Key Points
- Melatonin lowered elevated inflammation markers
- Abnormal hormone levels were regulated
- Treatment produced healthier eggs
- Fewer damaged and more healthy, mature follicles
- Better-preserved ovarian tissue structure
Methods
Twenty-eight female rats were divided into four groups. Researchers compared normal ovarian stimulation with an overstimulation model designed to mimic OHSS.
Pregnant mare serum gonadotropin (PMSG) was used to stimulate follicle growth, and human chorionic gonadotropin (hCG) was used to trigger ovulation.
- Control (no stimulation): No hormone treatment.
- Controlled ovarian stimulation (COS): 10 IU PMSG once on day 1, followed by 10 IU hCG once on day 5.
- Ovarian hyperstimulation syndrome (OHSS): 10 IU PMSG daily for four days starting on day 1, followed by 30 IU hCG on day 5.
- OHSS + melatonin: Same overstimulation protocol as the OHSS group, plus melatonin (50 mg/kg) given by injection starting 2 hours after each hormone dose and continued for 6 days.
Reduced Vascular and Inflammatory Signals
OHSS caused large increases in markers associated with overly leaky and inflamed blood vessels in the fluid around the ovaries (peritoneal fluid). Melatonin significantly reduced both signals.
"Peritoneal fluid levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-6 were elevated in the OHSS group, but melatonin treatment decreased these levels."
VEGF levels were especially high in untreated OHSS animals, reflecting severe vascular stress.
"There was a significant difference between the OHSS and OHSS + melatonin groups."
Inflammaging: How Chronic Low-Grade Inflammation Accelerates Aging
Improved Hormonal Balance
OHSS caused hormone levels to rise far above normal. Estradiol, a key estrogen hormone spiked in the OHSS group and dropped significantly with melatonin supplementation.
"The serum estradiol levels were highest in the OHSS group… Serum estradiol level in the COH group was not statistically different compared with the C and OHSS+melatonin groups."
This suggests that melatonin helped normalize excessive hormone output associated with OHSS, bringing estrogen levels closer to a healthier range.
Healthier Follicle Development
OHSS ovaries showed widespread structural damage, including large cystic follicles, hemorrhagic areas, and a marked increase in degenerating follicles.
In contrast, melatonin-treated ovaries showed:
- Fewer degenerating (atretic) follicles
- Increased numbers of Graafian (mature) follicles
- Better preservation of ovarian tissue organization
"In the melatonin-treated OHSS group, ovarian integrity was better preserved… follicles were increased, and atretic follicles were decreased."
These results suggest melatonin helped protect developing follicles from degeneration and supported more normal ovarian function.
Lower VEGF Expression in Ovarian Tissue
Inside the ovaries, intense VEGF-A and VEGF-C expression were linked to fluid leakage and tissue stress. Melatonin worked to lower this activity.
"In the melatonin-treated OHSS group, VEGF-A immunoreactivity was reduced compared with the OHSS group… VEGF-C immunoreactivity in granulosa cells was reduced compared with the OHSS group."
Together, these findings show that melatonin helped calm excessive blood vessel signaling within ovarian tissue, aligning with the observed decrease in peritoneal VEGF levels and reduced vascular disruption.
Conclusion
This study demonstrates that melatonin helped protect the ovaries from damage caused by severe OHSS. It lowered inflammatory and vascular stress signals, reduced follicular degeneration, and supported healthier tissue organization, to preserve ovarian structure.
"Melatonin improved the biochemical and histological markers of OHSS, providing protective effects on ovarian function."
"Melatonin preserved ovarian structure and supported follicular development."
While these findings are based on an animal model, they support further investigation into melatonin as a supportive strategy in managing or reducing OHSS-related ovarian damage.
"These findings suggest that melatonin could be a potential therapeutic agent for the treatment of OHSS."
