Deficient pregnenolone synthesis associated with congenital adrenal hyperplasia and organelle dysfunction

Abstract

Summary Steroid hormones are essential for the survival of all mammals. In adrenal glands and gonads, cytochrome P450 side chain cleavage enzyme (SCC or CYP11A1), catalyzes conversion of cholesterol to pregnenolone. We studied a patient with ambiguous genitalia by the absence of Müllerian ducts and the presence of an incompletely formed vagina, who had extremely high adrenocorticotropic hormone (ACTH) and reduced pregnenolone levels with enlarged adrenal glands. The testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells. Electron microscopy showed that the patient’s testicular mitochondrial size was small with little SCC expression within the mitochondria. The mitochondria were not close to the mitochondria-associated ER membrane (MAM), and cells were filled with the microfilaments. Our result revealed that absence of pregnenolone is associated with organelle stress, leading to altered protein organization that likely created steric hindrance in testicular cells. Learning points: Testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells; Testicular mitochondrial size was small with little SCC expression within the mitochondria; Absence of pregnenolone is associated with organelle stress.

Side‐chain cleavage enzyme deficiency: Systematic review and case series

“…The severe phenotype with residual enzyme activity was postulated to be due to impaired intramitochondrial import of the mutant enzyme. However, this postulation was questioned later as intramitochondrial levels of mutant enzymes were identical to those of wild protein in cell function studies 26 . Another recent study suggested a role for pregnenolone deficiency‐driven endoplasm reticulum (ER) stress in reduced steroidogenesis.…”

“…Another recent study suggested a role for pregnenolone deficiency‐driven endoplasm reticulum (ER) stress in reduced steroidogenesis. In the presence of ER stress, a mutant enzyme with predicted residual activity may have markedly reduced activity leading to a severe phenotype 26 …”

“…Another recent study suggested a role for pregnenolone deficiency-driven endoplasm reticulum (ER) stress in reduced steroidogenesis. In the presence of ER stress, a mutant enzyme with predicted residual activity may have markedly reduced activity leading to a severe phenotype 26. Notably, 46,XX SCCD patients with genotypes (p.Glu314Lys/X-CHS or p.Phe215Ser/p.Arg232Ter), that are specific to 46,XY SCCD-TMG, had age-appropriate gonadotropin levels and/or spontaneous puberty.…”

Adrenal, Gonadal and Peripherally Steroid Changes in Response to Extreme Physical Stress for Characterizing Load Capacity in Athletes

“…Low dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHES), dihydrotestosterone (DHTT), and TEST levels have been associated with cardiovascular disease [13][14][15]. 17α-hydroxypregnenolone (OHPE) and 17α-hydroxyprogesterone (OHPG) tests have been valuable in diagnosing congenital adrenal hyperplasia [16,17]. Metabolic syndromes, such as Addison's or Cushing's disease, are characterized by abnormal cortisol (CTOL) levels [18].…”