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Female Hormones and Crohn's Disease

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What Crohn's Disease has to say about "the Pill", your Period and Menopause

The relationship between female sex hormones, estrogen and progesterone, and Crohn's Disease is a controversial topic. Research has shown conflicting views on whether hormones increase or decrease a person's risk for Crohn's and/or exacerbation of the disease. The heart of differing views is likely due to the vast complexity of the Endocrine and Immune Systems coupled with the cyclic nature of Crohn's Disease (Remission cycling with Flares). A further complication stems from the fact that many women with Crohn's feel their Symptoms worsen during certain stages of the Menstrual Cycle. Although each woman is different, many feel exacerbation of the disease during or immediately prior to Menses, "the Period".

This CrohnsForum Newsletter Article aims to show the complexity behind the role of Female Sex Hormones and Crohn's Disease with the hope that we may help some women in their decision whether or not to add Oral Contraceptives (OC) or Hormone Replacement Therapy (HRT) to their medication regime.
Crohn's Disease, Hormones, and the Immune System in Gynecology
Most people with Crohn's Disease begin exhibiting symptoms around puberty indicating a possible role of sex hormones in the disease. A secondary peak in first time disease rates occurs in women around the time of Pre-Menopause and Menopause.

The finding of new Crohn's cases during a dramatic upregulation in hormone levels (during Puberty) but also during the waning of hormone levels (Pre-Menopause, Menopause) appears to be contrary on the surface, but are related through the role of sex hormones on Immune Function.

Oral Contraceptives and Hormone Replacement Therapy can "Quiet" Immune Response

Some women of fertile ages with uncontrolled Pro-Inflammatory Crohn's Flares in the absence of microbial infection may benefit from the Anti-Inflammatory effects of Oral Contraceptive Hormones. Studies have shown that women using oral contraceptives or on Hormone Replacement Therapy (HRT) have lower Natural Killer (NK) Cell activity than women not using hormones for replacement therapy or contraception.[13]
Natural Killer (NK) Cells:
NK Cells are part of the Innate Immune Response and are an important defender against Cancer and Cells Infected with Virus. NK Cells are able to recognize body cells that are sick, cancerous, dying or Infected. They can kill these cells and/or secrete multiple different Chemokines and Cytokines, can Activate Antigen Presenting Cells (APCs), Activate Macrophages to kill Intracellular Pathogens, help regulate the Th1 Immune Response, and reduce the ability of Cancerous or Infected Cells to Reproduce.[7]

NK Cells can secrete Pro-Inflammatory factors such as: IFN - gamma, MIP - 1 alpha and TNF - alpha. These Pro-Inflammatory factors are important to effective Immunity. However, in certain diseases, such as Crohn's Disease, these Pro-Inflammatory factors can exacerbate an already overactive Inflammatory response and may lead to a vicious cycle of Inflammation as seen in Crohn's Disease Flares.
Menstrual Cycle and Crohn's Disease
Many women experience exacerbated Crohn's-related symptoms during certain phases of the Menstrual Cycle. Although the focus of this newsletter article is primarily the Hormonal effects on Immunity, one should note that Hormones have dramatic effects on many body systems that may override those discussed here.

Many women experience an increase in Crohn's Disease symptoms during the Menstrual or Premenstrual periods of their monthly cycle.[10]Crohn's can also cause Gynecological manifestations such as Oophoritis or Salpingitis[1][10]

The Menstrual Cycle exhibits major swings in hormone levels, including Estrogens. Higher levels of Estrogen causes the vaginal epithelium (skin) to become thicker. The thickened epithelial barrier is more protective against Infection. The Vaginal epithelium is thickest in follicular phase of the Menstrual Cycle and lowest during Menstruation[19]
Ovulation (Mid - Cycle)
Female sex hormones affect Antibodies. Estradiol increases the number of B Cells that are secreting IgM - Type Antibodies, with peak response occuring around 780 - 2600 pmol/L Estradiol.[16] In most women this correlates with the time immediately preceding Ovulation. (see Figure 1, Pink Bar)

Figure 1: Hormones and the Menstrual Cycle. Estrogen and Progesterone



Heightened levels of Estradiol may also exacerbate allergic conditions or other Pro-Inflammatory conditions (including Arthritis, Asthma and Crohn's Disease) due to inhibition of suppressor T cell activity.[16] Persons with Rheumatoid Arthritis have higher levels of Estradiol in Serum and in Synovial Fluid.[13]
Luteal Phase (Post - Ovulation)
During the Luteal Phase of the Menstrual Cycle (see Figure 1, Gray Bar), Anti-Inflammatory factors appear to override those that are Pro-Inflammatory. This is suggested to be similar to what occurs in Pregnancy, as Cell - Mediated Immunity is downregulated.

Aphthous Ulcers are more common in women during the Luteal phase of the Menstrual Cycle.[26]

Unfortunately, during Pregnancy and in the Luteal phase of the Menstrual Cycle, this reduced Immunity may increase the risk of Infection.[10]

Disadvantages of Oral Contraceptives and Hormone Replacement Therapy

Oral Contraceptives are associated with an increased risk of Crohn's Disease in some women. There are three major reasons for this increased risk.
Hypercoagulability
Oral Contraceptive formulations containing high levels of Estrogens (greater than 50 micrograms) increase blood coagulability (blood clotting ability). This can cause the body to produce blood clots within the vessels that may impede blood flow and cause Heart Attack or Stroke. When blood clots form in vessels feeding GastroIntestinal tissues this causes Ischemia. Ischemic tissues may become "Leaky" and activate Pro-Inflammatory cells to migrate towards the tissue site which may induce or exacerbate Crohn's pathology. In severe or prolonged Ischemia, tissues can become Necrotic (die) and no longer effectively function as a barrier. Necrotic bowel is a very severe condition and may cause Intestinal Perforation.
Suboptimal Pathogen Clearance
The increased risk of Crohn's Disease in women taking Oral Contraceptives may be related to its Immune System "Quieting" effects. While this may be advantageous in persons with an excessive Pro-Inflammatory response in the Absence of Infection it may actually be detrimental to those attempting to rid the body of a Pathogen.

In the early stages of Infection, the Innate Immune System will respond very quickly, but with less specificity, than the delayed, Adaptive Immune System. In Crohn's patients, the Innate Immune Response can be less effective at clearing an Infectious agent. This is particularly true in Crohn's patients with NOD2 / CARD15 Gene Mutations. An inadequate clearance of microbes can cause them to grow out of control. This Microbial Dysbiosis is often a triggering factor in Crohn's Flares. The Anti-Inflammatory effects of Oral Contraceptives may be of benefit during an Over-Responsive Inflammatory system in the absence of Infectious agent(s), but may actually be detrimental in the early stages of Infection for patients with Crohn's Disease.
Estrogenic Stimulation of Inflammatory Factors
Macrophage infiltration is often a feature in Crohn's Flares. Estradiol has been shown to induce tissue recruitment of Macrophages which may exacerbate an already Inflammatory condition.[13]
Oral Contraceptives, especially older formulations containing high levels of Estrogens are correlated with an increase in the Humoral Immune Response.[13] Some of which heavily contribute to Crohn's Disease pathology.

Effects of Crohn's Disease on Sex Hormones

Not only can sex hormones exert an influence on Crohn's Disease activity, but Crohn's Disease activity can exert effects on Sex Hormones.
Zinc Deficiency Alters Hormone Levels
Crohn's Disease can cause Zinc Deficiency, especially in patients with severe symptoms. Research has shown that Zinc Deficiency causes an increased conversion of Testosterone into Estradiol (Estrogen like hormone). Lowered Testosterone levels in men and in women can cause decreased energy levels and Fatigue, a common complaint in Crohn's patients, especially during Flares. Zinc deficiency is also correlated with Lowered levels of: Estradiol, Testosterone and Lutenising Hormone (LH)[9]
Lutenising Hormone (LH) and Zinc Deficiency
Lutenising Hormone (LH) remains at baseline levels during the majority of the Menstrual Cycle. LH levels are dramatically increased immediately prior to (and triggering) Ovulation (see Figure 2, Orange Line). Suboptimal levels of LH (as seen in Zinc Deficiency) may cause Anovulatory Cycles (non-Ovulatory Cycles), Infertility or Inability to Maintain a Pregnancy.[14]

Figure 2: Hormones and the Menstrual Cycle. FSH and LH

Estrogen / Progesterone Hormones and Tumor Necrosis Factor (TNF)
Tumor Necrosis Factor - Alpha (TNF-alpha) levels increase in the Luteal phase of the Menstrual Cycle.[2] And, when stimilated with the highly Immunogenic Cell Wall Component of Gram Negative Bacteria, Lipopolysaccharide (LPS), Interleukin 1 - beta (IL1-beta) and TNF-alpha expression is higher in Luteal vs the Follicular phase of the menstrual cycle.[5]

Macrophages secrete basal levels of TNF - alpha when not in contact with LPS. TNF secretion is slightly higher in patients on Oral Contraceptive Hormones (Figure 3: No LPS, Blue Bars). Macrophages dramatically increase TNF secretion upon contact with LPS. In Oral Contraceptive users, LPS-Induced TNF release is blunted when compared with that of Non-OC patients. (Figure 3: LPS, Red Bars)

TNF-alpha is an extremely important Pro-Inflammatory signaling molecule of the Immune System. Persons that are unable to regulate TNF levels effectively can have severe pathology due to significantly under- or over-active Immune Response. In many patients with Crohn's Disease, the Pro-Inflammatory factors predominate (including TNF) for extended periods of time. Recent medical advances in therapeutics include Biologics which target and neutralize TNF, including: Cimzia (certolizumab), Enbrel (etanercept), Humira (adalimumab), Remicade (infliximab) and Simponi (golimumab).

Crohn's patients on Oral Contraceptives may have an ineffective response to Pathogenic Gram Negative bacteria resulting from suboptimal LPS-induced TNF upregulation. However, many persons with Crohn's Disease will mount an inappropriate Pro-Inflammatory response to the beneficial Gram Negative bacteria in the Intestinal Tract, Escherichia coli. This inappropriate immune response to normal GI Tract bacteria can dramatically exacerbate Crohn's symptoms. These patients may instead see sympom relief from the addition of Oral Contraceptive Hormones.

Figure 3: Oral Contraceptive Hormones and Tumor Necrosis Factor (TNF)

Figure generated from data in Stricker et al. 2006.[25]

Hormones, Menopause and Inflammation

Postmenopausal women often heal from injury more slowly than fertile age groups, have an increased Crohn's Disease risk, lower levels of circulating Antibodies, and have higher serum levels of Pro-Inflammatory Cytokines[18], including, IL6 - Interleukin 6[8].

The Low levels of Estrogen in Menopause results in a thinner vaginal epithelium and increases susceptibility to Infection[19]. Estrogen supplementation increases the thickness of vaginal epithelium and protects against viral infection.[19]

Macrophages are important defenders against Infection and removal of debris from injured tissue. However, in Chronic Inflammation Macrophages can secrete factors that have a detrimental effect on wound healing. Macrophages express genes for the Estrogen Receptor (ER) and Progesterone Receptor (PR).[13] Chronic Inflammation can lead to excessive tissue breakdown and can extend wound repair time after injury. In elderly patients, (postmenopausal women with low estrogen levels) estrogen supplementation causes wounds to heal more quickly.[18] This phenomenon is thought to be due to a reduction in Inflammation, as reduction in hormone levels in mice causes increased TNF-alpha secretion by Macrophages (and the Pro-Inflammatory response). TNF-alpha levels are decreased when mice are supplemented with Estrogen and slightly reduced when supplemented with Progesterone.[18]

In general, a reduction in steroid Hormones is correlated with more Inflammation Inducing Macrophages, or "Classically" Activated Macrophages, seen in greater numbers in Inflammatory Diseases.

The addition of Estrogen or Progesterone in deficiency correlates with: more effective Wound Healing and increased Angiogenesis[13], greater deposition of Extracellular Matrix (ECM) and "Alternatively" Activated Macrophages, which are seen in greater numbers in Fibrotic Diseases.

Concluding Remarks

The subject of Female Sex Hormone levels and their role in Crohn's Disease is a complex one. Extremely low hormone levels as seen in Post-Menopausal women are correlated with Pro-Inflammatory factors and a decreased ability to heal.

Hormone supplementation may cause hypercoagulability of the blood and can lead to blood clots, stroke, heart attack and other Ischemic conditions, including Ischemia of the Gastrointestinal Tract.

Estrogen and Estrogen-like compounds are shown to increase epithelial thickness (skin barrier) and reduce the vaginal pH (increases acidity) making it an unfavorable environment for viruses.[19] However, Estrogen administration also increases the ability of Escherichia coli bacteria to adhere to tissues of the Intestine, Vagina and Urinary Tract[9] The ability of Bacteria to adhere to tissue is an important factor in their ability to "take hold" and cause Infection. Bacterial adhesion may also be followed by Bacterial Invasion and Systemic Infection and Sepsis.

Progesterone based contraceptives can cause Microbial Dysbiosis within the vagina, and Candidiasis or Bacterial Vaginosis Infections[19]. Progesterone based contraceptives are also shown to decrease numbers of H2O2 positive Lactobacillus (but not Lactobacillus in general). Progesterone contraceptives also decrease epithelial thickness and the number of epithelial cell layers[15].

Progesterones and Androgens generally have an immunosuppressive effect[13]. Progesterone lowers Lymphocyte (Immune Cell) division in the Uterus[13] and can increase susceptibility to infection, including Sexually Transmitted Disease and Candidiasis[19]

The complicated nature of Crohn's Disease, the Immune Response and Hormonal Balance necessitates an Individualized decision process in regard to Oral Contraceptive Hormones and Hormone Replacement Therapies. The nature of Crohn's Disease does not allow for rules that apply to the masses. A trial and error period should also be expected. There are many choices today for Oral Contraceptives including very low dose hormones, different formulations of hormone precursors, Progesterone only, and multi-dose packs.

As always, CrohnsForum stresses the importance of any change in medication under the care of - and informed communication with your physicians. And, of course, we wish you the best of results in whatever treatment course you choose.

References

1. Allen DC and Calvert CH. Crohn's ileitis and salpingo-oophoritis. The Ulster Medical Journal. 1995; 64(1): 95-97. http://www.ncbi.nlm.nih.gov/pmc/arti...00067-0100.pdf

2. Amory JH, Lawler R, Hitti J. Increased tumor necrosis factor-alpha in whole blood during the luteal phase of ovulatory cycles. Journal of Reproductive Medicine. 2004; 49(8): 678-682.

3. Atkinson W, Houghton LA, Whorwell PJ, Whitaker P . Sex hormonal status effects meal stimulated plasma 5-Hydroxytryptamine (5-HT) levels in female patients with Diarrhoea predominant Irritable Bowel Syndrome (D-IBS). Gut. 2003; 52 pA38.2p

4. Bernstein, M. T.; Graff, L. A.; Targownik, L. E.; Downing, K.; Shafer, L. 7. A.; Rawsthorne, P.; Bernstein, C. N.; Avery, L. Gastrointestinal symptoms before and during menses in women with IBD. Aliment Pharmacol Ther. 2012; 36(2): 135-144.

5. Bouman A, Moes H, Heinman MJ, de Leij LF, Faas MM. The immune response during the luteal phase of the ovarian cycle: increasing sensitivity of human monocytes to endotoxin. Fertil Steril. 2001; 76: 555-559.

6. Braniste V, Leveque M, Buisson-Brenac C, Bueno L, Fioramonti J, Houdeau E. Oestradiol decreases colonic permeability through oestrogen receptor β-mediated up-regulation of occludin and junctional adhesion molecule-A in epithelial cells. The Journal of Physiology. 2009; 587: 3317-3328. http://jp.physoc.org/content/587/13/3317.full.pdf+html

7. Caligiuri MA. Human natural killer cells. Blood. 2008; 112(3): 461-469. http://bloodjournal.hematologylibrar....full.pdf+html

8. Cioffi M, Esposito K, Vietri MT, Gazzerro P, D'Auria A, Ardovino I, Puca GA, Molinari AM. Cytokine pattern in postmenopause. Maturitas. 2002; 41(3): 187-192.

9. El-Tawil AM. Oestrogens and Crohn's disease: the missed link. Andrologia. 2008; 40: 141-145.

10. Feller ER, Ribaudo S, Jackson ND. Gynecologic aspects of Crohn's Disease. American Family Physician. 2001. 64(10): 1725-1729. http://www.aafp.org/afp/2001/1115/p1725.pdf

11. Herceptin (trastuzumab). Genentech USA, Inc. http://www.gene.com/gene/products/in...rescribing.pdf

12. Heitkemper MM, Cain KC, Jarrett ME, Burr RL, Hertig V, Bond EF. Symptoms across the menstrual cycle in women with irritable bowel syndrome. 2003. 98(2): 420-431.

13. Khan KN, Kitajima M, Hiraki K, et al. Immunopathogenesis of Pelvic Endometriosis: Role of Hepatocyte Growth Factor, Macrophages and Ovarian Steroids. Am J Reprod Immunol. 2008; 60: 383-404.

14. Kumar P. Farouk Sait S. Lutenizing hormone and its dilemma in ovulation induction. Journal of Human Reproductive Sciences. 2011; 4(1): 2-7. http://www.jhrsonline.org/article.as...t=Kumar;type=2

15. Miller L, Patton DL, Meier A, Thwinn SS, Hooton TM, Eschenbach DA. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstet Gynecol. 2000; 96(3): 431-439.

16. Paavonen T, Andersson LC, Aldercreutz H. Sex hormone regulation of in vitro immune response. Estradiol Enhances Human B Cell Maturation via Inhibition of Suppressor T Cells in Pokeweed Mitogen-stimulated Cultures. Journal of Experimental Medicine. 1981; 154: 1935-1945. http://www.ncbi.nlm.nih.gov/pmc/arti...je15461935.pdf

17. Rituxan. Genentech USA, Inc. http://www.gene.com/gene/products/in...rescribing.pdf

18. Routley CE, Ashcroft GS. Effect of estrogen and progesterone on macrophage activation during wound healing. Wound Repair and Regeneration. 2008; 17:42-50.

19. Zdenek H, Stringer E, Mestecky J. Sex Steroid Hormones, Hormonal Contraception, and the Immunobiology of Human Immunodeficiency Virus-1 Infection. Endocr Rev. 2010; 31(1): 79-97. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852204

20. http://humupd.oxfordjournals.org/con...4/411.full.pdf
21. http://ajpgi.physiology.org/content/300/4/G621.full.pdf
22. http://gut.bmj.com/content/45/2/218.full.pdf+html
23. http://web.ebscohost.com/ehost/pdfvi...12&vid=1&hid=8
24. http://edrv.endojournals.org/content/27/6/575.full.pdf

25. Stricker R, Eberhart R, Chevailler M-C, Quinn FA, Bischof P, Stricker R. Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer. Clin Chem Lab Med. 2006; 44(7): 883-887.

26. Field EA, Allan RB. Oral ulceration aetiopathogenesis, clinical diagnosis and management in the gastrointestinal clinic. Alimentary Pharmacology & Therapeutics. 2003; 18: 949962. doi: 10.1046/j.1365-2036.2003.01782.x http://onlinelibrary.wiley.com/doi/1...03.01782.x/pdf

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