Breast cancer risk in BRCA1 mutation carriers: insight from mouse models.

Since its identification 20 years ago, the biological basis for the high breast cancer risk in women who have germline BRCA1 mutations has been an area of intense study for three reasons. First, BRCA1 was the first gene shown to associate with breast cancer risk, and therefore serves as model for understanding genetic susceptibility. Second, the type of breast cancer that occurs in these women has specific features that have engendered new hypotheses about the cancer biology. Third, it is hoped that understanding the origins of this disease may provide the means to prevent disease. Resolving this question has proven extremely challenging because the biology controlled by BRCA1 is complex. Our working model is that the high frequency of basal-like breast cancer in BRCA1 mutation carriers is the result of a self-perpetuating triad of cellular phenotypes consisting of: (i) intrinsic defects in DNA repair and centrosome regulation that lead to genomic instability and increases spontaneous transformation; (ii) aberrant lineage commitment; and (iii) increased proliferation due to in large part to increased IGF-1 activity. We propose that the last is key and is a potential entree for preventing breast cancer in BRCA1 mutation carriers.

Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression.

CONTEXT: Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. OBJECTIVES: The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. DESIGN: Four single-dose studies were conducted in 75 healthy volunteers. INTERVENTION: Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 µg octreotide were administered. MAIN OUTCOME MEASURE: We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. RESULTS: Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h × ng/ml); and median time ≥ 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. CONCLUSIONS: The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.

Prevention of breast cancer: the case for studying inhibition of IGF-1 actions.

Measures to prevent breast cancer are receiving particular attention by women at high risk from either clinico-pathologic findings or genetic susceptibility. Life-style and nutritional interventions have been difficult to quantify, but merit further study. Chemoprevention with tamoxifen and subsequently with the related raloxifene demonstrates some efficacy, but may be not be applicable to premenopausal women (with regard to raloxifene), or have low acceptance (with regard to tamoxifen). Based on the importance of the insulin-like growth factor-1 pathway in mammary gland development, and the availability of a potent inhibitor, pilot studies are ongoing to evaluate such an inhibitor in women with demonstrable high risk to develop breast cancer. Short-term interventions with the inhibitor have been completed, and subsequent interventions are planned.

Guidelines for acromegaly management: an update.

OBJECTIVE: The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. PARTICIPANTS: The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. CONCLUSIONS: The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.

Consensus statement: medical management of acromegaly.

In November 2003, the Pituitary Society and the European Neuroendocrine Association sponsored a consensus workshop in Seville to address challenging issues in the medical management of acromegaly. Participants comprised 70 endocrinologists and neurosurgeons with international expertise in managing patients with acromegaly. All participants participated in the workshop proceedings, and the final document written by the scientific committee reflects the consensus opinion of the interactive deliberations. The meeting was supported by an unrestricted educational grant from Ipsen. No pharmaceutical representatives participated in the program planning or in the scientific deliberations.

New roles and challenges in neurosurgery of acromegaly.

Acromegaly is a disease that shortens life expectancy (1-3) and causes severe systemic problems during life (4). It can arise and be recognized quickly if the onset is rapid, as in gigantism. Unfortunately there is usually a delay in diagnosis, on average 9 yr (4). The longer the delay the more likely patients are to develop partially or completely irreversible systemic problems, such as sleep apnea (5) and arthritis. Although some of the signs and co-morbidities of acromegaly are permanent, there is good evidence that cure of the disease reverses early mortality (3, 6, 7). It has been estimated that life expectancy is shortened by about 10 yr overall, and longer when diabetes or heart disease are already present at the time of diagnosis.

Diagnosis and treatment of acromegaly complications.

The Pituitary Society in conjunction with the European Neuroendocrine Association held a consensus workshop to develop guidelines for diagnosis and treatment of the co-morbid complications of acromegaly. Fifty nine pituitary specialists (endocrinologists, neurosurgeons and cardiologists) assessed the current published literature on acromegaly complications in light of recent advances in maintaining tight therapeutic control of GH hypersecretion. The impact of elevated GH levels on cardiovascular disease, hypertension, diabetes, sleep apnea, colon polyps, bone disease, reproductive disorders, and neuropsychologic complications were considered. Guidelines are proposed for effective management of these complications in the context of overall acromegaly control. When appropriate, requirements for prospective evidence-based studies and surveillance database development are enunciated. Effective management of co-morbid acromegaly complications will lead to improved morbidity and mortality in acromegaly.

Effects of a growth hormone receptor antagonist on bone markers in acromegaly.

OBJECTIVE: Excess GH secretion, as occurs in acromegaly, is associated with abnormalities in bone turnover markers and bone mineral density (BMD). GH administration in GH deficient patients causes an increase in bone turnover. IGF-I mediates many of the metabolic actions of GH, although GH may have direct effects upon bone. In patients with acromegaly who are treated with a GH receptor antagonist, selective blockade of the GH receptor results in a decrease in circulating IGF-I levels in the majority of cases. We hypothesized that, in acromegaly, antagonism of GH receptors would result in a decrease in serum markers of bone turnover, including serum procollagen I carboxy-terminal propeptide (PICP), osteocalcin and N-telopeptide (NTx). DESIGN AND SUBJECTS: Twenty-seven patients with acromegaly were enrolled as part of a multicentre 12-week trial of a GH receptor antagonist and were randomized to placebo (n = 7) or 10, 15 or 20 mg of pegvisomant (n = 20). MEASUREMENTS: Serum markers of bone turnover were determined at baseline and 12 weeks. RESULTS: Baseline bone turnover markers were above the upper limit of normal in 23%, 19% and 32% of subjects for osteocalcin, PICP and NTx, respectively. During the 12-week placebo-controlled period, there were significant decreases in serum markers of bone formation, osteocalcin (-2.2 +/- 0.44 vs. placebo +0.01 +/- 0.39 nmol/l, P = 0.009) and PICP (-23.6 +/- 9.6 vs. placebo +18.1 +/- 12.8 micro g/l, P = 0.022) and a serum marker of bone resorption, NTx (-4.4 +/- 1.4, placebo +1.0 +/- 0.3 nm, P = 0.024). CONCLUSIONS: Using a specific GH receptor antagonist, we found that normalization of IGF-I is associated with rapid reductions in markers of both bone formation and resorption, and that these processes remain coupled. These data confirm the highly significant effects of GH and IGF-I in modulating bone turnover. The independent contributions of GH and IGF-I to these effects and the long-term effects on BMD in this population remain to be determined.

Diagnosis and management of growth hormone deficiency in adults.

In adults, GHD is a clinical syndrome that occurs in patients with pituitary or hypothalamic disease. It may be asymptomatic or present with relatively nonspecific constitutional symptoms. Most patients have abnormal body composition, consisting of increased fat mass and decreased lean mass. Life expectancy is significantly decreased in hypopituitary patients with GHD, with cardiovascular disease a common cause of death. Treatment with growth hormone reverses abnormalities in body composition and may reduce cardiovascular risk factors; however, the long-term treatment outcomes regarding mortality, the incidence of cardiovascular disease, bone fractures, tumor development, and recurrence are not known. Longer prospective clinical studies are needed. The major manufacturers of growth hormone have initiated postmarketing surveillance databases to monitor the safety of growth hormone treatment.

Rheumatic manifestations of pituitary tumors.

Pituitary tumors may cause rheumatologic problems as a result of under production or overproduction of one pituitary hormone. Excessive growth hormone causes destruction of cartilage by a direct action. Facial and acral changes and arthralgias may be some of the first symptoms of acromegaly. The arthritis associated with acromegaly is often devastating. Carpal tunnel syndrome is very common in patients with acromegaly. Adrenocorticotropin (ACTH) has indirect effects via the action of glucocorticoid on bones, muscles, and the immune system. Proximal muscle weakness is a characteristic feature of Cushing's syndrome. Patients with Cushing's syndrome commonly have osteopenia and osteoporosis that lead to an increase in bone fractures. Avascular necrosis is associated with exogenous steroid administration. The effects of too much glucocorticoid or too rapid withdrawal can be severe. Gonadotropins act via the gonadal steroids and protect bone mass from loss. Prolactin is less involved in rheumatologic disease; the data for which are limited in humans. Pituitary tumors can have manifestations similar to rheumatologic disorders and should be included in the differential diagnosis of these diseases.

Repeat cycloplegic examinations at the Naval Operational Medicine Institute.

BACKGROUND: Cycloplegic examination is required for applicants who desire entry into Naval Aviation training. Before this study, all cycloplegic examinations performed at any site were repeated at the Naval Operational Medicine Institute (NOMI), Pensacola, FL, on all student naval aviator (SNA) candidates to assess for latent hyperopia which exceeded established limits for entry into training. HYPOTHESIS: Repeat cycloplegic examination does not vary sufficiently to change student status regarding physical qualification for training. METHODS: Data analysis of cycloplegic examinations repeated at the NOMI, for which the first and second examination were recorded in the Aviation Medical Data Retrieval System (AMDRS), over 10 yr. RESULTS: There were 3919 SNA applicants who had cycloplegic examinations repeated at NOMI. Of them, 3903 (99.59%) were within standards on the repeat examination. There were 16 candidates who were sent to NOMI with a previously disqualifying cycloplegic examination. On second cycloplegic examination, 15 were within standards for SNA. Only 15 of the SNAs with a first cycloplegic examination within standards were outside SNA standards on repeat examination. Of these 15, 12 were also outside SNA standards in distant visual acuity and/or in manifest refraction. The remaining 3 were found to have excessive myopia, not latent hyperopia, on the second cycloplegic examination. The standard deviation between the first and the second cycloplegic examination was computed to be less than 0.50 diopters in any meridian. CONCLUSION: The cycloplegic examination of SNA candidates need only be repeated if the first cycloplegic examination is outside the SNA limit or within two standard deviations of the SNA limit.

Hypogonadism in patients with acromegaly: data from the multi-centre acromegaly registry pilot study.

OBJECTIVE: Because acromegaly is an uncommon disorder, epidemiological data regarding the demographics of the disease such as the prevalence of hypogonadism have been limited. In order to derive clinical and epidemiological information, including underlying hormonal factors, regarding hypogonadism in patients with acromegaly, we performed a pilot study designed to develop a multi-centre acromegaly patient registry. DESIGN AND MEASUREMENTS: Medical records of patients with acromegaly seen between 1976 and 1996 at three Institutions were reviewed, and data were entered into a database using a secure internet website. Hypogonadism was defined as amenorrhoea in women and testosterone deficiency in men. Subanalysis was performed in patients with microadenomas and women less than 50 years of age, to include women of reproductive age. RESULTS: Information was available on 363 patients, of whom 54% were women. The mean age at diagnosis was 41 +/- 13 years. In subjects less than 50 years of age, hypogonadism was present in 59%. Hyperprolactinaemia was present in 45% and 21% of hypogonadal and eugonadal patients of reproductive age, respectively (P = 0.0003). GH levels were higher in patients with hypogonadism (P = 0.03). In patients < 50 years of age with microadenomas, hypogonadism was present in nine of the 22 (41%) patients, including 55% of the women and 27% of the men (P = ns). Hyperprolactinaemia was present in three of the 10 and four of the 14 of microadenoma patients with hypogonadism and eugonadism, respectively. CONCLUSION: We developed a web-based acromegaly patient registry and used it to show that hypogonadism is a frequent consequence of acromegaly, even in patients with microadenomas, who are not at risk from hypopituitarism due to local mass effects. We also demonstrated that prolactin and GH hypersecretion contribute to the pathogenesis of hypogonadism in acromegaly, and that hypogonadism may occur in microadenoma patients even in the absence of hyperprolactinaemia.

IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis.

Growth hormone (GH) is essential for rodent mammary gland development during puberty. It binds to GH receptors in the stromal compartment of the mammary gland and stimulates IGF-I mRNA expression. These findings lead to the hypothesis that GH acts through locally produced IGF-I, which in turn, causes development of terminal end buds (TEBs), the structures that lead the process of mammary gland development during puberty. Subsequent studies have in large measure proven this hypothesis. They include the observations that mammary development was grossly impaired in female mice deficient in IGF-I (IGF-I(-/-) knockout mice), and treatment of these mice with IGF-I plus estradiol (E2) restored pubertal mammary development while treatment with GH + E2 did not. Thus, the full phenotypic action of GH in mammary gland development is mediated by IGF-I. We have demonstrated one effect of GH on the mammary gland that does not appear to be mediated by the action of IGF-I. GH increased the level of estrogen receptor (ER) mRNA and protein in the nuclei of mammary fat pad cells, but IGF-I did not. In addition to the critical role of the GH/IGF-I axis during pubertal mammary development, other data suggest that IGF-I might also be of importance during pregnancy and lactation. In summary, the earliest phase of pubertal mammary development (formation of TEBs) requires IGF-I or GH in IGF-I sufficient animals. No other hormones have been shown to stimulate formation of TEBs unless GH or IGF-I is present. GH-induced IGF-I is of major importance in ductal morphogenesis, and may, in fact, be necessary for later stages of mammary development, as well.

Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.

BACKGROUND: Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. RESULTS: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups. CONCLUSIONS: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

Clinical and reimbursement issues in growth hormone use in adults.

Data published in the past decade have demonstrated that adults who are deficient in growth hormone (GH) experience deleterious clinical consequences without treatment. In 1996, the Food and Drug Administration approved the use of GH in adults who were GH deficient as a result of hypothalamic or pituitary disease. However, there are other conditions in adults for which GH treatment has also been approved (acquired immune deficiency syndrome [AIDS]-related wasting) or for which it is being considered, such as aging, catabolic states, and cardiomyopathy. Clinical issues revolve around the rationale for treatment; the diagnostic evaluation; the effects of GH therapy on body composition, bone density, lipids, and cardiac function; and appropriate dosing and follow up. Clearly, the use of GH in adults raises reimbursement issues as well. In this article, Dr. Beverly M.K. Biller provides an overview of the rationale for the treatment of adult-onset GH deficiency and reviews its etiology and clinical features as well as reimbursement and utilization issues related to treatment. Dr. Mary Lee Vance discusses various assays and criteria used in the diagnostic evaluation of the patient with adult-onset GH deficiency. Dr. David L. Kleinberg focuses on the effects of GH therapy on body composition, bone density, lipid profiles, and cardiac function, as well as on reimbursement issues regarding body composition studies. To complete the clinical portion of this session, Dr. David M. Cook addresses dosing and follow up. To address economic implications, Dr. Terry Gordon provides the payer's perspective on the diagnosis and treatment of adult-onset GH deficiency.

The effect of GH on estrogen receptor expression in the rat mammary gland.

Both GH and insulin-like growth factor I (IGF-I) synergize with estrogen to induce normal mammary gland development. However, the nature of this synergy has not been explored. To gain insight into the mechanism of these interactions we have examined the effects of these substances on the estrogen receptor (ER). ER levels in the mammary gland cytosols from hypophysectomized and oophorectomized rats, were measured using two assay systems: a dextran-coated charcoal procedure to measure binding to radiolabeled steroid, and an immunologic assay employing a specific antibody to the receptor. In both assays, levels of ER were at or near baseline detection (approximately 1-2 ng/mg protein). Treating animals with either bovine or human GH significantly increased ER activity (P<0.001), whereas prolactin (PRL) and/or estradiol treatment had no effect. That this increase was at the level of transcription was demonstrated by reverse transcriptase/polymerase chain reaction. Following a single injection of GH (50 microgram), a substantial increase in ER mRNA was observed by 10 h, with levels returning to baseline within 24 h; a concomitant increase in ER itself was also observed at the 10 h time point. The effect of GH appeared to occur mainly in the mammary stroma, because there were no differences in GH stimulation of ER between gland-free and gland containing mammary fat pads. Furthermore, analysis of mammary gland ER by immunocytochemistry demonstrated that while ER was present in the epithelial cells of non-treated animals, only GH treated animals had ER clearly visible in both glandular and fat cells of the tissue. In contrast, treating animals with des(1-3)-IGF-I did not result in reproducible increases in ER, nor in the staining of fat cell nuclei for ER. These data demonstrate a specific GH effect on the ER in the mammary fat cell.

Insulin-like growth factor I is essential for terminal end bud formation and ductal morphogenesis during mammary development.

Previous studies from this laboratory have emphasized the essential role of GH in pubertal mammary development and shown that insulin-like growth factor I (IGF-I) was capable of substituting for GH in this process in rats and mice. The present study shows that, even when GH is present, no mammary development is possible unless IGF-I is present. IGF-I(-/-) null female animals were found to have significantly less mammary development than age matched wild-type controls (P <0.006) using several endpoints including the number of terminal end buds or TEBs (1.3 vs. 7.3), percent of the fat pad occupied by glandular elements (6.5 vs. 100), and number of ducts (15 vs. too numerous to count). That the deficiency in mammary gland development was related to the absence of IGF-I was underscored by the observation that des (1-3) IGF-I administration to IGF-I(-/-) null animals for 5 days caused significant mammary gland development as measured by TEB formation and branching of ducts. The number of TEBs rose from a mean of 1.3 in controls to 20.5 without added E2 (P < 0.009), and from 1.7 to 21 when des (1-3) IGF-I was given together with E2 (P < 0.006). The number of ducts increased significantly from a mean of 12 to 27 in response to IGF-I and E2, and from 15 to 24.5 with IGF-I alone. In contrast, administration of human GH with E2 had no stimulatory effect on mammary development in these animals, indicating that the full effect of GH in this process is mediated by IGF-I. To determine whether IGF-I was also responsible for further ductal morphogenesis, we administered des (1-3) IGF-I + E2 to the knockout animals for 14 days and compared the effects of this combination of hormones on mammary development with those observed after 5 days. We found that there was a significant increase from 5 to 14 days in the number of TEBs (mean: 21 vs. 41) and the area of the mammary fat pad occupied by glands (mean: 10 vs. 20%). There was elongation and thickening of the ducts which accounted for the increased area that was occupied by ductal structures. There was no significant increase in the number of ducts. However, there was the appearance of a large number of buds along the length of the ductal structures, suggesting the beginning of side branching. These results suggest that IGF-I, when given along with E2, is responsible for ductal morphogenesis.

Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development.

Insulin-like growth factor I (IGF-I) has been implicated as a factor that may predispose one to prostate cancer. However, no specific relationship between IGF-I and prostate development or cancer in vivo has been established. To determine whether IGF-I was important in prostate development, we examined prostate architecture in IGF-I(-/-) null mice and wild-type littermates. Glands from 44-day-old IGF-I-deficient animals were not only smaller than those from wild-type mice, but also had fewer terminal duct tips and branch points and deficits in tertiary and quaternary branching (P < 0.0001), indicating a specific impairment in gland structure. Administration of des(1-3)-IGF-I for 7 days partially reversed the deficit by increasing those parameters of prostate development (P < 0.006). That IGF-I production probably mediates an effect of GH in this process was indicated by the observations that GH antagonist transgenic mice also had significantly impaired prostate development (P < 0.0002) and that bovine GH had no independent effect on stimulating prostate development in IGF-I null animals. The data indicate that IGF-I deficiency is the proximate cause of impaired prostate development and give credence to the idea that, like testosterone, GH and IGF-I may be involved in prostate cancer growth as an extension of a normal process.