Development and Function of the Adrenal Cortex and Medulla in the Fetus and Neonate

Antonini, Sonir Roberto Rauber; Stecchini, Monica F; Ramalho, Fernando Silva

doi:10.1016/b978-0-12-814823-5.00036-2

Cited by 6 publications

(8 citation statements)

References 58 publications

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“… 7 − 9 The early postnatal period is a transitional phase for the adrenal glands undergoing important structural remodeling with rapid involution of the inner fetal zone, the region of the adrenal cortex producing a large quantity of androgens that are essential for fetal development. 46 With the involution of the fetal zone, DHEA-S production by the adrenal is decreased, and the zona glomerulosa and fasciculata are rapidly developing. This maturation process is gestational age-dependent and can have profound effects on preterm infants and their survival rate.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, inhibition of CYP3A7 by ritonavir-lopinavir or nevirapine could suggest a common mode of action of these drugs hindering DHEA and DHEA-S metabolism in the neonatal liver and leading to an increase in circulating concentrations of these androgenic hormones and their precursors. It is notable that the neonates presenting adrenal hormonal imbalance after receiving the ARV treatment generally returned to normal levels a few days after stopping the treatment. − The early postnatal period is a transitional phase for the adrenal glands undergoing important structural remodeling with rapid involution of the inner fetal zone, the region of the adrenal cortex producing a large quantity of androgens that are essential for fetal development . With the involution of the fetal zone, DHEA-S production by the adrenal is decreased, and the zona glomerulosa and fasciculata are rapidly developing.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

Kandel

Lampe

2021

Chem. Res. Toxicol.

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Prophylactic antiretroviral therapy (ART) in HIV infected pregnant mothers and their newborns can dramatically reduce mother-to-child viral transmission and seroconversion in the neonate. The ritonavir-boosted lopinavir regimen, known as Kaletra, has been associated with premature birth and transient adrenal insufficiency in newborns, accompanied by increases in plasma dehydroepiandrosterone 3-sulfate (DHEA-S). In the fetus and neonates, cytochrome P450 CYP3A7 is responsible for the metabolism of DHEA-S into 16α-hydroxy DHEA-S, which plays a critical role in growth and development. In order to determine if CYP3A7 inhibition could lead to the adverse outcomes associated with Kaletra therapy, we conducted in vitro metabolic studies to determine the extent and mechanism of CYP3A7 inhibition by both ritonavir and lopinavir and the relative intrinsic clearance of lopinavir with and without ritonavir in both neonatal and adult human liver microsomes (HLMs). We identified ritonavir as a potent inhibitor of CYP3A7 oxidation of DHEA-S (IC 50 = 0.0514 μM), while lopinavir is a much weaker inhibitor (IC 50 = 5.88 μM). Furthermore, ritonavir is a time-dependent inhibitor of CYP3A7 with a K I of 0.392 μM and a k inact of 0.119 min –1 , illustrating the potential for CYP3A mediated drug–drug interactions with Kaletra. The clearance rate of lopinavir in neonatal HLMs was much slower and comparable to the rate observed in adult HLMs in the presence of ritonavir, suggesting that the addition of ritonavir in the cocktail therapy may not be necessary to maintain effective concentrations of lopinavir in neonates. Our results suggest that several of the observed adverse outcomes of Kaletra therapy may be due to the direct inhibition of CYP3A7 by ritonavir and that the necessity for the inclusion of this drug in the therapy may be obviated by the lower rate of lopinavir clearance in the neonatal liver. These results may lead to a reconsideration of the use of ritonavir in neonatal antiretroviral therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

Kandel

Lampe

2021

Chem. Res. Toxicol.

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“…A partir da 8ª semana de gestação, o córtex adrenal rudimentar já está conformado por uma camada interna, chamada zona fetal (zFt) e uma camada externa recém formada, chamada zona definitiva (zD). Apenas após a metade da gestação desenvolve-se uma terceira camada, a zona de transição (zT), que é derivada da zD e se localiza entre as zFt e zD (ANTONINI; STECCHINI; RAMALHO, 2020).…”

Section: Lista De Figurasunclassified

“…Esta rápida involução deve-se ao desaparecimento da zFt pelo processo de apoptose. Como consequência, o peso total das glândulas diminui em aproximadamente 50% (ANTONINI; STECCHINI; RAMALHO, 2020;ISHIMOTO;JAFFE, 2011).…”

Section: Lista De Figurasunclassified

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Papel do oncogene YAP1 no processo de tumorigênese e metástase e efeito de seu inibidor verteporfina nos tumores adrenocorticais pediátricos

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A new sonographic marker in the diagnosis of prenatal bilateral renal agenesis, segmental anterior deviation of the aorta

Özdemir

Kavak

et al. 2022

Case Reports in Perinatal Medicine

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Objectives Bilateral renal agenesis is a rare congenital anomaly that is associated with high neonatal mortality. Bilateral renal agenesis is most often present with anhydramniosis in the mid-trimester. Case presentation We report a case of bilateral renal agenesis diagnosed prenatally. We presented the ultrasound and pathology images of this fetus with a new sonographic sign, segmental anterior deviation in the abdominal aorta. Conclusions To our knowledge, this is the first reported case of a fetus with a segmental aortic anterior deviation.

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Development and Function of the Adrenal Cortex and Medulla in the Fetus and Neonate

Cited by 6 publications

References 58 publications

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

Papel do oncogene YAP1 no processo de tumorigênese e metástase e efeito de seu inibidor verteporfina nos tumores adrenocorticais pediátricos

A new sonographic marker in the diagnosis of prenatal bilateral renal agenesis, segmental anterior deviation of the aorta

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