Stress and Infertility

Everyone hears that stress can have a negative impact on your fertility and reproductive health, but have you ever wondered exactly how? Stress seems like such an abstract term, and not long ago the entire medical profession underestimated its effect on our health. We now know so much about the profound effects stress can have on our physiology and reproductive health. In fact, stress is one of the leading causes of all disease. It is likely that it has a major role to play in cases of unexplained infertility and can aggravate nearly any other reproductive health diagnosis.

Stress and stress hormones can cause infertility in the following major ways:

  1. Impairs follicle health and development. Stress reduces the secretion of estrogen from the follicle which reduces the thickness of the endometrium and the fertile mucous
  2. Reduces the secretion of progesterone from the corpus luteum in the luteal phase, and thus affects implantation. Stress can cause luteal phase defects.
  3. Affects the surge of luteinizing hormone (LH) from the pituitary gland which is responsible for stimulating ovulation.
  4. Increases prolactin secretion by the pituitary gland, which inhibits ovarian function
  5. Affects the part of the immune system responsible for preventing miscarriage in early pregnancy
  6. Negatively impacts many other health concerns which may impair fertility, such as thyroid health, autoimmune conditions, allergic conditions, pcos, endometriosis, and gastrointestinal concerns

What happens in the body during stress?

During stress, the adrenal glands which sit on top of the kidneys are stimulated to produce stress hormones including cortisol and adrenalin. This process happens due to a mechanism which begins in the brain, specifically, in the hypothalamus. Activation of the sympathetic nervous system (the flight or fight aspect of the nervous system) occurs. The hypothalamus, pituitary gland, and adrenal gland work together through feedback mechanisms to perceive stressors in the environment and produce stress hormones that enhance survival in challenging times. Though these hormones allow our bodies to successfully overcome major stresses and threats, they are often counterproductive when trying to conceive.

Mechanisms through which stress reduces fertility

Cortisol, a major stress hormone has been shown to affect reproduction in multiple ways. It interferes with the surge of luteinizing hormone(LH) from the pituitary, delaying it and making the surge less powerful. LH is responsible for the final development of the follicle into the corpus luteum and the release of the egg. This has many negative impacts on healthy ovulation and on the hormones required to sustain implantation. Formation of a healthy corpus luteum is required to produce progesterone which allows for full development of the endometrial lining and hence, implantation .

High levels of glucocorticoids (stress hormones) are also known to reduce estrogen secretion by the follicle. Low estrogen levels will reduce fertile mucous and the development of the endometrial lining. The reduced estrogen output by the follicle also indicates that its development may not be normal or adequate.

A study on a rural Mayan population found that women who had the highest stress (measured by urinary cortisol levels), had lower levels of progesterone between 4 and 10 days after ovulation. A drop in progesterone at this time interferes with implantation and full development of the endometrial lining.

How stress is related to early miscarriage

It has also been more recently discovered that adequate progesterone levels are required for immune tolerance during early pregnancy. There are significant changes which occur in the immune system during early pregnancy to prevent the mother’s immune system from rejecting the newly implanted embryo. The effect of stress on progesterone levels can interfere with this natural immune process, leading to early pregnancy loss.

A 1995 study found that women who had significant work related stresses were more likely to have experience miscarriages. This was especially significant in women over 32, and in women carrying their first child. Elevated urinary cortisol (a marker of stress) has been found in several studies to be associated with a higher rate of miscarriage.

Effects on IVF and ART

A 2005 study found that women who had lower adrenaline levels at the day of retrieval and lower adrenaline levels at the day of transfer had a higher success rate in IVF cycles. A study on Swedish women undergoing IVF found that those who did not conceive had an overall higher level of stress hormones including prolactin and cortisol in the luteal phase of their cycles, indicating that stress negatively affects implantation. An Italian study in 1996 showed that women who were more vulnerable to stress had a poorer result in IVF.

Conclusion

Evidence is growing for a new condition known as “pregnancy stress syndrome”. This syndrome indicates that women with heightened levels of stress and anxiety are more at risk for early pregnancy loss.  This syndrome also states that women with stress and anxiety have lower rates of success in assisted reproductive technology procedures. This “syndrome” may seem to be common sense to many of us. We must consider though how important this really is. The idea of pregnancy stress syndrome comes from a very large body of evidence which has found stress to have a major impact on female fertility through multiple pathways. If medicine is to achieve the best outcome for all infertility patients, patients and doctors alike should view the diagnosis of stress as important as other reproductive health related diagnoses.

References

Arck P, Hansen PJ, Jericevic BM, Piccinni MP, Szekeres-Bartho J. Progesterone during pregnancy: endocrine-immune cross talk in mammalian species and the role of stress. Am J Reprod Immunol 2007;58:268–79.

Csemiczky et al. The influence of stress and state anxiety on the outcome of IVF-treatment: Psychological and endocrinological assessment of Swedish women entering IVF-treatment. Acta Obstetricia et Gynecologica Scandinavica Volume 79 Issue 2: 113 – 118 Dec 2001.
Facchinetti et al. An increased vulnerability to stress is associated with a poor outcome of in vitro fertilization-embryo transfer treatment .Fertility and Sterility Volume 67, Issue 2, February 1997, Pages 309-314
Magiakou MA, Mastorakos G, Webster E, Chrousos GP. The hypothalamic–pituitary–adrenal axis and the female reproductive system. Ann NY Acad Sci 1997;816:42–56.
Nepomnaschy PA, Welch K, McConnell DS, Strassman BI, England BG. Stress and female reproductive function: a study of daily variations in cortisol, gonadotrophins, and gonadal steroids in a rural Mayan population. Am J Human Biol 2004;16:523–32.
Smeenk et al. Stress and outcome success in IVF: the role of self-reports and endocrine variables Human Reproduction 2005 20(4):991-996
Wagenmaker et al. Cortisol Interferes with the Estradiol-Induced Surge of Luteinizing Hormone in the Ewe. Biology of Reproduction March 1, 2009 vol. 80 no. 3 458-463.

Advertisements

H1N1 Treatments: Anti-Inflammatory Properties of Herbal Medicines

supplements

It is now commonly accepted that many severe or fatal reactions to influenza are caused by intense inflammatory overreactions of the immune system.    A group from the Research School of Biology, Australian National University released an article on September 24, 2009 compiling evidence on this topic.

Cytokines are chemicals which are produced in immunological inflammatory reactions in the body.  Studies indicate that certain plant extracts can be protective against lethal reactions for mice which are infected with a virulent influenza strain. This occurs through inhibition of novel inflammatory cytokine High Mobility Group Box 1 protein (HMGB1) by these plant extracts.  Angelica sinensis (also known as Dang Gui) and Salvia Miltiorrhzia (also known as Dan Shen) were two of the herbal medicines studied which had this effect on HMGB1.

A drug known as gemfibrozil (a drug normally used to lower blood lipids) prevented a significant proportion of mice infected with H1N2 influenza from developing a fatal disease in a 2007 study.  Gemfibrozil has a known ability to reduce expression of inflammatory cytokines, and this is thought to be the mechanism through which it protects against severe or fatal reactions in the mice.  The action of this drug adds to the evidence that it is the body’s overproduction of cytokines which is involved in these severe cases of influenza.

Other studies have investigated Red Clover, Ginseng, Isatis, and Andrographis indicating that they modulate and reduce various aspects of cytokine response.  Forsythia, Honeysuckle, Balloon Flower root, Licorice, Camilla sinensis (green tea) and Ginger have also been researched, results of which indicate that they reduce both production of pro-inflammatory cytokines and pro- inflammatory mediators (such as reactive oxygen species and nitric oxide).  This is likely caused by suppressing a gene known as NF-kB which is often elevated in severe viral disease states, and which is related to disease conditions leading to multiple organ failure such as those in fatal influenza sepsis.

Combinations of these herbs are often used in Traditional Chinese Medicine to treat influenza from the earliest stages onward.  For this reason it is particularly interesting to determine the immunological mechanisms through which they work.

In summary, this information indicates that it is the host response of the human body which may be involved in many of the fatal reactions in viral influenza infections.  Treatments which can modulate this response in a patient who has contracted a viral influenza are therefore of great interest.  More research needs to be done on these herbs since due to their mechanisms, they may be promising therapies to integrate with conventional influenza treatments.

References:

Alleva, L, Cai C, Clark I. 2009.  Using Complementary and Alternative Medicines to Target the Host Response in Severe Influenza.  Evid Based Complement Alternat Med.  Sep 24. [Epub ahead of print]

Aldieri E, Atragene D, Bergandi L, Riganti C, Costamagna C, Bosia A, et al. Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-kB activation. FEBS Lett 2003; 552:141–4.

Budd A, Alleva L, Alsharifi M, Koskinen A, Smythe V, Mullbacher A, et al. Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrob Agents Chemother 2007;51: 2965–8.

Chao WW, Kuo YH, Li WC, Lin BF. The production of nitric oxide and prostaglandin E2 in peritoneal macrophages is inhibited by Andrographis paniculata, Angelica sinensis and Morus alba ethyl acetate fractions. J Ethnopharmacol 2009;122:68–75.

Chen X, Wu T, Liu G. Chinese medicinal herbs for influenza: a systematic review. J Altern Complement Med 2006;12:171–80.

Chen X, Li W, Wang H. More tea for septic patients?—green tea may reduce endotoxin-induced release of high mobility group box 1 and other pro-inflammatory cytokines. Med Hypotheses 2006;66:

Chen XY, Wu TX, Liu GJ, Wang Q, Zheng J, Wei J, et al. Chinesemedicinal herbs for influenza. Cochrane Database Syst Rev

Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 2002;360:1831–7.

Czura CJ, Wang H, Tracey KJ. Dual roles for HMGB1: DNA binding and cytokine. J Endotoxin Res 2001;7:315–21.

Esmon CT. Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost 2006;1:49–60.

Hampton T. Virulence of 1918 influenza virus linked to inflammatory innate immune response. JAMA 2007;297:580.

Kwon HM, Choi YJ, Choi JS, Kang SW, Bae JY, Kang IJ, et al. Blockade of cytokine-induced endothelial cell adhesion molecule expression by licorice isoliquiritigenin through NF-kB signal disruption. Exp Biol Med (Maywood) 2007;232:235–45.

Lim DS, Bae KG, Jung IS, Kim CH, Yun YS, Song JY. Anti-septicaemic effect of polysaccharide from Panax ginseng by macrophage activation. J Infect 2002;45:32–8.

Pan TL, Leu YL, Chang YK, Tai PJ, Lin KH, et al. Antiviral effects of Salvia miltiorrhiza (Danshen) against enterovirus

Quan FS, Compans RW, Cho YK, Kang SM. Ginseng and Salviae herbs play a role as immune activators and modulate immune responses during influenza virus infection. Vaccine 2007;25:272–82.

Surh YJ, Lee JY, Choi KJ, Ko SR. Effects of selected ginsenosides on phorbol ester-induced expression of cyclooxygenase-2 and activation of NF-kB and ERK1/2 in mouse skin. Ann NY Acad Sci 2002;973:396–401.

Utsunomiya T, Kobayashi M, Pollard RB, Suzuki F. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrob Agents Chemother 1997;41:551–6. 53.

Wang J, Zhou H, Zheng J, Cheng J, Liu W, Ding G, et al. The antimalarial artemisinin synergizes with antibiotics to protect against lethal live Escherichia coli challenge by decreasing pro- inflammatory cytokine release. Antimicrob Agents Chemother 2006;50:2420–7. May 1215.

Wang H, Li W, Li J, Rendon Mitchell B, Ochani M, Ashok M, et al. The aqueous extract of a popular herbal nutrient supplement,
Angelica sinensis, protects mice against lethal endotoxemia and sepsis. J Nutr 2006;136:360–5.

Weir Chiang You, Wen Chuan Lin, Jia Tsz Huang and Chang Chi Hsieh.  2009. Indigowood root extract protects hematopoietic cells, reduces tissue damage and modulates inflammatory cytokines after total-body irradiation: Does Indirubin play a role in radioprotection? Phytomedicine.  July

Xie CH, Zhang MS, Zhou YF, Han G, Cao Z, Zhou FX, et al. Chinese medicine Angelica sinensis suppresses radiation-induced expression of TNF-alpha and TGF-beta1 in mice. Oncol Rep 2006;15:1429–36.