Heshmati, Hassan

Abstract Disclosure: H.M. Heshmati: None. H.S. Abu-Lebdeh: None. Background: Growth differentiation factor 15 (GDF15) is a peptide hormone produced by the placenta during pregnancy and by several other organs (e.g., prostate, bladder, kidney, pancreas, and endometrium). It is a member of the transforming growth factor-β superfamily. The gene encoding for GDF15 is located on chromosome 19. The mature GDF15 has 112 amino acids and binds to glial cell-derived neurotrophic factor family receptor alpha-like. GDF15 is involved in the maintenance of homeostasis and contributes to the pathogenesis of several medical conditions. This literature analysis provides an update on the relevance of GDF15 in health and few selected diseases. Methods: A systematic search of literature was conducted using the search terms growth differentiation factor 15, pregnancy, heart failure, anorexia, obesity, diabetes, and cancer. Results: In control subjects, the median serum GDF15 level is around 680 pg/mL and increases with aging. There is an increase in GDF15 secretion during pregnancy (third trimester serum levels > 20,000 pg/mL) and under other stressful conditions such as inflammation, myocardial ischemia, pulmonary diseases, diabetes, and cancer. GDF15 is involved in the maintenance of cell and tissue homeostasis. It has anti-inflammatory, immunomodulatory, and anorectic properties. The high serum GDF15 levels observed during pregnancy plays an important role in the feto-maternal immunotolerance. Low serum GDF15 levels have been reported in pregnancies with complications (e.g., preeclampsia and miscarriage). Serum GDF15 levels are negatively correlated with body mass index. Treatment with metformin in patients with or without type 2 diabetes stimulates GDF15 production, and this can explain, at least in part, the weight-loss property of metformin. In patients with heart failure or cancer, the increased serum GDF15 levels contribute to cachexia (anorexia and weight loss). Serum GDF15 level has the potential to be used as a biomarker for disease diagnosis and prognosis (e.g., biomarker for heart failure and pancreatic cancer). High serum GDF15 levels are associated with poor prognosis and predict all-cause mortality. Based on the GDF15 properties related to appetite and body weight control, GDF15 analogs and antagonists can be considered in the weight management of various conditions such as obesity (induction of anorexia with GDF15 analogs), and heart failure or cancer (reduction of cachexia with GDF15 antagonists). Conclusion: GDF15, a hormone synthesized by several organs including placenta, prostate, bladder, kidney, pancreas, and endometrium, has an important role in multiple physiological and pathological conditions. Its serum level can be considered as a biomarker for the diagnosis and prognosis of several diseases. GDF15 analogs and antagonists have the potential to be used in the weight management of obesity and cardiac or cancer cachexia. Presentation: Sunday, July 13, 2025

Abstract Disclosure: H.M. Heshmati: None. H.S. Abu-Lebdeh: None. Background: Fibroblast growth factor 21 (FGF21), a member of the human FGF superfamily, is a 181 amino acid peptide hormone primarily produced by the liver. The gene of FGF21, located on chromosome 19, was cloned in 2000. FGF21 is involved in the maintenance of metabolic homeostasis. This review presents an update on the relevance of FGF21 in the diagnosis and treatment of metabolic disorders including obesity, nonalcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes. Methods: A systematic search of literature was conducted using the search terms fibroblast growth factor 21, obesity, nonalcoholic fatty liver disease, dyslipidemia, and type 2 diabetes. Results: FGF21 is a stress hormone with effects on energy expenditure and metabolism of lipids and glucose. FGF21 exerts its endocrine action in the central nervous system and adipose tissue. The serum FGF21 levels in normal subjects increase with aging. Stressful conditions (e.g., fasting status, protein restriction, exercise, metabolic disorders, kidney diseases, cardiovascular diseases, and sepsis) increase FGF21 secretion. Serum FGF21 levels are increased in obesity, NAFLD, dyslipidemia, and type 2 diabetes. Some of these patients may have a state of FGF21 resistance. The resistance to FGF21 is related, at least in part, to the presence of high circulating levels of fibroblast activation protein, a protease that inactivates FGF21. It has been suggested that the exercise-induced weight loss can be due to increased FGF21 secretion and decreased FGF21 resistance in adipose tissue. Serum FGF21 level has the potential to be used as a biomarker for early diagnosis of metabolic disorders (e.g., NAFLD and type 2 diabetes). Based on different metabolic properties of FGF21, FGF21-based therapy has been considered as an attractive approach for the treatment of metabolic disorders. Since native FGF21 has poor pharmacodynamic properties (e.g., short half-life and proteolytic cleavage by proteases), long-acting FGF21 analogs (e.g., LY2405319, PF-05231023, pegozafermin, AKR-001, and LLF580) have been synthesized and tested in clinical trials for the treatment of obesity, NAFLD, dyslipidemia, and type 2 diabetes. The available results show that FGF21 analogs can reduce body weight, liver fat, blood lipids, and fasting insulin/insulin resistance. Overall, the treatment with these analogs is safe and well tolerated. Conclusion: FGF21 is a predominantly liver-derived peptide hormone regulating energy expenditure and metabolism of lipids and glucose. Serum FGF21 levels are increased in several metabolic disorders including obesity, NAFLD, dyslipidemia, and type 2 diabetes. FGF21 is an attractive target for the treatment of these metabolic disorders. Despite some promising results observed with the use of FGF21 analogs, more clinical studies are needed before recommending FGF21-based therapies in metabolic disorders. Presentation: 6/2/2024

Abstract Disclosure: H.S. Abu-Lebdeh: None. H.M. Heshmati: None. Background: Prostate cancer is among the most common malignancy in men and represents the second most common cause of cancer-related mortality among men in the US. Androgen-deprivation therapy with surgical or medical castration is widely used to treat hormone-sensitive prostate cancer. Disease progression despite androgen-deprivation therapy is a state defined as castration-resistant prostate cancer that is associated with poor survival rate. This review presents an update on the contribution of two adrenal androgens, 11-ketotestosterone and 11-ketodihydrotestosterone, to the castration-resistant prostate cancer. Methods: A systematic search of literature was conducted using the search terms prostate cancer, testosterone, dihydrotestosterone, adrenal androgens, 11-ketotestosterone, 11-ketodihydrotestosterone, androgen-deprivation therapy, castration, and castration-resistant prostate cancer. Results: In 2022, around 268,490 new cases of prostate cancer were diagnosed in the US with a mortality of 34,500 cases. Although androgen-deprivation therapy with castration is efficient at the beginning, most patients develop a state of castration resistance usually after 2-3 years as a result of the reactivation of androgen-receptor signaling despite low testosterone levels. The adrenal glands produce significant amounts of steroid hormones and metabolites. Among them, 11-ketotestosterone and 11-ketodihydrotestosterone are potent and efficacious androgens with potentially longer activity compared to testosterone and dihydrotestosterone because they are metabolized at a lower rate. Dihydrotestosterone derived from the metabolism of adrenal androgens (e.g., androstenedione and dehydroepiandrosterone) and especially 11-ketotestosterone and 11-ketodihydrotestosterone are important contributors to castration-resistant prostate cancer. In these cases, adrenal suppression with drugs causing a decrease in adrenal androgen production may improve the effectiveness of the androgen-deprivation therapy. Conclusion: In most patients with prostate cancer, androgen-deprivation therapy loses its effectiveness after 2-3 years leading to a state of castration-resistant prostate cancer. Two potent and highly efficacious androgen-receptor agonists of adrenal origin, 11-ketotestosterone and 11-ketodihydrotestosterone, are predominant androgens after castration and play an important role in the development and progression of castration-resistant prostate cancer. Their measurement in blood can be of clinical value during androgen-deprivation therapy. Concomitant treatment aimed to block the production of adrenal androgens is of potential interest in the management of these patients, but more studies are necessary to further investigate the benefits and adverse effects of this approach. Presentation: Saturday, June 17, 2023

Bone turnover has a circadian pattern, with bone resorption and, to a lesser extent, bone formation increasing at night. Serum cortisol also has a circadian pattern and is a potential candidate for mediating the circadian changes in bone turnover. Thus, we measured bone formation and resorption markers before (study A) and after (study B) elimination of the morning peak of cortisol. We also assessed effects of the circadian cortisol pattern on serum calcium, PTH, and urinary calcium excretion. Ten normal postmenopausal women, aged 63–75 yr (mean, 69 yr), were studied. Metyrapone was administered to block endogenous cortisol synthesis and either a variable (study A) or a constant (study B) infusion of cortisol was given to reproduce and then abolish the morning cortisol peak. Blood was sampled every 2 h for serum cortisol, ionized calcium, PTH, and bone formation markers[ osteocalcin and carboxyl-terminal propeptide of type I collagen (PICP)], and timed 4-h urine samples were collected for measurement of calcium, phosphorus, sodium, potassium, and bone resorption markers (N-telopeptide of type I collagen and free deoxypyridinoline).During study A, serum osteocalcin had a circadian pattern, with a peak at 0400 h and a nadir at 1400 h. During study B, however, the afternoon nadir of serum osteocalcin was eliminated (P < 0.001 and P < 0.005 for the difference in the patterns of peak and nadir, respectively, on the 2 study days). In contrast, the circadian patterns of serum PICP and urinary N-telopeptide of type I collagen and free deoxypyridinoline were virtually identical during the two studies. Urinary calcium excretion declined after the cortisol peak, without differences between the 2 study days in phosphorus or sodium excretion or in serum PTH. We conclude that the circadian variation in serum cortisol is responsible for the circadian pattern of serum osteocalcin, but not that of PICP or bone resorption markers. The physiological variation in serum cortisol may also reduce urinary calcium excretion.

Abstract Although median levels of bone turnover are increased in postmenopausal women, it is unclear whether the low circulating levels of endogenous estrogen exert a regulatory role on these levels. This issue was evaluated by assessing the effect of a blockade of estrogen synthesis on bone turnover markers in 42 normal women (mean age ± SD, 69 ± 5 years) randomly assigned to groups receiving the potent aromatase inhibitor letrozole or placebo for 6 months. Letrozole treatment reduced serum estrone (E1) and estradiol (E2) to near undetectable levels (p < 0.0001). This treatment did not affect bone formation markers but, as compared with the placebo group, increased bone resorption markers (urine 24-h pyridinoline [PYD] by 13.3% [p < 0.05] and 24-h urine deoxypyridinoline [DPD] by 14.2% [p < 0.05]) and decreased serum parathyroid hormone (PTH) by 22% (p = 0.002). These data indicate that in late postmenopausal women even the low serum estrogen levels present exert a restraining effect on bone turnover and support the concept that variations in these low levels may contribute to differences in their rate of bone loss.