Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ERα and ERβ. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ERα and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen r...

Mechanisms of Estrogen Action

Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.

Male reproductive health and environmental xenoestrogens

Antenatal corticosteroid therapy: A meta-analysis of the randomized trials, 1972 to 1994

Exposure of humans to bisphenol A (BPA), a monomer in polycarbonate plastics and a constituent of resins used in food packaging and dentistry, is significant. In this report exposure of rats to 2.4 microg/kg.d (a dose that approximates BPA levels in the environment) from postnatal d 21-35 suppressed serum LH (0.21 +/- 0.05 ng/ml; vs. control, 0.52 +/- 0.04; P < 0.01) and testosterone (T) levels (1.62 +/- 0.16 ng/ml; vs. control, 2.52 +/- 0.21; P < 0.05), in association with decreased LHbeta and increased estrogen receptor beta pituitary mRNA levels as measured by RT-PCR. Treatment of adult Leydig cells with 0.01 nm BPA decreased T biosynthesis by 25% as a result of decreased expression of the steroidogenic enzyme 17alpha-hydroxylase/17-20 lyase. BPA decreased serum 17beta-estradiol levels from 0.31 +/- 0.02 ng/ml (control) to 0.22 +/- 0.02, 0.19 +/- 0.02, and 0.23 +/- 0.03 ng/ml in rats exposed to 2.4 microg, 10 microg, or 100 mg/kg.d BPA, respectively, from 21-35 d of age (P < 0.05) due to its ability to inhibit Leydig cell aromatase activity. Exposures of pregnant and nursing dams, i.e. from gestation d 12 to postnatal d 21, decreased T levels in the testicular interstitial fluid from 420 +/- 34 (control) to 261 +/- 22 (P < 0.05) ng/ml in adulthood, implying that the perinatal period is a sensitive window of exposure to BPA. As BPA has been measured in several human populations, further studies are warranted to assess the effects of BPA on male fertility.

Inhibition of Testicular Steroidogenesis by the Xenoestrogen Bisphenol A Is Associated with Reduced Pituitary Luteinizing Hormone Secretion and Decreased Steroidogenic Enzyme Gene Expression in Rat Leydig Cells

Purpose: To review the literature on the long-term health effects of exposure to diethylstilbestrol (DES) among women prescribed DES during pregnancy (DES mothers), among their children exposed in ...

Diethylstilbestrol revisited: a review of the long-term health effects.

Follow-up study of male and female offspring of DES-exposed mothers.

At the Chicago Lying-In Hospital in the early 1950s gradually increasing doses of diethylstilbestrol (DES) were administered to 840 women beginning during the 10th-20th week of gestation with 5 mg/day and increasing by 5 mg every 2nd week to a maximum daily dose of 150 mg by the 34th week. Placebos were given to 806 women. There were 134 DES-esposed and 110 placebo-exposed male offspring who have been traced and evaluated. Of these now 21-23 year old men 89% were Causasians 10% Negro and 1% Oriental. The DES-exosed men had a significantly (p less than .05) higher incidence of epididymal and testicualr abnormalities than the unexposed controls. In 17 DES-exosed patients cystic masses in the area of the superior epididymis were aspirated. A straw-colored fluid without spermatozoa was found in 6 cases and a milky fluid containing sperm was found in 3. A cyst excised and studied histologically was lined with columnar epithelium without secretory cells or spermatozoa. Aspriation of similar masses in 2 control patients revealed spermatozoa in only 1. Cytologic examination of urine specimens and prostate fluids were similar in the 2 groups. Age of puberty and sexual functions were comparable. Circulating blood hormones assayed were the same. 1 DES-exposed patinet had bilateral hypotrophic testes azoospermia decreased plasma testosterone elevated plasma ICSH elevated follicle stimulating hormone and ennuchoid body habitus. Semen analyses showed a sperm density and fewer mobile spermatozoa in the DES-exposed cases. Sever pathologic blood changes were observed in 29% of 28 DES-exposed males and none in 18 control males. Genital abnormalities were found in 15 of 28 (53%) of the DES-ex posed group and 5 of 18 (25%) in the control group. Results show that transplacental effects of DES on the human male do occur. There may be considerable effect on spermatogensis and possibly on sperm maturation. Malignant cells were not found in any tissue or fluid.

G F Schumacher

Papers

Follow-up study of male and female offspring of DES-exposed mothers.

Structural and functional abnormalities in the sex organs of male offspring of mothers treated with diethylstilbestrol (DES).

Pathological semen and anatomical abnormalities of the genital tract in human male subjects exposed to diethylstilbestrol in utero