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.

Hormones and Mood : PMS and PMDD

The week before the period begins can be a difficult one emotionally for many women.  Different types of mood changes, as well as a range of physical symptoms can occur.  There have been difficulties for many years in finding the hormonal alterations which lead to premenstrual emotional symptoms.  However, the study of neuroendocrinology has uncovered information which indicates that hormones can very much affect our moods.

Premenstrual Syndrome (PMS) is defined as a collection of physical, psychological, and emotional symptoms which occur only during the luteal phase of the menstrual cycle and are of sufficient severity to interfere with some aspects of life. Premenstrual Dysphoric Disorder (PMDD) has a similar cyclical timing to PMS, but mood symptoms predominate and are severe. PMDD often interferes with the sufferer’s ability to function in her social or occupational life. The main symptoms are intense irritability, anxiety, and depression. Although it may contain some of the physical symptoms of PMS (such as bloating, cravings, fatigue, headaches) the symptoms are primarily related to mood. In both cases, symptoms resolve shortly after the onset of the menstrual period.

We have long known that the pituitary gland, the “master gland” is controlled by the hypothalamus in the brain. We now know that hormones produced by the glands such as the ovaries, testes, and adrenal (such as estrogen, progesterone, and testosterone) have effects on brain chemistry through different molecular mechanisms.

Hormones can affect the levels of neurotransmitters in the brain.   In addition to this, there are special hormones known as neuroactive steroids which are synthesized in the brain or central nervous system from other hormones.  These hormones powerfully and rapidly cause changes in brain function.

Hormones and the Menstrual Cycle

Estrogen and Mood

Mood symptoms of PMS and PMDD develop due to the shift in hormone levels related to ovulation.  It is well known that serotonin levels influence the mood, and estrogens have been found to increase serotonergic activity by increasing serotonergic receptors, transport and uptake.   Estrogen decreases after ovulation and then again at the end of the cycle just prior to the period and this is very likely to be one of the triggering causes of PMS and PMDD mood changes.

Progesterone and Mood

Several studies had initially shown no correlation between total progesterone and mood changes of PMS, however knowing that a large shift in progesterone correlates with the stage in the luteal phase when symptoms begin has led to more investigation in this area.

In the brain, ovary and adrenals, progesterone is converted to a neurosteroid called allopregnanolone, also known as tetrahydroprogesterone.  This hormone has been discovered to exert profound effects on mood and mental function.   A 2001 study found a relationship between low levels of allopregnanolone and severe symptoms of PMS and PMDD.  Another study found that commonly prescribed antidepressant medications such as fluoxetine (Prozac)  may in part work through increasing levels of allopregnenalone in the brain.

This specific type of progesterone may be of much interest to those who suffer specifically from premenstrual anxiety.  Allopregnanolone enhances the activity of GABA, the chief inhibitory neurotransmitter in the brain and it is through this mechanism that it exerts its effects on reducing anxiety.  In those women who have lower allopregnanolone levels, the activity of GABA would be reduced, leading to higher levels of anxiety or higher response to stress at the premenstrual time.  Lower levels of allopregnanolone may theoretically be caused by lower activity of the enzymes which create it, 5α reductase and  3α-hydroxysteroidoxidoreductase.  This may be partly genetic in onset (the first gene linked to estrogen in PMDD was discovered in 2007, none have yet to be discovered for allopregnanolone but research on this is in its beginnings).

Integrative Treatments for PMS and PMDD

In integrative medicine, there are two basic things to consider before deciding on treatment for luteal phase mood disorders.  Firstly, are the PMS/PMDD symptoms more akin to anxiety or to depression?  In those who exhibit more of a depressive syndrome, estrogen and serotonin are playing more of a role.  In patients who experience more anxiety and stress symptoms, it is low levels of progesterone/allopregnanolone  which cause symptoms.  It is important to consult your physician before starting any treatment, as specific therapies listed below may have interactions or side effects and use requires professional supervision.

Considerations for women experiencing more depressive symptoms would be :  St John’s wort.  This therapy has been studied and shown to have benefit for patients with PMS and PMDD.  Another consideration would be 5-HTP, which has not been specifically studied clinically for PMS, but does have promising evidence in the treatment of serotonin mediated depressive symptoms.

For patients in the category of anxiety, we must consider that the condition may be arising from either low progesterone, or from poor conversion of progesterone to allopregnanolone.  I would suggest salivary profiling to determine if total progesterone levels are low.  First line treatment options for women with low overall progesterone could include Vitex agnus castus throughout the cycle and vitamin B6.  This would aim to establish healthy corpus luteum function (and thereby increase progesterone) through pituitary regulation. Studies have shown that increasing progesterone levels increases allopregnanolone in the brain.  To reduce symptoms of anxiety : passionflower (which binds to benzodiazapene sites) or GABA can be prescribed to help modulate the reduced action of GABA. For many women, this condition is more evident in the late luteal phase where progesterone levels begin to drop, and therefore a targeted anti anxiety protocol can be used for these few days with a focus on the GABA receptors. In severe cases where progesterone is measured to be low through the luteal phase, a carefully titrated cyclic dosage of bio-identical progesterone can be prescribed by a physician.

In addition, for both types of PMS/PMDD discussed here, calcium and magnesium are important and effective therapies. Abnormal cellular and serum levels of these minerals have been linked to increased PMS mood symptoms.

With therapies targeted to the patient’s individual hormonal picture, PMS and PMDD can be managed for most women, and quality of life can be very much improved.

References

De Berardis et al. Treatment of premenstrual dysphoric disorder (PMDD) with a novel formulation of drospirenone and ethinyl estradiol. Ther Clin Risk Manag. 2007 August; 3(4): 585–590.

Eriksson O, Wall A, Marteinsdottir I, et al. Mood changes correlate to changes in brain serotonin precursor trapping in women with premenstrual dysphoria. Psychiatry Res. 2006 Mar 31;146(2):107-16. Epub 2006 Mar 2

Girdler SS, Straneva PA, Light KC, et al. Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder. Biol Psychiatry. 2001;49:788–97

Halbreich U, Rojansky N, Palter S, et al. Estrogen augments serotonergic activity in postmenopausal women. Biol Psychiatry. 1995;37:434–41.

Kaura V, Ingram CD, Gartside SE, et al. The progesterone metabolite allopregnanolone potentiates GABA(A) receptor-mediated inhibition of 5-HT neuronal activity. Eur Neuropsychopharmacol. 2006 in press

Christine E. Marx, Lawrence J. Shampine, Rahul T. Khisti, William T. Trost, Daniel W. Bradford, A. Chistina Grobin, Mark W. Massing, Roger D. Madison, Marian I. Butterfield, Jeffrey A. Lieberman, A. Leslie Morrow, Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: Implications for therapeutic actions, Pharmacology Biochemistry and Behavior, Volume 84, Issue 4, Neuroactive Steroids, Neurotransmitters’ Function and Neuropsychiatric Implications, August 2006, Pages 609-617

P Monteleone, S Luisi, A Tonetti, F Bernardi, AD Genazzani, M Luisi, F Petraglia, and AR Genazzani Allopregnanolone concentrations and premenstrual syndrome. European Journal of Endocrinology, Vol 142, Issue 3, 269-273

Rapkin et al. Progesterone Metabolite Allopregnanolone in Women With Premenstrual Syndrome. Obstetrics & Gynecology. 90(5):709-714, November 1997.

Susan Thys-Jacobs, Paul Starkey, Debra Bernstein, Jason Tian and The Premenstrual Syndrome Study Group, Calcium carbonate and the premenstrual syndrome: Effects on premenstrual and menstrual symptoms. American Journal of Obstetrics and Gynecology, Volume 179, Issue 2, August 1998, Pages 444-452

Wang M, Seippel L, Purdy RH, et al. Relationship between symptom severity and steroid variation in women with premenstrual syndrome: Study on serum pregnenolone, pregnenolone sulfate, 5a-pregnane-3, 20-dione and 3a-hydroxy-5a-pregnan-20-one. J Clin Endocrinol Metab. 1996;81:1076–82

Green Tea EGCG: a Natural Treatment for Uterine Fibroids

Green Tea

Uterine fibroids can be a very difficult condition to treat clinically.  The treatment is often surgical when symptoms are significant enough to cause problems.   Uterine fibroids are believed to affect at least 1/3 of North American Women.  They cause symptoms such as heavy bleeding, pressure effects on other organs, and fertility concerns:  all of which have large impacts on a woman’s health.   A study has recently come out from the Centre for Women’s Health Research at Meharry Medical College which concludes that EGCG, an extract from Green tea, may induce apoptosis (cell death) and reduce proliferation of uterine fibroid cells by affecting gene expression.  This is the second study from Meharry Medical College on this topic, the first having been released in May 2008.  The mechanism studied is in line with recent research indicating that uterine fibroids are correlated with genetic factors and gene expression,  evidence for which was examined in a review from the National Institute of Health Sciences, Comparative Pathobiology Group.  A study was also released in February 2008 which showed a positive effect of EGCG on fibroids in quail, an animal which is especially prone to these tumors.

Genetic effects of Green Tea on Fibroid Growth

In the study, the EGCG from green tea significantly decreased the expression of the genes PCNA, CDK4, and BCL2(genes which promote growth of fibroid cells) as well as increased the expression of the pro-apoptotic BAX(a gene which promotes cell degeneration in a fibroid cell) in a dose-dependent manner.   This indicates that EGCG works along multiple genetic pathways to inhibit fibroid tumor growth.

Fibroids and Hormones : Risk Factors

Factors which are currently thought to promote growth of fibroids are periods of excess estrogen, periods of unopposed estrogen(when there is insufficient progesterone to balance out estrogens), and xenoestrogens (environmental chemicals such as those found in some plastics or pesticides which mimic the effects of estrogen in the body). Risk factors for fibroids are many, and factors such as having an early age of onset of the menses or lack of ovulation give unopposed estrogen more time to stimulate fibroid growth.  Risk of fibroids is reduced by having children (also known as the effects of parity- risk is reduced most for women who have several children) which is now thought to be related to ischemic effects on the uterus after birth (reduced blood flow to the uterine tissues and involution of the uterus) which appear to reduce formation and growth of fibroids.  Fibroids are more common in women over 40, and this may be related to changes in hormonal mediators during perimenopause, or alternately from 20-30 consecutive years of exposure to estrogen.

Although it has been traditionally thought that estrogen is the only promoter of fibroid growth, research now points to progesterone as a stimulator of fibroid growth.  Fibroids contain both progesterone and estrogen receptors which are up and down regulated during the menstrual cycle.  A key to stimulation of fibroid growth may be in conversion enzymes.  Studies point to increased expression of an enzyme known as aromatase in women who have fibroids.  Aromatase is an enzyme which converts androgens to estrogen (androgens are male hormones, and the precursors to estrogen).  This information indicates that treatments which work at the level of this enzymatic activity (such as aromatase inhibitors – to be discussed on a future blog post) can bring more balance to the effects of of estrogen on tissues, especially if started at an early stage of the condition.

Fibroids:  The Liver and Diet

Another factor which can cause growth of fibroids relates to the clearance of hormones and conversion of estrogen to weaker forms by the liver.  If liver function is poor, more estradiol will circulate and increase growth of the fibroids.   Dietary factors which are also linked to risk of fibroids  include low fibre diets (fibre improves elimination of hormones).  Higher fat and lower fibre diets have also been linked to higher levels of estradiol according to a meta analysis of date from the Journal of the National Cancer institute, and obesity is also correlated with a higher risk for fibroids (androgens are converted to estrogens in adipose tissue).  Green tea  also has thermogenic (fat burning) effects according to multiple studies (effects beyond that of the caffeine it contains), so it may be helpful for women with fibroids from this standpoint as well.

A study from Japan indicated that green tea and other caffeinated beverages reduced serum estrogen by increasing sex hormone binding globulin, which is also of benefit in reducing the rate of estrogen stimulated fibroid growth.  Although other caffeinated beverages such as coffee also appeared to increase sex hormone binding globulin, only green tea was correlated to a day 11 lower serum estradiol.

Although more research is needed in this area before firm conclusions can be drawn on this topic, it seems that EGCG has multiple benefits for women who are at risk for fibroid development.  Though unlikely to shrink larger developed fibroids to a great extent, it may have a role to play in earlier stages and in prevention of these benign yet troublesome growths.

References

Alan A.Arslan, Leslie I.Gold, Khushbakhat Mittal, Ting-Chung Suen, Ilana Belitskaya-Levy, Moon-Shong Tang and Paolo Toniolo. 2005. Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review. Human Reproduction 20(4) pp. 852–863.

Baird D, and Dunson, D.  2003.  Why is Parity Protective for Uterine Fibroids.  Epidemiology.  March 14(2): 247-250.

Dong Zhang, Mohamed Al-Hendy, Ayman Al-Hendy. Green Tea Extract (EGCG) Inhibits Proliferation of Human Leiomyoma Cells. Biology of Reproduction. 67. 63. (2008)

Dulloo, A G : Seydoux, J : Girardier, L : Chantre, P : Vandermander, J. 2000.  Green tea and thermogenesis:  interactions between catechin-polyphenols, caffeine and sympathetic activity.  Int-J-Obes-Relat-Metab-Disord. 2000 Feb; 24(2): 252-8.

Folkerd EJ, Newton CJ, Davidson K, Anderson MC, James VH. 1984. Aromatase activity in uterine leiomyomata. J Steroid Biochem 20:1195–1200.

Gordon P. Flake, Janet Andersen, and Darlene Dixon. 2003.  Etiology and Pathogenesis of Uterine Leiomyomas: A Review. Environ Health Perspect.  June; 111(8): 1037–1054.

Ibrahim H. Ozercan, Nurhan Sahin, Fatih Akdemir, Muhittin Onderci, Soley Seren, Kazim Sahin, Omer Kucuk. 2008. Chemoprevention of fibroid tumors by [−]-epigallocatechin-3-gallate in quail.  Nutrition Research – February 28(2): 92-97

Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T. 1989. Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol 160:637–641.

Nagata C, Kabuto M, Shimizu H. 1998.  Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone-binding globulin in premenopausal Japanese Women.  Nutr Cancer 30(1):21-4

Sumitani H, Shozu M, Segawa T, Murakami K, Yang HJ, Shimada K, et al. 2000. In situestrogen synthesized by aromatase P450 in uterine leiomyoma cells promotes cell growth probably via an autocrine/intracrine mechanism. Endocrinology 141:3852–3861.

Wu A, et al. 1999.  Meta-analysis: Dietary Fat Intake, Serum Estrogen Levels, and the Risk of Breast Cancer. J Natl Cancer Inst 1999; 91:492-494, 529-534.

Yamamoto T, Takamori K, Okada H. 1984. Estrogen biosynthesis in leiomyoma and myometrium of the uterus. Horm Metab Res 16:678–679.

Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Rajaratnam V, Al-Hendy A.  2009.  Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells.  Fertil Steril. Oct 2009.  Epub ahead of print.