Tag: DES 2nd generation

Read all “DES 2nd generation” related posts published by Diethylstilbestrol “Journal of a DES Daughter”; a blog updated weekly about DES and its consequences.

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The “testicular dysgenesis syndrome” (TDS) hypothesis

Endocrine disruption: fact or urban legend? 2013

Abstract

“A current hypothesis has suggested that, in modern industrial societies, human male fertility is declining, whereas the incidence of diseases or birth defects of the male reproductive system is increasing. The hypothesis that human sperm count is declining whereas the incidence of testicular cancer, cryptorchidism (undescended testis) and hypospadias (abnormally placed urethral opening at the underside of the penis) is increasing and that these changes are associated with human exposure to hormonally active chemicals.

…, this hypothetical syndrome has been named the “Testicular dysgenesis syndrome” (TDS). It postulates that, in Western industrialised countries

  • human male fertility, in particular sperm count, has declined and continues to decline,
  • the incidence of human testicular cancer is increasing,
  • the incidence of cryptorchidism
  • and hypospadias in newborn male infants has increased.

An additional hypothesis is that the increased incidence in the TDS may be due to chemical EDC in the human environment.”

References

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Are DES Sons three times more likely to get testicular cancer ?

Male reproductive disorders in humans and prenatal indicators of estrogen exposure A review of published epidemiological studies, 2006.

Abstract

Cryptorchidism is an established risk factor, but the relative risk has been downgraded by newer and better studies. However, only about 10% of men with the disease have or have had undescended testes reflecting a lifetime risk in cryptorchid men of 2–3% corresponding to a risk which is about four times higher than in the general population. The peak incidence in young adults as well as the association with cryptorchidism and carcinoma in situ suggests that causal factors operate early in life.

We found 22 epidemiological studies exploring prenatal estrogen and the risk of testicular cancer. In nine studies hormones given early in pregnancy were evaluated but only few studies provide information on type of hormones. The most informative study is by Strohsnitter et al. who examined DES related testicular cancer in four different cohorts of 1709 exposed and 1904 non-exposed men. Data on drug doses and timing are of high quality. They found an elevated risk of testicular cancer in the exposed group [RR = 3.05 (0.65–21.96)]. In this study the risk for recall and selection bias is limited.

The epidemiological studies support the hypothesis that testicular cancer is associated with a higher prenatal estrogen exposure, except for inconsistent findings in studies of maternal obesity and preeclampsia.

References

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Sperm count and delayed conception

image of sperm-analysis

Male reproductive disorders in humans and prenatal indicators of estrogen exposure: A review of published epidemiological studies, 2006

Abstract

Estrogens may exert an adverse effect via FSH secreted from the fetal pituitary gland. FSH stimulates multiplication of fetal Sertoli cells, which are crucial for the sperm production after puberty. Exogenous estrogens, i.e. xenohormones, may reduce the number of Sertoli cells produced during fetal life, by enhancing the negative feedback of estrogenic control of the fetal pituitary FSH secretion.

Eight studies focussed on prenatal estrogen exposure and semen quality or time to pregnancy. Five of these were based upon diethylstilbestrol (DES) prescribed during pregnancy. DES is a potent estrogen (10 times more potent than 17β-estradiol) used widely from 1940s to 1971.

Gill et al. and Stenchever et al. found a significantly reduced sperm count in sons of mothers who had received DES from their first pregnancy trimester, while Andonian et al. and Leary et al. did not. Gill’s study encompassed 70% of both the placebo and DES exposed male offspring from the original Dieckmann’s randomised controlled DES trial from 1950 to 1952. The study is also published by Bibbo et al. who presented the preliminary results and by Schumacher et al., who included secondary semen samples from participants who initially were not invited to deliver a semen sample. This latter part of the study carries a risk of selection bias, as pointed out by the author, because of differential participation of DES exposed males with genital anomalies. These three studies have been considered as three independent studies, which they are not.

The study of Stenchever et al. only included 17 DES exposed and 12 non-exposed men, recruited through newspapers. The non-exposed group were students or physicians. To account for selection bias only men without knowledge of their fertility were included. Ascertainment of dose and time of administration is uncertain. We believe that this small study adds little additional information, if any.

The study of Leary et al. found no differences in sperm counts between DES exposed and non-exposed males. The study has a high number of participants and the assessment of the prenatal exposure is based upon medical records from the Mayo clinic, which are almost complete. The differences between Gill and Leary can be explained by the differences in the mean total DES dose (the Gill study 12.046 mg; the Leary study 1.429 mg).

The fifth DES study by Andonian et al. found no differences in semen quality measured by using Eliasson scores (a score based on sperm count, motility, motility grade and percent morphological normal sperm). The study only included 22 exposed and 22 non-exposed recruited through news media and exposure information was only obtained for 55% of the participants through copies of prescription, letters from attending obstetricians or copies of medical records.

It is possible that DES in high dosage given early in pregnancy (in first trimester) lower sperm counts, but it seems not to prolong TTP, as showed by Wilcox et al.. TTP is, however only strongly correlated to sperm counts for lower levels of counts.

In a case control study of 79 men with unexplained infertility and 104 men with normal fertility attending a fertility clinic, Ozturk et al. examined birth weight and semen quality by using mothers pregnancy records. No relation to semen quality was found.

One study examined the semen quality among monozygotic twins and dizygotic twins using single born brothers as a reference group. Although the estrogen level is substantial higher in twin pregnancies no differences in sperm count were found among the groups.

We identified only one semen study based upon prenatal xenoendocrine exposure only, namely a study from Taiwan where contamination of cooking oil with polychlorinated biphenyls (PCB’s) and polychlorinated dibenzofurans (PCDF) took place in 1979. However, lack of exposure assessment, uncertainty with respect to timing of exposure and the limited study size jeopardise causal inference.

In conclusion, few studies that are not flawed by methodological problems consistently indicate that DES administrated in high dose in first trimester (total 12 g) is associated with a 20% reduction of sperm count while DES at lower doses is not.

References

  • Male reproductive disorders in humans and prenatal indicators of estrogen exposure. A review of published epidemiological studies, Reproductive toxicology (Elmsford, N.Y.)., NCBI PubMed PMID: 16005180, 2006 Jan.
  • Male factor infertility featured image credit nycivf.
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DES and testicular cancer connection : routine self-exam recommended

The male offspring of women who took diethylstilbestrol during pregnancy have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. Routine prostate cancer screening and testicular self-examination should be encouraged.

Abstract

The sons of women who took DES during pregnancy are three times more likely to have genital structural abnormalities than men without such exposure. The most common abnormalities are epididymal cysts, undescended testes, and small testes. Epididymal cysts have no clinical implications, but undescended testes and small testes are associated with an increased risk of testicular cancer. Men with in utero DES exposure also have sperm and semen abnormalities but do not have a(n) (much) increased risk of infertility or sexual dysfunction.

There is some concern about the effects of DES on the prostate. One study that examined the prostatic utricle of male stillborns who were exposed to DES in utero showed a significantly higher incidence of squamous metaplasia in this müllerian-derived tissue.

A recent study showed a possibly increased incidence of testicular cancer in men with in utero DES exposure. Although this finding was not statistically significant, the investigators concluded that the connection between DES and testicular cancer “remains uncertain,” and suggested that ongoing clinical surveillance would be prudent. Therefore, the sons of women who took DES during pregnancy should be encouraged to practice routine testicular self-examination.

References

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Testicular cancer increased risk

Impact of exposure to endocrine disrupters in utero and in childhood on adult reproduction, 2002

Abstract

An increased risk of cryptorchidism has been observed in DES sons.

References

  • Impact of exposure to endocrine disrupters in utero and in childhood on adult reproduction, Best practice & research, Clinical endocrinology & metabolism, NCBI PubMed, PMID: 12064894, 2002.
  • Featured image maiastrategy.
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Cryptorchidism linked to testicular cancer

Update on cryptorchidism: endocrine, environmental and therapeutic aspects, 2003

Abstract

There is a clear trend for an increased incidence of testicular cancer and the causes are still unknown. An increased risk of cryptorchidism has been observed in the sons of mothers exposed to diethylstilbestrol during pregnancy. It is well established that cryptorchidism is a risk factor for testicular cancer.

The risk of testicular cancer could be linked to the persistance of gonocytes and the absence of normal spermatogenesis. The prevalence of carcinoma in situ in cryptorchid patients is about 2 to 3%. It has a potential evolutive risk toward invasive cancer, justifying for some testicular biopsies in adulthood . However, even if the apparent secular increased incidence of cryptorchidism is true, it is unlikely that it could explain in full the increased incidence of testicular cancer.

RR of testicular cancer in men with history of cryptorchidism varies between 5 and 10 depending on studies. In a Danish study, the RR was 5.2 for the cryptorchid testis. The risk was also increased at 3.6 for the contralateral testis. Two prospective cohort studies have found a RR of 4.7 and 7.4. The risk was higher for bilateral cryptorchidism with a RR up to 33 (2) or for an intra-abdominal testis (6-fold risk as compared to a testis in a lower position).

This increased risk of testicular cancer is a major concern, as it is a cancer of young men. Early orchidopexy is even more important in abdominal testis, since in the absence of surgical correction, the follow-up with screening for cancer would be seriously impaired.

Some studies suggest that the risk of testicular cancer may not be decreased after surgery, but they examined patients who underwent relatively late orchidopexy. Other studies are more optimistic, showing a weak tendency for a decreased odd ratio with a younger age at orchidopexy.

Prospective studies are necessary focusing on patients who underwent surgical treatment before age 1 or 2, compared to others treated later.

References

  • Update on cryptorchidism: endocrine, environmental and therapeutic aspects, Journal of endocrinological investigation, NCBI PubMed, PMID: 12952375, 2003.
  • Featured image Joel Bader.
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Immunological Effects Following In Utero Exposure to DES

Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998

Abstract

Human Data

There are limited human data on long term immunological effects subsequent to in utero exposure to DES.

Two small studies of immune response in women exposed in utero to DES have produced conflicting results. Evidence of hyperreactive immune systems, as measured by heightened lymphocyte responses to PHA and PWM, was noted in eight women exposed in utero to DES, all of whom had reproductive tract abnormalities and evidence of cervical and/or vaginal adenosis. In contrast, there were no effects on NK activity among 12 women exposed in utero to DES prior to the 18th week of gestation, all of whom had anatomical reproductive tract changes consistent with such exposures. The maternal DES dosages to which these women were exposed in utero were not available, but it appears that DES dosages were sufficient to cause reproductive tract abnormalities in both groups. The fact that different measures of immune function were used in each study also makes it difficult to compare results.

Two large DES-exposed cohorts have been studied to determine the potential immunologic consequences of in utero exposure to DES. General immune status and autoimmune conditions among DES-exposed persons (i.e., mothers, daughters, and sons) has been evaluated in the DESAD project (DES Adenosis), a multicenter epidemiological study of cohorts identified through the Mayo Foundation, University of California, Baylor College of Medicine, and Boston University. DES exposure of the DESAD cohort was confirmed between 1972 and 1983 by record review, and various health outcomes have been assessed annually thereafter by questionnaire. The other cohort is part of the DES Action USA Registry and involves periodic surveys of DES-exposed mothers and their offspring. While the majority of this cohort reports DES exposure, only about 30% have records documenting exposure.

In response to the 1985 questionnaire, 520 mothers, 1079 daughters, and 94 sons participating in a DES Action survey provided information about general immune statue, as well as possible autoimmune conditions. DES-exposed sons had significantly higher self-reported frequencies of asthma, arthritis, diabetes, and prostate problems relative to men surveyed in the 1985 National Health Interview Survey. All three DES-exposed groups reported higher rates of respiratory tract conditions; overall rates were two to three times higher than controls. The investigators had anticipated increased frequencies of diabetes in the DES-exposed groups, because DES was often prescribed for high-risk diabetic mothers and has also has a strong familial component. The same survey also reported an increased prevalence of the autoimmune diseases asthma, arthritis, and lupus in DES-exposed respondees.

In a survey of the DESAD cohort, one autoimmune disease, Hashimoto’s thyroiditis, occurred significantly more often in exposed women (5.8 per 1000) than unexposed (1.1 per 1000).408 For any self-reported autoimmune disease, the overall frequency among women exposed to DES in utero was 28.6 per 1000 vs. 16.3 per 1000 in unexposed women. Women with vaginal epithelial changes had almost 50% more autoimmune disease than women without such changes. Because DES-exposed subjects might be more inclined to report medical conditions, the validity of self-reported data is uncertain. Despite confirmation of DES exposure, maternal DES doses were not known for any study participants and typical maternal dosing regimens varied among study centers.

A second questionnaire-based study of the DESAD cohort found no evidence that DES-exposed persons differed from unexposed persons with regard to measures of general immune status, that is, lifetime history of common childhood diseases (i.e., measles, mumps, rubella, chickenpox, and strep throat) were similar for both groups. Prevalence rates of less common diseases (i.e., mononucleosis, oral herpes, pneumonia, appendicitis, and hepatitis) were also similar in both groups. There was a significant increase in the prevalence of rheumatic fever in the DES-exposed individuals compared with unexposed individuals. This finding was based on few cases so the significance is uncertain, particularly because the prevalence of strep throat, which often precedes rheumatic fever, was the same in both groups. In a smaller subset of women (33 DES exposed and 21 unexposed) serum antibody titers to six human viral diseases (measles, varicella-zoster, rubella, cytomegalovirus, influenza A, and herpes simplex) were determined, but no significant differences between DES exposed and unexposed persons were detected. Additional research of these issues is required, particularly functional immune testing in individuals with different in utero exposures to DES, to determine the ultimate validity of the findings and possible associations with maternal DES doses. This will be particularly important as the DES-exposed cohort ages and the expectation of normal age-related declines in immune function occur.

There are limited data on the immunological consequences of adult exposure to exogenous estrogens. Estrogen replacement therapy has been reported to cause decreases in the mixed lymphocyte reaction and increased levels of serum total cortisol. These changes were not correlated and are of unknown clinical significance but suggest that additional research is needed to evaluate the potential immunological consequences of adult exposure to exogenous estrogenic substances.

Anima Data

The immunological effects reported in humans exposed in utero to DES are generally consistent with data from rodents treated neonatally with DES. Neonatally DES-exposed female mice have decreased T-cell populations, decreased response to T-cell independent antigens (i.e., LPS), and impaired NK cell function (not observed in humans) with an increased susceptibility to transplanted and primary carcinogen-induced tumors.

Other studies demonstrate that in utero exposure of male and female mice to DES resulted in enhanced humoral immune function in males and either no effect or a slight suppression in females. In contrast, mice exposed to DES in utero show defects in T-cell, B-cell, and NK cell function, but some of these impairments become detectable only as the animals age. Spleen cell responses to mitogen stimulation showed diminished responses to PHA and LPS, as well as reductions in a mixed lymphocyte culture and graft vs. host response in mice exposed in utero to DES. These reductions generally followed a pattern of initial hyperstimulation of spleen cell response in 1-month-old mice followed by a gradual decline in immune responsiveness at about 2 to 9 months of age. Because the dose of DES used in this study (1 µg/d) is about 10 times the amount needed to produce the same genital tract alterations as 20 µg of 17β-estradiol, the authors speculate whether lower DES doses would still produce immunosuppression. Studies on the immune effects of neonatal estrogen exposure in mice demonstrate that DES is more potent than 17β-estradiol in producing such effects, but there are also DES dose levels at which no effects occur. Following five daily doses of DES (0.01, 0.1, 1, or 5 µg) only the 5 µg dose resulted in a persistent reduction of in vitro mitogen response to Con A or LPS.

Overall, a substantial amount of animal data demonstrate numerous immunological effects following in utero exposure to DES, including abnormal B-cell and T-cell responses and diminished NK activity. Most of these effects persist for the lifetime of the animal and some may even become more severe with age. The relationship between these effects and neoplasia in rodents is unknown, as is the relevance of these findings to possible health consequences in humans.

While in utero exposure to estradiol has also been reported to result in some immunological impairment, it is not as severe as that produced by DES. The data on DES and estradiol demonstrate that dose-response relationships for possible immunological effects from in utero or neonatal exposures may be important. The fact that estradiol might have immunological consequences less than DES highlights the need to understand the comparative potency aspects of this phenomenon. Finally, the observation that some adverse immunological effects become more severe with age suggests that continuing surveillance of men and women exposed in utero to DES is warranted.

References

  • Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
  • Featured image wikipedia.
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Alterations of sexual behavior – Human DES data

Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998

Abstract

Several studies have addressed the potential effects of prenatal DES exposure on sexual behavior in adult human males and females. Due to the inherent complexity of human sexuality, the results of these studies are difficult to interpret; however, they do not appear to corroborate the findings observed in rats following in utero exposure to TCDD. Unfortunately, many of the studies investigating potential DES effects on human sexual behavior do not describe maternal DES dosages. While some subtle effects on sexual behavior of male and female offspring exposed to DES in utero have been observed, limited dose-response data suggest that these are likely associated with high total maternal DES doses and durations of exposure.

Psychosexual behavior was investigated in 62 adult males following in utero exposure to DES (n = 17), DES + natural progesterone (n = 22), natural progesterone only (n = 10), or synthetic progesterone (n = 13). DES dosages ranged from 50 to 14,000 mg with a mean of 3979 mg; duration of administration was from 0.5 to 29 weeks with a mean of 13.5 weeks. A large number of psychological tests were administered to subjects exposed and unexposed; sexual fantasies and behavior were also assessed. Comparison with matched unexposed men revealed a few subtle differences of unknown importance. Relative to the unexposed men, the DES-exposed group showed higher scores on the feminine scale of a sex role inventory, but also showed a greater interest in sports. With respect to adult sexual orientation, there were no differences between DES-exposed men and unexposed in either homosexual fantasies or behavior.

The relation between prenatal hormone exposure and sexual behavior in both men and women was evaluated in an extensive review of 19 relevant studies. Total mean DES doses in the few studies that reported such data averaged approximately 2500 mg administered for an average (mean) of 14 weeks during pregnancy. Findings from the 19 studies reviewed were classified into eight behavioral categories: play and recreation interests, peer relations, aggression/assertion, interest in marriage and maternalism, gender identity/role and personality, sexual maturation and behavior, cognitive abilities and academic achievement, and athletic ability/physical coordination. Compared with unexposed males, DES-exposed males were significantly less likely to categorize themselves as “likes to fight” (aggression/assertion) and somewhat less likely to report “usually wins fights”, responses that were considered “feminized”. Overall, there was a non significant tendency toward feminization on the aggregate aggression score. In another study of males exposed in utero to DES, in the category of vocational interest, DES-exposed males, relative to unexposed males, reported an increased interest in social services and in writing (although the latter was non significant). Although these traits were characterized as “feminized”, DES-exposed males were (non significantly) more likely relative to unexposed males, to have an increased number of male friends and elevated interest in sports and in TV shows with aggressive themes (“masculinized” characteristics). With respect to sexual orientation there were no differences between DES exposed and unexposed men. For women exposed in utero to DES, one initial study suggested a tendency toward bisexual or homosexual ratings on a number of measurement scales. However, in a larger follow-up study, DES-exposed women were not different from unexposed women on the same measurement tests employed in the initial study. In their discussion of the potential effects of prenatal hormone exposure on sexual behavior, Reinisch et al. noted that the behavioral repertoires of males and females overlap to a large extent; thus, no particular behavior is exclusively male or female. In addition, individuals can exhibit high frequencies of both masculine and feminine behavior (androgynous), low levels of both kinds of behavior (undifferentiated), or high levels of one type of behavior and low levels of the other (masculine or feminine).

Another extensive review of studies addressing gender-related behavior in women exposed in utero to DES concluded that there was no clear-cut difference between unexposed and DES-exposed women. In all seven studies reviewed there were more behavior trait similarities between DES-exposed and unexposed women than differences. This finding was considered striking by the investigators considering that the bias of their studies was that there would be differences between groups because the experimental protocols employed were specifically designed to detect differences and not similarities. Consideration of pre- and postnatal influences, including social, economic, and environmental factors suggests that unexplained individual variation appears more important than in utero exposure to DES.

A recent, extensive study investigated the effects of prenatal exposure to DES and sexual orientation in three groups of DES-exposed women (DES1, DES2, and DES3).The DES1 and DES2 groups had a high prevalence of DES-related vaginal or cervical abnormalities (90% and 97%, respectively).
In 13 of the 30 DES1 women with sufficient exposure information, total maternal DES dosage ranged from 210 to 10,475 mg with a median of 1800 mg. In 5 of 30 DES2 women with sufficient data, total maternal DES dosage ranged from 252 to 19,800 with a median of 3600 mg. While the precise maternal dosages in the DES3 group were unknown, vaginal epithelial changes associated with DES were present in 50% of the woman, and the available records suggested that total maternal DES dosages were lower than the recommended regimens of the time.
This study demonstrated that more DES-exposed than unexposed women were rated as bisexual or homosexual. Although the DES-exposed women were significantly more likely than the unexposed women to report bisexuality and homosexuality, the actual differences between the two groups were modest; a predominantly homosexual orientation was reported as lifelong by only 4 of 96 DES-exposed women, while only six women reported current homosexual orientation. Most of the differences between DES-exposed and unexposed women were limited to degrees of bisexuality, and for many, bisexuality was confined to imagery and not behaviorally expressed. Of interest is the fact that most of the differences were observed when the DES1 and DES2 groups were compared with unexposed women; only one difference was noted when the DES3 group was compared with unexposed women. While there were significant overall differences between DES-exposed and unexposed women, the relative absence of effects for the DES3 group suggests a dose-related effect on sexual orientation. It is also worth noting that, even though this was a study that focused predominantly on women, potential effects in men in the same cohort were also evaluated with the same set of questions. In men, there was no apparent relation between in utero DES exposure and alterations in sexual behavior.

References

  • Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
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Effects of DES on Male Fertility

Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998

Abstract

The possible relationship between in utero exposure to DES and male fertility was investigated through physical examination, seminal fluid analysis, and an in vitro sperm penetration assay (SPA) in zone-free hamster eggs in 17 men exposed in utero to DES, 12 non-DES-exposed men, and 11 fertile control men. Fourteen of 17 DES-exposed and 2 of 12 non-DES-exposed. men had SPA results compatible with infertility. All 11 fertile controls had SPA values in the fertile range. This study showed a significant difference between the mean sperm count in the DES-exposed group (66.4 million/ml) and the nonexposed group (101.7 million/ml). There were no differences between the exposed and nonexposed groups in either sperm morphology or motility. The likelihood of selection bias may be large because the men who participated in the study were aware that it was designed to evaluate effects of in utero DES exposure on male infertility. The high frequency of genital abnormalities (52%) such as epididymal cysts or abnormalities of the prostate, testicle, or penile meatus in this DES-exposed population compared with genital abnormalities (32 to 37%) reported in other studies suggests selection bias in this study.

In a subsequent and larger study using the same in vitro sperm penetration assay, there were no differences in sperm penetration between DES-exposed men (n = 51) and nonexposed men (n = 29) as well as no differences in sperm concentration, motility, or seminal leukocytes in DES-exposed and nonexposed men. Furthermore, although the frequency of genital abnormalities was related to in utero DES exposure (37% in DES-exposed men compared with 4% in nonexposed men), it was not related to reduced egg penetration. In contrast to the original study, 292 the principal aims of the follow-up study were not revealed to study participants.

In the largest fertility study of adult men exposed in utero to DES, there were three times more self-reported genital malformations in men with in utero exposure to DES (n = 253) than placebo-exposed controls (n = 241). However, despite the increased incidence of genital malformations, there was no significant difference in fertility between men exposed in utero to DES and unexposed men by any measure, including whether they had impregnated a woman, age at the birth of their first child, average number of children, medical diagnosis of a fertility problem, or length of time to conception. Furthermore, there were no differences between DES-exposed men and unexposed with respect to sexual function as measured by frequency of intercourse or reported episodes of decreased libido. The cohort of men in this study were exposed in utero during a randomized clinical trial of DES use during pregnancy at the University of Chicago in the early 1950s.

An earlier study of the same clinical trial cohort showed decreased sperm counts and abnormal sperm morphology in DES-exposed men (91 million/ml in 134 men) compared with nonexposed controls (115 million/ml in 87 men). Thus, it appears that high in utero total maternal doses of DES (11,500 to 12,600 mg) can lower sperm counts without affecting fertility. The failure of high maternal doses of DES administered over approximately 28 weeks to adversely affect the fertility of male offspring exposed in utero challenges the notion that in utero exposure to environmental estrogens (net exposure or body burdens), which are significantly less potent than DES, might impair male fertility.

References

  • Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
  • Featured image mytimesnow.
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Decreased Sperm Quality

Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998

Abstract

It is biologically plausible that in utero exposure to estrogen can affect sperm counts.

In studies with mice, in utero exposure to DES is associated with decreased sperm production and abnormal sperm morphology in adult offspring.

There are also numerous studies of adult male humans prenatally exposed to DES, however, with respect to decreased sperm counts, the results of these studies are mixed.

  • Decreased sperm count (115 million/ml in 87 controls vs. 91 million/ml in 134 DES exposed) and abnormal Eliasson scores in 18% of 134 DES-exposed men compared with 8% in 87 placebo-exposed controls have been reported. This study was conducted on a cohort of men exposed in utero to DES according to the dosing protocol in use at the University of Chicago where mean total maternal DES dosages were, on average, 11,603 mg.
  • Another small study reported lower average sperm counts in 20 DES-exposed men and pathologic Eliasson scores in 18 DES-exposed men, but no unexposed comparison group was used and maternal DES dosages were unknown.
  • In contrast, in a cohort of men from the Mayo Clinic exposed in utero to DES in which total mean maternal DES doses were approximately 1.4 g there were no differences between 110 DES-exposed men and unexposed men in sperm count, motility, or abnormal Eliasson scores.

While clinical data suggest that in utero exposure to DES at some maternal dose level can result in decreased sperm counts, the data also suggest the existence of an apparent maternal dose threshold for such effects.
Even at the dose levels of DES that produced adverse effects on sperm following in utero exposure, the magnitude of such effects is not large with average sperm counts reduced from 115 million/ml in men not exposed to DES to 91 million /ml in DES exposed men. While this shows a DES effect, it also demonstrates that an estrogen as potent as DES does not produce a decrease in mean sperm counts approaching the levels at which fertility might be affected. Despite the small sample size the failure of the maternal DES dosages used at the Mayo Clinic to cause any effects on sperm count or morphology underscores this point. As noted later in this review, fertility in the high dose cohort of men (University of Chicago cohort) was not adversely affected, even after in utero exposure to DES at maternal doses sufficient to produce adverse effects on sperm counts and morphology.

This raises the question of whether in utero exposure to environmental estrogens, which are significantly less potent than DES, could cause a decline in sperm counts.

References

  • Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
  • Featured image mytimesnow.
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