Faculty Bibliography

Women carriers of mutations in the tumor suppressor gene, BRCA1, have an up to 80% risk of developing breast cancer, as well as a 40% risk of ovarian cancer. Men who develop breast cancer are frequently BRCA1 mutation carriers. Moreover, cancers associated with BRCA1 mutations are frequently triple-negative (negative for estrogen receptor, progesterone receptor and HER2 amplification), which have a very poor prognosis. Experimental data have shown that BRCA1 has a dual role in the mammary epithelium in both DNA damage repair and in epithelial lineage commitment that contribute to the high frequency of triple-negative breast cancer. Brca1 deficiency in experimental models is also associated with increased phosphorylation of the IGF-1 receptor which in turns, leads to the MAPK signaling activation and results in increased proliferation. We evaluated a novel IGF-1 inhibitor in the Brca1 loxP/loxP C57bl/6 mouse that develops an early mammary gland hyper-proliferative phenotype characterized by aberrant ductal morphogenesis and DCIS around 9 months of age. Centrosome aberrations, defined cells with more than 2 centrosomes, were significantly increased the mammary epithelium of these mice compared to C57bl/6 control mice (19.8%+/-0.8%, n=13 vs 8.4%+/-0.9%, n=6, p<0.001). We also identified a novel population of cells expressing both a luminal and myoepithelial lineage markers present in the Brca1 loxP/loxP C57bl/6 mice that were rare in control mice (22.5%+/-0.9%, n=5 vs 3.9%+/-0.4%, n=7, p<0.001). Four month old Brca1 loxP/loxP and C57bl/6 mice were treated with either pasireotide (aka SOM230), a multiligand somatostatin analog that directly blocks IGF-1 action in the mammary gland or PQ401, a IGF-IR small molecule inhibitor, administered for 7 days by subcutaneous Alzet pumps Pasireotide and PQ401 inhibited IGF-1 mediated phosphorylation of target proteins, IGF-IR, ERK and AKT in the Brca1 mammary glands. Both treatments resulted in rapid reversion of the Brca1 mutant gross morphological phenotype.!

Mammary development begins in puberty in response to an estrogen (E(2)) surge. E(2) does not act alone. It relies on pituitary growth hormone (GH) to induce insulin-like growth factor I (IGF-I) production in the mammary stromal compartment. In turn, IGF-I permits E(2) (and progesterone) action. During puberty, E(2) and IGF-I synergize for ductal morphogenesis. During pregnancy, progesterone joins IGF-I and E(2) to stimulate secretory differentiation necessary to produce milk. Prolactin stimulates milk production, while transforming growth factor-beta inhibits proliferation. The orchestrated action of hormones, growth factors, and receptors necessary for mammary development and function are also critical in breast cancer

Mammary hyperplasia increases breast cancer risk. Tamoxifen prevents breast cancer in women with atypical hyperplasia, but has serious side effects. As estradiol action requires IGF-I, direct inhibition of IGF-I action theoretically might be an efficacious alternative to tamoxifen. After hypophysectomy and oophorectomy, 21-day-old female rats were treated with GH and E(2.) After 7 days all terminal end buds (TEBs) and 75% of ducts became hyperplastic. Co-treatment with pasireotide, a somatostatin analog that blocks GH secretion and IGF-I action in the mammary gland, prevented hormone-induced hyperplasia. The number and size of TEBs and moderately or floridly hyperplastic ducts was reduced by pasireotide (P < 0.01). In contrast, the same concentration of octreotide, which has a more selective somatostatin receptor subtype binding profile, was less effective than pasireotide. Tamoxifen inhibited hyperplasia when used alone with GH + E(2), but did not add to the inhibitory effect of pasireotide when the two treatments were combined. Both pasireotide and tamoxifen acted via the IGF-I receptor signaling pathway and both were found to inhibit mammary cell proliferation and stimulate apoptosis. The number of epithelial cells expressing phosphorylated insulin receptor substrate (IRS)-1 in response to GH and E(2) was reduced by pasireotide, as was staining intensity. These results support the concept that IGF-I inhibition, in this case by pasireotide, inhibits E(2) and GH-induced mammary hyperplasia. As tamoxifen did not further increase the inhibitory effect of pasireotide, the peptide appears to be at least as effective as tamoxifen in preventing GH + E(2)-induced mammary hyperplasia

OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia. PARTICIPANTS: The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented

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

CONTEXT: Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient (GHD) adults are limited. OBJECTIVES: The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults. DESIGN: The study was a 6-month double-blind, placebo-controlled randomized trial. SETTING: The study was conducted at the General Clinical Research Center. PARTICIPANTS: Thirty hypopituitary adults with GHD were studied. INTERVENTION: Subjects were randomized to recombinant human GH or placebo for 6 months, followed by open-label recombinant human GH for 12 months. MAIN OUTCOME MEASURES: Primary endpoints were exercise duration, maximal oxygen consumption, and left ventricular ejection fraction. Secondary endpoints were echocardiographic indices of systolic and diastolic function, left ventricular mass, lipids, and body composition. RESULTS: In the 6-month double-blind phase, mean GH dose was 0.64 mg/d. Mean IGF-I sd score increased from -4.5 to -1.0. Exercise duration, maximal oxygen consumption, left ventricular ejection fraction, and other echocardiographic parameters were normal at baseline and did not change. GH decreased total and low-density lipoprotein cholesterol by 7.5% (P = 0.016) and 14.7% (P = 0.002) (P = 0.04 vs. placebo). Mean lean body mass increased by 2.2 kg (P = 0.004), fat mass decreased by 1.7 kg (P = 0.21), and percent body fat decreased by 2.5% (P = 0.018), although between-group changes were not significant. CONCLUSIONS: Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol, increased IGF-I, and increased lean body mass. These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment

CONTEXT AND OBJECTIVE: Metabolic and body compositional consequences of GH deficiency (GHD) in adults are associated with a phenotype similar to the metabolic syndrome (MetS). PATIENTS: We assessed MetS prevalence in adult GHD patients (n = 2531) enrolled in the Hypopituitary Control and Complications Study. Prevalence was assessed at baseline and after 3 yr of GH replacement in a subset of 346 adult-onset patients. RESULTS: Baseline MetS crude prevalence was 42.3%; age-adjusted prevalence in the United States and Europe was 51.8 and 28.6% (P < 0.001), respectively. In the United States, age-adjusted prevalence was significantly higher (P < 0.001) than in a general population survey. Increased MetS risk at baseline was observed for age 40 yr or older (adjusted relative risk 1.34, 95% confidence interval 1.17-1.53, P < 0.001), females (1.15, 1.05-1.25, P = 0.002), and adult onset (1.77, 1.44-2.18, P < 0.001). In GH-treated adult-onset patients, MetS prevalence was not changed after 3 yr (42.5-45.7%, P = 0.172), but significant changes were seen for waist circumference (62.1-56.9%, P = 0.008), fasting glucose (26.0-32.4%, P < 0.001), and blood pressure (59.8-69.7%, P < 0.001). Significantly increased risk of MetS at yr 3 was associated with baseline MetS (adjusted relative risk 4.09, 95% confidence interval 3.02-5.53, P < 0.001) and body mass index 30 kg/m(2) or greater (1.53, 1.17-1.99, P = 0.002) and increased risk (with a P value < 0.1) for GH dose 600 microg/d or greater (1.18, 95% confidence interval 0.98-1.44, P = 0.088). CONCLUSION: MetS prevalence in GHD patients was higher than in the general population in the United States and higher in the United States than Europe. Prevalence was unaffected by GH replacement, but baseline MetS status and obesity were strong predictors of MetS after GH treatment