrinkage in the majority of patients.     

Cabergoline in acromegaly

Acromegaly, a rare disease due to growth hormone (GH) hypersecretion by a pituitary adenoma, is associated with severe comorbidity and premature death if not adequately treated. The usual first-line treatment is surgery. Various drugs, including somatostatin receptor ligands, dopamine agonists and GH receptor antagonists, are now available for use if surgery fails to suppress GH/IGF-I hypersecretion. Cabergoline, now the preferred dopamine agonist for treating hyperprolactinemia, is also used off-label for treating acromegaly. Cabergoline monotherapy is reported to normalize IGF-I levels in more than one-third of patients with acromegaly. When a somatostatin receptor ligand proves ineffective, cabergoline add-on therapy normalizes the IGF-I level in 40–50% of patients. Finally, when combined with the GH receptor antagonist pegvisomant in patients with mild uncontrolled disease, cabergoline helps to achieve normal IGF-I levels while avoiding the need for high-dose pegvisomant. Cabergoline is also inexpensive and well tolerated; in particular, it does not appear to promote heart valve disease.     

Arthropathy in acromegaly

Articular involvement in acromegaly is one of the most frequent clinical complications and may be present as the earliest symptom in a significant proportion of patients. The involvement of other organs may be of clinical importance and contribute to increased morbidity and mortality of patients suffered from acromegaly. Early diagnosis and proper treatment of the diseases can prevent the development of irreversible complications of the disease and improve the quality of life in patients suffering from the disease.