Cytochrome b(5) modulation of 17{alpha} hydroxylase and 17-20 lyase (CYP17) activities in steroidogenesis. (1/28)

CYP17 is a steroidogenic enzyme located in the zona fasciculata and zona reticularis of the adrenal cortex and gonad tissues and which has dual functions - hydroxylation and as a lyase. The first activity gives hydroxylation of pregnenolone and progesterone at the C(17) position to generate 17alpha-hydroxypregnenolone and 17alpha-hydroxyprogesterone, while the second enzymic activity cleaves the C(17)-C(20) bond of 17alpha-hydroxypregnenolone and 17alpha-hydroxyprogesterone to form dehydroepiandro-sterone and androstenedione respectively. The modulation of these two activities occurs through cytochrome b(5). Association of cytochrome b(5) and CYP17 is thought to be based primarily on electrostatic interactions in which the negatively charged residues pair up with positively charged residues on the proximal surface of the CYP17 molecule. Non-specific interactions of the hydrophobic membrane regions of cytochrome b(5) and CYP17 are also thought to play a crucial role in the association of these two haemoproteins. Although cytochrome b(5) is known to stimulate CYP activity by contributing the second electron in the catalytic cycle, in the case of CYP17, the mechanism of cleavage stimulation proceeds via an allosteric mode. It is hypothesised that cytochrome b(5) promotes the cleavage by aligning the iron-oxygen complex attack onto the C(20) rather than the C(17) atom of the steroid substrate molecule. Thus, further understanding of the mechanism of modulation by cytochrome b(5) of the hydroxylase and lyase activities should shed new insights on developing therapeutic targets in CYP17-linked biochemical processes such as adrenarche, polycystic ovary syndrome and prostate cancer.  (+info)

Early puberty-menarche after precocious pubarche: relation to prenatal growth. (2/28)

OBJECTIVE: Girls with precocious pubarche (PP; pubic hair at <8 years of age) as a result of an early or amplified adrenarche (high dehydroepiandrosterone-sulfate [DHEAS]) tend to be hyperinsulinemic, in particular when born with low birth weight (LBW). The objective of this study was to assess the interrelationship among prenatal growth, PP, the timing of puberty-menarche, and adult stature. METHODS: We studied 187 PP girls longitudinally: (1) at birth, (2) in prepuberty, (3) at onset of puberty, (4) at menarche, and (5) on reaching adult stature. This PP cohort was divided into subgroups of higher birth weight (>0 SD), intermediate birth weight (0 to -2 SD), and lower birth weight (less than -2 SD). RESULTS: At the time of PP diagnosis, age, bone age, and BMI were similar across birth weight subgroups; circulating sex hormone-binding globulin and body height were reduced in PP girls with lower birth weight, and these remained so throughout pubertal development. Onset of puberty occurred earlier in PP girls with lower birth weight; so did menarche. Adult height differed by an average of 6.5 cm (approximately 1 SD) between the upper and lower birth weight subgroups; this difference was essentially achieved before puberty and even before PP. Menarche before age 12.0 years was twofold more prevalent in PP girls than in control subjects. Among PP girls, age at menarche was advanced by 8 to 10 months in lower versus higher birth weight girls. Menarche before age 12.0 years was threefold more prevalent among LBW-PP girls than in control subjects (approximately 75% vs approximately 25%). CONCLUSIONS: The link between prenatal growth restraint and early menarche is herewith extended to PP girls. In particular LBW-PP girls may become a target group for interventions directed toward normalization of pubertal onset and progression.  (+info)

Adrenarche in the rat. (3/28)

Normal pubertal development in humans involves two distinct processes: maturation of adrenal androgen secretion (adrenarche) and activation of the hypothalamic-pituitary-gonadal axis (gonadarche). One factor thought to contribute to the adrenarche in man is increased adrenal 17-hydroxylase (CYP17) activity. In the rat, there is evidence for adrenal involvement in the initiation of puberty, but the adrenal glands of this species are generally thought to express CYP17 only very poorly at best. To further examine the nature of postnatal adrenal development in rat, plasma samples and adrenal tissues were taken from animals aged 2-90 days, circulating adrenal steroids assayed, and adrenal zones assessed quantitatively. A relative increase in zona reticularis, and peaks of circulating cortisol, androstenedione, and 17-OH-progesterone were observed around postnatal days 16-20, clearly before the development of the gonads, which begins at 30-35 days. Quantitative reverse transcriptase PCR confirmed a peak in mRNA coding for CYP17 in adrenal tissue from rats of similar age. The results suggest that the rat adrenal has the capacity to secrete steroids arising from 17-hydroxylation, and that this may contribute to a process similar to human adrenarche.  (+info)

Differences in endocrine parameters and psychopathology in girls with premature adrenarche versus on-time adrenarche. (4/28)

Girls with premature adrenarche (PA) are at risk for multiple problems related to exaggerated androgen synthesis. Whether PA carries a risk of psychopathology remains unknown. This study examined group differences in: (a) anthropometric and endocrine parameters, and (b) mood and behavior problems, in 6-8 year-old girls with PA (n = 40) compared to on-time adrenarche girls (n = 36). PA girls were taller (p < or =0.05) and heavier (p < or =0.01) than the on-time adrenarche girls but body mass index showed no difference. PA girls had significantly (p <0.05) higher adrenal androgen and testosterone concentrations but not cortisol or leptin. PA girls also had significantly more oppositional defiant disorder, and higher symptom counts reflecting anxiety, mood or disruptive behavior disorders. PA girls may be more vulnerable to psychopathology than on-time adrenarche girls. The challenge of future studies is to determine which PA girls are at risk for psychopathology and which are more resilient.  (+info)

Morphological adrenarche in rhesus macaques: development of the zona reticularis is concurrent with fetal zone regression in the early neonatal period. (5/28)

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Adrenal changes associated with adrenarche. (6/28)

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Body composition in premature adrenarche by structural MRI, 1H MRS and DXA. (7/28)

BACKGROUND: Premature adrenarche (PA) is recognized to be a possible precursor of polycystic ovarian syndrome, type 2 diabetes mellitus and cardiovascular disease. Visceral adiposity and increased intramyocellular lipid (IMCL) are associated with insulin resistance and increased risk of cardiovascular disease. AIM: To determine whether prepubertal girls with PA have altered visceral adiposity and/or increased muscle lipid content compared to prepubertal girls without PA using proton magnetic resonance imaging (MRI) and spectroscopy (1H MRS). PATIENTS AND METHODS: We performed total body dual energy X-ray absorptiometry (DXA) scans, MRI of the trunk, and MRS of the tibialis anterior muscle in the right calf on six girls with PA and eight prepubertal controls. RESULTS: Amount of visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), and VAT to SAT ratio did not differ significantly between the PA and control girls. Those with PA, however, had significantly greater IMCL than controls (p = 0.004). CONCLUSIONS: This study adds further evidence that PA is not a benign condition, and future studies investigating early intervention with dietary and exercise counseling may help diminish potential risk for diabetes mellitus and/or cardiovascular disease.  (+info)

Utility of early insulin response and proinsulin to assess insulin resistance. (8/28)

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