|Effects of Antenatal Exposure to Phytoestrogens on Human Male Reproductive and Urogenital Development|
|Wednesday, 16 November 2005 17:31|
Recently in the news we have been hearing about declines in male fertility and increases in reproductive birth defects in males. We have discovered substitutes and replacements for products that have been part of our culture for hundreds of years, and we readily embrace new developments and technologies that make our lives easier. Now more than ever consumers are being exposed to many factors that may disrupt our delicate hormonal balances.
In the review entitled "A Sea of Estrogens," author John Biggs warns us about the introduction of a whole range of endocrine disrupters into our food and the environment.1 Endocrine disruptors, including pesticides, industrial chemicals, pharmaceuticals and even plant hormones are having fundamental effects on immune function and the reproductive system. These compounds mimic hormones produced and regulated by the bodyâ€™s delicate hypothalamal-hypophyseal-gonadal axis. Some of the most common industrial hormones are those that mimic the effects of estrogens, including dichlorodiphenyl-trichloroethane (DDT), bisphenol A, diethylstilbestrol (DES), genistein and enterodiol. When ingested, these estrogen-mimicking compounds (EMC) alter the normal levels of estrogen in both females and males by binding to and activating estrogen receptors.
CONSEQUENCES FOR MEN
Since elevated estrogen levels are not normal for men, scientific investigators have been raising questions about the effects of these environmental estrogens on the male endocrine system. Many scientists have noted a host of consequences that accompany elevated estrogen levels. In men who ingest these EMCs, common symptoms include low semen concentrations, poor semen quality, lack of sperm motility, and eventually a reduced sexual appetite,2 problems that can usually be reversed when exposure to estrogens is terminated. For the developing male fetus, however, these environmental estrogens can have severe and life-long detrimental consequences to reproductive and urogenital development.
Hormones in the body work in exquisitely fine balance, with complicated feedback loops, to provide a mechanism of control for all of the bodyâ€™s autocrine and paracrine functions. Early anatomists described the hypothalamus and pituitary glands as the "masters" of bodily functions,3 viewing the intricate synergy of these organs as the driving force of the entire body. Since the times of classical anatomy in the late 1800s and in the early 1900s, scientists have confirmed the importance of these organs through ablation procedures. It was easy for them to remove the pituitary gland, for example, and observe how the animal would cope without it. They were able to see how this little organ influenced almost every component of life, and how its removal was detrimental to the longevity of the animal. Later, scientists tested the effects of these "master organs" by observing the effects of artificial supplementation of certain hormones released by, produced at, or controlled by the various hypothalamal-hypophyseal axes.
Early on, they were able to define the interplay between the parts of these axes at which the action of change would take place. They determined the role of the gonad, for example, in the release of sex hormones such as testosterone in males and estrogen in females. This led to the recognition of the hypothalamal-hypophyseal-gonadal axis, where sex hormone levels in the blood feedback negatively to halt synthesis and secretion of the hormones until blood levels become stabilized. We now know that this kind of mechanism allows normal function in every organ system encapsulated by our body.
Early in life, a bipotential gonad develops, and within the medullary (central) region of that gonad lies the key to gender determination. At the inception of the embryo, as sperm meets egg, sex chromosomes from the mother (X) and from the father (either X or Y) are combined to provide the potential of gender--but not the key to sexual differentiation. Sexual differences are determined by a gene on the Y chromosome called the SRY gene. The SRY gene, acting like a transcription factor, mediates chromatin crossing over, which is vital in sexual differentiation. As a result of the presence of that specific gene, the female program of development, which is the modus operandi of biology, is suppressed and the growth of a testis is allowed to occur. In the absence of the SRY gene, a gonad develops into an ovary even if the genetic makeup of the embryo is XY.4
As a function of the SRY gene, cells of the normal gonad differentiate to produce the hormones and factors that allow for masculinization or feminization. In males, the presence of SRY together with testis-determining factor causes two main cell types to develop in the gonad, namely the sertoli and leydig cells. Leydig cells work in conjunction with the hypothalamal-hypophyseal axis and begin to produce the appropriate hormones for reproductive and urogenital formation. In the testis, testosterone will begin to be the predominantly produced hormone. The presence of testosterone has a twofold effect on the developing fetus: first, testosterone helps to further the development of the wolffian ducts (the embryonic antecedents of the vas deferens and ureter); and secondly, testosterone is converted into androgens (dihydro-testosterone) via 5-alpha-reductase. The presence of mullerian inhibiting substance (MIS) along with androgens causes the degeneration of the mullerian ducts (the embryonic antecedents of teh upper vagina, cervix, uterus and oviducts) and spurs the development of the wolffian ducts, the penile shaft, the glans, and the descent of the testicles from the abdominal cavity.
In females, however, the absence of the SRY gene causes the bipotential gonad to continue developing into an ovary. The ovary does produce testosterone, but most of that testosterone is quickly aromatized (converted by enzymatic action) into estrogens, none of which can be converted back into androgens. The lack of MIS, the lack of significant androgen levels, and the presence of estrogens allow the formation of the ovaries, fallopian tubes, uterus, cervix, upper and lower vagina and clitoris. Together these organs form the main components for reproduction later in life and for the elimination of wastes in the form of urine upon birth.5
Significant deviations in the levels of the appropriate sex hormones can cause severe consequences in reproductive and urogenital development, especially at the time of fetal growth and the pre-pubertal period. In humans, the process of masculinization or feminization is not a black and white proposition but a process that takes place on a continuum over the years. The Prader scale measures a personâ€™s development on that continuum by looking at the development and at the location of the urethral opening, clitoral hypertrophy, and the location of the testicles or labia compared to the glans or clitoris, respectively.6 The development of the male body plan, and hence the process of de-feminization, depends on the presence of androgens along with the absence of estrogens, while the development of the female body plan, and hence the process of de-masculinization, depends on the presence of estrogens along with the lack of androgens. Humans differ from other animals in this regard, as animals do not develop so gradually along this continuum and the importance of sexual self-identification for animals is much less significant than it is for humans.
Research performed on human males with androgen insensitivity syndrome compared to the classical sexual development models which were created from research on rats, indicates that the rat model does not account for the sensitivity of the hypothalamal-hypophyseal-gonadal axis with fluctuations in hormonal levels, namely androgens and estrogens.7
PROBLEMS WITH DES
Over the years, several researchers have attempted to investigate the extent to which estrogen-mimicking chemicals affect the development of male children in utero. The first of such papers, published in 1976, detailed the negative effects of the EMC diethylstilbestrol (DES).8 Researchers looked at how treatment of pregnant women with DES affected their male offspring. They found that male offspring of women who had received DES as treatment prior to fertilization or were receiving DES post-implantation for prevention of miscarriage had much higher rates of severe reproductive and urogenital abnormalities. This important double blind study looked at 119 control males and 134 DES-exposed males ages 21-23 via physical examination, urine cytology (pre and post ejaculation), prostate fluid cytology and biopsies (for cyst diagnosis). Researchers compared urogenital pathologies, blood hormone levels and complete semen analysis and found results consistent with their original hypothesis of increased abnormalities in the DES-exposed males. Findings included increased unilateral and bilateral epididymal cysts, increased unilateral and bilateral testicular hypertrophy, decreases in flaccid penis length (hypoplastic penis length less than 4 cm), slight decreases in blood follicle stimulating hormone (FSH) and testosterone levels, and severely decreased sperm count and sperm motility. The authors concluded, "Administration of DES during pregnancy appears to be followed by latent effects on the male genital tract. . . impair[ing] fertility in a certain number of patients."
A paper published in 1983 detailed the extent to which DES caused problems for children and adults whose mothers were treated with DES during preganacy.9 Researchers found that male children who were exposed to DES during gestation were 80 percent more likely to be born with a genital deformation. Even males who were born with normal-appearing genitalia had decreased testicular volume when fully matured.
ESTROGENS IN SOY
A number of studies have focused on the effects of the phytoestrogen genistein, found in soy foods, on males. In 1995, researchers demonstrated the effects of exposure in utero to genistein on the rat endocrine system.10 They injected groups of rats with various EMCs during gestation days 16-20 out of the total 23 days. Groups were injected with EMCs in the following manner: group 1 received 25000 micrograms of genistein; group 2 received 5000 micrograms of genistein; group 3 received 5 micrograms of DES; and group 4 received 50 micrograms of estradiol benzoate. A fifth group served as a control and received plain corn oil. The team looked at a long list of urogenital and endocrinological effects, including anogenital distance (AGD) or the length of tissue separating the anus and genitalia, volume of the sexually dimorphic nucleus in the preoptic area of the hypothalamus (SDN-POA) and the age of onset of puberty. Results of this study provided evidence that exposure to genistein in utero can influence markers known to be sensitive to estrogens. The findings also showed that the time of exposure during gestation, and the amount of the phytoestrogen ingested, are important factors in determining the extent of the pathology exhibited at birth and during the pubertal years. Although genistein did not adversely affect pregnancy, survival or delivery, exposure in early gestation caused a shortening in AGD and overall feminization of external male genitalia, even at low doses.
Another study demonstrated that genistein in soy products causes a decrease in SDN-POA volume in the hypothalamus, resulting in smaller differences in dimorphic behaviors (behaviors that differ according to sex) in the rats.11 Low-dose genistein also proved to delay puberty as the necessary hypothalamal-hypophyseal-gonadal axis surges were decreased, resulting in mixed signals for development of masculinization in young rats.
From these findings the researchers were able to conclude that genistein, at high and low levels, influences the hypothalamal-hypophyseal-gonadal axis-dependent aspects of development by modifying both "morphologic and neuroendocrine endpoints." In other words, genistein caused changes in thinking and behavior patterns, as well as in reproductive development.
Further research by the same team demonstrated how serious these morphological changes can be to male subjects.12 This research showed conclusively that low levels of genistein decreased sexual dimorphism in rats, causing both males and females to act in the same manner during courtship, sexual arousal and during intercourse. In effect, male rats were expressing female sexual behaviors including lordosis, the typical female mating stance. In essence, exposure to genistein in the womb rendered the males non-receptive to typical female behaviors.
This research provides proof that phytoestrogens are strong enough to affect the endocrine system of the developing fetus and that they are not regulated or broken down by the motherâ€™s hypothalamic responses.
Many papers written on the topic of organic estrogens and endocrine disrupters speak about a general feminization of male genitalia as the main visible pathology. This feminization includes undescent of the testes from the abdominal cavity as is seen in cryptorchidism, reduced number and quality of semen, and a dramatic decrease in penile size as is seen in hypospadias, a birth defect of the penis. These pathologies are becoming more and more frequent in number during the various stages of development, from fetal growth to post-puberty.13
During normal fetal development, the testicles descend as a result of a reduction in gubernacular turgidity and intra-abdominal pressure which pushes the testis into the scrotum.14 When estrogen levels are elevated during the time of testicular descent, the androgens that reduce gubernacular turgidity are not produced and secreted at the right levels for descent to take place. This means that the child is born and grows with either one or both of the testicles undescended. After birth the undescended testicle is either surgically lowered from the abdominal cavity into the scrotum or it remains in the abdomen where it stops functioning as a reproductive and endocrine gland. If both testicles remain undescended and they are not surgically lowered within the first few months of life, then the male is rendered impotent and will require removal of the testicles because of an increased cancer risk.
Sperm counts have seen significant decreases worldwide, falling 50 percent from levels measured in the 1930s.15,16,17 Statistics such as these are a nightmare to todayâ€™s man. In a comprehensive review of 61 studies on the topic of worldwide sperm count reductions published in 1996, researchers found an association with agriculture and low sperm count.18 Areas with the lowest average sperm counts include the state of Iowa, and the countries of Thailand and Nigeria. In New York sperm counts decreased from 120.6 x 106 sperm per ml of ejaculate in 1938 to 79.0 x 106 sperm per ml of ejaculate in 1976.
A Japanese researcher, M. Fukutake, makes a connection between consumption of soy products and a decrease in sperm counts.19 In his 1996 paper, he noted the fact that affluent nations with increasing reductions in sperm counts have been importing more and more soy and soy-products, which historically have been consumed only in the Orient.
More recent findings show that the numbers of functional sperm are even lower than those cited above and researchers are finding a large number of immobile, double-headed, double-tailed, and broken sperm that have no real function because of their inability to fertilize an egg, even in close proximity.20 The scientific explanation for this reduction in sperm quality has to do with an overall reduction in androgens that occurs when there are significant levels of estrogen in the body. The reduction in androgens causes sertoli cell function to be disturbed, leading to impaired germ cell differentiation.
The final, and perhaps most troubling trend is that of a significant decrease in penile size. Studies show an alarming number of men who, post puberty, never develop an increase in the flaccid size of their penis.21 Patients with hypospadias have a total flaccid penile length of less than 4 centimeters. This has serious implications in reproduction and in self-esteem for males. In reproduction, when the shaft of the penis is longer, sperm have less of a distance to travel post ejaculation. This is a problem that comes to fruition only after puberty; thus, ingestion of phytoestrogens even after birth, during the pre-pubertal years, can cause reduced development of the penile shaft.
In the post-pubertal years, exposure to high levels of genistein, as is seen in strict vegetarians who replace animal proteins with soy-based foods, has general feminizing effects on their male anatomy, including reduced sperm production, a decrease in viable sperm, breast development and a reduction in sex drive due to an overall decrease in androgens.22
SOY INFANT FORMULA
In a July 2002 article published in Vegetarian Times, author Maria Rabat strongly defended the use of soy infant formla, claiming that it has no negative impact on the child due to its ease of decomposition in the body and that negative feedback in the motherâ€™s endocrine system will not allow increases of plasma estrogen concentrations, thus protecting the child in utero from negative impact.23 This defense follows an article published a year earlier in the Journal of the American Medical Association.24 Lead researcher Brian Strom concluded that the use of soy-based formulas during infancy is safe and has no negative endocrinological impact on the hypothalamal-hypophyseal-gonadal axis of the male, citing a lack of significant phytoestrogen concentrations in the highly processed infant formulas.
However, these two sources of information have reason for severe bias in favor of increased consumption of soy products. Vegetarian Times magazine is significantly supported by the multi-million dollar soy industry in the US. And Brian Stromâ€™s research was funded directly by The Society for the Consumption of Soy Products. A major flaw in Stromâ€™s research was the fact that he relied on data from rat studies, citing the similarity of the rat and human endocrine system. As it has been noted previously, the developing rat is less responsive to long-term changes in physiology due to moderate variations in hormone levels.
Both Rabat and Strom ignore a damning paper published in early 1997.25 Researchers found that circulating concentrations of isoflavones in infants fed soy-based formula were 13,000-22,000 times higher than plasma estradiol concentrations in milk formula-fed infants. The authors noted that these levels of estrogens would be sufficient to exert biological effects, whereas the contribution of isoflavones from breast-milk and cow-milk were found to be negligible.
We now have an impressive body of work on the issue of phytoestrogens and male reproduction. These studies have spanned three generations and have taken into account both the human and the rat model of endocrine function. In summary, males exposed to genistein have a shorter ano-genital distance and testis size, and delayed preputial separation. Perinatal exposure to genistein also contributes to long-term dysfunction in reproductive behavior. Adult male rats exposed to genistein are less likely to mount, intromit and ejaculate during mating tests. Male rats exposed to genistein also have lower testosterone concentrations in adulthood. Perinatal genistein exposure resulted in transient and lasting alterations in masculinization of the reproductive system.
The best way to avoid complications in the reproductive health of male offspring is to avoid foods and chemicals that act as estrogen mimics. This starts with mothers, prenatally limiting their exposure to estrogen-containing products in their diets, from birth control pills and from other sources such as pesticides. During pregnancy, the motherâ€™s diet should be quite restrictive of phytoestrogens and therefore of soy-based products. Once the child is born, the best form of nutrition which can be given to the child is breast milk. While breast feeding, mothers should continue to avoid birth control pills and soy foods. Most importantly, soy-based infant formula should be avoided. These formulas, despite common claims to safety, are dangerous to the reproductive health of the male infant.
The endocrinological axes that dictate so many of the bodyâ€™s processes are in fact very delicate. Despite the many variations that our bodies can handle, significant and prolonged variations of gonadal hormones will cause an effect at target tissues. The balance between androgens and estrogens is of fundamental importance in determining normal or abnormal development of the male reproductive tract.26
In so many cases children who are genetically healthy are subjected to avoidable morphologies due to our unwillingness or indifference to limiting estrogen-containing products in our everyday lives. One Canadian professor, when he was asked why he dedicated his time and interest to this topic of male genital feminization, put it this way: "We should be thinking at this point of our children and grandchildren. What are we going to tell them if they are sterile or have an altered sexual development?"27
We owe it to our children to offer them the reproductive health that will allow them to have a normal sex life and to father children, simply by limiting amounts of organic estrogens in their diets. Above all else, we owe it to ourselves to be the best possible parents in truly caring for the future of our children by ensuring that our children, and therefore we, truly have a future.
Soy Protest and the FDA
During the period of public comment in April on Solaeâ€™s petition to the FDA for a health claim for soy protein and cancer, the Foundation requested its members as well as the interested public to submit their comments on the petition. We believe that well over a hundred such comments were sent to the FDA. We thank all who took the time to let the FDA know of their concerns regarding the consumption of soy protein products. The FDA is posting these comments at http://www.fda.gov/ohrms/dockets/04q0151/04q0151.htm.)
Because overwhelming evidence points to the fact that the consumption of soy protein-based food products can cause certain types of cancer, the Foundation decided to submit a petition directly to the FDA requesting that all foods containing soy protein and its derivatives be labeled with a health warning. We are in the process of developing such a petition. According to our counsel, this may be the first of its kind and this may be the first non-food producer to submit a petition to the FDA.
|Last Updated on Tuesday, 09 June 2009 17:04|