More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal "salt wasting" crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions--transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.

/pdf/congenital-adrenal-hyperplasia-due-to-21-hydroxylase-4s6a8fstbw.pdf

Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Hirsutism: Implications, etiology, and management☆

Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.

/pdf/the-pathogenesis-of-polycystic-ovary-syndrome-pcos-the-38p7ugs9et.pdf

The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.

Introduction The presence of corticosteroid-binding globulin (CBG) in plasma was detected about 30 yr ago, and of sex hormone-binding globulin (SHBG) about 20 yr ago. In the interval since their discovery, sophisticated binding and RIAs have been devised for their measurement; their concentrations in plasma and other biological fluids, from milk to saliva, have been measured in myriad clinical conditions in humans, and numerous experimental ones in animals; their phyletic distribution has been examined; they have been isolated and their complementary DNAs (cDNAs) cloned; their binding specificities for steroids have been examined in heroic detail; hormonal and drug influences on their plasma concentration in vivo, and their secretion by liver cells in vitro, have been widely explored; they have been the subject of two long, splendid monographs (1, 2) and many shorter reviews (3–11) [wherein the original citations for the first part of this sentence may be found]—and yet we still have not come to a consens...

The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances.

http://www.klinikum-dessau.de/fileadmin/user_upload/Hautklinik/PDF-Files/235_clinder-acne-etiol.pdf

Acne and sebaceous gland function

To determine the adrenal contribution to elevated plasma androgens in 31 young hyperandrogenemic women with acne and/or hirsutism, we compared their responses to ACTH with those of 14 normal women. Each subject was given a low dose (10 μg/m2) of synthetic ACTH-(l–24) (Cortrosyn) after administration of 1.5 mg dexamethasone the night before the test. Thirty and 60 min responses of plasma 17α-hydroxy-pregnenolone (17-Preg), 17α-hydroxyprogesterone, (17-prog), dehydroepiandrosterone (DHEA), androstenedione, 11-deoxycortisol, and cortisol were measured. Eighteen (58%) patients had increased responses of at least one 17-ketosteroid or adrenal androgen precursor. All patients had cortisol responses within the range of those of the 14 normal subjects. Nine patients (29%) had evidence of steroid biosynthetic enzyme deficiencies, either mild congenital adrenal hyperplasia or the heterozygote state; after ACTH, 4 of these patients had elevated 17-prog in the range of values in heterozygote carriers of 21-hydroxylas...

Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche.

We have tested the hypothesis that adrenarche results from an altered biosynthetic response to ACTH. Adrenarche is the maturational increase in the production of adrenal 17-ketosteroids, particularly dehydroepiandrosterone (DHA) and DHA-sulfate (DHAS). Apparent steroidogenic efficiency was estimated from relationships between plasma steroid intermediates after administering ACTH-(l–24). ACTH testing was performed after giving a bedtime dose of dexamethasone to suppress the early morning ACTH surge. Three groups of patients were studied: 6 prepubertal children, 10 females with isolated adrenarche, and 8 normal adult females in the follicular phase of their menstrual cycles. Prepubertal DHAS was 11, adrenarchal 105, and adult 208 μg/dl. Adults had 5-fold greater DHA and about 2-fold greater androstenedione (AD) and 17-hydroxyprogesterone (17-PROG) than prepubertal children. Overnight dexamethasone suppression led to reduction of most steroids in most groups. Thirty minutes after a 10-eg ACTH bolus, prepuber...

Adrenarche: Changing Adrenal Response to Adrenocorticotropin

To investigate the basis of the hirsutism and elevated plasma dehydroepiandrosterone (DHA) and/or DHA sulfate (DHAS) in hyperprolactinemic women, we measured androgen binding parameters and an extensive profile of plasma androgens in normal (NL) and hyperprolactinemic women (HYPRL). ACTH tests and dexamethasone (dex) suppression tests were performed in subgroups. Free testosterone levels were higher in HYPRL (13.1 ± 2.3 vs. 7.18 ± 0.72 pg/ml; P < 0.025), although total testosterone was comparable. This disparity was related to plasma testosterone- estradiol-binding globulin (TEBG) levels being one third lower in HYPRL (mean ± SE, 27.4 ± 4.0 nM) than in NL (41.2 ± 3.7 nM; P < 0.0125). Less striking elevations of plasma DHAS, androstenedione, and 11-deoxycortisol were found in HYPRL. Plasma total dihydrotestosterone [17β-hydroxy-5α-androstan-3-one (tDHT)7] was nearly 30% lower in HYPRL (11.2 ± 2.6 ng/dl) than in NL (15.6 ±1.3 ng/dl; P < 0.025), whereas free DHT was normal. Ratios of tDHT to precursors were ...

Multiple androgenic abnormalities, including elevated free testosterone, in hyperprolactinemic women.

ACTH tests were performed with and without dexamethasone (dex) pretreatment to clarify the nature of the relationship between the absolute and incremental response (Δ) to ACTH in normal men and women, hirsute women, adrenarchal children, and women heterozygous for congenital adrenal hyperplasia (CAH). The purposes were to test the effect of dex preparation on adrenal responsiveness to ACTH and the efficacy of the dex-pretreated ACTH test in detecting heterozygosity for CAH. Cosyntropin was given as a 10 μg⁄m2 iv bolus dose at 0800-1000 h; dex (1 mg⁄m2) was given at 2200-2400 h the night before. Dex did not alter the absolute plasma steroid levels achieved in response to ACTH. However, since post-dex baseline concentrations of adrenal steroids were lower, the Δ to ACTH was significantly greater for the major adrenal secretory products, 17«-hydroxypregnenolone (3β,17α-dihydroxypregn-5-ene-20- one), dehydroepiandrosterone, and cortisol (F). For example, for all paired tests, the mean plasma F values achieved...

Dexamethasone preparation does not alter corticoid and androgen responses to adrenocorticotropin.

DISPARITIES between biologic and immunologic potency estimates of several peptide hormones have been observed.1 , 2 The biologic implication of these differences is uncertain. Differences in estima...

James Helke

Papers

Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche.

Adrenarche: Changing Adrenal Response to Adrenocorticotropin

Multiple androgenic abnormalities, including elevated free testosterone, in hyperprolactinemic women.

Dexamethasone preparation does not alter corticoid and androgen responses to adrenocorticotropin.

Reduction of the potency of luteinizing hormone by estrogen.