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What Is the Role of “Growth Hormone” When You Have Stopped Growing? Growth hormone clearly plays a key role in development during youth, but research in adults implicates it as an agent in cellular aging processes. Shlomo Melmed, MD, ChB, the first recipient of the Transatlantic Alliance Award, co-sponsored by the Endocrine Society and the European Society of Endocrinology, discusses the misconceptions of administering growth hormone in adults. Children need growth hormone to grow into their adult height, but the hormone’s function among adults is unclear. The pituitary secretes less growth hormone as a person ages, but new research is elucidating a potentially important role for nonpituitary growth hormone generated in the periphery in regulating cellular proliferation associated with aging. AT A GLANCE Growth hormone levels decline with age — which may be a protective mechanism in slowing some of the effects of aging. Nonpituitary growth hormone in the colon epithelium has been shown to inhibit the tumor suppressor gene p53, resulting in pro-proliferative effects. Low levels of growth hormone in adulthood appear to be associated with greater longevity, whereas higher levels are associated with the adverse effects of aging. Unraveling the effects of this mysterious hormone has been a focus of the work of Shlomo Melmed, MB ChB, dean of the faculty of medicine at Cedars-Sinai in Los Angeles. Melmed is the inaugural winner of the Transatlantic Alliance Award, an honor co-sponsored by the Endocrine Society and the European Society of Endocrinology to recognize an international leader who has made significant advancements in endocrine research on both sides of the Atlantic. As part of the award, Melmed gave a presentation at both ENDO 2022 in Atlanta in June, and at the European Congress of Endocrinology 2022 in Milan entitled, “Growth Hormone: An Adult Endocrine Misnomer?” Dangers of Too Little or Too Much The growth hormone level declines dramatically with age such that it is barely detectable in the circulation by age 80, but even at low levels it is clearly playing an important role. “Adults deficient in pituitary growth hormone have a unique phenotype,” Melmed says. “They develop central obesity and may have high blood pressure and lethargy. Growth hormone in adulthood is needed to maintain body homeostasis, i.e., the appropriate ratio between lean body mass and fat mass. When these GH-deficient adults [receive] very low doses of growth hormone, body changes are recalibrated and homeostatic changes that occur with hormone deficiency may be reversed.” On the other hand, the deleterious effects of too much growth hormone from an over-secreting pituitary adenoma are well-known. “Patients with acromegaly have phenotypic features often associated with aging,” Melmed says. “They have heart disease, diabetes, hypertension, and osteoporosis, and may develop tumors. Many afflictions of aging are present, and the linkage of too much growth hormone with adverse effects on the aging process is clinically intuitive.” Nonpituitary Growth Hormone However, evidence is mounting that growth hormone that originates not from the pituitary but in the periphery could have significant effects. Melmed and others have been conducting cellular, animal, and human studies on the effects of autocrine and paracrine growth hormone. For example, the hormone appears to be produced by the epithelial cells of the colon and neighboring cells, where it acts locally to activate the growth hormone receptor, to engender cell cycle changes and DNA damage, and to promote pro-proliferative changes, Melmed says. One of its most important actions may be to inhibit the tumor suppressor gene p53, which is a powerful constraint on cell proliferation and tumor formation. “We found that growth hormone locally suppresses p53, thereby unleashing the cell to become more pro-proliferative,” Melmed says. “We performed a series of cellular and animal experiments to show that the molecular profile of aging may be accelerated by increasing growth hormone signaling, and if you block growth hormone action you may suppress deleterious aging effects on the cell cycle, including attenuation of DNA repair,” Melmed says. For example, their experiments showed that the drug pegvisomant, a growth hormone receptor inhibitor used to treat patients with acromegaly, can elevate p53 levels and enable a protective environment in the colon epithelium. “The role of growth hormone in regulating proliferation of colon cells could explain why patients with acromegaly have an abundance of colon polyps,” he tells Endocrine News. Evidence from Families Melmed says that other tantalizing clues implicating growth hormone in aging include the pioneering work of Endocrine Society Koch Awardee Anderzj Bartke, who showed that GH-deficient mice live longer. Furthermore, a Netherlands study of the relatives of centenarians found that these long-lived individuals and their family members have very low growth hormone levels. There have also been studies of several families around the world who have inactivating growth hormone receptor mutations with short stature and an extremely low incidence of cancer. “We re-introduced a normal growth hormone receptor into the mutated fibroblasts, and down-regulated their high p53 expression, another proof of principle in humans that local growth hormone may enable a pro-proliferative micro-environment,” Melmed says. “We propose, based upon the body of cellular, animal, and human data that have been generated by other colleagues and ourselves, that blocking growth hormone action may protect from adverse cellular effects of aging. We have no evidence that aging could be reversed, but blocking growth hormone signaling could mitigate pro-proliferative cell cycle events and DNA damage associated with aging,” Melmed says. “Adults deficient in pituitary growth hormone have a unique phenotype. They develop central obesity and may have high blood pressure and lethargy. Growth hormone in adulthood is needed to maintain body homeostasis, i.e., the appropriate ratio between lean body mass and fat mass. When these GH-deficient adults [receive] very low doses of growth hormone, body changes are recalibrated and homeostatic changes that occur with hormone deficiency may be reversed.” He notes that these findings have an immediate practical application as a counter to the large illicit market in which people, especially athletes, are taking growth hormone as a performance-enhancing drug “in an attempt to enhance athletic performance or to improve their longevity” when the evidence indicates that “the opposite is true, and growth hormone may in fact be harmful.” Seaborg is a freelance writer based in Charlottesville, Va. He wrote about the Endocrine Society’s latest Clinical Practice Guideline, “Management of Hyperglycemia in Hospitalized Adult Patients in Non-Critical Care Settings: An Endocrine Society Guideline,” in the July issue. From https://endocrinenews.endocrine.org/an-adult-endocrine-misnomer/?fbclid=IwAR0EIssqVRbv9SYloB5tHVIqIeQ6J7xjYYFgbszWVTX4eWS0uUWJShWPVKA-
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An updated guideline for the treatment of Cushing’s disease focuses on new therapeutic options and an algorithm for screening and diagnosis, along with best practices for managing disease recurrence. Despite the recent approval of novel therapies, management of Cushing’s disease remains challenging. The disorder is associated with significant comorbidities and has high mortality if left uncontrolled. Source: Adobe Stock “As the disease is inexorable and chronic, patients often experience recurrence after surgery or are not responsive to medications,” Shlomo Melmed, MB, ChB, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, and an Endocrine Today Editorial Board Member, told Healio. “These guidelines enable navigation of optimal therapeutic options now available for physicians and patients. Especially helpful are the evidence-based patient flow charts [that] guide the physician along a complex management path, which usually entails years or decades of follow-up.” Shlomo Melmed The Pituitary Society convened a consensus workshop with more than 50 academic researchers and clinical experts across five continents to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, participants reviewed data from January 2015 to April 2021 on screening and diagnosis; surgery, medical and radiation therapy; and disease-related and treatment-related complications of Cushing’s disease, all summarized in recorded lectures. The guideline includes recommendations regarding use of laboratory tests, imaging and treatment options, along with algorithms for diagnosis of Cushing’s syndrome and management of Cushing’s disease. Updates in laboratory, testing guidance If Cushing’s syndrome is suspected, any of the available diagnostic tests could be useful, according to the guideline. The authors recommend starting with urinary free cortisol, late-night salivary cortisol, overnight 1 mg dexamethasone suppression, or a combination, depending on local availability. If an adrenal tumor is suspected, the guideline recommends overnight dexamethasone suppression and using late-night salivary cortisol only if cortisone concentrations can also be reported. The guideline includes several new recommendations in the diagnosis arena, particularly on the role of salivary cortisol assays, according to Maria Fleseriu, MD, FACE, a Healio | Endocrine Today Co-editor, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland. Maria Fleseriu “Salivary cortisol assays are not available in all countries, thus other screening tests can also be used,” Fleseriu told Healio. “We also highlighted the sequence of testing for recurrence, as many patients’ urinary free cortisol becomes abnormal later in the course, sometimes up to 1 year later.” The guideline states combined biochemical and imaging for select patients could potentially replace petrosal sinus sampling, a very specialized procedure that cannot be performed in all hospitals, but more data are needed. “With the corticotropin-releasing hormone stimulation test becoming unavailable in the U.S. and other countries, the focus is now on desmopressin to replace corticotropin-releasing hormone in some of the dynamic testing, both for diagnosis of pseudo-Cushing’s as well as localization of adrenocorticotropic hormone excess,” Fleseriu said. The guideline also has a new recommendation for anticoagulation for high-risk patients; however, the exact duration and which patients are at higher risk remains unknown. “We always have to balance risk for clotting with risk for bleeding postop,” Fleseriu said. “Similarly, recommended workups for bone disease and growth hormone deficiency have been further structured based on pitfalls specifically related to hypercortisolemia influencing these complications, as well as improvement after Cushing’s remission in some patients, but not all.” New treatment options The guideline authors recommended individualizing medical therapy for all patients with Cushing’s disease based on the clinical scenario, including severity of hypercortisolism. “Regulatory approvals, treatment availability and drug costs vary between countries and often influence treatment selection,” the authors wrote. “However, where possible, it is important to consider balancing cost of treatment with the cost and the adverse consequences of ineffective or insufficient treatment. In patients with severe disease, the primary goal is to treat aggressively to normalize cortisol concentrations.” Fleseriu said the authors reviewed outcomes data as well as pros and cons of surgery, repeat surgery, medical treatments, radiation and bilateral adrenalectomy, highlighting the importance of individualized treatment in Cushing’s disease. “As shown over the last few years, recurrence rates are much higher than previously thought and patients need to be followed lifelong,” Fleseriu said. “The role of adjuvant therapy after either failed pituitary surgery or recurrence is becoming more important, but preoperative or even primary medical treatment has been also used more, too, especially in the COVID-19 era.” The guideline summarized data on all medical treatments available, either approved by regulatory agencies or used off-label, as well as drugs studied in phase 3 clinical trials. “Based on great discussions at the meeting and subsequent emails to reach consensus, we highlighted and graded recommendations on several practical points,” Fleseriu said. “These include which factors are helpful in selection of a medical therapy, which factors are used in selecting an adrenal steroidogenesis inhibitor, how is tumor growth monitored when using an adrenal steroidogenesis inhibitor or glucocorticoid receptor blocker, and how treatment response is monitored for each therapy. We also outline which factors are considered in deciding whether to use combination therapy or to switch to another therapy and which agents are used for optimal combination therapy.” Future research needed The guideline authors noted more research is needed regarding screening and diagnosis of Cushing’s syndrome; researchers must optimize pituitary MRI and PET imaging using improved data acquisition and processing to improve microadenoma detection. New diagnostic algorithms are also needed for the differential diagnosis using invasive vs. noninvasive strategies. Additionally, the researchers said the use of anticoagulant prophylaxis and therapy in different populations and settings must be further studied, as well as determining the clinical benefit of restoring the circadian rhythm, potentially with a higher nighttime medication dose, as well as identifying better markers of disease activity and control. “Hopefully, our patients will now experience a higher quality of life and fewer comorbidities if their endocrinologist and care teams are equipped with this informative roadmap for integrated management, employing a consolidation of surgery, radiation and medical treatments,” Melmed told Healio. From https://www.healio.com/news/endocrinology/20211029/updated-cushings-disease-guideline-highlights-new-diagnosis-treatment-roadmap
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LOS ANGELES — More than a century has passed since the neurosurgeon and pathologist Harvey Cushing first discovered the disease that would eventually bear his name, but only recently have several key discoveries offered patients with the condition real hope for a cure, according to a speaker here. There are several challenges clinicians confront in the diagnosis and treatment of Cushing’s disease, Shlomo Melmed, MB, ChB, FRCP, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, said during a plenary presentation. Patients who present with Cushing’s disease typically have depression, impaired mental function and hypertension and are at high risk for stroke, myocardial infarction, thrombosis, dyslipidemia and other metabolic disorders, Melmed said. Available therapies, which range from surgery and radiation to the somatostatin analogue pasireotide (Signifor LAR, Novartis), are often followed by disease recurrence. Cushing’s disease is fatal without treatment; the median survival if uncontrolled is about 4.5 years, Melmed said. “This truly is a metabolic, malignant disorder,” Melmed said. “The life expectancy today in patients who are not controlled is apparently no different from 1930.” The outlook for Cushing’s disease is now beginning to change, Melmed said. New targets are emerging for treatment, and newly discovered molecules show promise in reducing the secretion of adrenocorticotropic hormone (ACTH) and pituitary tumor size. “Now, we are seeing the glimmers of opportunity and optimism, that we can identify specific tumor drivers — SST5, [epidermal growth factor] receptor, cyclin inhibitors — and we can start thinking about personalized, precision treatment for these patients with a higher degree of efficacy and optimism than we could have even a year or 2 ago,” Melmed said. “This will be an opportunity for us to broaden the horizons of our investigations into this debilitating disorder.” Challenges in diagnosis, treatment Overall, about 10% of the U.S. population harbors a pituitary adenoma, the most common type of pituitary disorder, although the average size is only about 6 mm and 40% of them are not visible, Melmed said. In patients with Cushing’s disease, surgery is effective in only about 60% to 70% of patients for initial remission, and overall, there is about a 60% chance of recurrence depending on the surgery center, Melmed said. Radiation typically leads to hypopituitarism, whereas surgical or biochemical adrenalectomy is associated with adverse effects and morbidity. Additionally, the clinical features of hypercortisolemia overlap with many common illnesses, such as obesity, hypertension and type 2 diabetes. “There are thousands of those patients for every patient with Cushing’s disease who we will encounter,” Melmed said. The challenge for the treating clinician, Melmed said, is to normalize cortisol and ACTH with minimal morbidity, to resect the tumor mass or control tumor growth, preserve pituitary function, improve quality of life and achieve long-term control without recurrence. “This is a difficult challenge to meet for all of us,” Melmed said. Available options Pituitary surgery is typically the first-line option offered to patients with Cushing’s disease, Melmed said, and there are several advantages, including rapid initial remission, a one-time cost and potentially curing the disease. However, there are several disadvantages with surgery; patients undergoing surgery are at risk for postoperative venous thromboembolism, persistent hypersecretion of ACTH, adenoma persistence or recurrence, and surgical complications. Second-line options are repeat surgery, radiation, adrenalectomy or medical therapy, each with its own sets of pros and cons, Melmed said. “The reality of Cushing’s disease — these patients undergo first surgery and then recur, second surgery and then recur, then maybe radiation and then recur, and then they develop a chronic illness, and this chronic illness is what leads to their demise,” Melmed said. “Medical therapy is appropriate at every step of the spectrum.” Zebrafish clues Searching for new options, Melmed and colleagues introduced a pituitary tumor transforming gene discovered in his lab into zebrafish, which caused the fish to develop the hallmark features of Cushing’s disease: high cortisol levels, diabetes and cardiovascular disease. In the fish models, researchers observed that cyclin E activity, which drives the production of ACTH, was high. Melmed and colleagues then screened zebrafish larvae in a search for cyclin E inhibitors to derive a therapeutic molecule and discovered R-roscovitine, shown to repress the expression of proopiomelanocortin (POMC), the pituitary precursor of ACTH. In fish, mouse and in vitro human cell models, treatment with R-roscovitine was associated with suppressed corticotroph tumor signaling and blocked ACTH production, Melmed said. “Furthermore, we asked whether or not roscovitine would actually block transcription of the POMC gene,” Melmed said. “It does. We had this molecule (that) suppressed cyclin E and also blocks transcription of POMC leading to blocked production of ACTH.” In a small, open-label, proof-of-principal study, four patients with Cushing’s disease who received roscovitine for 4 weeks developed normalized urinary free cortisol, Melmed said. Currently, the FDA Office of Orphan Products Development is funding a multicenter, phase 2, open-label clinical trial that will evaluate the safety and efficacy of two of three potential doses of oral roscovitine (seliciclib) in patients with newly diagnosed, persistent or recurrent Cushing disease. Up to 29 participants will be treated with up to 800 mg per day of oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts based on efficacy outcomes. “Given the rarity of the disorder, it will probably take us 2 to 3 years to recruit patients to give us a robust answer,” Melmed said. “This zebrafish model was published in 2011, and we are now in 2019. It has taken us 8 years from publication of the data to, today, going into humans with Cushing’s. Hopefully, this will light the pathway for a phase 2 trial.” ‘ Offering optimism’ Practitioners face a unique paradigm when treating patients with Cushing’s disease, Melmed said. Available first- and second-line therapy options often are not a cure for many patients, who develop multimorbidity and report a low quality of life. “Then, we are kept in this difficult cycle of what to do next and, eventually, running out of options,” Melmed said. “Now, we can look at novel, targeted molecules and add those to our armamentarium and at least offer our patients the opportunity to participate in trials, or at least offer the optimism that, over the coming years, there will be a light at the end of the tunnel for their disorder.” Melmed compared the work to Lucas Cranach’s Fons Juventutis (The Fountain of Youth). The painting, completed in 1446, shows sick people brought by horse-drawn ambulance to a pool of water, only to emerge happy and healthy. “He was imagining this ‘elixir of youth’ (that) we could offer patients who are very ill and, in fact, that is what we as endocrinologists do,” Melmed said. “We offer our patients these elixirs. These Cushing’s patients are extremely ill. We are trying with all of our molecular work and our understanding of pathogenesis and signaling to create this pool of water for them, where they can emerge with at least an improved quality of life and, hopefully, a normalized mortality. That is our challenge.” – by Regina Schaffer Reference: Melmed S. From zebrafish to humans: translating discoveries for the treatment of Cushing’s disease. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles. Disclosure: Melmed reports no relevant financial disclosures. From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B585002ad-640f-49e5-8d62-d1853154d7e2%7D/new-discoveries-offer-possible-cushings-disease-cure
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