Faculty Bibliography

Thyroid cancer (TC) is the most common endocrine malignancy, with an approximately three-fold higher incidence in women. TCGA data indicate that androgen receptor (AR) RNA is significantly downregulated in PTC. In this study, AR-expressing 8505C (anaplastic TC) (84E7) and K1 (papillary TC) cells experienced an 80% decrease in proliferation over 6 days of exposure to physiological levels of 5α-dihydrotestosterone (DHT). In 84E7, continuous AR activation resulted in G1 growth arrest, accompanied by a flattened, vacuolized cell morphology, with enlargement of the cell and the nuclear area, which is indicative of senescence; this was substantiated by an increase in senescence-associated β-galactosidase activity, total RNA and protein content, and reactive oxygen species. Additionally, the expression of tumor suppressor proteins p16, p21, and p27 was significantly increased. A non-inflammatory senescence-associated secretory profile was induced, significantly decreasing inflammatory cytokines and chemokines such as IL-6, IL-8, TNF, RANTES, and MCP-1; this is consistent with the lower incidence of thyroid inflammation and cancer in men. Migration increased six-fold, which is consistent with the clinical observation of increased lymph node metastasis in men. Proteolytic invasion potential was not significantly altered, which is consistent with unchanged MMP/TIMP expression. Our studies provide evidence that the induction of senescence is a novel function of AR activation in thyroid cancer cells, and may underlie the protective role of AR activation in the decreased incidence of TC in men.

Primary aldosteronism remains a leading cause of secondary hypertension, and its diagnosis and management continue to pose a challenge for clinicians. In this article, we review the diagnosis of primary aldosteronism along with its cardiovascular manifestations. Treatment is described depending on the diagnostic outcome, focusing on medical management with mineralocorticoid receptor antagonists and unilateral adrenalectomy. Although screening and diagnosing hyperaldosteronism follows well-known algorithms, in practice, physicians may find difficulty establishing the best course of action due to complexity in testing and confirming laterality of aldosterone production by the adrenals. Recognizing and treating primary aldosteronism requires a multidisciplinary approach with primary care physicians, cardiologists, endocrinologists, and radiologists working collaboratively.

Pheochromocytomas are rare endocrine tumors that can have a significant impact on a variety of organ systems, including the cardiovascular system. Although the pathophysiology is not completely understood, pheochromocytomas exert their effects through high levels of catecholamines, mainly epinephrine and norepinephrine, which stimulate adrenergic receptors, including those within the cardiovascular system. Although the most common cardiovascular manifestation is hypertension, patients with pheochromocytoma can present with arrhythmia, hypotension, shock, myocardial ischemia, cardiomyopathy, aortic dissection, and peripheral ischemia. The medical management of the cardiovascular effects of pheochromocytoma is via blockade of adrenergic receptors, usually through the use of alpha blockers, with the addition of beta blockers if needed. However, only surgical resection of the pheochromocytoma is potentially curative, and this tumor requires unique management perioperatively. Because of the variability of presentation and the significant morbidity and mortality of patients with an undiagnosed pheochromocytoma, this entity should not be overlooked in the evaluation of patients with a wide variety of cardiovascular disorders.

We describe detailed administration of thyroidal and extrathyroidal doses of radioiodine to a patient with end-stage renal disease on hemodialysis. A thorough description of area under curve measurements in a patient with compromised renal function has rarely been described in the literature. Few publications have described thyroid cancer management of patients on hemodialysis, and we believe our management will aid in patient treatment in the future.

Protein tyrosine kinase inhibitors are currently an important drug class in the treatment of leukemia. They represent targeted cancer therapy and have become the treatment of choice in chronic myeloid leukemia. Tyrosine kinases are enzymes expressed in multiple tissues and are involved in several signaling pathways influencing cellular growth. Below we describe a patient who developed an unusual complication of tyrosine kinase inhibitor therapy: thyrotoxicosis due to destructive thyroiditis. We review the pathophysiology of tyrosine kinase inhibitor-induced thyroid dysfunction particularly with regard to new second-generation tyrosine kinase inhibitors.

Growth hormone (GH) exerts its effects through insulin-like growth factor-1, and although ubiquitous in human tissues, it has a significant role in cardiovascular function. In recent years, there has been a great deal of interest in GH as an etiologic factor in many cardiovascular disease states. Acromegaly, a state of endogenous GH excess, results in myocardial hypertrophy and decreased cardiac performance with increased cardiovascular mortality. Additional insight into the role of excess GH on the cardiovascular system has been gained from data collected in athletes doping with GH. Likewise, GH deficiency is associated with increased mortality, possibly from the associated increase in atherosclerosis, lipid abnormalities, and endothelial dysfunction. However, further research is required to clarify the benefit of GH treatment in both deficient states and in heart failure patients.

The Accreditation Council for Graduate Medical Education common program requirements for Practice-based Learning and Improvement in Internal Medicine specify that trainees must "systematically analyze [his/her] practice using quality improvement methods, and implement changes with the goal of practice improvement" and that the training program "must include use of performance data" in the assessment of the resident's practice. Before implementation of an electronic health record at our academic medical center, we found meeting these requirements to be challenging. This prompted us to set up the New Innovations (New Innovations, Inc, Uniontown, OH) Software Suite's Patient Continuity module to permit analysis and tracking of both quality of care indicators and patient continuity. By using the system, our residents were better able to monitor their patient panel sizes and composition and to correlate their practices with quality of care data. Residency programs, which currently utilize New Innovations software but lack an electronic health record, may find the continuity clinic module useful for engaging their house staff in structured practice improvement initiatives and in satisfying the Accreditation Council for Graduate Medical Education's common program requirements for practice-based learning.

XXY men (Klinefelter syndrome) are testosterone deficient, socially isolated, exhibit impaired gender identity, and may experience more homosexual behaviors. Here, we characterize social behaviors in a validated XXY mouse model to understand mechanisms. Sociability and gender preference were assessed by three-chambered choice tasks before and after castration and after testosterone replacement. Metabolomic activities of brain and blood were quantified through fractional synthesis rates of palmitate and ribose (GC-MS). XXY mice exhibit greater sociability than XY littermates, particularly for male mice. The differences in sociability disappear after matching androgen exposure. Intact XXY, compared with XY, mice prefer male mice odors when the alternatives are ovariectomized female mice odors, but they prefer estrous over male mice odors, suggesting that preference for male mice may be due to social, not sexual, cues. Castration followed by testosterone treatment essentially remove these preferences. Fractional synthesis rates of palmitate are higher in the hypothalamus, amygdala, and hippocampus of XXY compared with XY mice but not with ribose in these brain regions or palmitate in blood. Androgen ablation in XY mice increases fractional synthesis rates of fatty acids in the brain to levels indistinguishable from those in XXY mice. We conclude that intact XXY mice exhibit increased sociability, differences in gender preference for mice and their odors are due to social rather than sexual cues and, these differences are mostly related to androgen deficiency rather than genetics. Specific metabolic changes in brain lipids, which are also regulated by androgens, are observed in brain regions that are involved in these behaviors.

Cardiovascular disease remains the leading cause of death in most of the developed world despite advances in both prevention and treatment. At the same time, the incidence rates of cardiovascular disease differ greatly between the genders, with men more likely than women to manifest ischemic heart disease. This observation has prompted new research initiatives to explain the discrepancy in heart disease prevalence and incidence between the sexes. Whether androgens affect cardiovascular disease adversely remains a contentious issue, with some data pointing to a deleterious effect of androgens on lipid profiles, and other studies revealing androgens' possible benefits on cardiovascular function. This review will examine the relationship between the endogenous production of androgen as well as the exogenous replacement of testosterone in men and the possible links to cardiovascular disease. The role of testosterone in male cardiovascular health is not completely understood, and additional studies are needed to explain its effect on atherosclerosis and its complications.