Teratogenic effects of Silastic intrauterine devices in the rat with or without added medroxyprogesterone acetate

Barlow, Susan; Knight, A. F.

doi:10.1016/s0015-0282(16)46823-8

Cited by 11 publications

(5 citation statements)

References 16 publications

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“…Stimulation of the growth of pubic hair in female patients without a significant slowdown in skeletal maturation (35) suggested weak androgenic activity of large doses of MPA (200-300 mg every 7-10 days). However, prenatal exposure to MPA was reported to cause mild clitoral hypertrophy and posterior labial fusion in the female and hypospadias in the male (36)(37)(38)(39), contraindicating its use during pregnancy. Because of its progestational effect, MPA was formerly used to prevent spontaneous abortion.…”

Section: Discussionmentioning

confidence: 99%

Distinguishing Androgen Receptor Agonists and Antagonists: Distinct Mechanisms of Activation by Medroxyprogesterone Acetate and Dihydrotestosterone

Kemppainen

Langley

Wong

et al. 1999

Molecular Endocrinology

166

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Natural and pharmacological androgen receptor (AR) ligands were tested for their ability to induce the AR NH2-terminal and carboxyl-terminal (N/C) interaction in a two-hybrid protein assay to determine whether N/C complex formation distinguishes in vivo AR agonists from antagonists. High-affinity agonists such as dihydrotestosterone, mibolerone, testosterone, and methyltrienolone at concentrations between 0.1 and 1 nM induce the N/C interaction more than 40-fold. The lower affinity anabolic steroids, oxandrolone and fluoxymesterone, require concentrations of 10-100 nM for up to 23-fold induction of the N/C interaction. However no N/C interaction was detected in the presence of the antagonists, hydroxyflutamide, cyproterone acetate, or RU56187, at concentrations up to 1 microM, or with 1 microM estradiol, progesterone, or medroxyprogesterone acetate; each of these steroids at 1-500 nM inhibited the dihydrotestosterone-induced N/C interaction, with medroxyprogesterone acetate being the most effective. In transient and stable cotransfection assays using the mouse mammary tumor virus reporter vector, all ligands displayed concentration-dependent AR agonist activity that paralleled induction of the N/C interaction, with antagonists and weaker agonists failing to induce the N/C interaction. AR dimerization and DNA binding in mobility shift assays and AR stabilization reflected, but were not dependent on, the N/C interaction. The results indicate that the N/C interaction facilitates agonist potency at low physiological ligand concentrations as detected in transcription, dimerization/DNA binding, and stabilization assays. However the N/C interaction is not required for agonist activity at sufficiently high ligand concentrations, nor does its inhibition imply antagonist activity.

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Section: Discussionmentioning

confidence: 99%

Distinguishing Androgen Receptor Agonists and Antagonists: Distinct Mechanisms of Activation by Medroxyprogesterone Acetate and Dihydrotestosterone

Kemppainen

Langley

Wong

et al. 1999

Molecular Endocrinology

166

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“…Claiming that limb reduction defects result from a coexisting IUD is indeed superficially an attractive hypothesis~ The author is aware of at least one animal study [58] consistent with a teratogenic relationship. Fetuses born of rats wearing a Silastic device showed increased anomaly rates compared to animals without devices.…”

Section: Intrauterine Devices (Iud): Claims Of Teratogenicitymentioning

confidence: 99%

Relationship between congenital anomalies and contraception

1985

Adv Contracept

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“…Other primate animal studies in which pregnant animals were exposed to progestins were negative for increases in genital or nongenital malformations (Courtney and Valerio, 1972;Aksel et al, 1991). Barlow and Knight (1983) exposed pregnant rats to MPA-containing silastic rods from day 9 to day 19 of pregnancy. Although the expected masculinization and feminization of the fetuses occurred with the higher exposures, there was no increase in the frequency of nongenital congenital malformations in the MPA-treated groups.…”

Section: Have Investigators Been Able To Develop a Teratogenic Animalmentioning

confidence: 99%

Nongenital malformations following exposure to progestational drugs: The last chapter of an erroneous allegation

Brent

2005

Birth Defect Res A

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In the late 1960s and 1970s, a number of epidemiological studies were published indicating that pregnant women who were exposed to an array of sex steroids delivered infants with an increased incidence of nongenital congenital malformations. Because of these publications, the Food and Drug Administration (FDA), in conjunction with various pharmaceutical companies, labeled the therapeutic exposure of progestational drugs and contraceptives in pregnant women as a risk factor for limb-reduction defects (LRDs) and congenital heart defects (CHDs). Subsequently there was a rapid decrease in the exposure of pregnant women to these drugs and the initiation of numerous lawsuits alleging that a particular progestational drug was responsible for a child's nongenital congenital malformation. Wilson and Brent (1981) published an article indicating that epidemiological and animal studies of these drugs, and basic science did not support the package insert's warnings. Many new and previous animal and epidemiological studies did not support the FDA box warning. In 1987 the FDA held a hearing in which the FDA, the Teratology Society, the Centers for Disease Control and Prevention, the American College of Obstetrics and Gynecology, and other organizations supported the position that progestational agents did not result in nongenital malformations. An editorial appeared in Teratology congratulating the FDA for removing the warning label on oral contraceptives regarding nongenital malformations. In 1999 the FDA published new wording for package inserts that removed warnings for nongenital malformations for all progestational agents. In spite of the recent changes in the package inserts, lawsuits have alleged that progestational drugs cause nongenital malformations. It took 22 years from the time a box warning was required by the FDA until the warnings were removed in 1999. The 1999 FDA publication, which is a scholarly and objective document, should put an end to 2 decades of concern and anxiety for pregnant women or women of reproductive age. Could scientists, the pharmaceutical companies, or the FDA have prevented the mislabeling of progestational drugs with regard to their teratogenic risks? Was the epidemiological or teratology community at fault because they did not critique and respond to the early publications? Did the FDA act too slowly? The epidemiologic analyses, animal studies, and basic science principles have been reviewed, and it is obvious that clinically utilized progestational drugs do not cause nongenital malformations (i.e., LRDs and CHDs).

show abstract

Teratogenic effects of Silastic intrauterine devices in the rat with or without added medroxyprogesterone acetate

Cited by 11 publications

References 16 publications

Distinguishing Androgen Receptor Agonists and Antagonists: Distinct Mechanisms of Activation by Medroxyprogesterone Acetate and Dihydrotestosterone

Distinguishing Androgen Receptor Agonists and Antagonists: Distinct Mechanisms of Activation by Medroxyprogesterone Acetate and Dihydrotestosterone

Relationship between congenital anomalies and contraception

Nongenital malformations following exposure to progestational drugs: The last chapter of an erroneous allegation

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