Pregnancy normalized familial hyperaldosteronism type I: a novel role for progesterone?

Campino, Carmen; Trejo, Pamela; Carvajal, Cristián A.; Vecchiola, Andrea; Valdivia, Carolina; Fuentes, César M.; Delgado, J F; Lagos, Carlos F.; Aglony, Marlene; Carrasco, Claudia; Martínez‐Aguayo, Alejandro; García, Hernán; Loureiro, Carlos Alfredo; Fardella, Carlos E.

doi:10.1038/jhh.2014.49

Cited by 22 publications

(14 citation statements)

References 10 publications

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“…Moreover, our previous study in a pregnant woman carrying familial hyperaldosteronism type I demonstrated an improvement in blood pressure, concomitant with the normalization of ARR. Following childbirth, progesterone and estradiol decreased, aldosterone increased, plasma renin activity was suppressed, and ARR was very high [10]. These observations support our previously reported in vitro study in which both the wild-type and chimeric aldosterone synthase enzyme activities were inhibited by progesterone, but estradiol demonstrated no effect [11].…”

Section: Introductionsupporting

confidence: 89%

“…Few studies have analyzed the effect of testosterone on aldosterone production, and the majority of these studies were performed using animal or experimental models. During our study with a male index case carrying FH-I and his pedigree consisting of 4 generations, we observed that aldosterone and ARR decreased with age [10]. Based on this family observation, we postulated that changes in male gonadal hormones observed during the transition from childhood to adulthood might also alter aldosterone levels, which in turn might explain the normalization of ARR in adulthood.…”

Section: Introductionmentioning

confidence: 67%

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Testosterone inhibits human wild-type and chimeric aldosterone synthase activity in vitro

Vecchiola

Fuentes

Carvajal

et al. 2020

Preprint

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BackgroundFamilial hyperaldosteronism type I is caused by the generation of a chimeric aldosterone synthase enzyme (ASCE) which is regulated by ACTH instead of angiotensin II. We have reported that in vitro, the wild-type (ASWT) and chimeric aldosterone synthase (ASCE) enzymes are inhibited by progesterone and estradiol did not affect.AimTo explore the direct action of testosterone on ASWT and ASCE enzymes.MethodsHEK-293 cells were transiently transfected with vectors containing the full ASWT or ASCE cDNAs. The effect of testosterone on AS enzyme activities were evaluated incubating HEK-cells transfected with enzymes vectors and adding deoxycorticosterone (DOC) alone or DOC plus increasing doses of testosterone. Aldosterone production was measured by HPLC-MS/MS. Docking of testosterone within the active sites of both enzymes was performed.ResultsIn this system, testosterone inhibited ASWT (90% inhibition at five µM, IC50=1.690 µM) with higher efficacy and potency than ASCE (80% inhibition at five µM, IC50=3.176 µM). Molecular modelling studies showed different orientation of testosterone in ASWT and ASCE crystal structures.ConclusionsThe inhibitory effect of testosterone on ASWT or ASCE enzymes is a novel non-genomic testosterone action, suggesting that further clinical studies are needed to assess the role of testosterone in the screening and diagnosis of primary aldosteronism.

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Section: Introductionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 67%

Testosterone inhibits human wild-type and chimeric aldosterone synthase activity in vitro

Vecchiola

Fuentes

Carvajal

et al. 2020

Preprint

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“…An unusual feature of PA during pregnancy is that the degree of disease may be either improved or aggravated. In some women with PA, the high blood concentrations of pregnancy‐related progesterone are antagonistic at the mineralocorticoid receptor and partially block the action of aldosterone; these patients in fact have an improvement in the degree of hypertension and hypokalaemia during pregnancy . In other pregnant women, increased expression of the luteinizing hormone–choriogonadotropin receptor in APAs harbouring beta‐catenin mutations has been documented, and the degree of hypertension and hypokalaemia can be aggravated by the increased pregnancy‐related blood levels of human chorionic gonadotropin .…”

Section: Pa In the Setting Of Pregnancymentioning

confidence: 99%

Diagnosis and treatment of primary aldosteronism: practical clinical perspectives

2018

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Primary aldosteronism (PA), the most common form of secondary hypertension, can be either surgically cured or treated with targeted pharmacotherapy. PA is frequently undiagnosed and untreated, leading to aldosterone‐specific cardiovascular morbidity and nephrotoxicity. Thus, clinicians should perform case detection testing for PA at least once in all patients with hypertension. Confirmatory testing is indicated in most patients with positive case detection testing results. The next step is to determine whether patients with confirmed PA have a disease that can be cured with surgery or whether it should be treated medically; this step is guided by computed tomography scan of the adrenal glands and adrenal venous sampling. With appropriate surgical expertise, laparoscopic unilateral adrenalectomy is safe, efficient and curative in patients with unilateral adrenal disease. In patients who have bilateral aldosterone hypersecretion, the optimal management is a low‐sodium diet and lifelong treatment with a mineralocorticoid receptor antagonist administered at a dosage to maintain a high–normal serum potassium concentration without the aid of oral potassium supplements.

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“…5 Genetic variation in the mineralocorticoid receptor may also contribute to the variability in blood pressure response in pregnancy. 6,9,11 Potassium levels down to 3.3 mmol/L are within reference range in healthy pregnancy. 15 Hypokalaemia may also improve in pregnancy due to the antikaliuretic effects of progesterone.…”

Section: Discussionmentioning

confidence: 88%

“…Progesterone, increases 1000-fold during pregnancy and competitively binds to aldosterone receptors, which leading to a physiological elevation in aldosterone in healthy pregnancies. 5,[9][10][11][12] Additionally, the ovaries and placental tissues secrete renin, further raising renin and aldosterone levels. 5,10,12 Estrogen stimulates hepatic angiotensinogen production, again leading to down-stream up-regulation of aldosterone.…”

Section: Discussionmentioning

confidence: 99%

High aldosterone, hypertension and adrenal adenoma in a 36-year-old pregnant patient: Is this primary aldosteronism?

et al. 2018

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A 36-year-old woman presented at 16 weeks’ gestation with severe hypertension. In comparison to the non-pregnant reference normal ranges, potassium was 3.1-3.9 mmol/L, aldosterone 2570-3000 pmol/L (N 250-2885) renin was unsuppressed (24-76.4 ng/L (N1.7–23.9)), with aldosterone to renin ratios in the reference range. An adrenal MRI scan demonstrated a 1.8 × 1.4 cm left adrenal adenoma. Primary aldosteronism was strongly suspected and surgery considered. However, she was managed conservatively with labetalol and modified-release nifedipine with no obstetric complications. Post-partum blood pressures remained elevated with normal aldosterone (539 pmol/L), unsuppressed renin (5.2 ng/L) and normal aldosterone-to-renin ratio (104 (N < 144)). Suspected primary hyperaldosteronism is challenging to investigate and manage in pregnancy. The accepted screening and confirmatory tests are either contraindicated or not validated in pregnancy. Pregnancy has significant effects on the renin-angiotensin-aldosterone pathway leading to physiologic elevations in both aldosterone and renin. While primary hyperaldosteronism has been associated with poor pregnancy outcomes, optimal management in pregnancy is not clearly established.

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Pregnancy normalized familial hyperaldosteronism type I: a novel role for progesterone?

Cited by 22 publications

References 10 publications

Testosterone inhibits human wild-type and chimeric aldosterone synthase activity in vitro

Testosterone inhibits human wild-type and chimeric aldosterone synthase activity in vitro

Diagnosis and treatment of primary aldosteronism: practical clinical perspectives

High aldosterone, hypertension and adrenal adenoma in a 36-year-old pregnant patient: Is this primary aldosteronism?

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