A Story with No End, Yet
Estrogens-both endogenous and exogenous-strongly stimulate prolactin (PRL) secretion in men. Even the most “physiological” oral anticonceptive agents (0.a.c.) cause a small, but statistically significant rise in plasma PRL levels. Hyperprolactinemia may lead to gonadal dysfunction and galactorrhea. The synthetic estrogen diethylstilbestrol (DES) is approximately 20 times as active as the natural estrogen 17 P-estradiol. DES-administration during pregnancy is likely to increase PRL concentrations in the fetus and the mother, depending on the time of administration, duration and dosage. Prenatal exposure to DES can induce PRL-producing pituitary tumors in animals.
Diethylstilbestrol (DES)-Related Endocrine Disturbances in Women, Departments of ‘Psychiatry, Internal Medicine, and Gynecology, Academic Medical Center, Amsterdam, The Netherlands, American Health Foundation, New York, New York. academia.edu/23230973, June 1995.
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From 1940 to 1971 DES was prescribed to more than 5 million women in the USA, and more than 2 million in Europe. Although the frequency of menstrual disorders, hirsutism and infertility is increased in DES-daughters, almost no systemic endocrine evaluation has been performed. High PRL levels were reported in 38 of 1,079 DES-daughters (3.5%), and in 7 (0.6%) a pituitary tumor was present: In 1991 we reported 3 DES-related prolactinomas. Subsequently we measured PRL, TSH, 17 P-estradiol, progesterone, sex hormone binding globulin (SHBG), testosterone, free androgen index (FAI), dihydroepiandrosterone-sulphate (DHEA-S) and cortisol by in-house and commercial radioimmunoassays in 20 DES-daughters, (age 21 -38 yrs; median 26), 7 of whom used an oral contraceptive. All the women had DES-specific gynecologic abnormalities. PRL levels were compared with 2 control groups of premenopausal women not exposed to DES. Because of the skewed distribution of PRL concentrations, the geometric mean value (GMV) was calculated.
PRL levels (TABLES 1 and 2) of DES-daughters with 0.a.c. (GMV 11.82, 95% confidence interval (CI) 3.62-38.52) were higher than those without 0.a.c. (GMV 8.88, 95% CI 2.61-30.16). PRL values of the 20 DES-daughters (GMV 9.81, 95% CI 2.93-32.86) were significantly higher than those of the two control groups (GMV 6.52, 95% CI 1.68-25.32 and GMV 7.73, 95% CI 3.2-18.64), respectively. Plasma TSH levels ranged from 1.3-14.4 mU/l (mean 3.19). The mean TSH concentration in the 7 women on 0.a.c. was slightly elevated: 5.2 mU/1 (N 0.4-4.0). In two women TSH was clearly elevated with 13.5 and 14.4 mU/l, indicating primary hypothyroidism.
Plasma testosterone concentrations varied from 1.0-5.5 nmoM (mean 2.9) in the women without 0.a.c. and from 2.0-4.2 nmoM (mean 3.0) in the women with 0.a.c. In 8 DES-daughters plasma testosterone levels exceeded the upper limit of the normal range (2.0-3.4 nmoY1). In the women without 0.a.c. plasma 17 P-estradiol, progesterone and SHBG concentrations were within normal limits, as was the FAI.
Plasma DHEA-S levels ranged from 2.5-17.8 pmoVl (mean 7.6) in the women without 0.a.c. In 3 women DHEA-S was at the upper limit or above the normal range (10,ll.S and 17.8, respectively: N 2- 10 ymol/l). Plasma DHEA-S levels were normal in the women with 0.a.c.: 3.1 -6.0 ymoYl (mean 4.3). Plasma cortisol levels (N 0.22- 0.65 pmoY1) were normal in the women without 0.a.c. (0.28-0.61 prnom, mean 0.43), and varied from 0.36-1.36 pmoVl (mean 0.83) in the women with 0.a.c.
PRL levels in 20 DES-daughters were significantly higher than in unexposed women. In three DES-daughters (15%) plasma TSH was elevated indicating primary hypothyroidism. Moreover, in 8 DES-daughters (40%) plasma testosterone concentrations were elevated.
There is an increased frequency of estrogen-dependent cancers in the DESexposed population-mothers, daughters and sons (mamma, vagina, cervix, prostate). Several mechanisms might be involved in tumor induction. In animals, DES causes deficiencies in immune function, leading to impaired immune surveillance. Almost no systemic evaluation of the DES population has been done thus far, but alterations in immune responsiveness, as well as an increased occurrence of autoimmune disease, have been reported:. Prolactin is an immunomodulatory hormone. Secondly, DES and its metabolites can cause somatic mutation of cells. Thirdly, a DES-induced hormonal imbalance may increase cancer risk in the target organs of sex hormones later in life, either by itself or by increasing susceptibility to other carcinogens. Extensive controlled, prognostic studies on the effects of DES exposure on the endocrine and immune system in humans, are badly needed. In DES-exposed subjects, especially in the presence of elevated PRL levels, withholding of additional estrogen therapy-o.a.c., and menopausal substitution therapy-is advisable.
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