Autophagy, Leptin, Circadian Signaling, and Female Reproductive Aging - A Mechanistic Framework for Fasting in Fertility and Perimenopause

© Courtney Hunt, MD, 2026

Abstract

Autophagy is widely promoted as a universal intervention for metabolic health and longevity. However, in women, fasting-induced autophagy produces heterogeneous effects on fertility and reproductive aging. This discrepancy is best explained by differences in leptin signaling and its circadian integration via hypothalamic pro-opiomelanocortin (POMC) neurons. This review outlines how leptin status determines whether autophagy is reparative or pathologic, how circadian signaling gates autophagy timing, and why misapplication of fasting accelerates reproductive decline in low-leptin states while improving outcomes in leptin-resistant states. This framework forms the basis of the educational model used in my clinical and teaching groups.

Introduction

Female reproductive physiology is tightly coupled to long-term energy availability. Ovulation, luteal function, and the rate of ovarian reserve utilization are governed not only by gonadal hormones, but by hypothalamic interpretation of metabolic sufficiency. Leptin serves as the primary endocrine signal communicating this information to the brain.

Autophagy, while essential for cellular maintenance, is a downstream stress response. In female biology, its activation must be interpreted within the context of leptin signaling and circadian timing. Failure to do so has contributed to increasing rates of ovulatory dysfunction, infertility, and early perimenopausal symptoms in metabolically “healthy” women practicing chronic fasting.

Autophagy as a Conditional Cellular Program

Autophagy is activated under conditions of reduced insulin signaling, suppressed mTOR activity, and increased AMPK signaling. Its primary roles include:

    •    Clearance of damaged mitochondria (mitophagy)

    •    Recycling of oxidized proteins

    •    Reduction of intracellular stress

Autophagy is not inherently reparative. It is an adaptive response to energetic stress. In female systems, the critical question is whether autophagy occurs in an environment that signals energetic sufficiency or energetic threat. That determination is leptin-dependent.

Leptin as an Energy and Reproductive Signal

Leptin reflects long-term energy availability and adipose sufficiency rather than acute caloric intake. In the hypothalamus, leptin signaling interfaces with:

    •    Kisspeptin neurons regulating GnRH pulsatility

    •    Thyroid axis output

    •    Cortisol rhythm modulation

    •    Ovarian follicular recruitment

Leptin therefore functions as a gatekeeper for reproduction. Disruption of leptin signaling—either through resistance or deficiency—fundamentally alters how fasting and autophagy are interpreted by the brain.

Circadian Integration via POMC Neurons

Leptin signaling is time-encoded through hypothalamic pro-opiomelanocortin (POMC) neurons located in the arcuate nucleus. These neurons integrate:

    •    Leptin and insulin signals

    •    Light–dark input from the suprachiasmatic nucleus

    •    Stress and glucocorticoid tone

Under physiologic conditions, circadian light exposure entrains POMC firing, reinforcing daytime metabolic activity and suppressing autophagy during periods when reproduction and repair must coexist. Autophagy is therefore a circadian process, peaking during biological night and constrained during the day.

Disruption of leptin signaling destabilizes this timing mechanism.

High Leptin States: Restorative Autophagy

High-leptin states are characterized by elevated circulating leptin with central leptin resistance, commonly seen in insulin resistance, PCOS, inflammatory states, and some perimenopausal transitions.

In this context:

    •    Inflammation and hyperinsulinemia suppress effective autophagy

    •    Circadian amplitude is blunted

    •    Mitochondrial turnover is impaired

Fasting in high-leptin states reduces insulin, improves leptin sensitivity at POMC neurons, and restores circadian-aligned autophagy. This results in improved ovarian mitochondrial quality, reduced oxidative stress, and restoration of hypothalamic-ovarian signaling.

In these women, fasting is therapeutic.

Low Leptin States: Pathologic Autophagy

Low-leptin states occur in lean women, athletes, chronic dieters, and women combining ketogenic diets with prolonged fasting. Here, leptin signaling to the hypothalamus is reduced, and fasting reinforces a perception of famine.

Consequences include:

    •    Suppressed GnRH pulsatility

    •    Erratic FSH signaling

    •    Luteal phase defects

    •    Anovulation

    •    Early perimenopausal symptoms despite preserved estrogen production

Autophagy in this state becomes chronic rather than circadian, shifting from targeted repair to generalized substrate scavenging. Cortisol rhythms dominate, sleep becomes fragmented, and reproductive function is deprioritized.

In this context, fasting accelerates reproductive aging.

Perimenopause as an Energy Signaling Transition

Early perimenopause is frequently misattributed to estrogen deficiency. In reality, it often reflects declining hypothalamic energy confidence driven by leptin and circadian disruption. Aggressive fasting in low-leptin women suppresses daytime POMC signaling, increases nocturnal cortisol, and advances hypothalamic aging signals.

This explains why many women experience worsening symptoms as they adopt increasingly restrictive dietary practices in midlife.

Clinical Implications and Educational Framework

Autophagy must be applied strategically rather than universally.

    •    High-leptin women benefit from structured fasting aimed at restoring leptin sensitivity.

    •    Low-leptin women require energy repletion, circadian stabilization, and avoidance of prolonged fasting.

Failure to distinguish these states results in inappropriate interventions and preventable reproductive dysfunction.

This distinction is the foundation of my groups.

They are designed to teach women how to identify their leptin state, understand circadian signaling, and apply—or withhold—fasting in a way that supports fertility and slows reproductive aging rather than accelerating it.

Conclusion

Autophagy is a powerful cellular process, but in female physiology it is subordinate to leptin signaling and circadian timing. When fasting is applied without regard to these systems, the result may be improved metabolic markers at the cost of fertility and earlier perimenopause.

Female biology does not respond to chronic energy ambiguity with longevity. It responds with conservation.

Understanding when autophagy heals—and when it harms—is essential for protecting reproductive health in midlife.

References

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    2    Morton GJ et al. Central nervous system control of food intake and body weight. Nature. 2014.

    3    Hill JW et al. Leptin regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2008.

    4    Qi L, Sabatini DM. mTOR signaling in metabolism and disease. Cell. 2020.

    5    Mauvais-Jarvis F. Sex differences in metabolic homeostasis. Biol Sex Differ. 2015.

    6    Tsang AH et al. Circadian control of metabolism and reproduction. Endocr Rev. 2020.

    7    Schneider JE. Energy balance and reproduction. Physiol Behav. 2004.

© Courtney Hunt, MD, 2026