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.

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Acupuncture for ovulation disorders and PCOS.

Polycystic ovarian syndrome is the number one reproductive disease in women.   This disease disrupts normal ovulatory cycles which can result in heartbreaking infertility for millions of women.  Known hormonal changes in PCOS include excess androgens (ie: testosterone), and insulin resistance.  Most thought now is leaning towards insulin resistance being the primary cause of PCOS, with genetic factors playing a role, but once the cycle of anovulation begins it feeds back on itself, causing the condition to remain in a vicious cycle.  Women with PCOS have not only insulin resistance, but also have neuroendocrine imbalances, resulting in elevated LH (lutenizing hormone) levels.  Having a high LH to FSH ratio is one of the hallmarks of polycystic ovarian syndrome or persistent anovulation.  In response to a combination of high LH and insulin resistance, the follicles in the ovary will begin to secrete too many male hormones (androgens) which then inhibit the hormonal pathways that are needed to stimulate ovulation.

Various medications are traditionally used to induce ovulation in women with PCOS.  A growing body of evidence now exists indicating that low-frequency electroacupuncture is as effective as commonly used medications in inducing ovulation.  Furthermore, this form of acupuncture can benefit many of the hormonal imbalances seen in polycystic ovarian syndrome.  Thousands of women worldwide use acupuncture therapy for PCOS and so I’d like to discuss how it works, and why it is so beneficial to induce ovulation.

General principles of how electroacupuncture stimulates the ovaries through the nervous system

Electroacupuncture has been found to profoundly effect the reproductive organs, through mechanisms in the sympathetic nervous system, endocrine system, and neuroendocrine system.  When needles are inserted into certain points and stimulated in a specific manner, this produces a neurological reflex transmitted to the organ correlated with that nerve pathway.  For example, needles inserted into the leg muscles below the knee, lower back, or abdomen in specific regions cause a response which measurably affects the ovary.  In addition, the nervous system will transmit a signal to the brain, and the brain then emits a response which affects the organ from a central mechanism.  These effects have been investigated through measurements of hormones, neuropeptides, and circulatory changes on both animals and humans receiving this specific type of electroacupuncture.

Nervous system alterations in PCOS

Evidence indicates that women with pcos have abnormal circulating levels of a neurohormone called β-endorphin.  β-endorphin is known to increase insulin production and reduce insulin excretion by the liver, which is very much implicated in PCOS.   It has also been found that women with PCOS have unusually high amounts of sympathetic nerve fibres in their ovaries.  These nerve fibres cause unusual stimulation of the ovary by the sympathetic nervous system (the part of the nervous system associated with “flight or fight” responses in the body, among other processes).  Stimulation of these nerve fibres can cause the ovaries to produce androgens, which then impair normal ovulation.  Women with PCOS have also been found to have high amounts of nerve growth factors in their ovaries, something which is associated with high levels of sympathetic nervous system activity.   Disturbances in central and peripheral β-endorphin release, high androgens, insulin resistance, abdominal obesity, and cardiovascular disease are associated with increased sympathetic nervous system activity, and all of these are also associated with the pathology of PCOS.  In a recent study by Elizabet Stener-Vitorin in Sweden, direct intraneural testing found a strong correlation between levels of sympathetic nervous system activity and testosterone levels in women with PCOS.  Those who had the highest amounts of sympathetic nervous system activity were found to have the highest testosterone levels and the most severe PCOS conditions.

What evidence exists for acupuncture inducing ovulation?

Several studies exist on low frequency electroacupuncture and ovulation induction.  In one trial, the effect of a series of 14 electroacupuncture treatments on 24 anovulatory women with pcos was investigated.  In 38% of these women, regular ovulation was induced.   Three months after the last treatment, LH/FSH ratios and testosterone levels were significantly decreased, a sign of improvement in PCOS pathology.   In another study done on a group of women given human menopausal gonadotrophin (a commonly used drug in the treatment of infertility), acupuncture was compared to hCG injections in order to assess its effect on ovulation.  Traditionally hCG is given to stimulate ovulation during medicated cycles at fertility clinics.  It was found that a single acupuncture treatment induced ovulation as effectively as the as the hCG injection and reduced the incidence of ovarian hyperstimulation syndrome, a painful side effect of medicated cycles.  Other studies have also indicated enhanced ovarian response when acupuncture is added to medicated cycles.  Female rats with PCOS induced by chronic exposure to DHT (a form of testosterone) were given low frequency electroacupuncture and physical exercise.  The treatment increased the amount of healthy follicles in the ovaries,  and significantly normalized cycles.

Effects of electroacupuncture on nervous system changes in PCOS

It has also been found that electro-acupuncture can regulate parts of the central nervous system related to dysfunction in PCOS.  Specifically, beneficial effects on neurohormones such as GnRH(Gonadotropin releasing hormone) and androgen receptor proteins, indicate that electro-acupuncture significantly benefits the hypothalamic-pituitary-ovarian axis and through this can help to restore normal cycling.  Electroacupuncture was also found in 3 recent studies to increase ovarian blood flow through effects on sympathetic nervous system pathways.  In addition, it has been found in two studies to reduce high peripheral circulating β-endorphins in women with PCOS, and thereby improve insulin resistance.   As sympathetic nerve activity appears to contribute to the development and maintenance of PCOS, the beneficial effects of electroacupuncture, and also exercise, may be mediated by nervous system modulation to the ovaries.

Electro-acupuncture appears to work through multiple pathways to disrupt the “vicious cycle” of PCOS.  Even though much more research needs to be done to determine all of the mechanisms involved, its safety and low incidence of side effects makes it an excellent therapy to stimulate ovulation naturally for the many women who suffer with this disease.

References
Andersson, S., Lundeberg, T., 1995. Acupuncture — from empiricism to science:functional background to acupuncture effects in pain and disease. Med. Hypotheses 45, 271–281.

Cai, X., 1997. Substitution of acupuncture for HCG in ovulation induction. J. Tradit. Chin. Med. 17, 119–121.

Carmina, E., Ditkoff, E.C., Malizia, G., Vijod, A.G., Janni, A., Lobo, R.A., 1992. Increased circulating levels of immunoreactive beta-endorphin in polycystic ovary syndrome is not caused by increased pituitary secretion. Am. J. Obstet. Gynecol. 167,

Chen, B.Y., Yu, J., 1991. Relationship between blood radioimmunoreactive beta-endorphin and hand skin temperature during the electro-acupuncture induction of ovulation. Acupunct. Electrother.

Lobo, R.A., Granger, L. R., Paul, W.L., Goebelsmann, U., Mishell Jr., D.R., 1983. Psychological stress and increases in urinary norepinephrine metabolites, platelet serotonin, and adrenal androgens in women with polycystic ovary syndrome. Am. J. Obstet. Gynecol. 145, 496–503.

Feng, Y., Johansson, J., Shao, R., Manneras, L., Fernandez-Rodriguez, J., Billig, H., Stener-Victorin, E., 2009. Hypothalamic neuroendocrine functions in rats with dihydrotestosterone-induced polycystic ovary syndrome: effects of low-frequency electroacupuncture. PLoS ONE 4, e6638. produces skeletal muscle vasodilation following antidromic stimulation of unmyelinated afferents in the dorsal root in rats. Neurosci. Lett. 283, 137–140.

Jin, C.L., Tohya, K., Kuribayashi, K., Kimura, M., Hirao, Y.H., 2009. Increased oocyte production after acupuncture treatment during superovulation process in mice. J. of Reprod. & Conception 20, 35–44.

Manneras, L., Cajander, S., Lonn, M., Stener-Victorin, E., 2009. Acupuncture and exercise restore adipose tissue expression of sympathetic markers and improve ovarian morphology in rats with dihydrotestosterone-induced PCOS. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R1124–R1131.

Stener-Victorin, E., Wu, X., Effects and mechanisms of acupuncture in the reproductive system, Auton. Neurosci.(2010)

Stener-Victorin, E., Lindholm, C., 2004. Immunity and beta-endorphin concentrations in hypothalamus and plasma in rats with steroid-induced polycystic ovaries: effect of low-frequency electroacupuncture. Biol. Reprod. 70, 329–333.

Stener-Victorin, E., Waldenstrom, U., Tagnfors, U., Lundeberg, T., Lindstedt, G., Janson, P.O., 2006. Effects of electro-acupuncture on anovulation in women with polycystic ovary syndrome. Acta Obstet. Gynecol. Scand.

Stener-Victorin, E., Lundeberg, T., Waldenstrom, U., Manni, L., Aloe, L., Gunnarsson, S., Janson, P.O., 2000a. Effects of electro-acupuncture on nerve growth factor and ovarian morphology in rats with experimentally induced polycystic ovaries. Biol. Reprod. 63, 1497–1503.

Stener-Victorin, E., Lundeberg, T., Waldenstrom, U., Bileviciute-Ljungar, I., Janson, P.O., 2001. Effects of electro-acupuncture on corticotropin-releasing factor in rats with experimentally-induced polycystic ovaries. Neuropeptides 35, 227–231.

Stener-Victorin, E., Kobayashi, R., Kurosawa, M., 2003a. Ovarian blood flow responses to electro-acupuncture stimulation at different frequencies and intensities in anaesthetized rats. Auton. Neurosci.: Basic and Clin. 108, 50–56.

Stener-Victorin, E., Lundeberg, T., Cajander, S., Aloe, L., Manni, L., Waldenstrom, U., Janson, P.O., 2003b. Steroid-induced polycystic ovaries in rats: effect of electro- acupuncture on concentrations of endothelin-1 and nerve growth factor (NGF), and expression of NGF mRNA in the ovaries, the adrenal glands, and the central nervous system. Reprod. Biol. Endocrinol. 1, 33.

Stener-Victorin, E., Fujisawa, S., Kurosawa, M., 2006. Ovarian blood flow responses to electroacupuncture stimulation depend on estrous cycle and on site and frequency of stimulation in anesthetized rats. J. Appl. Physiol. 101, 84–91.

Stener-Victorin, E., Jedel, E., Manneras, L., 2008. Acupuncture in polycystic ovary syndrome: current experimental and clinical evidence. J. Neuroendocrinol. 20, 290–298.

Stener-Victorin, E., Jedel, E., Janson, P.O., Sverrisdottir, Y.B., 2009. Low-frequency electro-acupuncture and physical exercise decrease high muscle sympathetic nerve activity in polycystic ovary syndrome. Am.J.Physiol.Regul.Integr.Comp.Physiol. 297 (2), R387R395.

Zhao, H., Tian, Z.Z., Chen, B.Y., 2003a. An important role of corticotropin-releasing hormone in electroacupuncture normalizing the subnormal function of hypothalamus–pituitary–ovary axis in ovariectomized rats. Neurosci. Lett. 349, 25–28.

Black cohosh may reduce side effects of Clomid / clomiphene

Clomid is one of the most commonly used pharmaceuticals in the treatment of fertility concerns today.  It is often the first therapy used.  Clomid (also known as clomiphene) binds to estrogen receptors, inhibiting the action of estrogen (which is produced by developing follicles) on the hypothalamus in the brain.   As a result, the pituitary gland perceives estrogen levels to be low (when they actually are not), and it responds by producing increased levels of both LH and FSH.  This causes increased follicle production by the ovaries, and stimulation of ovulation.pregnancy with clomid therapy

As effective as this therapy can be at inducing ovulation, studies have indicated fertility specific side effects of clomiphene, many of which are caused by its antagonism to estrogen. The major fertility related side effects are: 1) thinning of the endometrial lining and 2) reduction of cervical mucous required for entry of sperm into the uterus.

One of the isomer forms of clomiphene has a slow excretion rate from the body (it can take more than 6 weeks to be excreted).  If clomiphene therapy is used for longer than two months, side effects can be more pronounced, resulting in greater thinning of the endometrial lining which is needed for healthy implantation. In women over 40, endometrial lining thins naturally, and perhaps this is why clomiphene is often not an effective treatment in this group of patients.

For many women, the ovulation induction produced by this medication can be the answer to ovulation difficulties however therapy often must be stopped after a short period due to side effects over time. Estrogen therapy has been studied in conjunction with Clomid presumably to offset the anti-estrogenic effects of the medication, with mixed results.  Some studies have found giving additional estrogen to women to be helpful, and others have found it to be of no benefit.

Recently, two studies have been completed on combining black cohosh (also known as Cimicifuga racemosa) with clomiphene in patients seeking treatment for infertility.  Cimicifuga is a botanical therapy, often used in womens health to treat menopausal conditions such as hot flashes.  Estrogenic effects of black cohosh remain highly debated, with early studies indicating that it  directly affects estrogen receptors, and more recent studies showing that the effect of the plant may occur from an entirely different mechanism.  Without yet knowing the exact mechanisms through which black cohosh works, several convincing studies have indicated it to be beneficial in the clinical treatment of hormonal disorders.  A recent study has indicated that black cohosh may reduce proliferative effects of estrogens on tissues, which is in line with the effect of many phytoestrogens, however the mechanism for this remains to be elucidated.

In the first study conducted in 2008, black cohosh was found to significantly increase estradiol and LH concentrations in patients taking clomiphene therapy.   Endometrial thickness, serum progesterone and clinical pregnancy rate in patients were significantly higher in the black cohosh group as compared to control.

The second study was completed in 2009. In this study of patients taking clomiphene, black cohosh given in the follicular phase was compared to estrogen therapy, presumably in order to determine which could reduce side effects more effectively. The black cohosh group needed significantly fewer days for healthy follicular development, had a thicker endometrial lining and had higher estradiol concentration at the time of HGG ovulation trigger when compared to the estrogen replacement therapy group.  Clinical pregnancy rate was 14.0% in the estrogen replacement group versus 21.1% in the black cohosh group. Although this did not reach clinical significance, it appears that the black cohosh group did display many benefits overall when compared to the estrogen replacement group. When results from the previous study are also considered, it appears that this therapy may warrant serious consideration and further study for those undergoing clomiphene treatment.

More studies will need to be conducted in order to determine the mechanisms of this herbal medicine’s benefits for patients undergoing modern assisted reproductive technology therapies.

References:

Homburg, I.  Clomiphene citrate—end of an era? a mini-review.  Human Reproduction 2005 20(8):2043-2051

Insler, V MB, BCh; Zakut, H MD; Serr, D M MB, ChB. Cycle Pattern and Pregnancy Rate Following Combined Clomiphene-Estrogen Therapy. April 73 (4) 4

Massai et al.  Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment.  Fertil Steril. 1993 Jun;59(6):1179-86

Osmers et al. Efficacy and Safety of Isopropanolic Black Cohosh Extract for Climacteric Symptoms. Obstetrics & Gynecology:  May 2005 – Volume 105 – Issue 5, Part 1 – pp 1074-1083

Sandro Gerli, Hossein Gholami, Antonio Manna, Antonio Scotto Di Frega, Costantino Vitiello, Vittorio Unfer, Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study, Fertility and Sterility, Volume 73, Issue 1, January 2000, Pages 85-89

Shahin AY, Ismail AM, Shaaban OM. Supplementation of clomiphene citrate cycles with Cimicifuga racemosa or ethinyl oestradiol–a randomized trial. Reprod Biomed Online. 2009 Oct;19(4):501-7.

Shahin, Ahmed Y.1; Ismail, Alaa M.1; Zahran, Kamal M.1; Makhlouf, Ahmad M.1 Adding phytoestrogens to clomiphene induction in unexplained infertility patients – a randomized trial. Reproductive BioMedicine Online, Volume 16, Number 4, April 2008 , pp. 580-588(9)