|
<Back
| Home | Basics |
Departments | Get
Involved | Site Map | What's
New
 The
Effects of Antenatal Exposure to Phytoestrogens on Human Male Reproductive
and Urogenital Development
by Bernard Poggi
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 body’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 body’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.
SEXUAL DIFFERENTIATION
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 person’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 mother’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
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 today’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.
SERIOUS IMPLICATIONS
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 mother’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 Strom’s research was funded directly
by The Society for the Consumption of Soy Products. A major flaw in
Strom’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.
SUMMING UP
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 mother’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 body’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.
References
1. Biggs, John H. 1995. A Sea of Estrogens. Alive: Canadian Journal
of Health & Nutrition, Feb95 Issue 149, 28-30.
2. DeRosa C and others. Environmental Exposures that Affect the Endocrine
System: Public Health Implications. Journal of Toxicology and Environmental
Health, Part B, 1998;1:3-26.
3. Crocker C, in a lecture about the hypothalamus and pituitary, Biology
612, San Francisco State University, May 7, 2003.
4. Moffat C, in a lecture about phenotypic sexual differentiation
and determination, San Francisco State University, February 6, 2003.
5. Norris, DO. Vertebrate Endocrinology, third ed, p 368.
6. Prader A. The Prader Scale. Helv Paediatr Acta, 1954;9;231.
7. Moffat C, in a lecture on the sensitivity and accuracy of the rat
model in humans, namely that of androgens and estrogens, San Francisco
State University, February 13, 2003
8. Gill WM and others. Structural and Functional Abnormalities in
Sex Organs of Male Offspring of Mothers Treated with Diethystilbestrol
(DES). The Journal of Reproductive Medicine 1976;16(4):147-153.9.
9. Ross RK. Effect of in-utero exposure to diethylstilbesterol on
age at onset of puberty and on post-pubertal hormone levels in boys"
Canadian Medical Association Journal, 1983;128(10):1197-98.
10. Levy JR and others. The Effect of Prenatal Exposure to the Phytoestrogen
Genistein on Sexual Differentiation in Rats. The Society for Experimental
Biology and Medicine 1995;208:60-66.
11. Flynn, KM and others. Effects of Genistein Exposure on Sexually
Dimorphic Behaviors in Rats, Toxicological Sciences, 2000;55:311-319.
12. Ferguson SA and others. Developmental neurotoxicity of endocrine
disrupters: focus on estrogens. Neurotoxicology, 2000 Dec;21(6):947-56.
13. Sharpe RM and others. Infant feeding with soy formula milk: effects
on the testis and on blood testosterone levels in marmoset monkeys during
the period of neonatal testicular activity. Hum Reprod 2002 Jul;17(7):1692-703;
Strauss L and others. Genistein exerts estrogen-like effects in male
mouse reproductive tract. Mol Cell Endocrinol 1998 Sep 25;144(1-2):83-93
14. Husmann DA and Levy JB. Current Concepts in Pathophysiology of
testicular undescent. Urology, 1995 August;46(2):267-276.
15. Auger J and others. Decline in semen quality among fertile men
in Paris during the past 20 years. N Engl J Med, 1995;332:281-285.
16. Carlson E and others. Evidence for decreasing quality of semen
during the past 50 years. Br Med J, 1992;305:609-613.
17. Sharpe RM and Skakkebaek NE. Are Oestrogens Involved in Falling
Sperm Counts and Disorders of the Male Reproductive Tract? The Lancet,
1993 May 29;341(8857):1392-1395.
18. Fisch H and Goluboff ET. Geographic variations in sperm counts:
a potential cause of bias in studies of semen quality. Fertility
and Sterility, 1996 May;65(5): 1044-1046
19. Fukutake M and others. Quantification of Genistein in Soybeans
and Soybean Products. Food and Chemical Toxicology, 1996;34:457-461.
20. O’Donnell L and others. Phyto-estrogens and Infant Formulas.
Endocr Rev 2001 Jun;22(3):289-318; Sharpe RM and Skakkebaek NE. Are
Oestrogens Involved in Falling Sperm Counts and Disorders of the Male
Reproductive Tract? The Lancet, 1993 May 29;341(8857):1392-1395.
21. Irvine CH and others. Phytoestrogens in soy-based infant foods:
concentrations, daily intake, and possible biological effects. Proc
Soc Exp Biol Med 1998 Mar 217:3 247-53.
22. Damgaard IN and others 2002. Impact of Exposure to Endocrine Disrupters
in utero and in childhood on Adult Reproduction. Best Practice &
Research Clinical Endocrinology and Metabolism 2002:16(2):289-309.
23. Rabat, Maria. Plant Estrogens. Vegetarian Times July
2002, Issue 299, 53-56.
24. Strom B and others. Exposure to Soy-Based Formulas in infacy and
Endocrinological and Reproductive Outcomes in Young Adulthood. Journal
of the American Medical Association, 2001 Nov 12;286(19):2402-3.
25. Setchell and others. Exposure of Infants to Phytoestrogens from
Soy-based infant formula. The Lancet 1997;3530(9070):23-27.
26. Rivas A and others. Evidence for Importance of the Androgen-Estrogen
Balance. Endocrinology 2002;143(12):4797-4808.
27. Biggs, John H. 1995. A Sea of Estrogens. Alive: Canadian Journal
of Health & Nutrition, 1995 Feb, Issue 149, 28-30.
Sidebar
Soy Protest and the FDA
During the period of public comment in April on Solae’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.
About the author
 At
the age of five, Bernard Poggi underwent three years of intensive
chemotherapy for leukemia and suffered many years of side effects. At the age
of 16 he started a program for gang youth in northern California for which he
received several awards on both the state and national levels. He graduated from
San Francisco State University with a major in biology (physiology) and a minor
in Business Administration in 2003. He currently works doing office management
and volunteers with several community faith-based and cultural organizations which
help new immigrants and those in need. His ethos: to serve humanity in order to
reduce human strife--physically, socially and spiritually.
<Back
| Home | Tour
| Calendar | Contact
Us | Funding | Join
Now
|