Endometriosis: Melatonin More Effective than an Estrogen Blocker?

Overview of Endometriosis

Endometriosis is thought to affect about 1 in 10 women during reproductive years, and up to 50% of infertile women, making it quite a common, and usually painful, condition.

The symptoms of endometriosis include:

• Pain in the lower abdomen, lower back, pelvis, rectum, or vagina
• Pain during sexual intercourse or during defecation
• Abnormal / heavy / irregular / painful menstruation
• Constipation, nausea, or cramping
• Chronic fatigue
• Infertility

Endometriosis is the growth of endometrial-like tissue outside of the uterus, and acts and bleeds like normal endometrial tissue does. Since this tissue is not where it should be, the bleeding becomes trapped and can cause pain and/or cysts to form. After repeated cycles of this, scar / fibrous tissue can form, and can cause structures / organs to start “sticking” to each other.

There are various ways endometriosis is medically treated. These treatments include:

• Birth control pills – if you don’t have your period, then you don’t bleed in general
• Gonadotropin-releasing hormone (Gn-RH) agonists or antagonists – these essentially put you in an induced “menopausal state” where your body stops creating estrogen / progesterone. Side effects include vaginal dryness, hot flashes, and bone loss.
• Progestin Therapy – in high doses, these also can block your period from coming, which will halt, but usually not reverse, the growth of endometrial tissue and pain, similar to regular birth control.
• Aromatase Inhibitors – these also block the production of estrogen, particularly inside the endometrial tissue, and likely are more effective for post-menopausal woman, as much of the estrogen is produced outside of the ovaries after menopause. A lot of the time this is combined with one of the above therapies.

Alternative Treatments: What Most Women Aren’t Told

However, there are alternative options that can be tried first (if one wanted to try conservative treatment with far fewer side effects first) or can be used alongside conventional treatments

Disclaimer: none of the below is medical advice in any way. I am not personally treating you, so I don’t know your medical history or other details. Everything on this page is for informational use only to be discussed with your treating physician.

Melatonin is one very promising alternative treatment for endometriosis

Melatonin is a hormone produced by the pineal gland when there is a lack of light hitting the eye, thus, during night time. Melatonin is a powerful antioxidant, anti-inflammatory agent, and has shown to protect for various cancers. Melatonin levels naturally decline with age, and many people produce less melatonin now due to watching TV or looking at devices like their phone at night. Melatonin has been safely supplemented in pill form for decades now, mainly for sleep, with very few side effects. Taking melatonin does NOT make your body produce less melatonin – this is a common myth.

It was discovered that melatonin had beneficial effects when applied directly to endometrial tissue.

Researchers took samples of normal endometrial tissue from women without endometriosis and took samples of endometrial tissue from women with endometriosis, and studied what happened when they applied melatonin to these cells.

They found that melatonin blocked the growth, migration (what allows the endometrial tissue to “spread”), and invasion (what allows the endometrial tissue to “take root” somewhere else), stimulated by estrogen, of both normal endometrial tissue and endometrial tissue outside of the uteru.(1)

In other words, melatonin blocked the “growth effect” of estrogen and allowed the endometrial tissue to stay right where it was and not spread.

This finding then gained support with a few rodent trials, which showed that melatonin treatment to the mice began decreasing the size of endometrial tissue that was surgically implanted in rodents.(2, 3, 4, 5, 6, 7, 8) The weight of endometrial tissue in the control group in that first study was 155.8 mg, while after 10mg/kg (in rodent dosages, see below for dosage information) of melatonin treatment for 4 weeks, the weight was 49.6 mg, a 68.1% difference!(2) All of the other studies also showed a very positive response.

Moreover, there was a large difference in COX-2 positivity (one of the enzymes responsible for generating inflammatory compounds in cells) with the control group having 91% positivity and the melatonin group having 18.1% positivity. There was also a decrease in lipid peroxidation and an increase in endogenous anti-oxidants.(2)

The results from melatonin were also better than the results obtained from treating the mice with letrozole (an aromatase inhibitor that lowers estrogen)! Melatonin caused more regression of the endometrial tissue and also lowered the rate of recurrence more after the treatment was stopped compared to the aromatase inhibitor.(3) This study used a very high dose of melatonin, though (however, the researchers determined that is was still safe at this dose for the rats).

Then It Was Tested In Humans

With all of the positive rodent studies, melatonin was tested in humans in 2013 with a phase II, randomized, double-blind, placebo-controlled trial, the highest form of research.

They gave 40 females with endometriosis either placebo or 10 mg of melatonin each night for two months.(9) Treatment with melatonin…

• Reduced daily pain scores by 39.8%
• Reduced painful menstruation by 38.01%
• Improved sleep quality
• Reduced the need for analgesics, like Tylenol, by 80%
• and Reduced BDNF levels independently of its effect on pain (estrogen increases BDNF in endometrial tissue and this has been associated with increased pain sensitivity)

Not bad for a supplement with the only side effect being better sleep!

Along with melatonin’s promising role in reducing the risk of endometrial cancer,(10, 11) researchers are starting to urge the use melatonin for endometriosis along with other female gynecological conditions such as PCOS and recurrent spontaneous abortion.(12)

How To Take Melatonin

Melatonin is typically taken in doses between 0.3 – 10 mg a couple of hours before bed. The timing of melatonin is important, because taking melatonin during the day / morning can mess up circadian rhythms. (For those who tend to wake up in the middle of the night, time-release may be better, but this increases the risk of grogginess in the morning.)

To see which brand of melatonin I recommend, click here

If you wanted to copy the human study, that would be 10 mg of immediate release melatonin a couple of hours before bed.

However, rodent studies indicate that higher doses work better.(4) If you wanted to “mimic” what that first rodent study did (which reduced the growth by 68.1%), you would need to take 0.736 mg / lbs of body weight. Thus, if you weigh 120 lbs, you would need to take around 88 mg of melatonin per night. This would definitely be a “high dose”, but is similar to doses some are using for integrated cancer treatments. This type of dose would definitely need to be discussed with your doctor, as it is “experimental”, but most people can tolerate it okay if they slowly build up to it. This would mean starting with something like 1 or 5 mg per night, and then each week increasing the dose a bit, and monitor for how you feel. Most common side effect would be grogginess in the morning. If currently trying to get pregnant, a very high dose may interfere with this (or it may help (13) – especially in endometriosis, but this is just a hypothesis). Again, this dose is unusual for supplementation, but studies show that side effects tend to be mild. Alternatively, you could pick a dose between the one used in the human study and this high dose (i.e. between 10 and ~80 mg).

To see which brand of melatonin I recommend, click here.

Ask any questions below!! I really hope this helps you or a loved one.

References:

1. Qi S, Yan L, Liu Z, et al. Melatonin inhibits 17β-estradiol-induced migration, invasion and epithelial-mesenchymal transition in normal and endometriotic endometrial epithelial cells. Reprod Biol Endocrinol. 2018;16(1):62. Published 2018 Jun 23. doi:10.1186/s12958-018-0375-5
2. Güney M, Oral B, Karahan N, Mungan T. Regression of endometrial explants in a rat model of endometriosis treated with melatonin. Fertil Steril. 2008;89(4):934-942. doi:10.1016/j.fertnstert.2007.04.023
3. Yildirim G, Attar R, Ozkan F, Kumbak B, Ficicioglu C, Yesildaglar N. The effects of letrozole and melatonin on surgically induced endometriosis in a rat model: a preliminary study. Fertil Steril. 2010;93(6):1787-1792. doi:10.1016/j.fertnstert.2009.09.021
4. Cetinkaya N, Attar R, Yildirim G, et al. The effects of different doses of melatonin treatment on endometrial implants in an oophorectomized rat endometriosis model. Arch Gynecol Obstet. 2015;291(3):591-598. doi:10.1007/s00404-014-3466-3
5. Yıldırım G, Attar R, Fıçıcıoğlu C, et al. The combination of letrozole and melatonin causes regression in size not histopathological scores on endometriosis in an experimental rat model. J Turk Ger Gynecol Assoc. 2009;10(4):199-204. Published 2009 Dec 1.
6. Paul S, Bhattacharya P, Das Mahapatra P, Swarnakar S. Melatonin protects against endometriosis via regulation of matrix metalloproteinase-3 and an apoptotic pathway. J Pineal Res. 2010;49(2):156-168. doi:10.1111/j.1600-079X.2010.00780.x
7. Abdel-Hamid HA, Zenhom NM, Toni ND. Melatonin reduced endometrial hyperplasia induced by estradiol in female albino rats. Gen Physiol Biophys. 2019;38(1):63-71. doi:10.4149/gpb_2018035
8. Kocadal NÇ, Attar R, Yıldırım G, et al. Melatonin treatment results in regression of endometriotic lesions in an ooferectomized rat endometriosis model. J Turk Ger Gynecol Assoc. 2013;14(2):81-86. Published 2013 Jun 1. doi:10.5152/jtgga.2013.53179
9. Schwertner A, Conceição Dos Santos CC, Costa GD, et al. Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial. Pain. 2013;154(6):874-881. doi:10.1016/j.pain.2013.02.025
10. Dana PM, Sadoughi F, Mobini M, et al. Molecular and Biological Functions of Melatonin in Endometrial Cancer. Curr Drug Targets. 2020;21(5):519-526. doi:10.2174/1389450120666190927123746
11. Viswanathan AN, Schernhammer ES. Circulating melatonin and the risk of breast and endometrial cancer in women. Cancer Lett. 2009;281(1):1-7. doi:10.1016/j.canlet.2008.11.002
12. Yang HL, Zhou WJ, Gu CJ, et al. Pleiotropic roles of melatonin in endometriosis, recurrent spontaneous abortion, and polycystic ovary syndrome. Am J Reprod Immunol. 2018;80(1):e12839. doi:10.1111/aji.12839
13. Fernando S, Rombauts L. Melatonin: shedding light on infertility?–A review of the recent literature. J Ovarian Res. 2014;7:98. Published 2014 Oct 21. doi:10.1186/s13048-014-0098-y