Abstract and Introduction
Context: Fasting is stressful for the human body. It is managed by metabolic adaptations maintaining energy homeostasis and involves steroid hormone biosynthesis, but the exact interplay between energy and steroid metabolism remains elusive. Women with polycystic ovary syndrome (PCOS) suffer from disturbed metabolism and androgen excess, while in women with anorexia nervosa, cortisol and androgen production are decreased. By contrast, starvation of steroidogenic cells shifts adrenal steroid biosynthesis toward enhanced androgen production.
Aim: This study investigated the effect of fasting on steroid production in healthy women.
Methods: Twenty healthy young women fasted for 48 hours; steroid profiles from plasma and urine samples were assessed at baseline, after 24 hours, and 48 hours by liquid and gas chromatography–mass spectrometry.
Results: Fasting did not change overall steroidogenesis, although it increased progestogen production and lowered relative mineralocorticoid, glucocorticoid, and androgen production. The largest decrease in urine metabolites was seen for β-cortol, dehydroepiandrosterone, and androstenediol; higher levels were found for pregnanediol in urine and progesterone and aldosterone in serum. Activity of 17α-hydroxylase/17,20-lyase (CYP17A1), essential for androgen biosynthesis, was decreased after fasting in healthy women as were 21-hydroxylase (CYP21A2) and 5α-reductase activities. By contrast, hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) activity for cortisol inactivation seemed to increase with fasting.
Conclusion: Significant changes in steroid metabolism occurred after 48 hours of fasting in healthy women. In contrast to metabolic changes seen at baseline in PCOS women compared to healthy women, and after starving of steroidogenic cells, no androgen excess was observed after short-term fasting in healthy young women.
The physiological regulation of short-term and long-term fasting comprises a big challenge to the human body for maintaining energy balance. The metabolic response to fasting is characterized by a switch from carbohydrate to fat metabolism. During fasting, insulin secretion is inhibited, and glucagon promotes glycogenolysis as well as gluconeogenesis and inhibits glyconeogenesis. Fasting can lead to changes in the redox state of nicotinamide adenine dinucleotide (NAD), a cofactor involved in a variety of oxidation–reduction enzymatic reactions important for glycolysis, fatty acid oxidation, the Krebs cycle, and the function of complex I of the mitochondrial respiratory chain.[3,4] Likewise, several enzymes of steroid hormone biosynthesis use NAD as an electron source for their catalytic reactions. But the redox state of NAD is also the main regulator of sirtuins, protein deacetylases, and ADP-ribosyltransferases that directly link cellular metabolic signaling to the state of protein posttranslational modifications.
Alterations of steroid metabolism have been reported for several disorders affecting energy homeostasis, including anorexia nervosa, obesity, and thyroid disorders. In particular, it was observed that chronic fasting in young adult women with anorexia nervosa led to a significant decrease of urinary cortisol (F) and total androgen metabolites compared with healthy controls, and these changes were reversible upon refeeding. Women with polycystic ovary syndrome (PCOS) also typically present with an altered steroid profile (eg, hyperandrogenism), and in most cases with obesity and disturbed glucose homeostasis due to insulin resistance. Clinical studies show that moderate weight loss improves both insulin resistance and androgen excess in women with PCOS.[11,12] However, the exact interrelationship between the steroid hormone biosynthesis, the metabolism, and the energy balance is poorly understood. Metformin has shown an effect on glucose as well as androgen metabolism in several clinical and basic studies. When studying the underlying mechanism of action of this effect in vitro, it was found that complex I of the respiratory chain is targeted by metformin. In addition, steroidogenic adrenocortical NCI-H295R cells cultured in starved condition were found to undergo a marked change in steroid metabolism with a shift toward enhanced androgen production proven by a 50% increase in androstenedione (A4) and nearly doubled activity of the 17,20-lyase activity.
Even mechanisms underlying the effect of fasting on steroidogenesis in healthy individuals are incompletely studied. The abovementioned metabolic changes relate to short-term fasting, which is defined by a duration of 2 to 4 days in most studies. Short-term fasting has been suggested to decrease the negative feedback of insulin and leptin on the central nervous system with a decrease of leptin by 75%. This leads to a stimulation of the hypothalamic-pituitary-adrenal axis and thus an increase in F levels by 1.5-fold,[9,15,16] indicating that there is an interconnection between adrenal steroid biosynthesis and energy homeostasis.
The aim of this study was to investigate the effect of short-term fasting on steroidogenesis in healthy young women to reconcile the differences shown in previous clinical studies of abnormal metabolic states, like anorexia nervosa or PCOS, vs in vitro data. Specifically, we assessed whether short-term fasting in vivo would also lead to an increase in androgen production as observed in vitro. In a prospective study, healthy young women fasted for 48 hours and their urine and plasma steroid metabolomes were assessed at 3 timepoints.
J Endo Soc. 2022;6(7) © 2022 Endocrine Society