Pouneh K. Fazeli

Cushing disease is the most common form of endogenous hypercortisolism and can be associated with familial endocrine syndromes, including multiple endocrine neoplasia type 4 (MEN4). We report a case of a father and daughter who both presented with Cushing disease and were found to have the same variant of unknown significance in the CDKN1B gene (c.280 C>T, p.P94S), the gene responsible for MEN4. They were treated surgically and are in remission from Cushing disease. This case raises the possibility that the variant could be pathogenic, despite in silico predictions to the contrary.

Humans have evolved adaptive mechanisms that enable survival even with zero calories for periods of months or longer. Intermittent ‘low-dose’ exposure to the metabolic stress of fasting may also activate pathways that promote metabolic health and longevity, although such benefits have not been proven in humans. Here we present our perspective of the current rationale and evidence base to support fasting for gain in metabolic health. In the absence of individual level risk factors for potential harm, such as frailty, osteoporosis or osteopenia, or a current/historical eating disorder, a trial of intermittent fasting or time-restricted eating to promote weight loss and metabolic health is reasonable for the motivated patient who is overweight or obese. We conclude, however, that the current state of evidence is limited and not sufficient to justify widespread adoption of fasting practices, nor is it sufficient to exclude the possibility that fasting holds a key to a longer life. We provide a template for the types of studies that will be required to optimize fasting protocols and establish therapeutic proof of concept. In our opinion, incorporation of mechanistic and multi-omics endpoints will be critical to understand potential mechanisms of benefit in humans; pathways that could ultimately be targeted with a fasting mimetic drug to obviate the need for long-term adherence to onerous dietary restriction.

Current guidelines support a clinical diagnosis of menopause for most women [1–3], but the presumption that midlife amenorrhea invariably reflects ovarian senescence may obscure other important eti...

Summary Women with anorexia nervosa have low bone mineral density and increased fracture risk. We conducted a randomized, placebo-controlled trial investigating the effects of 6 months of teriparatide in anorexia nervosa. Teriparatide led to trends in improvements in bone structure. Longer-term studies are needed to evaluate the benefit of teriparatide in anorexia nervosa. Purpose Women with anorexia nervosa have low BMD and increased fracture risk. Currently, there are no approved therapies for bone loss in anorexia nervosa. This study investigated the effects of teriparatide (TPT) on bone microarchitecture and structure in anorexia nervosa. Methods We conducted a randomized placebo-controlled study including women with anorexia nervosa and a T-score: ≤ − 2.5. Twenty-one women were randomized to (1) TPT (N = 10; 47.7 ± 8.6yrs) or (2) placebo (N = 11; 47.7 ± 7.7yrs) for 6 months. Primary outcomes included changes in trabecular and cortical bone microarchitecture (HR-pQCT) and hip structural analysis parameters (HSA program). Secondary outcomes included bone turnover markers (ELISA). Results After TPT treatment, no changes were observed in bone microarchitecture, but trends in HSA parameters in the intertrochanteric region (IT) of the proximal femur were noted. IT cortical thickness increased by 13% (p = 0.075 vs. baseline) after TPT (vs. a non-significant decrease in IT cortical thickness in placebo), and IT buckling ratio decreased 9% (vs baseline) in the TPT group (vs a 5% increase in placebo, p = 0.076). After TPT treatment, circulating levels of osteocalcin and osteopontin increased significantly in TPT (osteocalcin: 216.4%, p = 0.01 vs. baseline and osteopontin: 68.6%, p = 0.03 vs. baseline). No significant changes in osteocalcin or osteopontin levels were observed in the placebo group. Conclusion Six months of TPT treatment in women with anorexia nervosa led to trends in improvements in bone structure. Long-term studies are needed to evaluate the potential benefit of TPT in anorexia nervosa.

Context: Optimizing bone mass accrual early in life is a strategy for mitigating fracture risk in older age. Objective: This study aimed to identify factors associated with lower than expected bone mass in healthy young adult men. Methods: Data from 39 male participants (21 areal bone mineral density [aBMD] Z scores <−1.0 at either the total hip, femoral neck, or lumbar spine [Lower]; 18 Z scores ≥1.0, but not <−1.0 at any site [controls; Con]) were analyzed from a larger study. aBMD and body composition were assessed by dual-energy x-ray absorptiometry (DXA), and bone quality was evaluated at the tibia using high resolution–peripheral quantitative computed tomography (HR-pQCT). Fasted concentrations of bone turnover markers, testosterone, estradiol, parathyroid hormone (PTH), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-1 binding protein 5 (IGFBP-5) were measured via enzyme-linked immunosorbent assays. Results: The Lower group was older (age in years: Lower 25 [6]; Con 21 [5]; P = .037), shorter (m; Lower 1.74 [0.10]; Con 1.79 [0.10]; P = .024), and had less lean mass than Con (kg; Lower 54.2 [6.2]; Con 60.3 [6.9]; P = .018). Tibial bone microarchitecture (trabecular number 1/mm; Lower 1.7 [0.2]; Con 1.9 [0.2]; P = .004; trabecular separation mm; Lower 0.6 [0.1]; Con 0.5 [0.1]; P = .002) and strength (stiffness kN/mm Lower 207.7 [43.3]; Con 274.7 [39.7] and failure load kN Lower 11.3 [2.2]; Con 14.8 [2.0]; P < .001) were compromised in Lower. Alkaline phosphatase was greater (Lower 1528.2 [933.8]; Con 605.4 [624.1]; P = .003), and IGF-1 (Lower 265.5 [93.6]; Con 340.4 [106.5]; P = .027) was lower in Lower. Osteoblast activity (P ≥ .361) and gene expression were similar between groups (P ≥ .451). Conclusion: Men with relatively lower than expected aBMD demonstrated compromised bone microarchitecture and lower lean mass, indicating the importance of targeted intervention for lean mass accrual during young adulthood.

The adaptive starvation response allows us to survive periods of starvation—a characteristic of the environment in which humans evolved. We are now in an evolutionary transition from a global environment that was characterized by periods of famine to a world where obesity and caloric excess have become a new reality, but the mechanisms of fasting physiology remain relevant. First, many parts of the world are still plagued by famine with insufficient food resources and therefore the adaptive mechanisms required for survival during periods of decreased caloric intake are not simply relevant to our evolutionary past. Second, the obesity epidemic provides strong rationale for understanding the biology of fasting, as the same efficiencies that have evolved to allow us to survive periods of starvation also likely drive a genetic predisposition to obesity, and therefore some of the adaptive mechanisms may be maladaptive in the setting of food excess. A third compelling reason to explore the biology of fasting is that in model organisms, caloric restriction, without overt starvation, is an intervention that prolongs lifespan. The purpose of this review is to provide an overview of the biology of fasting. We will highlight potential mechanisms of benefit from fasting as well as examine data from model organisms and humans that indicate potential health risks of fasting, particularly related to bone fragility. Finally, we will review clinical studies to date that have investigated the effects of fasting on metabolic outcomes and suggest signals of benefit.

Physiological adaptations to fasting enable humans to survive for prolonged periods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization of fatty acids and glycerol from adipocyte lipid stores by canonical neutral lipases, including the rate limiting adipose triglyceride lipase (Pnpla2/ATGL), is critical to the adaptive fasting response. Here we discovered an alternative mechanism of lipolysis in adipocytes involving a lysosomal program. We functionally tested lysosomal lipolysis with pharmacological and genetic approaches in mice and in murine and human adipocyte and adipose tissue explant culture, establishing dependency on lysosomal acid lipase (LIPA/LAL) and the microphthalmia/transcription factor E (MiT/TFE) family. Our study establishes a model whereby the canonical pathway is critical for rapid lipolytic responses to adrenergic stimuli operative in the acute stage of fasting, while the alternative lysosomal pathway dominates with prolonged fasting.

Objective To examine the effect of underweight maternal body mass index (BMI) on pregnancy complications and neonatal outcomes. Design Cohort study. Setting Tertiary academic center. Patients A total of 16,361 mothers who delivered a singleton between 2015-2021 with either a BMI 2 (n=732) or normal BMI (18.5> BMI 2, n=15,629) at the initial prenatal visit or within six months of the initial visit. Main Outcome Measures Birthweight, gestational age, neonatal intensive care unit admission, preterm birth, and fetal death; obstetrical complications including pre-eclampsia/eclampsia, premature rupture of membranes, preterm premature rupture of membranes, and post-partum hemorrhage. Results Underweight women were younger and less likely to have private insurance (p<0.01 for both) than normal-weight women. Approximately 23% of infants born to underweight mothers were small for gestational age (SGA) and 15% were low birthweight versus 13.5% and 9% of infants of normal-weight mothers, respectively (p<0.01 for both). These differences remained significant after adjusting for potential confounders. In adjusted logistic regression models, underweight women had a decreased risk of premature rupture of membranes and post-partum hemorrhage compared to normal-weight women. Conclusions Underweight BMI during pregnancy is associated with an increased risk of small for gestational age and low birth weight infants and a decreased risk of premature rupture of membranes and post-partum hemorrhage. These findings suggest underweight BMI during pregnancy increases the risk of adverse neonatal outcomes, while maternal-related pregnancy outcomes are less affected.