Thyroid and Fertility

Thyroid 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

There 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 residue, 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 Men

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.   This 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.

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 http://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

For 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

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 http://drfionamcculloch.wordpress.com.

H1N1 Treatments: Anti-Inflammatory Properties of Herbal Medicines

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

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

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

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

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

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

References:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Green Tea EGCG: a Natural Treatment for Uterine Fibroids

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

Genetic effects of Green Tea on Fibroid Growth

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

Fibroids and Hormones : Risk Factors

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

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

Fibroids:  The Liver and Diet

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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