©Pamela W. Smith, MD, MPH, MS

Description

In endometriosis, the cells that form the endometrium grow outside of the uterus usually in the abdomen, pelvis fallopian tubes, or ovaries. However, the endometrial tissue can grow anywhere including the eyes and can also migrate to the spinal cord and cause severe lower back pain. The areas of tissue growing outside of the uterus are called implants. The tissue thickens, breaks down, and bleeds every month. The implants produce their own estrogen by aromatization. Consequently, even if the patient is prescribed medications to lower estrogen, the implants still produce their own estrogen and cause the surrounding areas to grow.

Implants can also go into the muscle wall of the uterus, which is called adenomyosis, and can cause bleeding into the uterine muscle during the menstrual cycle and cause pain.^1-4   

Endometriosis affects 10% to 15% of women that are menstruating between the ages of 24 and 40.⁵  In 2010, the prevalence of endometriosis in women aged 15 to 49 years was about 176 million worldwide.⁶ In addition, the annual economic burden of endometriosis, including direct health care costs and indirect productivity loss, was estimated to be 22 billion USD in 2002 and 69.4 billion USD in 2009 in the United States.⁷  Endometriosis is linked to 25% of the cases of infertility.⁸

The pain and the symptoms the patient experiences with endometriosis may not correlate with the extent of the disease. The amount of pain seems to be related to the depth of the lesions and not the number of lesions. Signs and symptoms include excessive bleeding during or between cycles, infertility, dyspareunia, dysmenorrhea, and pelvic pain. Less common symptoms of endometriosis include the following⁹:

• Back pain that radiates down the legs
• Blood in the bowels, nose, or eyes
• Diarrhea
• Fainting
• Fatigue
• Pain during urination
• Painful bowel movements
• Vomiting

Etiology

The cause has yet to be determined of endometriosis. The following are risk factors for this disease process^10-14: 

• Family history
• Diet low in fruit
• Diet low in green vegetables
• Estrogen dominance
• High intake of red meat
• High fat diet
• History of abuse
• Naturally red hair
• Lack of exercise from an early age
• D&C history
• Use of intrauterine devices
• High stress
• Menstrual cycles that occur more frequently than every 28 days, with menstrual bleeding lasting more than seven days
• History of repeated uterine and vaginal infections

• Immune dysfunction
  • There may be a lack of good immune surveillance in the pelvic area.¹⁵
  • Patients with endometriosis have suppressed NK cell activity in their peritoneal fluid.
  • High levels of IgG and IgM are also seen in patients with endometriosis.
  • High levels of autoantibodies against ovary and endometrial cells occur in this disease process.^16-20
  • Both types of immunity, cell-mediated and humoral, have been implicated in endometriosis with immunologic defects present in all forms of the disease.²¹
  • Macrophages are found in greater numbers in the early stages of endometriosis.²²
  • Cytokines, macrophages, T lymphocytes, and TNF are increased in the peritoneal fluid and their increase is related to the severity of the disease.^23-25
  • Growth factors, angiogenic factors, and lipid peroxidation in the peritoneal fluid may also stimulate endometrial cell growth.²⁶

Genetic influences are likely involved in the etiology of endometriosis. Endometriosis occurs more commonly in family groups, including twin studies.^27-30  Furthermore, abnormalities in detoxification enzymes, tumor suppressor genes, and other genetic actors may be involved in the development and also the progression of endometriosis.^31-32

Environmental toxins may also play a role. The patient may have a genetic predisposition (SNP) that increases their risk of developing the disease when exposed to any of the following toxins^33-35:  Bisphenol-A, Parabens, Phthalates, Pesticides, Dioxins, PCBs solvent, Formaldehyde.

The following are other possible risk factors for the development of endometriosis^36-40:   

• Exposure to environmental estrogens or estrogen disruptors (weed killers, plastics, detergents, household cleaners, and tin can liners)
• Liver dysfunction
• Poor estrogen metabolism
• Prenatal exposure to high levels of estrogen

Conventional Therapies

The following are conventional treatment for endometriosis.^41-42

• Gonadotropin-releasing hormone agonists
• Progestins
• Oral contraceptives
• Danazol
• Surgical removal of affected tissue

None of the above treatments is preferred over the other. All can have significant side effects. Likewise, all are associated with a high recurrence rate (20% to 50%) when the treatment is discontinued except for total abdominal hysterectomy with bilateral salpingo-oophorectomy.⁴³

Precision Medicine Therapies

The following are functional medicine therapies for endometriosis.

Dietary Factors

• Instruct the patient to decrease caffeine intake: A study revealed that women that drank more than 5-7 grams a month of caffeine had a higher risk of developing endometriosis.⁴⁴
• Instruct the patient to decrease their intake of trans-fats. One study showed that women that ate the most trans-fats were almost 50% more likely to develop endometriosis than women that did not intake a lot of trans-fats.⁴⁵
• Other researchers have suggested that avoiding gluten, dairy, refined sugar, and alcohol may also be helpful for patients with endometriosis. Therefore, have the patient avoid these foods and drinks.⁴⁶
• Instruct the patient to increase consumption of foods that contain sulfur such as onions, garlic, and leeks which increase the body’s ability to detoxify and builds the immune system. These foods also contain quercetin which stimulates the immune system, blocks the inflammatory response, protects against oxidation, and helps inhibit tumor growth.⁴⁷
• Furthermore, instruct the patient to increase vegetable intake, such as broccoli, Brussels sprouts, cauliflower, cabbage, and kale, that contain indole-3-carbinol so that the body will break down estrogen into more desirous forms.⁴⁸
• Have the patient consume foods and drinks that are organic as much as possible.
• Instruct the patient to increase foods that are high in fiber.
• Instruct the patient to decrease their intake of red meat.
• Have the patient eat foods that cleanse the liver: carrots, lemons, artichokes, beets, watercress, and dandelion greens.⁴⁹

Nutrients

• Vitamin C is helpful for patients with endometriosis. It has the following functions in the body^50-52:
  • Increases cellular immunity
  • Decreases autoimmune progression
  • Decreases fatigue
  • Enhances immunity
  • Decreases capillary fragility
  • Decreases tumor growth
  • Dose:  6-10 grams a day to bowel tolerance
• Beta-carotene
  • Beta-carotene can moderately affect Il-6 which is implicated in endometriosis.⁵³
  • Beta-carotene helps enhance immunity and promotes phagocytosis.^54-55
  • Dose: 50,000 IU a day. (Do not use more than 8,000 IU in patients that smoke). Since this is a large dose, consider lower doses in all individuals.⁵⁶
• Vitamin E
  • Vitamin E helps to inhibit the arachidonic acid pathway which aids in the prevention of the release of chemicals that can cause edema, inflammation, and contraction of the smooth muscle.⁵⁷
  • Free radical production may contribute to the inflammation and excessive growth of the tissue of the endometrium. Vitamin E is an excellent free radical scavenger and when used with n-acetyl cysteine (NAC) has been shown to decrease tissue proliferation.^58-61
  • Long-term use of NAC depletes the body of zinc and copper. Therefore make sure the patient takes a multivitamin.
  • Long-term use of NAC can increase the risk of the patient developing cysteine kidney stones. If they are predisposed to this condition, have the patient take 500-1,000 mg a day of vitamin C.
  • Dose 400-800 IU a day of natural vitamin E. Vitamin E is a blood thinner, therefore use with caution in patients on blood thinners.
• Essential fatty acids ⁶²
  • Omega-3-fatty acids decrease inflammation and therefore may be helpful in endometriosis. Dose: 1,000 mg daily
  • Gamma-linoleic acid decreases inflammation and may also be helpful. Dose: 1,000 mg a day of one of the following: borage oil or evening primrose oil.
  • Alpha-linolenic acid decreases inflammation and may also be helpful such as flax seed, pumpkin, or walnuts.
• B vitamins
  • B vitamins may help detoxify estrogen in the body by improving methylation. Have the patient take a B complex vitamin BID.⁶³
• Selenium^64-66
  • Selenium aids in the synthesis of antioxidant enzymes that are responsible for detoxification of the liver, stimulates WBCs, and stimulates thymic function.
  • Patients with decreased selenium levels have sub-optimal cell-mediated immunity and decreased T cells.
  • Low selenium patients have increased inflammation.
  • Dose: 200-400 micrograms daily. Patients can become toxic when using selenium, therefore measure levels in the body before supplementing.
• Lipotropic Factors^67-68
  • Lipotropic factors aid in enhancing liver function and detoxification.
  • Lipotropic factors promote the flow of fat and bile containing estrogen metabolites from the liver to the colon.
  • Lipotropic factors include the following: choline, methionine, cysteine. Do not supplement with choline if the patient has an elevated TMAO level.

Botanicals⁶⁹

• Dong quai maybe helpful for patients with endometriosis since it is an antispasmodic, analgesic, anti-inflammatory, and has tonic effects. It also functions as an antioxidant and free radical scavenger. Likewise, Dong quai has immunomodulatory effects since it stimulates phagocytic activity and increase the production of IL-2.  
• Echinacea is an herbal therapy that enhances phagocytosis and stimulates cytokine production. It increases immunoglobulin production and is anti-inflammatory. Echinacea is furthermore an antioxidant and free radical scavenger. Echinacea should not be used on a daily basis.^70-74
• Blue vervain stimulates LH and FSH and is immunomodulatory by inhibiting phagocytosis by granulocytes. It is used for endometriosis, irregular cycles, nervous conditions, exhaustion, and sluggish liver.^75-76
• Cotton root has short-term efficacy of up to 90% in treating endometriosis. Long-term effectiveness of treating endometriosis after 1 and 3 years is 54% to 63%. Patients that are treated with cotton root generally have amenorrhea for up to 6 months in 80% of women.⁷⁷ Gossypol is the active component in the roots and seeds of cotton, and it antagonizes the actions of estrogen and progesterone. Cotton root may mimic pseudo-menopause. It is not available in Western countries.
• The patient may need to take a potassium supplement if they are taking cotton root since it may cause hypokalemia. High dosages may cause any of the following symptoms: Elevated liver enzymes, nausea, edema, palpitations, rash, reduced appetite, fatigue, possible inhibition of thyroid function, possible decrease in mitochondrial energy metabolism.

• Taraxacum officinale (Dandelion root)⁷ helps to detoxify the liver and gall bladder. It contains vitamins A, C, and K and also contains calcium and choline.
• Leonorus cardiaca (Motherwort)⁷⁹ decreases spasms and helps with the pain that occurs with endometriosis. It also sooths nerves.
• Xanthoxylum americanum (Prickly ash)⁸⁰ stimulates blood flow and increases transport of oxygen and nutrients. It removes waste products and helps with pelvic circulation.
• Vitex agnus castus (Chaste tree)⁸¹ increases progesterone by increasing LH and makes estrogen less available to stimulate the tissues of the endometrium
• Pine bark (Pycnogenol)⁸² is the trademarked name for a mixture of forty different antioxidants from the bark of the maritime pine tree (Pinus maritime). It is an oligomeric proanthocyanidin (OPC). It inhibits matrix metalloproteinases and other inflammatory cells and inhibits cyclooxygenases 1 and 2. In a randomized medical trial, women with endometriosis were given pycnogenol 30 mg versus leuprorelin acetate IM every 4-6 weeks for 24 weeks. The pycnogenol group had a 1/3 reduction in symptoms but maintained cycles and normal estrogen levels during therapy. The leuprorelin group had a greater response during treatment but relapsed after the medication was stopped. They also had low estrogen levels during treatment. The dose of pycnogenol was 60-150 mg a day.⁸³
• Turska’s formula⁸⁴ may interfere with the placement of the endometrial implants, and it also enhances the immune system.
  • Turska’s formula contains the following: Aconite napelus (Monkshood),  Gelsemium sempervirens (Yellow jasmine), Bryonia alba (Bryony), Phytolacca americana (Poke root)
  • Dose: Aconite 11/2 drams, Bryonia 11/2 drams, Gelsemium 11/2 drams, Phytolacca 3 drams, and ½ dram water. Take five drops four times a day.

Progesterone modifies the action of E2, which decreases the amount of time estrogen stays on the receptor sites and decreases the number of uterine contractions that can cause pain. Have the patient do a 28-day salivary test to determine if progesterone levels are low and the dose of progesterone to give. If using a one-day testing kit, then test hormone levels on days 4, 14, and 21.^85-86

Melatonin has many functions in the body including but not limited to being an antioxidant, analgesic, and anti-inflammatory agent. A double-blind, randomized, placebo-controlled study gave women with endometriosis 10 mg of melatonin at bedtime for two months. Melatonin improved pain, dysmenorrhea, dyspareunia, dysuria, and pain during defecation in a statistically significant number of patients.⁸⁷   Measure melatonin levels by saliva testing and treat accordingly.

Candidiasis: Anecdotally some patients have done better with symptoms of endometriosis on a diet that decreases yeast-containing foods and treatment with an antifungal medication.⁸⁸ Ordering a GI health test for your patient, and treating yeast if present, is worth considering in individuals with endometriosis. 

Published April 8, 2023

 

References

1. McQuade, A., et al., Endometriosis In: Romm, A., Botanical Medicine for Women’s Health. St. Louis: Churchill Livingstone/Elsevier, 2010, p. 225-35.
2. Gaby, A., Endometriosis. In Nutritional Medicine, 2^nd Ed., Concord, NH: Fritz Perlberg Publishing, 2017.
3. Smith, P., What You Must Know About Women’s Hormones. 2^nd Ed. Garden City Park, NY: Square One Publishers, 2022.
4. Hudson, T., Endometriosis. In Pizzorro, J., and Murray, M., (Eds.) Textbook of Natural Medicine. Philadelphia: Churchill Livingston/Elsevier, 2013, p. 1349-54.
5. Wheeler, J., Epidemiology of endometriosis-associated infertility.  Jour Repro Med 1989; 34(1):41-46.
6. Adamson, G., et al., Creating solutions in endometriosis: global collaboration through the World Endometriosis Research Foundation. Jour Endometr 2010; 2:3-6.
7. Soliman, A., et al., Health care utilization and costs associated with endometriosis among women with Medicaid insurance.  Jour Manag Care Spec Pharm. 2019; 25:566–72.
8. Speroff, L., et al., Clinical Gynecologic Endocrinology and Infertility. Baltimore: Lippincott Williams & Wilkins, 1999.
9. Ibid., Hudson.
10. Ibid., McQuade.
11. Ibid., McQuade.
12. Ibid., Smith.
13. Ibid., Gaby.
14. Ibid., Speroff.
15. Leibovic, D., et al., Immunobiology of endometriosis, Fertil Steril 2001; 75:1-10.
16. Wilson, T., et al., Decreased natural killer cell activity in endometriosis patients: relationship to disease pathogenesis, Fertil Steril 1994; 62(5):1086-88.
17. Oosterlynick, D., et al., Immunosuppressive activity of peritoneal fluid in women with endometriosis, Obstet Gynecol 1993; 82(2):206-11.
18. Gleicher, N., et al., Is endometriosis an autoimmune disease? Obstet Gynecol 1987; 70:115-22.
19. Gleicher N., et al., Abnormal (auto) immunity and endometriosis, Int Jour Gynecol Obstet 1993; 40(Suppl) S21-S27.
20. Mathur, S., et al., Autoimmunity to endometrium and ovary in endometriosis, Clin Exp Immunol 1982; 50:259-66.
21. Nomiyama, M., et al., Local immune response in infertile patients with minimal endometriosis, Gynecol and Obstet Invest 1997; 44:32-7.
22. Halme, J., et al., Increased activation of pelvic macrophages in infertile women with mild endometriosis, Amer Jour Obstet Gynecol 1983; 145:333-37.
23. Oosterlynck, D., et al, Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium, Fertil Steril 1991; 56:45-51.
24. Chegini, N., Peritoneal molecular environment, adhesion formation, and clinical implication, Front Biosci 2002; 1e91-e115.
25. Bazvani, R., et al., Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis, Reproduction 2002; 123:217-26.
26. Ibid., Hudson.
27. Simpson, J. et al., “Heritable aspects of endometriosis,” Amer Jour Obstet Gynecol 1980; 137:327-31.
28. Ibid., Hudson.
29. Kennedy, S., et al., Familial endometriosis, Jour Assist Repro Genet 1995; 12:32-34.
30. Stefansson, H., et al., Genetic factors contribute to the risk of developing endometriosis, Human Repro 2002; 17:555-59.
31. Wang, Y., et al., Statistical methods for detecting genomic alterations through arraybased comparative genomic hybridization (CGH), Front Biosci 2004; 9:540-49.
32. Hadfield, R., et al., Linkage and association studies of the relationship between endometriosis and genes encoding the detoxification enzymes GSTM1, GSTTI, and CYP1A1, Mol Hum Repro 2001; 7(11):1073-78.
33. Cobelis L., et al., High plasma concentrations of di(2-ethylhexyl)-phthalate in women with endometriosis, Human Repro 2003; 18(7):1512-15.
34. Hellier, J., et al., Organochlorines and endometriosis, Chemosphere 2008; 71(2):20310.
35. Mayani, A., et al., Dioxin concentrations in women with endometriosis, Human Reproduction 1997; 12:373-75.
36. Ibid., Hudson.
37. Davis, D., et al., Can environmental estrogen cause breast cancer? Scient Amer 1995 Oct: 166-72.
38. Rier, S., et al., Immunoresponsiveness in endometriosis: implications of estrogenic toxicants, Envir Health Prespect 1995; 103(Suppl 7): 151-56.
39. Ranton, J., et al., Radiation-induced endometriosis in Maccaca mulatta, Radiat Res 1991; 126:141-46.
40. Rier, S., et al., Endometriosis in rhesus monkeys (Maccaca mulatta) following chronic exposure to 2,3,7,8, tetrachlorodibenzo-p-dioxin, Fundam Appl Toxicol 1993; 21:43141.
41. Ibid., Speroff.
42. Youngkin, E., et al., Women’s Health: A Primary Care Clinical Guide. Stamford, CT: Appleton and Lange, 1998.
43. Ibid., Youngkin.
44. Grodstein, F., et al., Relation of female infertility to consumption of caffeinated beverages, Amer Jour Epidemiol 1993; 137:1353-60.
45. Missmer, S., et al., A prospective study of dietary fat consumption and endometriosis risk, Human Repro 2010 25(6):1528-35.
46. Mills, D., Endometriosis. A Key to Healing and Fertility Through Nutrition. London: Thorsons, 2002.
47. Leibovitz, B., et al., Bioflavonoids and polyphenols: medical applications, Jour Opt Nutr 1993; 2:17-35.
48. Michnovicz, J., et al., Altered estrogen metabolism and excretion in humans following consumption of indle-3-carbinol, Nutr Cancer 1991; 16:59-66.
49. Ibid., Hudson.
50. Anderson, R., The immunostimulatory, anti-inflammatory and anti-allergic properties of ascorbate, Adv Nut Res 1984; 6:19-45.
51. Leibovitz, B., et al., Ascorbic acid and the immune response, Adv Exp Med Biol 1981; 135:1-25.
52. Ibid., Hudson.
53. Sawatri, S., et al., Retinoic acid suppresses interleukin-6 production in human endometrial ells, Fertil Steril 2000; 73(5):1012-19.
54. Ongsakul, M.., et al., Impaired blood clearance of bacteria and phagocytic activity in vitamin A deficient rats, Proc Soc Exp Biol Med 1985; 178:204-08.
55. Alexander, M., eta l., Oral beta-carotene can increase the number of okT4+ cells in human blood, Immunol Lett 1985; 9:221-24.
56. Ibid., Hudson.
57. Ibid., Hudson.
58. Porpora, M., et al., A promise in the treatment of endometriosis: an observational cohort study on ovarian endometrioma reduction by N-aceylcysteine, Evid Based Complement Alternat Med 2013; 2013:240702.
59. Foyouzi, N., et al., Effects of oxidants and antioxidants on proliferation of endometrial stromal cells, Fertil Steril 2004; 82(Suppl 3):1019-22.
60. Murphy, A., et al., Endometriosis: a disease of oxidative stress? Semin Reprod Endocrinol 19988; 16(4):263-73. Review.
61. Ibid., Hudson.
62. Ibid., Hudson.
63. Biskind, M., et al., Effect of vitamin B complex deficiency on inactivation of estrone in the liver, Endocrinology 1942; 31:109-114.
64. Spalholtz, J., et al. Immunologic responses of mice fed diets supplemented with selenite selenium, Proc Soc Exp Biol Med 1973; 143:685-89.
65. Ibid., Hudson.
66. Kiremidjian-Schumacher, L., et al., Selenium and immune responses,” Environ Res 1987; 42:277-303.
67. Ibid., Hudson.
68. Murray, M., et al., Immune Support in Encyclopedia of Natural Medicine. Rocklin, CA: Prima Publishing, 1998.
69. Ibid., McQuade.
70. Low Dog, T., Women’s Health in Complementary and Integrative Medicine: A Clinical Guide. St. Louis: Elsevier, 2004.
71. Blumenthal, M., The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicine. Boston: American Botanical Council, 1998.
72. Speroni, E., et al., Anti-inflammatory and cicatrizing activity of Echinacea pallida Nutt root extract, Jour Ethnopharmacol 2002; 79(2):265-72.
73. ESCOP: ESCOP Mongraphs: The Scientific Foundation for Herbal Medicinal Products, Stuttgart: Thieme, 2003.
74. Wichtl, M., Herbal Drugs and Phytopharmaceuticals: A Handbook for Practice on a Scientific Basis. 4 Ed. Stuttgart: Medpharm 2004.
75. Ibid., McQuade.
76. Ibid., Wichtl.
77. Dharmananda, S., Therapeutic approaches to endometriosis: traditional Chinese specific condition review, Prot Jour Botanic Med 1996; 1(4):36-44.
78. Ibid., Hudson.
79. Chevalier, A., Leonorus cardiaca. World Health Organization. Monographs on Medicinal Plants Commonly Used in the Newly Independent States. Encyclopedia of Medicinal Plants. New York: Doring Kindersley Limited, 1996, p. 398-418.
80. Ibid., Hudson.
81. Decapite, L., Histology, anatomy and antibiotic properties of Vitex agnus castus, Ann Facul Agr Univ Studi Perugia 1967; 22:109-2 6.
82. Ibid., Hudson.
83. Kohama, T., et al., Effect of French maritime pine bark extract on endometriosis as compared with leuprorelin acetate, Jour Reprod Med 2007; 52(8):7-3-08.
84. Ibid., Hudson.
85. Ibid., Hudson.
86. Ibid., Smith.
87. Schwertner, A., et al., Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial, Pain 2013; 154:874-81.
88. Ibid., Gaby.

Published April 8, 2023

About the Author

Pamela Wartian Smith, MD, MPH, MS spent her first twenty years of practice as an emergency room physician with the Detroit Medical Center in a level 1 trauma center and then 28-years as an Anti-Aging/Functional Medicine specialist. She is a diplomat of the Board of the American Academy of Anti-Aging Physicians and is an internationally known speaker and author on the subject of Anti-Aging/Precision Medicine. She also holds a master’s in public health degree along with a master’s degree in metabolic and nutritional medicine. Dr. Smith is in private practice and is the senior partner for The Center For Precision Medicine with offices in Michigan and Florida.

Dr. Pamela Smith is the founder of The Fellowship in Anti-Aging, Regenerative, and Functional Medicine and is the past co-director of the master’s program in metabolic and nutritional medicine at The Morsani College of Medicine, University of South Florida. She is the author of eleven best-selling books. Her book: What You Must Know About Vitamins, Minerals, Herbs, and So Much More was published 2020. Her best seller, Max Your Immunity, was released in late 2021. Her newest book: What You Must Know About Women’s Hormones, 2nd was released in the spring. Her book, Maximize Your Male Hormones, has just been released.

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