Does Melatonin Interfere with Hormone Feedback Loops?
Melatonin at standard therapeutic doses (3-5 mg) does not meaningfully disrupt hypothalamic-pituitary endocrine feedback loops in healthy adults, though it may modestly enhance gonadotropin responses in specific contexts without causing clinically significant hormonal dysregulation. 1
Evidence from Acute Pharmacological Studies
The most rigorous controlled trials demonstrate that melatonin administration does not alter baseline pituitary-gonadal, pituitary-thyroid, or pituitary-adrenal axis function:
A pharmacological dose of 80-240 mg melatonin (far exceeding therapeutic doses) increased serum melatonin levels 1,500-fold but did not alter LH, FSH, testosterone, TSH, GH, or cortisol levels in healthy males. Only prolactin showed consistent elevation. 2
Administration of 100 mg melatonin at opposite circadian phases (morning vs. evening) did not change pituitary responses to GnRH or TRH stimulation, nor did it alter adrenocortical responses to ACTH in healthy males. This demonstrates that even supraphysiologic doses fail to disrupt normal feedback mechanisms. 3
Hormonal response patterns remained superimposable between melatonin and placebo groups across multiple pituitary and adrenocortical axes. 3
Context-Dependent Gonadotropin Modulation
While melatonin does not disrupt baseline feedback loops, it can enhance pituitary sensitivity to GnRH under specific conditions:
In women during the follicular phase (but not luteal phase), 3 mg melatonin enhanced LH and FSH responses to submaximal GnRH stimulation, suggesting a phase-specific "endocrine window" rather than feedback loop disruption. 4
This enhancement represents increased pituitary responsiveness rather than dysregulation of the hypothalamic-pituitary-gonadal axis. 4
Chronic Use in Perimenopausal Women
Longer-term data suggest potential restorative effects rather than disruption:
In perimenopausal and menopausal women with low baseline melatonin levels, 3 mg melatonin nightly for 6 months decreased LH in younger women (43-49 years) and decreased FSH in those with low baseline melatonin, while increasing thyroid hormone levels. 5
These changes suggest a recovery toward more youthful hormonal patterns rather than pathological disruption of feedback mechanisms. 5
A negative correlation existed between baseline melatonin levels and LH/FSH before treatment, suggesting that declining endogenous melatonin may permit—rather than prevent—age-related gonadotropin elevation. 5
Clinical Safety Profile
The American Academy of Sleep Medicine guidelines confirm the hormonal safety of therapeutic melatonin:
Standard therapeutic doses of 3-5 mg melatonin have a favorable safety profile with only mild, self-limiting adverse effects; no serious endocrine disruption has been documented across age groups. 1
Long-term pediatric studies (up to 24 months) showed no significant differences in pubertal development (Tanner staging) in children using melatonin compared to non-users, confirming no clinically meaningful disruption of the hypothalamic-pituitary-gonadal axis during critical developmental periods. 6
Melatonin should be used with caution in patients taking warfarin or those with epilepsy, and monitoring for impaired glucose tolerance is advised in those with diabetes risk factors. 1
Important Caveats
The doses studied in most endocrine research (80-240 mg) far exceed therapeutic recommendations (3-5 mg), making hormonal effects at standard doses even less likely. 2, 3
Melatonin is regulated as a dietary supplement in the U.S., raising concerns about purity and reliability of stated doses; choose United States Pharmacopeial Convention Verified formulations when possible. 1
The American Academy of Sleep Medicine recommends against long-term use beyond 3-4 months for chronic insomnia due to insufficient long-term safety data, though available evidence suggests good tolerability. 1