Abnormal semen analyses in the DES-exposed males

oligospermia
Oligozoospermia, refers to semen with a low concentration of sperm and is a common finding in male infertility.

Abstract

DES Effect on Males, Pediatrics, January 1978, VOLUME 61 / ISSUE 1 61/1/154.3.

We have found defects in the urogenital tract of males exposed to diethylstilbestrol (DES) in utero, but the anomalies are different than those expected from the data of Henderson and co-workers. They reported an increased incidence of suspected urethral stenosis in boys exposed to DES. Their conclusion was drawn from the response of 225 DES-exposed males to a questionnaire.

We have thoroughly examined 163 DES-exposed males and found a significantly increased incidence of

  • oligospermia,
  • hypotrophic testes,
  • low ejaculate volumes,
  • epididymal cysts,
  • and microphallus.
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Spermatozoal analysis in the DES-exposed males

Abstract

Pathological semen and anatomical abnormalities of the genital tract in human male subjects exposed to diethylstilbestrol in utero, The Journal of urology, NCBI PubMed PMID: 850321, 1977 Apr.

The in utero effects of diethylstilbestrol on the human male genital tract are reported in our followup study of male offspring of mothers treated with diethylstilbestrol.

Anatomical and functional abnormalities were significantly greater in male patients exposed to diethylstilbestrol compared to male controls whose mothers were all participants in a prospective, randomized double-blind study on the effects of diethylstilbestrol on pregnancy at our hospital during the early 1950s.

Epididymal cysts, hypotrophic testes and capsular induration of the testes were among the more common genital lesions found in more than 25 per cent of 159 male patients exposed to diethylstilbestrol compared to a 6.8 per cent incidence in 161 male controls.

Spermatozoal analysis revealed severe pathological changes (Eliasson score more than 10) in 32 per cent of 31 patients exposed to diethylstilbestrol and 0 per cent of 20 male controls. Abnormal findings on physical examination combined with severe sperm abnormalities (Eliasson score more than 10) were found in 23 per cent of the male patients exposed to diethylstilbestrol versus none of the male controls.

Cytologic examinations revealed no malignant cells from urine samples before and after prostatic massage or ejaculation, prostatic fluids and aspirates from epididymal cysts.

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Reproductive outcomes in men with prenatal exposure to diethylstilbestrol

This 2005 study suggested that DES-exposed men are more likely than the unexposed to have an experience with infertility ; the effect/risk increasing iwith advancing age.

Abstract

Reproductive outcomes in men with prenatal exposure to diethylstilbestrol, Fertility and sterility, NCBI PubMed PMID: 16359959, 2005 Dec.
Full study: Fertility and sterility, December 2005 Volume 84, Issue 6, Pages 1649–1656, S0015-0282(05)02956-0, 2005 Dec.

OBJECTIVE
To examine prenatal diethylstilbestrol (DES) exposure in relation to male reproductive outcomes.

DESIGN
Prospective observational study.

SETTING
Participants were identified through record review, clinical trial participation, or an obstetrics clinic.

PATIENT(S)
A total of 1,085 DES-exposed and 1,047 unexposed men.

INTERVENTION(S)
Participants were exposed prenatally to DES through the mother’s obstetrics care or clinical trial participation.

MAIN OUTCOME MEASURE(S)
Infertility; never fathering a pregnancy or live birth; number of pregnancies or live births fathered.

RESULT(S)
We found little evidence that prenatal DES exposure affects the likelihood of never fathering a pregnancy or live birth, or influences the mean number of fathered pregnancies or live births.

  • Our data suggest that DES-exposed men are slightly more likely to experience infertility (relative risk [RR] = 1.3, 95% confidence interval [CI] = 1.0-1.6).
  • The DES dose and gestational timing did not influence infertility or the number of pregnancies or live births fathered, but results were inconsistent for dose effects on the likelihood of never fathering a pregnancy or a live birth.

CONCLUSION(S)
Prenatal DES exposure may be associated with a slightly increased risk of having an infertility experience, but does not increase the likelihood of never fathering a pregnancy or a live birth, or the number of pregnancies or live births fathered.

Although speculative, this data may reflect an increased effect of DES on infertility with advancing age.

Click to download the full study.

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Infertility among women exposed prenatally to diethylstilbestrol

This 2001 study, which is larger and includes a considerably longer follow-up period than any previous study, indicates that women exposed to diethylstilbestrol in utero have an increased risk of infertility, both primary and secondary, and that the increase is primarily due to tubal and uterine factors. I is for Infertility.

Abstract

Infertility among women exposed prenatally to diethylstilbestrol, American journal of epidemiology, NCBI PubMed PMID: 11495854, 2001 Aug.
Full study: Am. J. Epidemiol, doi: 10.1093/aje/154.4.316, January 17, 2001.

Although it is well established that women exposed to diethylstilbestrol in utero have an increased risk of spontaneous abortion, ectopic pregnancy, and preterm delivery, it is not known whether they also have an increased risk of infertility. The authors assessed this question in data from a collaborative follow-up study of the offspring of women who took diethylstilbestrol during pregnancy.

In 1994, 1,753 diethylstilbestrol-exposed and 1,050 unexposed women from an ongoing cohort study (National Cooperative Diethylstilbestrol Adenosis Study and Dieckmann cohorts) provided data on difficulties in conceiving and reasons for the difficulty. Age-adjusted relative risks were computed for the association of diethylstilbestrol exposure with specific types of infertility.

  • A greater proportion of exposed than unexposed women were nulligravid (relative risk (RR) = 1.3, 95% confidence interval (CI): 1.1, 1.5),
  • and a greater proportion had tried to become pregnant for at least 12 months without success (RR = 1.8, 95% CI: 1.6, 2.1).
  • Diethylstilbestrol exposure was significantly associated with infertility due to uterine and tubal problems, with relative risks of 7.7 (95% CI: 2.3, 25) and 2.4 (95% CI: 1.2, 4.6), respectively.

The present findings indicate that diethylstilbestrol-exposed women have a higher risk of infertility than do unexposed women and that the increased risk of infertility is primarily due to uterine or tubal problems.

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Female fertility prognosis and diethylstilbestrol. Personal data and review of the literature

In spite of their difficult past reproductive history 4 young DES-women conceived successfully with adapted psychological and medical care in 1998 in France. Las manos del destino.

Abstract

Female fertility prognosis and diethylstilbestrol, Journal de gynécologie, obstétrique et biologie de la reproduction, NCBI PubMed PMID: 9648005, 1998 Apr.
Full study: em-consulte, Doi : JG-05-1998-27-3-0368-2315-101019-ART95, 1998.

Diethylstilbestrol (DES) exposure in utero in females is a cause of clear-cell adenocarcinoma of the cervix and of several anatomical and functional disorders of the genital tract. DES exposure must be evoked whenever counselling women for reproductive disorders.

In France around 80,000 women have had in utero DES exposure. The cases of four young women who consulted our Reproduction Center for reproductive disorders illustrate the usual difficulties faced by these patients.

In spite of their difficult past reproductive history (uterine malformations, repeated miscarriages, ectopic pregnancies) and low fertility rate, all four women conceived successfully, either after spontaneous or induced ovulation. We stress the need for adapted psychological and medical care which can lead to successful childbearing in the vast majority of these high-risk patients.

Click to download the full study.

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Fertility in men exposed prenatally to diethylstilbestrol

In this 1995 survey of nearly 500 exposed and unexposed men, researchers say they found no evidence that diethylstilbestrol impairs male fertility.

Abstract

Fertility in men exposed prenatally to diethylstilbestrol, The New England journal of medicine, NCBI PubMed PMID: 7723797, 1995 May 25.
Full study: The NEJM, DOI: 10.1056/NEJM199505253322104, 1995 May 25.

BACKGROUND
Prenatal exposure to diethylstilbestrol causes infertility in male mice and has been associated with malformations of the genital tract in men. However, little is known about the fertility of men who have been exposed prenatally to diethylstilbestrol.

METHODS
In 1950 through 1952, 1646 pregnant women were enrolled in a randomized, placebo-controlled clinical trial of diethylstilbestrol at Chicago Lying-in Hospital. We interviewed men who were born to the women during that study about their fertility.

RESULTS
Four decades after their birth, we were able to trace 548 of the surviving sons (68 percent). Ninety percent consented to be interviewed (253 who had been exposed to diethylstilbestrol in utero and 241 who had not been exposed).

  • Congenital malformations of the genitalia were reported three times as often by the diethylstilbestrol-exposed men as by the sons of the women in the placebo group.
  • Within the exposed group, malformations were reported twice as often among those exposed to diethylstilbestrol before the 11th week of gestation as among those exposed later (P = 0.05).
  • Men with genital malformations were nonetheless as fertile as other men.
  • The diethylstilbestrol-exposed men (with or without genital malformations) had no impairment of fertility by any measure, including whether they had ever impregnated a women, age at the birth of their first child, average number of children, medical diagnosis of a fertility problem, or length of time to conception in the most recent pregnancy of the female partner.
  • Finally, diethylstilbestrol-exposed men had no impairment of sexual function, as indicated, for example, by the frequency of intercourse or reported episodes of decreased libido.

CONCLUSIONS
High doses of diethylstilbestrol did not lead to impairment of fertility or sexual function in adult men who had been exposed to the drug in utero.

NB: this data focused exclusively on fertility outcomes, it does not address any of DES side-effects and/or health effects of diethylstilbestrol that might emerge at older ages.

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Infertility among daughters either exposed or not exposed to diethylstilbestrol

infertility
The estimated cumulative rate of first pregnancy was 16% for the DES-exposed.

Abstract

Infertility among daughters either exposed or not exposed to diethylstilbestrol, American journal of obstetrics and gynecology, NCBI PubMed PMID: 3348310, 1988 March.

Infertility was examined among 343 diethylstilbestrol-exposed and 303 unexposed daughters whose mothers participated in an evaluation of diethylstilbestrol use during pregnancy 35 years ago.

Of the married individuals who were not using contraception and who were actively trying to conceive, a greater proportion of diethylstilbestrol-exposed women than unexposed subjects experienced primary infertility (33% versus 14%, p less than 0.001). Among those with primary infertility, abnormal hysterosalpingograms were observed in 46% of the diethylstilbestrol-exposed group and in none of the unexposed group (p less than 0.02), while tubal abnormalities were found in 42% of the exposed and in none of the unexposed (p = 0.02). First pregnancies were achieved by 40 (58%) women exposed to diethylstilbestrol and 18 (64%) unexposed subjects. Twenty-four (60%) of the exposed women and 15 (83%) of the unexposed individuals who conceived had a live-born infant who survived. The estimated cumulative rate of first pregnancy was 16% for the exposed group and 36% for the unexposed group at 12 months after the diagnosis of primary infertility (p less than 0.05).

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Pregnancy: DES Effects in DES Mothers and in DES Daughters

image of a pregnant-woman
Diethylstilbestrol causes a variety of birth-related adverse outcomes in DES daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death.

DES Pregnancy: DES Mothers

Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects, National Institutes of Health, NCBI PubMed PMCID: PMC3817964, 2013 June.

Although women were prescribed DES to improve the outcomes of their given pregnancy, the results of a double-blind clinical trial of over 1500 women at the University of Chicago by Dieckmann and coworkers in 1953 demonstrated that DES did not reduce the incidence of spontaneous abortion, prematurity or postmaturity, and the study suggested that DES enhanced premature labor. However, it continued to be used for another nearly 20 years.

DES Pregnancy: DES Daughters

Hoover determined that DES daughters have an increased risk for many pregnancy-related issues including spontaneous abortion (<14 weeks gestation), ectopic pregnancy, loss of pregnancy in the second trimester (14–27 weeks), preeclampsia, preterm delivery (<37 weeks), stillbirth (at >27 weeks), and neonatal death within the first month of life. Many of these outcomes including ectopic pregnancy, miscarriage, and premature delivery have been reported in more than one study, and appear to be exacerbated effects for which DES was prescribed to prevent.

The effects of prenatal DES exposure on the ability to reproduce are substantial. The risk for infertility (defined as ? 12 months of trying to conceive) among DES daughters is reported to be 33% compared to 14% in unexposed women (p<0.001), and full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64.1% of DES exposed women (RR=0.76, 95% CI, 0.72–0.80). The Dutch DES cohort reports that 33% of DES daughters are nulliparous at the age of ? 40 yr, compared with only 17% in the Dutch population. Kaufman and co-workers also reported that that once pregnant, 20% of DES daughters experience preterm delivery (versus 8% of unexposed population (RR=2.93; 95% CI, 2.23–3.86)), their risk of ectopic pregnancy was 3 to 5 times higher than unexposed women (RR=3.84; 95% CI, 2.26–6.54), and 20% of the DES-exposed group had a miscarriage during the first pregnancy (versus 10% unexposed (RR=2.00; 95% CI, 1.54–2.60). These adverse pregnancy-related outcomes in DES daughters are also experienced by unexposed women, but the excess risk in those outcomes (not stillbirth) owing to in utero DES exposure was significant. Also, there are strong data suggesting that the presence of vaginal epithelial changes at cohort entry examination adds to the cumulative risk for DES-induced infertility, spontaneous abortion, preterm delivery, and ectopic pregnancy.

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Hysteroscopic metroplasty: term delivery rate after T-shaped uterus surgery

Term delivery rate after hysteroscopic metroplasty in patients with recurrent spontaneous abortion and T-shaped.

Abstract

Term delivery rate after hysteroscopic metroplasty in patients with recurrent spontaneous abortion and T-shaped, arcuate and septate uterus, Gynecologic and obstetric investigation, NCBI PubMed PMID: 21150155, 2011 Dec.

BACKGROUND
To evaluate the improvement of the term delivery rate after hysteroscopic metroplasty surgery in various uterine malformations.

METHODS
170 patients were eligible for the present retrospective case series study. Data were weighted for the number of pregnancies observed (n = 218) after surgical intervention, stratified to the number of previous abortions (at least 2) and type of malformation.

RESULTS
Before surgery, the overall term delivery rate was 5.5%. After surgery, the overall term delivery rate was 59% (absolute benefit increase, ABI, was 54.5) and correlated with the number of previous abortions (69.7% ABI = 64.2, 56.5% ABI = 51 and 26.3% ABI = 20.8 for 2, 3-4 and >4 abortions, respectively; p = 0.0008, log-rank test). Data stratified according to uterine malformations yielded the following term delivery rate: 66.7% for T-shaped uterus, 62.8% for septum/partial septum and 55.6% for arcuate uterus (NS, log-rank test). The number of previous abortions and maternal age also affected the term delivery rate. Their effect upon the term delivery rate, expressed as an odds ratio, was 1.73 (95% CI: 1.20-2.49) and 1.11 (95% CI: 1.05-1.18), respectively.

CONCLUSION
The term delivery rate was about 10-fold higher after surgery. T-shaped uterus surgery yielded the best term delivery rate.

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Surgical correction of a T-shaped uterus and DES Daughters pregnancy outcome

image of 3D-T-shaped-uterus
Reconstruction in 3D-US of T-shaped uterus. Hysteroscopic metroplasty improves the live birth rate for women with a T-shaped uterus and a history of primary infertility, recurrent abortion or preterm delivery, although it is not a treatment of infertility.

Abstract

Surgical approach to and reproductive outcome after surgical correction of a T-shaped uterus, Human reproduction (Oxford, England), NCBI PubMed PMID: 21398337, 2011 Jul.
Full text: Human Reproduction, Vol.0, No.0 pp. 1–5, 2011, doi: 10.1093/humrep/der056, March 11, 2011.

BACKGROUND
The aim of this study was to describe the surgical approach to, and evaluate the reproductive outcome of, a T-shaped uterus.

METHODS
The study included 97 women who were eligible for hysteroscopic surgery, by either monopolar or bipolar electrosurgical instruments. All had diagnostic hysteroscopy 2 months afterwards to assess the success of the procedure and determine whether any synechiae were present.

RESULTS
Forty-eight women (49.5%) became pregnant after metroplasty. The overall live birth rate per pregnancy before surgery was 0%; for these patients, it increased to 73%, and their miscarriage rate fell from 78 to 27% (P < 0.05). For all 57 pregnancies in 48 women, the ectopic pregnancy rate was 9% (n = 5), the miscarriage rate 28% (n = 16), the preterm delivery rate 14% (n = 8), the term delivery rate 49% (n = 28) and the live birth rate was 63% (n = 36).

CONCLUSIONS
Hysteroscopic metroplasty improves the live birth rate for women with a T-shaped uterus and a history of primary infertility, recurrent abortion or preterm delivery, although it is not a treatment of infertility.

Discussion

A T-shaped uterus can be a primary or congenital malformation (related to DES exposure or other causes) or can be acquired due to marginal adhesions with a T-shaped appearance. The description of the surgical technique and the results of this series are important regardless of the cause of the anomaly.

Two-third of our cases had history of DES exposure, and the results of this series are encouraging for all malformations requiring modification of the cavity volume. The question of systematic cervical cerclage during pregnancy after metroplasty remains open.

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