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.

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.

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

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)

Thyroid and Fertility

Woman thinkingThyroid problems are extremely common, and because they can be asymptomatic, it can be difficult to know if a condition is present.  The thyroid is absolutely essential for healthy fertility.  Dysfunction can cause ovulatory disorders, menstrual irregularity, and recurrent miscarriage.  The thyroid gland is key to support ovarian function. If thyroid function is low, the eggs will not mature fully and, ovulation can be either delayed or prevented.  Surprisingly, 5-20 percent of women in their reproductive years have a thyroid condition.

Autoimmune thyroid disease is one major cause of many thyroid conditions.     Women who test positive for thyroid antibodies will generally develop hypothyroidism at a rate of 20% per year.  Often times, when a fertility general health screening is done, the only test completed for the thyroid is TSH (Thyroid Stimulating Hormone).  TSH is a useful test to screen for hypo or hyperthyroidism, however it does not detect autoimmune conditions.  Autoimmune thyroid antibodies can be present with no symptoms of hypothyroidism at all.  In autoimmune thyroiditis, TSH levels are often normal so it is important to complete a full thyroid panel. This can determine if there is a risk of developing hypothyroidism which could threaten a pregnancy.  When a woman becomes pregnant, there are widespread hormonal changes in the body, including an increased demand for thyroid function.   If autoimmune antibodies are present, this can trigger miscarriage due to inability of the thyroid to compensate normally for pregnancy.  Many cases of recurrent miscarriage or premature birth are related to thyroid disease so this is a very important part of fertility screening in those who suffer from miscarriages. One of the protective functions of pregnancy is a decrease in immunity, so it is unlikely that a new flare up of Grave’s disease (an autoimmune disease which causes symptoms of hyperthyroidism and goitre) will occur during pregnancy, however often we see worsening of hypothyroidism.

Another condition which can be present in those with thyroid disease is primary ovarian failure.  This is caused by autoantibodies to the ovary and is associated with autoantibodies to the thyroid.  This condition, although not common, can be devastating for women.

In men, hypo- or hyper- thyroidism can cause poor development of sperm, so for all men with sperm quality concerns, the thyroid should be screened.   Although thyroid disease is more common in women, it can still happen for many men and go undetected.

Symptoms of Hypothyroidism:

fatigue, weakness, weight gain, dry skin or hair, feeling cold, constipation, irritability, depression, muscle cramps, menstrual irregularities.

Symptoms of Hyperthyroidism:

anxiety, feeling hot, insomnia, heart palpitations, weight loss, hunger, sweating, trembling

To optimize fertility the following lab testing for thyroid should be done.  Explanation of thyroid lab values and normal ranges are included.

TSH – Thyroid Stimulating Hormone.

This is a hormone released by the pituitary gland(in the brain) which stimulates the thyroid to release thyroid hormones.  It is controlled by feedback mechanisms, when thyroid hormone is low in the bloodstream, the pituitary gland will increase its output of TSH to stimulate more release of thyroid hormones.

Normal Levels :  0.4 – 4 mIU/L.   If levels are above 2, and especially if thyroid antibodies are present with signs and symptoms of hypothyroidism, this is suspect of “subclinical hypothyroidism” and may present risks for fertility.

Free T4 – Thyroxine.

A thyroid hormone produced by the thyroid gland.  This is the most abundant thyroid hormone in the body.  It is also the weaker of the thyroid hormones.  It represents 80% of the thyroid hormones in the body, and its major function is to be converted into the stronger T3 hormone.  This is a measure of the T4 which is not bound to carrier proteins.

Normal Levels:   8.5-15.2 pmol/L

Free T3 – Triiodothyronine.

A thyroid hormone produced from the conversion of T4 by enzymes.  This is a much stronger thyroid hormone and has powerful effects on the body’s metabolism.  It represents 20% of the total thyroid hormones in the body. The conversion of T4 into T3 can also be impaired, so this is important to investigate.  This is a measure of the T3 which is not bound to carrier proteins.

Normal Levels:  3.5 – 6.5 pmol/L

Reverse T3

When there is sufficient T3, the body will convert excess T4 into a compound known as reverse T3.  This compound is inactive, and serves to protect the body from excessive overstimulation by thyroid hormone. It can bind to receptors where T3 would normally bind, however it does not stimulate the receptor as T3 would. In some cases, the body may actually convert T4 excessively into reverse T3, which can result in metabolic abnormalities. This condition should be screened for whenever signs and symptoms (including low body temperature) are present in fertility patients.

Normal Levels:  200-300 pmol/L

Thyroid peroxidase antibodies

These are antibodies against an enzyme known as Thyroid Peroxidase.  Thyroid peroxidase is involved in the conversion of T4 to T3.  If antibodies exist, this can cause a conversion disorder which results in hypothyroidism.

Normal Levels: <35

Antithyroglobulin antibodies

These are antibodies directed against a protein known as Thyroglobulin.  Thyroglobulin is present in the thyroid gland and is essential for the production of thyroid hormones.  These antibodies can trigger destruction of the thyroid gland.

Normal Levels:  <20

Treatment for thyroid conditions can involve thyroid hormones, nutritional supplements, amino acids and herbal medicines, depending on which type of thyroid condition is present.  Naturopathic treatment for thyroid is often integrated with conventional thyroid medications when needed to optimize response for fertility concerns.

Reference:

Mosby’s Manual of Diagnostic and Laboratory Tests

Soy and Fertility in Men

Father and BabyThere is so much controversy about the effect of soy foods on men’s fertility.  With each study that is released, a news article follows declaring it to be either safe or harmful for men’s fertility.   I would like to go through some of the studies in this area and review the significance of them before drawing a conclusion based on the current evidence.  Soy is well-known for its health benefits for men, including the reduction of risk for both cardiovascular disease and prostate cancer.  Due to these benefits, it has become a larger part of the North American diet than it ever has been in the past so it is important to fully understand its impact on hormones and fertility.

Effects of Soy on Infants and During Pregnancy on Adult Male Fertility

The following studies investigate reproductive effects on men who were given soy products either through infant formula, or while their mothers were pregnant.  This is a very sensitive time of development for the reproductive organs, so much concern remains about the possibility of permanent negative effects.

Soy Formula in Infant Male Marmoset Monkeys causes no Adverse Effects
This study concluded that infant feeding with soy formula has no major adverse reproductive effects in male marmoset monkeys. Although it did not appear to affect fertility, soy infant formula did alter testis size and cell composition.

Again I would like to mention here that both rats and monkeys produce much higher levels of equol (an estrogen like substance which is much stronger than soy isoflavones) in their intestines than humans in general.  The equol is produced through fermentation of isoflavones by bacteria which reside in the intestine.  It’s hard to compare humans directly with rats or monkeys especially when it comes to estrogenic effects.  Studies investigating the effects of phytoestrogens on the fertility of different animal species have been very inconsistent. This indicates that soy has very species specific effects on fertility and highlights the need for more studies on humans before we can draw definitive conclusions.

Study on Vegetarian Mothers and Hypospadias in Infants
This famous study investigated the difference between vegetarian and omnivorous women and the likelihood of a condition known as hypospadias in their newborns.  Hypospadias is a condition (which is currently on the rise) where the urethral opening is in a lower position.  This study found that significantly more of the vegetarian mothers had babies with hypospadias.  As vegetarians have a greater exposure to phytoestrogens than do omnivores, the researchers concluded that phytoestrogens may have a negative effect on the developing male reproductive system. However, this study was not specific for soy, it only examined whether or not vegetarians tended to have more infants with hypospadias. Other factors cannot be excluded for example, vegetarians could be more likely to be deficient in other vitamins or nutrients such as B12, and could also be consuming a larger amount of estrogenic pesticide Soy Infant Formularesidue, and this study did not question participants about consumption of organic foods.   It was also found that the vegetarian mothers who did not take iron supplements had more infants with hypospadias.  In Japan, there are 1/10th the number of infants born with hypospadias as there are in North America and yet there is a much higher level of phytoestrogen consumption.  Therefore, this study is not fully conclusive that phytoestrogens are the cause of this developmental condition since there are too many unaccounted for variables.

Study on Soy Formula in Infants and Reproductive Outcome In Young Adulthood
This study on 811 men and women, who were fed either soy or cow milk formula as infants were assessed in young adulthood for their pubertal maturation, menstrual and reproductive history, height/weight, and current health.  It concluded that exposure to soy formula does not appear to lead to different general health or reproductive outcomes than exposure to cow milk formula in infancy. This study did not go into details asking about length of time to conceive. Also, no reproductive health markers were reported for male subjects with the exception of sexual maturation. Although men were questioned about pregnancy outcomes in partners the results were not reported.

In conclusion on the subject of male reproduction and feeding of infant soy formula, it appears that overall there may be a risk for some long-term reproductive developmental changes, however, the full effects of this are unknown and may not go so far as to cause fertility concerns.  However, as we know from so much current data, breast milk is a far superior nutrition method for infants, and avoids any of the risks that soy formula may hold.

Studies on Male Adult Animals

Phytoestrogenic Plant given to Adult Male Mice – Some Effects on Reproduction
A phytoestrogenic plant(pueraria mirifica) was given in two doses, one high and one low,  to a group of adult male mice. Neither treatment had effect on testicular weight, sperm count, LH, FSH or testosterone. However the high (100mg/kg) dose reduced the weight of epididymis, seminal vesicle and sperm motility.  There were no effects on fertility. This effect was seen to be reversible after the phytoestrogen was stopped. However, this plant, though it does contain some of the same components as soy, is not identical to soy.

Acute Exposure of Adult Male Rats to Dietary Phytoestrogens Causes Temporary Reduction in Fertility
This study found that lipid peroxidation damage of sperm was increased in rats fed a high phytoestrogen diet for 3 days.   No such changes were noted in low phytoestrogen group.  As in the previous study, this effect was temporary, with fertility returning to control levels by day 12. Rats who were fed the phytoestrogens for longer than 6 days did not show this reduction in fertility and in fact showed no change in any reproductive parameters.

Phytoestrogens cause no Negative Effects on Fertility of Rhesus Monkeys
In this study, phytoestrogens were given to rhesus monkeys at the age of puberty.  They had no adverse effects on the reproductive systems of male or females as evaluated by hormone concentrations.  Cardiovascular benefits were observed in the monkeys receiving the phytoestrogens.

Studies on Adult Men

Soy Products Related with Slightly Lower Testosterone and Lower Estradiol in Japanese MenMale Symbol

This study on Japanese men investigated the relationship between soy product intake and serum testosterone and estrogen concentrations.  The results found that blood levels of estradiol concentration were significantly lower with increased soy product intake, and blood estrone levels were not related to soy intake.  Testosterone levels were also lower with increased soy intake but this effect was so slight it did not reach significance in the study.  This study also concluded that this may be part of the reason soy reduces risk of prostate cancer in men.

Soymilk Given to Japanese Men Results in Lower Estrogen Concentrations

This  second study on Japanese men investigates the effects of drinking 400 mL daily soymilk on serum estrogen and testosterone concentrations.  In contrast to the previous study, the results of this study indicate that soymilk consumption is associated with lower levels of the estrone form of estrogen.  In this study there was no effect of soymilk on any of the other hormones measured including testosterone, estradiol, and sex hormone binding globulin.

These two studies indicate that soy can affect serum estrogen levels.  It is known from other research that estrogen is required for proper formation of sperm, but also, that elevated levels of estrogen can interfere with fertility (especially if testosterone to estrogen ratios are altered).  So, what we can say is that a good level of balance of estrogen is required for optimal male fertility, and the real question is, does soy interfere with the balance of estrogen enough to impact actual fertility parameters in males.  These two studies do not answer this question, so we need to look more to studies on soy consumption and the end result on adult male fertility.

Soy Food Intake Related to lower Sperm Concentration Among Men from an Infertility Clinic
This very well-known study took a group of men from a fertility clinic and evaluated the relationship between soy food intake and sperm quality and count.  It found that there was a relationship between the intake of soy foods and the reduction of sperm concentration.  72% of men in this study were either overweight, or obese according to their BMI levels.  The relationship was more pronounced in the men who had the highest sperm concentration and among overweight or obese men. Soy foods did not reduce sperm motility, sperm morphology, or ejaculate volume.  This suggests that because androgens are converted into estrogen in fatty tissue,  this may increase tissue sensitivity to phytoestrogens in those who have higher amounts of body fat.   This study did not consider that those who eat more soy could be exposed to more estrogenic pesticides (it did not ask about consumption of organic versus non organic soy).  It also did not account for the addition of soy in many foods that may not have been reported by the participants (such as soy based additives in baked goods, processed foods and so forth).  Therefore, although this study is quite interesting, it not conclusive.   Couple preparing a healthy mealThis study does however,  make an important association between elevated body mass index, and effects of soy on fertility in men.

Healthy Adult Men of Normal BMI: Soy Isoflavones have No Negative Effect on Sperm Parameters

This new study from the University of Guelph which involved healthy adult men with a healthy body mass index investigated the effects of isoflavones on sperm parameters.  In this study, men were given a daily serving of soy isoflavones in low concentration, high concentration, and then isoflavone free milk protein isolate.  The different substrates were given for 57 days each separated by a 28 day ‘break period’.  The study showed no significant effect of soy isoflavones on sperm concentration, motility and morphology of the men.  This study adds to the evidence that soy has a much lesser effect on semen parameters in men of healthy body mass index.

Summary

In summary, more research needs to be done before we can have any conclusive answers about the impact of soy on male fertility.  There are many conflicting studies on this subject, which indicates we need to investigate further.  There are a few points though that we can learn from the current research which can probably be protective to male fertility, and also allow men to have some of the health benefits that soy foods can provide.

1)  Soy can have a temporary, acute effect on adult male reproductive parameters if taken in high quantities, especially if not normally included in the diet.  Therefore, it would not be a good idea to consume large amounts of soy directly around the time when your partner is ovulating.

2)  Soy appears to reduce sperm concentration in males who are overweight or obese, so if you are overweight, try to achieve a healthy BMI.  In cases where BMI is high, soy foods might not be the best staple for the diet while trying to conceive.

3)  It is probably likely that small amounts of organic soy have little negative effect on reproduction in males of healthy body mass index and can provide health benefits such as improvement of cardiovascular profiles, and reduction of risk for prostate cancer.  More research still needs to be done in order to truly understand the impact of soy fertility of healthy adult males.

References

Anthony et al. J Nutr. 1996 January; 126(1): 43–50. Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys.Beaton et al. Soy protein isolates of varying isoflavone content do not adversely affect semen quality in healthy young men. Fertility Sterility in press

Chavarro et al. Hum Reprod. 2008 November; 23(11): 2584–2590Soy food and isoflavone intake in relation to semen quality parameters among men from an infertility clinic

Eddy et al. Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology 1996 137 4796 – 4805.

A Glover et al. Acute exposure of adult male rats to dietary phytoestrogens reduces fecundity and alters epididymal steroid hormone receptor expression. J Endocrinol. 2006

Hess RA. Estrogen in the adult male reproductive tract: a review. Reprod Biol Endocrinol 2003; 1: 52.

Jaroenporn S et al. Effects of pueraria mirifica, an herb containing phytoestrogens, on reproductive organs and fertility of adult male mice. Endocrine 30(1) August 2006.
Jay et al. Aromatase Inhibitors for Male Infertility. The Journal of Urology – February 2002 (Vol. 167, Issue 2, Part 1, Pages 624-629)

Karen et al. Infant feeding with soy formula milk: effects on puberty progression, reproductive function and testicular cell numbers in marmoset monkeys in adulthood. Hum. Reprod. 21: 896-904.

Nagata et al. Nutr Cancer. 2000; 36(1): 14–18. Inverse association of soy product intake with serum androgen and estrogen concentrations in Japanese men.

Nagata et al. Cancer Epidemiol Biomarkers Prev. 2001 March; 10(3): 179–184. Effect of soymilk consumption on serum estrogen and androgen concentrations in Japanese men.

North et al. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. BJU Int. 2000 January; 85(1): 107–113.

Rozman et al. NTP-CERHR Expert Panel Report on the Reproductive and Developmental Toxicity of Soy Formula. Birth Defects Res B Dev Reprod Toxicol. 2006 August; 77(4): 280–397.

Strom et al. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA 2001 August 15; 286(7): 807–814.

Creative Commons License
Soy and Fertility Part 2. Phytoestrogens and Fertility in Men by Dr. Fiona McCulloch ND is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.5 Canada License.
Based on a work at drfionamcculloch.wordpress.com.
Permissions beyond the scope of this license may be available at https://drfionamcculloch.wordpress.com.

Soy and Fertility in Women

In this post (part 1) I will summarize the research on soy and phytoestrogens on female fertility and in my next post I will discuss male fertility (part 2). Soy has been researched quite extensively for its benefits on cancer and heart disease prevention, but there is plenty of conflicting information regarding soy and fertility. Firstly I want to say that research on this is still in the making, and many more studies will need to be done on more adult women in order to come to any real conclusions.

Soy Formula and Newborns

Many studies on soy and fertility are related to newborn intake of soy. There has been much concern with feeding newborns soy formula as a substitute for dairy formula or breast milk (around 25% of infants are fed soy formula). The concern is that there may be permanent reproductive effects of soy in newborns as opposed to temporary effects of soy in adults. The reproductive system is in a very sensitive time of development in the newborn. Most studies in this area have been done on animals, specifically rats and there are very large differences in estrogen metabolism between rats and humans which I will discuss below. There is very scarce research on adult women and soy.

Study on Women exposed to Soy Formula as Infants

A study published in the Journal of the American Medical Association on young adults fed soy based formula in infancy showed the following results for women: No significant changes in pregnancy outcomes in women who were fed soy formula, although they did have increased length of menstrual cycle and of discomfort with the menses (which could be related to newborn exposure to high levels of phytoestrogens in formula). This study did not go into details asking women about length of time to conceive and use of reproductive technology to conceive, so it is lacking some information for our purposes. Also, this study did not account for current intake of soy products.

Studies : Soy Formula Given to Infants Show Differing Outcomes in Hormonal Response

A study on infants fed soy formula for 6 months concluded that long-term feeding of soy formula in infants did not produce estrogen-like hormonal effects. They suggested that their findings confirm the theory that phytoestrogens have a low affinity for estrogen receptors and therefore produce only weak biologic effects. Another study, however, found that infants who were fed soy formula had early onset of thelarche (breast development) compared to children who were not. It appears then, that there is much conflicting information on soy formula in infants and their later fertility, but what we do know is that breast milk is always best. Support for breastfeeding can help to ensure healthy reproductive capacity for future generations.

Soy Intake and Effects on Fertility

pregnancy testFor the purpose of fertility patients, we are looking more at the consumption of soy in the diet, and sadly, there is little human data on this subject in females.

Phytoestrogen Intake in Japanese Women and changes in Estrogen levels

In a study on Japanese women they found that of those who consumed the highest dietary amounts, there was a lower estradiol level on day 11 and 22 of the cycle. The study concluded that this would therefore lead to lower risk for breast cancer. Since this study did not evaluate reproduction specifically, we can’t say that this change would have any effect on fertility, however it does show that high soy intake can modify hormone balance in premenopausal women.

Animal Studies
There is little information on soy and reproduction in adult females, but we can look to some animal studies for more information:

Soy administration to Rhesus Monkeys – No Negative Reproductive Outcome

A study done on rhesus monkeys at the age of puberty showed that monkeys fed soy protein with isoflavones had lower risks of cardiovascular disease and no changes in reproductive markers(in neither hormone levels nor reproductive organs) compared to those not given isoflavones.

Mice given Genistein as Newborns have Impaired Implantation as Adults

For mice given 50 mg/kg genistein(a fairly high dose) as newborns, it was found that there were changes in the uterus/endometrium of the mice when they became adults which impaired implantation of embryos. Again, this is on newborn exposure and does not apply so much to adult women taking soy, because effects of phytoestrogens on adults tend to be temporary whereas when they are on newborn animals they tend to affect development.

Administration of High Doses of Phytoestrogens in Adult Mice

Long term administration of a phytoestrogenic herb Pueraria merifica in mice found that taking a low dose(10 mg/kg) of phytoestrogen had no impact on hypothalamic-pituitary-ovarian-uterine axis, and that taking a high dose of 100 mg/kg had adverse effects on mating efficiency and reproduction. The higher dose could be correlated to taking a high potency phytoestrogen/soy protein formula, and the lower dose could be correlated to a small dietary quantity.
Criticisms of this study according to our purposes are that this study did not involve soy, but another plant phytoestrogen.

Problems in Comparing Humans to Monkeys and Rodents in Studies on Soy and Reproduction

I would like to make a very important point here. Rodents and monkeys in general are very potent intestinal producers of an estrogen called equol. A study in the American Journal of Clinical Nutrition found that equol accounted for 71-90% of the summed isoflavones in rat serum and 54% of isoflavones in chimpanzee serum. Equol is a byproduct of intestinal bacteria as they break down phytoestrogens such as soy. It has been found though, that only around 20-50% the adult human population make equol after ingesting soy foods and most of the human population does not produce equol at all. Equol production is correlated to greater health benefits of soy such as prevention of hormonally mediated cancers and has a much more potent effect than genistein (an isoflavone from soy). Studies show that equol producing individuals show stronger responses to high isoflavone diets. This may also indicate that in certain women, soy may have a more pronounced effect on fertility but for the majority, it may have a much lower impact than what is seen in rats/mice/monkeys. This implies that much more research will need to be conducted on humans and that we should not jump to any conclusions based on animal studies. Something else very important to consider here, is that human infants do not make equol until they are over 4 months old. This makes it difficult to correlate studies done on newborn mice/rats who are given soy with infants given soy formula.

Adult women and soy – Equol production and Effects on Estrogen Levels

A study done on Irish women given a soy beverage investigated the differences in human metabolism of soy. Most of the women after drinking the soy, had a moderate drop in their salivary estrogen levels. In 34% of the group, estradiol levels raised significantly.

The group who had the rise in estrogen levels a) had significantly less children b) had lower isoflavone excretion in urine (c) were more likely to be equol producers (67% compared to 41.7%), and (d) more likely to be to be first-degree relatives of breast cancer patients. It was also found that the patients who had higher body mass index were more likely to be first degree relatives of breast cancer patients. This study indicates that the gut has a large role to play in the effect of soy on hormones and also, especially that if body mass index is high, the effects of estrogen are disruptive. We also know that from other studies that obesity negatively impacts fertility and causes risk for estrogen positive diseases such as breast cancer and fibroids.

Study on Soy and IVF Cycles – Soy improves outcome of IVF

There is one placebo controlled trial using 1500 mg of isoflavones from soy with progesterone injection in the luteal phase, compared to groups given placebo and progesterone injection.  274 cycles were investigated in this study.  Results indicated that implantation rate, clinical pregnancy rate, and ongoing pregnancy/delivered rate were significantly higher in the group given the soy phytoestrogens.  This study included only women under age 40, and who had been given downregulation prior to their cycle.  This indicates that the phytoestrogens from soy may actually prove to be therapeutic in IVF cycles, particularly where there was downregulation given (medication which shuts down the natural menstrual cycle prior to the IVF cycle).  Since this is just one study, and since not all ivf cycle are downregulated this this treatment method would require more research, but it may prove to be promising.

What about Soy and the Fertility of the Asian Population?

Many patients also ask about soy and the Asian population. In Asia since soy consumption is very common, if soy had a negative impact on fertility it might be quite evident.  In Asia, obesity is not nearly as prevalent as it is in North America. Estrogen is produced in fat cells from conversion of androgens. Therefore, if you are considering the average North American (63% of whom are overweight or obese) we can’t really compare the two groups. There have been correlations made between men of higher body mass index and effects of soy on fertility. for more complete analysis of this subject we would also have to consider the gut production of equol.

Summary

According to the research we currently have available and also taking into account traditional dietary intake, the following points should be considered:

1) body mass index is of utmost importance, if you keep your weight healthy, you will increase your fertility and reduce risk for disease. Follow the traditional Asian or Mediterranean plant-based diet and keep your bmi in the healthy range. This will do you far more good than entirely eliminating soy and continuing along the path of the typical North American diet low in fibre and filled with unhealthy fats, sugar and empty carbohydrates. A major study out of Harvard shows that a diet high in plant foods and whole grains, and low in empty carbohydrates, sugars and low quality fats had a 69% lower risk for having ovulatory disorders related to infertility.

2) moderation is the key. avoid using large amounts of soy products and protein, particularly around ovulation and implantation (around 7-10 days after ovulation). Small amounts of soy in the diet should cause no problem according to what we currently know and it may have many other health benefits. In North America we have the tendency to isolate soy proteins and isoflavones, the result of this on reproduction is quite unknown. I would suggest whole foods and moderate consumption.

3) if you are having longstanding fertility concerns, and are a consumer of large amounts of soy, you may consider eliminating it for some time, especially if you are overweight.

4) millions of women have consumed soy products and become pregnant, so it is not something to worry excessively about. Stress can have much more profound effects on your fertility than a small amount of soy.

5) genetic modification has not been considered in these studies. If you do choose to include soy in your diet, use non GMO. Soy can also be sprayed with pesticides which often have estrogenic effects, so choose organic soy.

References

Anthony et al. Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J Nutr. 1996 Jan;126(1):43-50.Burton, J and Wells, M. The effect of phytoestrogens on the female genital tract. J Clin Pathol. 2002 June; 55(6): 401–407.Chavarro et al. Diet and Lifestyle in the Prevention of Ovulatory Disorder Infertility. Obstetrics & Gynecology: November 2007 – Volume 110 – Issue 5. pp 1050-1058

Freni-Titualer et al. Premature thelarche in Puerto Rico. A search for environmental factors. Am J Dis Child. 1986 Dec;140(12):1263-7.

Giampietro et al. Soy protein formulas in children: no hormonal effects in long-term feeding. J Pediatr Endocrinol Metab. 2004 Feb;17(2):191-6.

Gu et al. Metabolic Phenotype of Isoflavones Differ among Female Rats, Pigs, Monkeys, and Women. J. Nutr. 2006 136: 1215-1221

Hall et al. Equol producer status, salivary estradiol profile and urinary excretion of isoflavones in Irish Caucasian women, following ingestion of soymilk. Steroids. 2007 Jan;72(1):64-70.

Jefferson et al. Neonatal Exposure to Genistein Disrupts Ability of Female Mouse Reproductive Tract to Support Preimplantation Embryo Development and Implantation. Biol Reprod. 2009 Mar;80(3):425-31

Nagata et al. Decreased serum estradiol concentration associated with high dietary intake of soy products in premenopausal Japanese women. Nutr Cancer. 1997;29(3):228-33.

Rozman et al. NTP-CERHR Expert Panel Report on the Reproductive and Developmental Toxicity of Soy Formula. Birth Defects Res B Dev Reprod Toxicol. 2006 August; 77(4): 280–397.

Setchell et al. S-Equol, a potent ligand for estrogen receptor {beta}, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin Nutr 2005 81: 1072-1079

Strom et al. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA. 2001 Aug 15;286(7):807-14.

Sukanya et al. Assessment of Fertility and Reproductive Toxicity in Adult Female Mice after Long-Term Exposure to Pueraria mirifica Herb. J. Reprod. Dev. Vol. 53, 995-1005 (2007)

Vittorio Unfer, Maria Luisa Casini, Sandro Gerli, Loredana Costabile, Marcella Mignosa, Gian Carlo Di Renzo Fertility and Sterility – December 2004 Vol. 82, Issue 6, Pages 1509-1513

Creative Commons License
Soy and Fertility Part 1- Phytoestrogens and Fertility in Women by Dr. Fiona McCulloch ND is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.5 Canada License.
Based on a work at drfionamcculloch.wordpress.com.
Permissions beyond the scope of this license may be available at https://drfionamcculloch.wordpress.com.

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