Regulation of steroidogenesis in a primary pigmented nodular adrenocortical disease-associated adenoma leading to virilization and subclinical Cushing's syndrome.
BACKGROUND
Primary pigmented nodular adrenocortical disease (PPNAD) can lead to steroid hormone overproduction. Mutations in the cAMP protein kinase A regulatory subunit type 1A (PRKAR1A) are causative of PPNAD. Steroidogenesis in PPNAD can be modified through a local glucocorticoid feed-forward loop.


OBJECTIVE
Investigation of regulation of steroidogenesis in a case of PPNAD with virilization.


METHODS
A 33-year-old woman presented with primary infertility due to hyperandrogenism. Elevated levels of testosterone and subclinical ACTH-independent Cushing's syndrome led to the discovery of an adrenal tumor, which was diagnosed as PPNAD. In vivo evaluation of aberrantly expressed hormone receptors showed no steroid response to known stimuli. Genetic analysis revealed a PRKAR1A protein-truncating Q28X mutation. After adrenalectomy, steroid levels normalized. Tumor cells were cultured and steroidogenic responses to ACTH and dexamethasone were measured and compared with those in normal adrenal and adrenocortical carcinoma cells. Expression levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) types 3 and 5 and steroid receptors were quantified in PPNAD, normal adrenal, and adrenal adenoma tissues.


RESULTS
Isolated PPNAD cells, analogous to normal adrenal cells, showed both increased steroidogenic enzyme expression and steroid secretion in response to ACTH. Dexamethasone did not affect steroid production in the investigated types of adrenal cells. 17β-HSD type 5 was expressed at a higher level in the PPNAD-associated adenoma compared with control adrenal tissue.


CONCLUSIONS
PPNAD-associated adenomas can cause virilization and infertility by adrenal androgen overproduction. This may be due to steroidogenic control mechanisms that differ from those described for PPNAD without large adenomas.
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Johannes
J
Hofland
Wouter W
WW
de Herder
Lieke
L
Derks
Leo J
LJ
Hofland
Peter M
PM
van Koetsveld
Ronald R
RR
de Krijger
Francien H
FH
van Nederveen
Anelia
A
Horvath
Constantine A
CA
Stratakis
Frank H
FH
de Jong
Richard A
RA
Feelders
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000236:Adenoma / Q000150:complications / Q000503:physiopathology / Q000601:surgery; D000303:Adrenal Cortex Diseases / Q000150:complications / Q000503:physiopathology* / Q000601:surgery; D000311:Adrenal Glands / Q000378:metabolism*; D018246:Adrenocortical Adenoma / Q000150:complications* / Q000503:physiopathology / Q000601:surgery; D000324:Adrenocorticotropic Hormone / Q000502:physiology; D000328:Adult; D003480:Cushing Syndrome; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D005260:Female; D006801:Humans; D013739:Testosterone / Q000097:blood; D014770:Virilism / Q000209:etiology*
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D013739:Testosterone; D000324:Adrenocorticotropic Hormone; D015067:17-Hydroxysteroid Dehydrogenases