A potential mechanism in medroxyprogesterone acetate teratogenesis

Kimmel, Gary L.; Hartwell, B. S.; Andrew, F. D.

doi:10.1002/tera.1420190207

Cited by 22 publications

(7 citation statements)

References 29 publications

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“…Although a large number of studies have failed to show progesterone as a human teratogen (10,12,21). It would be pertinent to note that almost all of the major studies performed to explore the link of exogenous progesterone with birth defects were carried out in the 1970s and 1980s, when in-vitro fertilization was not as common as it is nowbeing the mechanism of conception in almost 1% of all live births in developed countries.…”

Section: Discussionmentioning

confidence: 99%

The role of folic acid in prevention of neural tube defects caused by high dose progesterone.

Iqbal

Qamar²,

Butt³

et al. 2011

Turkish Neurosurgery

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AIm:To describe the effect of high dose progesterone (HDP) alone, or in combination with folic acid (FA), on occurrence of neural tube defects (NTDs) in chick embryo. mAterIAl and methOds: 60 Fertile, specific eggs of Fyoumi species of chick were selected at zero hr of incubation. They were incubated at 37.5 ºC and 75% relative humidity until the embryos reached stage eight of development. At this stage the eggs were divided into four groups consisting of 15 eggs/group. The 1st group was incubated without any operation. The 2nd group was injected with physiological saline. The 3rd and 4th groups were injected with HDP (20x physiologic dose of progesterone) and HDP with supplement of 5 micrograms/embryo of FA, respectively. After 48 hrs of incubation, all embryos were reviewed for the presence of NTDs under light microscopy.results: None of the eggs in the control, and saline injection groups showed NTDs, whereas 75 % (9/12) of the embryos in the 3rd group, and 58.3 % (7/12) of the chick embryos in 4th group showed NTDs. COnClusIOn: Exogenous progesterone at levels twenty times above its physiologic range in chick embryos causes NTDs. FA supplementation decreases the frequency of NTDs but does not abolish them.KeywOrds: Neural tube defects, Progesterone, Folic acid, Chick embryo, Neural tube closure ÖZ AmAÇ: Yalnızca Progesteron ve progesterona ilave olarak Folik asit ile ile kombine edilmiş uygulamanın civciv embiryosunda nöral tüp defekti oluşumu üzerine olan etkisi. yÖntem ve GereÇ: Çalışmada, inkübasyonun 0. saatinde 60 fertil Fyoumi türü civciv embiryosu kullanıldı.Tüm embiryolar gelişimlerinin 8. evresine kadar, 37,5 ºC ve 75 % nemli ortamda inkübasyona tabi tutuldu. Bu evrede embiryolar 15'erli 4 gruba ayrıldı. Birinci grup herhangi bir işleme maruz bırakılmaksızın inkübasyona tabi tutuldu. İkinci gruba serum fizyolojik injeksiyonu yapıldı. Üçüncü gruba yüksek doz progesteron (fizyolojik dozun 20 katı), dördüncü gruba yüksek doz progesterona ek olarak 5 mikrogram folik asit injeksiyonu yapıldı. Bu işlemlerden sonraki 48 saat boyunca inkübe edilen embriyolar ışık mikroskobunda nöral tüp defekti gelişimi açısından incelemeye alındı.BulGulAr: Kontrol grubunda ve serum fizyolojik injeksiyonu yapılan grupta nöral tüp defekti saptanmazken, 3. grupta % 75 oranında (9/12), 4. grupta ise % 58,3 (7/12) oranında nöral tüp defekti geliştiği görüldü.sOnuÇ: Fizyolojik dozun 20 katında uygulanan progesteron civciv embriyolarında nöral tüp defekti oluşumuna neden olmaktadır. Folik asit desteği nöral tüp defekti oluşum sıklığını azaltsa da defektin görülmesini tam olarak ortadan kaldıramamaktadır.

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Section: Discussionmentioning

confidence: 99%

The role of folic acid in prevention of neural tube defects caused by high dose progesterone.

Iqbal

Qamar²,

Butt³

et al. 2011

Turkish Neurosurgery

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“…MPA has some unusual qualities with regard to its receptor affinity and cross-specificity (Carbone et al, 1990a, b;Kimmel et al, 1979). MPA can affect the development of the palate in the rabbit because it reacts with the glucocorticoid receptor, but only in doses far above the human therapeutic level.…”

Section: In the Teratogenic Animal Model Does The Frequency Of Malfomentioning

confidence: 97%

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).

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“…Although long-term safety of progesterone supplementation in pregnancy remains a justified concern, studies including follow-up for a mean of 11.5 years could document no teratogenic or fetotoxic effects. 79 The teratogenic effects reported with MPA in earlier studies 80 were not verified on subsequent, better-designed studies with longer follow-up. 81 ACOG recommends that the use of progesterone supplementation in pregnancy to prevent PTD should be restricted to women with a documented history of prior spontaneous PTD.…”

Section: Role Of Local or Systemic Hormonal Effectsmentioning

confidence: 97%

From Concept to Practice: The Recent History of Preterm Delivery Prevention. Part II: Subclinical Infection and Hormonal Effects

Vidaeff¹,

Ramin²

2006

Am J Perinatol

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Under the new cervical insufficiency postulate, the final common pathway theoretically may be influenced by multiple interventions including not only cerclage, but also antibiotics, anti-inflammatory drugs, or progesterone. Since the late 1970s, accumulating evidence has implicated intrauterine infection as a cause of preterm labor. The use of antimicrobial therapy for the prevention of preterm delivery (PTD), although plausible and appealing, has remained largely ineffective so far. A decade of antimicrobial intervention trials to prevent infection-mediated PTD has had disappointing results. Several randomized clinical trials have assessed the role of bacterial vaginosis (BV) treatment in prevention of PTD. The inconsistent results of these trials suggest that other processes, possibly immunomodulation, may be important. Additional factors, still unidentified, pertaining to infectious agent virulence or host immune response modulation, may be responsible for the increased risk of PTD in only a small subset of pregnant women with BV. Even a particular genetic susceptibility was proposed as an intervening factor in the correlation between BV and PTD. Autocrine, paracrine, and endocrine processes in the fetal-placental-uterine unit may contribute to the premature activation of parturitional mechanisms. Progesterone has been used in an attempt to prevent PTD since the 1970s, but the evidence accumulated until the 1990s was fraught by mixed results, and was based mostly on underpowered studies with variable eligibility criteria, including history of spontaneous abortion as an indication for treatment. Two recent randomized, controlled clinical trials restimulated the interest in progesterone supplementation, suggesting that progesterone treatment may influence favorably the rate of preterm delivery, as well as perinatal mortality and morbidity. A major impediment in accepting progesterone as the magic bullet in the prevention of PTD is that its mechanism of action is less well understood than that of all the other prophylactic measures discussed in this review. The optimal formulation, route of administration, dose, and gestational age at initiation have yet to be established. Our ability to quantify prospectively the risk of PTD in a given patient is limited. Moreover, there are limited evidence-based strategies available for prevention of PTD, reflecting our incomplete understanding of the nature of preterm labor. Although an effective instrument in PTD prevention is still elusive, the studies conducted so far have led to a shift in our understanding of cervical insufficiency, infection-mediated PTD, and hormonal influences in human parturition.

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A potential mechanism in medroxyprogesterone acetate teratogenesis

Cited by 22 publications

References 29 publications

The role of folic acid in prevention of neural tube defects caused by high dose progesterone.

The role of folic acid in prevention of neural tube defects caused by high dose progesterone.

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

From Concept to Practice: The Recent History of Preterm Delivery Prevention. Part II: Subclinical Infection and Hormonal Effects

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