21512 Estrogens

Pharmacology and toxicology

It is only during pregnancy that, in addition to estrone and estradiol, estriol (which otherwise only appears as a metabolite) and estetrol are synthesized to a large extent.

Physiologically as well as pharmacologically, estrogens act as a stimulus to uterine and fallopian tube growth and, most particularly. to the growth of the endometrium. In addition, estrogens produce thickening of the vaginal epithelium, an increase in cervical mucus production, and widening of the cervical canal. The earlier (sometimes routine) use of estrogens to improve contractions has been superseded by more effective pharmaceuticals.

Therapeutically, estrogens are used in oral contraceptives, as replacement therapy during the menopause, and for treatment of some malignancies. Among the available substances are estradiol and its derivatives, ethinylestradiol (the estrogen in most of the estrogen-containing birth control pills), mestranol, estrone, conjugated equine estrogens, polyestradiol, estriol, fosfestrole, chlorotri-anisen, and epimestrol.

The relatively low dosage preparations for hormonal contraception (preparations of combined estrogen and gestagen), including emergency contraception (the "morning-after pill"), have been quite well-studied because of their frequent accidental use during pregnancy. They do not involve detectable risk as far as is known today (Aim 2005* Raman-Wilms 1995, Kallen 1991, Harlap 1985A), and do not produce disturbances of gender differentiation when treatment is given during the sensitive phase from the eighth week of pregnancy. However, it should be mentioned that after the early reported association (based on case reports from the 1970s) between use of hormonal medications and heart defects, VACTERL (or VATER) syndrome, etc., newer publications citing increased rates of (urinary tract) anomalies have appeared (see Li 1995).

Several studies have analyzed the relationship between oral contraceptives and Down syndrome, some of them with negative results (Kallen 1989, Harlap 1985B, Ericson 1983), but others have suggested that women who take oral contraceptives during the month just before conception (Mikkelsen 1991) or who fall pregnant following oral contraceptive failure (Harlap 1980) have an increased risk for Down syndrome. A more recent case-control study has demonstrated an increased risk of 2.8-fold for infants with Down syndrome in women younger than 35 years of age if the mother became pregnant while she was taking oral contraceptives (Martmez-Frias 2001).

The effects on later fertility have been hypothesized but not confirmed by controlled studies. An older publication reported deviant psychosexual development in boys whose diabetic mothers were treated with estradiol and progesterone (Yalom 1973). There are no indications that these developmental disturbances occur in connection with currently used estrogenic medications. Likewise, there is no strong epidemiological evidence to indicate that prenatal exposure to estrogens increases the risk to abnormal development of the male reproductive organs (Storgaard 2006).

There is insufficient experience with high dosage use of estrogen in, for example, malignancies. Experimental animal studies suggest that high doses of many different estrogens can produce histologic changes in the genital tract of the offspring similar to those after exposure to diethylstilbcstrol. A human estrogen-exposure syndrome analogous to that occurring after diethylstilbcstrol has not been described with regard to other estrogens.

Recommendation. During pregnancy there is no indication for estrogen treatment. The (accidental) use of oral contraceptives in early pregnancy does not require either a termination of the pregnancy or additional diagnostic studies. This statement also applies to emergency contraception (the "morning-after pill") and amenorrhea treatment with ethinylestradiol and norethisterone acetate (see progestins) or other oral contraceptive preparations. The accidental administration of high-dose preparations for other indications has no risk-based reason for a termination of pregnancy either. In cases of repeated high-dose administration, at least, a detailed ultrasound examination could verify a normal morphologic development of the fetus.

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