Integrative genomic analysis reveals a conserved role for prolactin signalling in the regulation of adrenal function

Ruggiero, Carmen; Altieri, Barbara; Arnold, Edith; Siqueiros‐Márquez, Lourdes; Doghman, Mabrouka; Detomas, Mario; Durand, Nelly; Jarjat, Marielle; Kurlbaum, Max; Chatonnet, Fabrice; Deutschbein, Timo; Clapp, Carmen; Lalli, Enzo

doi:10.1002/ctm2.630

Cited by 5 publications

(6 citation statements)

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“…Recently, it was proposed that adrenal renewal is sexually dimorphic 36,56 . In our study, we were not able to find any significant transcriptomic differences between the two sexes, potentially due to the small sample size (tissue from two females versus four males) and the limited number of (few hundreds of) detected expressed genes per nucleus.…”

Section: Discussionmentioning

confidence: 99%

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

Altieri

Secener

Sai

et al. 2022

Preprint

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The human adrenal gland is a complex endocrine tissue. Developmental studies on this tissue have been limited to animal models or human foetus. Here, we present a cell atlas analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland development and tumourigenesis. We identified two populations of potential progenitor cells resident within the adrenal cortex: adrenocortical progenitors NR2F2+-ID1+ cells, located within and underneath the capsule, and medullary progenitors SYT1+-CHGA- cells, located in islets in the subcapsular region. Using pseudotime analyses, we provided evidence of the centripetal nature of adrenocortical cell development and of the essential role played by the Wnt/β-catenin pathway in the adrenocortical self-renewal. By comparing transcriptional profiles of cells of normal adrenal glands and adrenocortical adenomas we revealed a high heterogeneity with six adenoma-specific clusters. Overall, our results give insights into adrenal plasticity and mechanisms underlying adrenocortical tumourigenesis.

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Section: Discussionmentioning

confidence: 99%

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

Altieri

Secener

Sai

et al. 2022

Preprint

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“…[21,22] We have shown that in basal conditions PRL-dependent signalling is significantly activated in the adult mouse female adrenal gland compared to the male. [18] Both higher circulating PRL levels [23] and higher adrenal expression of the PRLR in females may contribute to this phenomenon. The sexually dimorphic expression of PRLR is conserved in human (Figure 1B) and rat [24] adrenal glands.…”

Section: Animal Studiesmentioning

confidence: 99%

“…[ 49 ] We have reported that in our PRLA patient cohort there was significant upregulation of DHEAS (Figure 1G) while the circulating levels of all the other steroids investigated were not significantly modified at the basal state and after short‐term stimulation with ACTH. [ 18 ] It is possible that the effects of hyperprolactinemia on ACTH‐stimulated steroid secretion would be revealed only after a longer period of stimulation with corticotropin, as shown in the study by Kandeel et al. [ 44 ] Further evidence for a causal effect of high PRL to increase DHEAS levels is provided by their significant reduction after therapy with dopamine agonists which inhibit PRL, but not ACTH, secretion (Figure 1G).…”

Section: Introductionmentioning

confidence: 98%

“…All PRLR isoforms are significantly upregulated in the adult female adrenal gland compared to the male. [ 18 ] Previous studies using a reporter fluorescent mouse strain localized PRLR in all zones of the adrenal cortex, while no expression was present in the medulla. [ 20 ] Signalling from the PRLR is functional in the adrenal cortex.…”

Section: Introductionmentioning

confidence: 99%

“…[ 40,42,45,47 ] It is remarkable that in our study relatively smaller increases in circulating PRL levels were sufficient to elevate DHEAS levels in women with PRLA compared to men, as shown by the increased PRL/DHEAS ratio in male compared to female patients. [ 18 ] In addition, Williams et al have described seven cases of PRLA associated with primary aldosteronism, a leading cause of endocrine hypertension. Those authors showed that PRLR is expressed at higher levels in aldosterone‐producing adenomas compared to normal adrenal cortex and that PRL can increase CYP11B2 expression and aldosterone production in the H295R human adrenocortical cell line.…”

Section: Introductionmentioning

confidence: 99%

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Prolactin as an adrenocorticotropic hormone: Prolactin signalling is a conserved key regulator of sexually dimorphic adrenal gland function in health and disease

Lalli

Figueiredo²

2022

BioEssays

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A large number of previous reports described an effect of the pituitary hormone prolactin (PRL) on steroid hormone production by the adrenal cortex. However, those studies remained anecdotal and were never converted into a conceptual and mechanistic framework, let alone being translated into clinical care. In the light of our recently published landmark study where we described PRL signalling as a pivotal regulator of the sexually dimorphic adrenal phenotype in mouse and of adrenal androgen production in humans, we present here the overarching hypothesis that PRL signalling increases the activity of Steroidogenic Factor-1 (SF-1/NR5A1), a transcription factor that has an essential role in adrenal gland development and function, to regulate adrenal cortex growth and hormonal production in physiological and pathological conditions. PRL can then be considered as a bona fide adrenocorticotropic hormone synergizing with ACTH in the endocrine control of adrenal cortex function.

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ACTH and prolactin synergistically and selectively regulate CYP17 expression and adrenal androgen production in human foetal adrenal organ cultures

Schneider,

Ruggiero,

Renault

et al. 2023

European Journal of Endocrinology

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Objective The essential role of ACTH on the growth and function of the human foetal adrenal (HFA) has long been recognized. In addition, many studies have suggested a role of the pituitary hormone prolactin (PRL) in the regulation of the HFA, but the effects of this hormone on steroidogenesis and gene expression are still unknown. Our objective was to investigate the effect of ACTH and PRL on the steroidogenic capacities of the HFA. Design In vitro/ex vivo experimental study. Methods We used a hanging drop in vitro organ culture system. First trimester HFA samples were cultured for 14 days in basal conditions or treated with ACTH, PRL, or a combination of the 2 (3 to 11 replicates depending on the experiment). Steroids were measured by liquid chromatography/tandem mass spectrometry or immunoassay, gene expression by RT-qPCR, and protein expression by immunoblot. Results ACTH significantly increased corticosterone, cortisol, and cortisone production, both by itself and when used together with PRL. PRL stimulation by itself had no effect. Combined stimulation with ACTH + PRL synergistically and selectively increased adrenal androgen (DHEAS and Δ4-androstenedione) production and CYP17A1 expression in the HFA, while treatment with each single hormone had no significant effect on those steroids. Conclusions These results have important implications for our understanding of the hormonal cues regulating adrenal steroidogenesis in the HFA during the first trimester in physiological and pathological conditions and warrant further studies to characterize the molecular mechanisms of converging ACTH and PRL signalling to regulate CYP17A1 expression.

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Integrative genomic analysis reveals a conserved role for prolactin signalling in the regulation of adrenal function

Cited by 5 publications

References 10 publications

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

Prolactin as an adrenocorticotropic hormone: Prolactin signalling is a conserved key regulator of sexually dimorphic adrenal gland function in health and disease

ACTH and prolactin synergistically and selectively regulate CYP17 expression and adrenal androgen production in human foetal adrenal organ cultures

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