21513 Progestins gestagens Pharmacology and toxicology

ftogesterone is manufactured by the theca and lutein cells in the ovary; during pregnancy, it is also produced in larger quantities by the placenta. Progesterone is metabolized by the fetus and placenta. The placenta is able to oxidize individual metabolites enzymatically to progesterone again. Progesterone is excreted as pregnandiol and decomposed in part to pregnantriol. Although progesterone is available as a pharmaceutical preparation, it is not well-absorbed orally. Alteration of the progesterone molecule produces progestins such as medroxyprogesterone acetate, which are better absorbed but differ from progesterone in some of their pharmacologic activities. Progestins are also obtained from modification of testosterone, with removal of one carbon to decrease the androgenicity of these preparations.

The following substances are available as pharmaceuticals: chlor-madinon, desogestrel, drospirenon, dydrogestone, ethynodiol diac-etate, gestonorone, gestodene, hydroxyprogesterone, levonorgestrel, lynestrenol. rnedrogestone, medroxyprogesterone, megestrol, norethis-terone (norethindrone) and its acetate, norethynodrel, norgestimate, and norgestrel.

For about 40 years, progesterone and its partially or completely synthesized derivatives (i.e. 17-hydroxyprogesterone) have been used to treat threatened or habitual miscarriage, although there is still no proof of the effectiveness of this therapy. A WHO Symposium on Drug Treatment during Pregnancy established the ineffectiveness of this sort of therapeutic effort, which was widespread in Germany. France and Italy, but not in Scandinavia (WHO Report 1984). The only indication for hormonal prevention of miscarriage which is currently discussed is hCG therapy for the rare corpus luteum insufficiency. However, therapy with progestins continues to be recommended, nowadays mostly with natural progesterone. In addition, it is common to use a progestin to support corpus luteum function after in vitro fertilization and embryo transfer.

Recently, randomized controlled trials have shown that treatment with progesterone started in the second trimester of pregnancy reduces the risk of delivery before 37 weeks' gestation, among pregnant women at increased risk of spontaneous preterm birth. However, as the authors of a recent meta-analysis emphasize, the effect on neonatal morbidity is still uncertain (Mackenzie 2006).

A possible association between hormone therapy and hypospadias has been previously debated (Kallen 1992). More recently, a statistically significant risk for hypospadias in the newborn of mothers exposed to progestins for the purpose of becoming pregnant or preventing pregnancy loss (from 4 weeks before conception until the end of the first trimester) has been observed in a retrospective case-control study (OR = 3.7; CI 2.3-6.0), whereas progestin intake for the purpose of oral contraception was not associated with an increased risk for hypospadias (Carmichael 2005). Wogclius (2006) could not confirm this association with a case-control study on oral contraceptive use during early pregnancy. Nevertheless, more controlled studies are necessary to conclude a relationship between progestins and hypospadias. There are no epidemiological studies that support a significant relationship between progestational drugs and congenital malformations (Brent 2005, Martinez-Frias 1998).

Disturbances of gender differentiation have not been observed with use of progestins in contraceptive doses when given during the sensitive phase from the eighth week of pregnancy. However, when higher doses of the 19-nor-ethinyl-testosterone derived progestins are used in this sensitive phase, a transient clitoris hypertrophy may occur due to the androgenic properties of Ihese agents. Effects on later fertility have been hypothesized but not confirmed by controlled studies. An older publication reported deviant psychosexual development in children whose diabetic mothers were treated with estradiol and progesterone or high-dosage norethisterone derivatives (e.g. Yalom 1973). There are no indications that these developmental disturbances occur in connection with currently-used progestin medications. Development through adolescence appears age-appropriate according to large long-term studies on medroxy-progesterone-depot preparations (Pardthaisong 1992).

The use of emergency contraception (postcoital contraception, the "morning-after pill") is presently increasing, especially the new regimen consisting of only levonorgestrel. To date, there appears to be no increased risk for congenital birth defects among pill users who become pregnant; however, the suspicion exists for a potential risk for ectopic pregnancy following emergency levonorgestrel contraception (Basu 2005, Gainer 2004, Harrison-Woolrych 2003, Fabunmi 2002). Nevertheless, the risk for ectopic pregnancy would probably be very small.

There is insufficient documented experience with administration of high-dose progestins, such as used in therapy for malignancies, in pregnancy.

Tibolone is a progestin-like agent that has been used with or without estrogen for the treatment of menopausal symptoms. There is no information concerning pregnancy outcome after exposure to this agent, which is used in postmenopausal women.

Recommendation. During pregnancy, there is no valid indication for the therapy with progestins. Use of progestins to prevent miscamage is not Indicated. Contraceptives taken by accident in early pregnancy are not grounds for termination of pregnancy or for additional diagnostic procedures. This statement applies to the contraceptive preparations that are in use today and to emergency contraception (the "morning-after pill") as well as to treatment for amenorrhea with norethisterone acetate and ethinylestradiol, or other oral contraceptive preparations, or miscarriage prophylaxis with progesterone derivatives. Since emergency contraception is not 100% effective, pill users should be warned about the small risk of ectopic pregnancy in cases of method failure. The accidental administration of high-dose preparations for other indications has no risk-based reason for a termination of pregnancy either. A detailed ultrasound examination could verify a normal morphologic development of the fetus.

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