Embryotoxicity and maternal serum concentrations of medroxyprogesterone acetate (MPA) in baboons (Papio cynocephalus

doi:10.1016/0010-7824(85)90020-4

Contraception

Volume 32, Issue 5, November 1985, Pages 497-515

https://doi.org/10.1016/0010-7824(85)90020-4 Get rights and content

Abstract

A single dose of MPA (Depo-Provera; Upjohn Co.; USA) was administered intramuscularly on day 27 (± 2) of gestation to three dosage groups of pregnant baboons. The dosage expressed as mg/kg corresponded to 1 (2.5 mg/kg), 10 (25 mg/kg) and 40 (100 mg/kg) times the human contraceptive dose equivalent (HDE) based on body weight. Injectable MPA was not teratogenic in baboons at 1x HDE. The teratogenicity was confined to the higher doses which included malformations of the external genitalia at 10x and 40x HDE and adrenal gland hypoplasia at 40x HDE. The maternal serum MPA concentrations were high during the critical period of adrenal and genital development. The pattern of MPA concentrations in maternal sera was similar between animals in the low dose group (10x HDE). In contrast, animals in the high dose group (40x HDE) showed interanimal variations in maternal serum concentrations of MPA. This study has demonstrated that injectable MPA is not teratogenic in baboons at human contraceptive dose equivalent and, even at higher doses, does not result in any nontarget organ malformations.

References (42)

J.G. Wilson et al.
Are female sex hormones teratogenic?
Am. J. Obstet. Gynecol.
(1981)
F.J. Saunders et al.
Effects of ethynodiol diacetate and mestranol in rats and rabbits on conception, on the outcome of pregnancy, and on the offspring
Toxicol. Appl. Pharmacol.
(1967)
F. Neumann et al.
S.M. Barlow et al.
Teratogenic effects of silastic intrauterine devices in the rat with or without added medroxyprogesterone acetate
Fertil. Steril.
(1983)
L.R. Wharton et al.
Experimental production of genital lesions with norethindrone
Am. J. Obstet. Gynecol.
(1964)
M. Hiroi et al.
Radioimmunoassay of serum medroxyprogesterone acetate (Provera) in women following oral and intravaginal administration
Steroids
(1975)
K. Fotherby et al.
Pharmacokinetic study of different doses of Depo-Provera
Contraception
(1980)
G. Mora et al.
Plasma levels of medroxyprogesterone acetate (MPA), estradiol, and progesterone in the rhesus monkey after intramuscular administration of Depo-Provera
Contraception
(1976)
M.M. Grumbach et al.
The effect of androgens on fetal sexual development: Androgen-induced female pseudohermaphrodism
Fertil. Steril.
(1960)
R.N. Shain et al.

A. Rosenfield et al.

The Food and Drug Administration and medroxyprogesterone acetate. What are the issues?

JAMA

(1983)

M. Sun

Panel says Depo-Provera not proved safe

Science

(1984)

J. Weisz et al.

Report of the public board of enquiry on Depo-provera

(1984)

M. Lalit Ambani et al.

Are hormonal contraceptives teratogenic?

Fertil. Steril.

(1977)

M.H. Briggs et al.

Sex hormone exposure during pregnancy and malformations

Adv. Steroid Biochem. Pharmacol.

(1979)

J.L. Schardein

Congenital abnormalities and hormones during pregnancy: A clinical review

Teratology

(1980)

J.L. Simpson

Z. Katz et al.

Teratogenicity of progestogens given during the first trimester of pregnancy

Obstetrics and Gynecology

(1985)

K.L. Peterson et al.

The effect of various steroids on mating behavior, fertility and fecundity of rats

Int. J. Fertil.

(1965)

S.K. Roy et al.

Foetal effect of norethynodrel in rats

Indian J. Exp. Biol.

(1967)

J.T. Gidley et al.

Teratogenic and other effects produced in mice by norethynodrel and its 3-hydroxymetabolites

Teratology

(1970)

Cited by (14)

In an in-vitro model using human fetal membranes, 17-α hydroxyprogesterone caproate is not an optimal progestogen for inhibition of fetal membrane weakening
2017, American Journal of Obstetrics and Gynecology
Citation Excerpt :
Studies with primary human chorion cells, in a mouse inflammatory-mediated parturition model, and our previously published data suggest MPA may be more promising than 17OHP-C for the prevention of preterm birth.57,75-78 Clinicians have hesitated in utilizing MPA for the prevention of spontaneous preterm birth because of potential androgenic fetal effects, but published studies have been contradictory, and some long-term studies of first-trimester human fetal exposure have even been reassuring.79-84 However, clinical trials of MPA, all performed decades ago, failed to demonstrate efficacy in preventing spontaneous preterm births in at-risk pregnancies.85-89
The progestogen 17-α hydroxyprogesterone caproate (17-OHPC) is 1 of only 2 agents recommended for clinical use in the prevention of spontaneous preterm delivery, and studies of its efficacy have been conflicting. We have developed an in-vitro model to study the fetal membrane weakening process that leads to rupture in preterm premature rupture of the fetal membranes (pPROM). Inflammation/infection associated with tumor necrosis factor-α (TNF-α) induction and decidual bleeding/abruption associated thrombin release are leading causes of preterm premature rupture of the fetal membranes. Both agents (TNF-α and thrombin) cause fetal membrane weakening in the model system. Furthermore, granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical intermediate for both TNF-α and thrombin-induced fetal membrane weakening. In a previous report, we demonstrated that 3 progestogens, progesterone, 17-alpha hydroxyprogesterone (17-OHP), and medroxyprogesterone acetate (MPA), each inhibit both TNF-α– and thrombin-induced fetal membrane weakening at 2 distinct points of the fetal membrane weakening pathway. Each block both the production of and the downstream action of the critical intermediate granulocyte-macrophage colony-stimulating factor.
The objective of the study was to characterize the inhibitory effects of 17-OHPC on TNF-α– and thrombin-induced fetal membrane weakening in vitro.
Full-thickness human fetal membrane fragments from uncomplicated term repeat cesarean deliveries were mounted in 2.5 cm Transwell inserts and cultured with/without 17-alpha hydroxyprogesterone caproate (10^–9 to 10^–7 M). After 24 hours, medium (supernatant) was removed and replaced with/without the addition of tumor necrosis factor-alpha (20 ng/mL) or thrombin (10 U/mL) or granulocyte-macrophage colony-stimulating factor (200 ng/mL). After 48 hours of culture, medium from the maternal side compartment of the model was assayed for granulocyte-macrophage colony-stimulating factor and the fetal membrane fragments were rupture strength tested.
Tumor necrosis factor-alpha and thrombin both weakened fetal membranes (43% and 62%, respectively) and increased granulocyte-macrophage colony-stimulating factor levels (3.7- and 5.9-fold, respectively). Pretreatment with 17-alpha hydroxyprogesterone caproate inhibited both tumor necrosis factor-alpha– and thrombin-induced fetal membrane weakening and concomitantly inhibited the induced increase in granulocyte-macrophage colony-stimulating factor in a concentration-dependent manner. However, contrary to our prior reports regarding progesterone and other progestogens, 17-alpha hydroxyprogesterone caproate did not also inhibit granulocyte-macrophage colony-stimulating factor–induced fetal membrane weakening.
17-Alpha hydroxyprogesterone caproate blocks tumor necrosis factor-alpha– and thrombin-induced fetal membrane weakening by inhibiting the production of granulocyte-macrophage colony-stimulating factor. However, 17-alpha hydroxyprogesterone caproate did not also inhibit granulocyte-macrophage colony-stimulating factor–induced weakening. We speculate that progestogens other than 17-alpha hydroxyprogesterone caproate may be more efficacious in preventing preterm premature rupture of the fetal membranes–related spontaneous preterm birth.
Toxicology of depot medroxyprogesterone acetate
1994, Contraception
Depo-Provera (depot-medroxyprogesterone acetate or DMPA), administered either subcutaneously or intramuscularly, has undergone a thorough toxicological evaluation in a number of animal species. DMPA has been tested in short- and long-term toxicity studies in rodents, rabbits, and monkeys. It has been examined for its effects on reproduction in mice, rats, and rabbits, and for carcinogenic potential in rats, mice, beagle dogs, and rhesus monkeys. Genotoxicity tests have been performed in vitro and in vivo. This paper describes the toxicology data submitted to the US FDA in support of the New Drug Application (NDA) for Depo-Provera as well as data published in the literature. When interpreted in the light of the available pharmacokinetic information, these data demonstrate that DMPA is not significantly different from other contraceptive progestogens in its toxic and tumorigenic potential.
Developmental effects of progesterone and its derivatives
1988, Reproductive Toxicology
NTP Research Report on the Scoping Review of Prenatal Exposure to Progestogens and Adverse Health Outcomes Research Report 17
2020, NTP Research Report Series
Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk: Tenth edition
2014, Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk: Tenth Edition
Pre- and Postnatal Development in the Cynomolgus Monkey Following Administration of ABT-874, a Human Anti-IL-12/23p40 Monoclonal Antibody
2012, Birth Defects Research Part B - Developmental and Reproductive Toxicology

View all citing articles on Scopus

View full text

Embryotoxicity and maternal serum concentrations of medroxyprogesterone acetate (MPA) in baboons (Papio cynocephalus

Abstract

Am. J. Obstet. Gynecol.

Toxicol. Appl. Pharmacol.

Fertil. Steril.

Am. J. Obstet. Gynecol.

Steroids

Contraception

Contraception

Fertil. Steril.

The Food and Drug Administration and medroxyprogesterone acetate. What are the issues?

JAMA

Panel says Depo-Provera not proved safe

Science

Report of the public board of enquiry on Depo-provera

Are hormonal contraceptives teratogenic?

Fertil. Steril.

Sex hormone exposure during pregnancy and malformations

Adv. Steroid Biochem. Pharmacol.

Congenital abnormalities and hormones during pregnancy: A clinical review

Teratology

Teratogenicity of progestogens given during the first trimester of pregnancy

Obstetrics and Gynecology

The effect of various steroids on mating behavior, fertility and fecundity of rats

Int. J. Fertil.

Foetal effect of norethynodrel in rats

Indian J. Exp. Biol.

Teratogenic and other effects produced in mice by norethynodrel and its 3-hydroxymetabolites

Teratology

Embryotoxicity and maternal serum concentrations of medroxyprogesterone acetate (MPA) in baboons ( $Papio cynocephalus$