The antiestrogen fulvestrant paradoxically amplified ghrelin-stimulated growth hormone secretion in postmenopausal women, acting like estrogen on GH release while blocking estrogen's effects on prolactin.
GH more than doubled with fulvestrantFasting growth hormone levels increased from 0.096 to 0.23 μg/L in postmenopausal women receiving the antiestrogen fulvestrant — a paradoxical estrogen-like effect that also amplified ghrelin-stimulated GH release.
What the researchers found
Fulvestrant (FUL) vs placebo in postmenopausal women produced paradoxical mixed effects:
Estrogen-like actions: Fasting GH increased from 0.096 to 0.23 μg/L (p=0.033), IGFBP-3 increased from 3.6 to 4.0 mg/L (p=0.041). FUL potentiated GH responses to L-arginine/saline (p=0.007), L-arginine/ghrelin (p=0.008), and L-arginine/GHRH+ghrelin (p=0.031), but not L-arginine/GHRH alone.
Anti-estrogen actions: Prolactin decreased from 7.1 to 5.5 μg/L (p=0.05), IGFBP-1 decreased from 44 to 27 μg/L (p=0.048).
Neutral effects: Testosterone, estradiol, estrone, SHBG, IGF-I, LH, and FSH were unaffected.
Why it matters
This study reveals unexpected complexity in how estrogen receptor antagonists interact with peptide-driven GH secretion. Understanding these interactions is important for managing GH deficiency in aging women and for interpreting the effects of antiestrogen treatments (like those used in breast cancer) on the growth hormone axis. The finding that fulvestrant acts as an estrogen agonist on GH challenges simple models of estrogen receptor pharmacology.
How the study worked
Randomized, double-blind, placebo-controlled, parallel-cohort study at the Mayo Center. 24 postmenopausal women (ages 50-77, BMI 19-32) received either placebo (n=14) or fulvestrant (n=10) for 3 weeks, followed by infusions of L-arginine combined with saline, GHRH, ghrelin, or both peptide secretagogues. GH was sampled every 10 minutes over 6 hours. Sex steroids were measured by mass spectrometry.
What this study cannot tell us
The sample size was small (24 participants, only 10 receiving fulvestrant). The study was 3 weeks long, which may not capture longer-term effects. The mechanism by which fulvestrant acts as an estrogen agonist on GH secretion is not fully explained. The postmenopausal population studied may not represent premenopausal women or men. The doses and clinical relevance of the peptide secretagogue infusions may differ from physiological conditions.
How to read the evidence
This is a randomized, double-blind, placebo-controlled trial, providing strong study design. However, the small sample size (24 total, 10 in the treatment arm) limits the statistical power and generalizability of the findings.
When this study was published
Published in 2014, this study provides foundational data on antiestrogen-peptide hormone interactions. The tissue-specific pharmacology of fulvestrant described here remains relevant to current clinical practice.
The bigger picture
This study illuminates the tissue-specific nature of estrogen receptor signaling — fulvestrant acts as an agonist in the GH axis while antagonizing estrogen in other tissues. This concept of selective estrogen receptor modulation has implications beyond GH biology, affecting how we understand breast cancer treatments, hormone replacement therapy, and the complex interplay between sex hormones and peptide hormones like ghrelin and GHRH in aging.
Questions still open
- Through which specific estrogen receptor mechanism does fulvestrant enhance ghrelin-stimulated GH secretion?
- Do other selective estrogen receptor modulators (like tamoxifen) show similar paradoxical GH-stimulating effects?
- Could this interaction between antiestrogens and ghrelin be therapeutically exploited to treat GH deficiency in postmenopausal women?
Common questions
Why did an anti-estrogen drug increase growth hormone?
What is ghrelin and how does it relate to growth hormone?
Read the original research
Estrogen-like potentiation of ghrelin-stimulated GH secretion by fulvestrant, a putatively selective ER antagonist, in postmenopausal women.
The Journal of clinical endocrinology and metabolism, 99(12), E2557-64
Citation
Veldhuis, Johannes D; Yang, Rebecca J; Wigham, Jean R; Erickson, Dana; Miles, John C; Bowers, Cyril Y. (2014). Estrogen-like potentiation of ghrelin-stimulated GH secretion by fulvestrant, a putatively selective ER antagonist, in postmenopausal women.. The Journal of clinical endocrinology and metabolism, 99(12), E2557-64. https://doi.org/10.1210/jc.2014-2633