Steroid biosynthesis

About: Steroid biosynthesis is a research topic. Over the lifetime, 1721 publications have been published within this topic receiving 58977 citations.

The inherited metabolic diseases

Abstract: Disorders of carbohydrate metabolism, D.B. Dunger and J.B. Holton amino acid disorders, R.J. Pollitt disorders of organic acid metabolism, R.A. Chalmers lysosomal storage disorders, C.A. Pennock peroxisomal disorders, R.B.H. Schutgens and R.J.A. Wanders defects of the mitochondrial respiratory chain, L.A. Bindoff and D.M. Turnbull purine and pyrimidine disorders, H.A. Simmonds the prophyrias, G.H. Elder collagen disorders, A.C. Nicholls inherited disorders of steroid biosynthesis, G.M. Addison lipid disorders, C.H. Bolton metal disorders, P.J. Aggett red cell disorders, A.J. Grimes and N.G.P. Slater.

Clinical and molecular review of atypical congenital adrenal hyperplasia.

Abstract: Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders. It comprises a group of autosomal recessive disorders caused by the mutations in the genes encoding for steroidogenic enzymes that involved cortisol synthesis. More than 90% of cases are caused by a defect in the enzyme 21-hydroxylase. Four other enzyme deficiencies (cholesterol side-chain cleavage, 17α-hydroxylase [P450c17], 11β-hydroxylase [P450c11β], 3β-hydroxysteroid dehydrogenase) in the steroid biosynthesis pathway, along with one cholesterol transport protein defect (steroidogenic acute regulatory protein), and one electrontransfer protein (P450 oxidoreductase) account for the remaining cases. The clinical symptoms of the different forms of CAH result from the particular hormones that are deficient and those that are produced in excess. A characteristic feature of CAH is genital ambiguity or disordered sex development, and most variants are associated with glucocorticoid deficiency. However, in the rare forms of CAH other than 21-hydroxylase deficiency so-called "atypical CAH", the clinical and hormonal phenotypes can be more complicated, and are not well recognized. This review will focus on the atypical forms of CAH, including the genetic analyses, and phenotypic correlates.

Congenital adrenal hyperplasia: clinical symptoms and diagnostic methods.

Abstract: The aim of this paper is a straightforward presentation of the steroidogenesis process and the most common type of congenital adrenal hyperplasia (CAH) - 21-hydroxylase deficiency - as well as the analytical diagnostic methods that are used to recognize this disease. CAH is a family of common autosomal recessive disorders characterized by impaired adrenal cortisol biosynthesis with associated androgen excess due to a deficiency of one or more enzymes in the steroidogenesis process within the adrenal cortex. The most common and prototypical example of the CAH disorders group (90-95%) is caused by 21-hydroxylase deficiency. Less frequent types of CAH are 11β-hydroxylase deficiency (up to 8% of cases), 17α-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency, P450 oxidoreductase deficiency and StAR deficiencies. In the 21-hydroxylase and 11β-hydroxylase deficiency, only adrenal steroidogenesis is affected, whereas a defect in 3β-hydroxysteroid dehydrogenase or 17α-hydroxylase also involves gonadal steroid biosynthesis. Many countries have introduced newborn screening programs based on immunoassays measuring 17-hydroxyprogesterone from blood spots used for other neonatal screening tests which enable faster diagnosis and treatment of CAH. Currently, chromatographic techniques coupled with mass spectrometry are gaining popularity due to an increase in the reliability of the test results.

Dynamics of steroid biosynthesis during the luteal-placental shift in rhesus monkeys.

Abstract: We studied the dynamics of steroid secretion during the luteal-placental shift of early pregnancy in rhesus monkeys. Daily blood samples were obtained from six pregnant rhesus monkeys during the cycle of conception and for the first 44 days of pregnancy to examine the relationships among aromatizable androgens, estrogens, progesterone (P), and CG in the peripheral circulation. To elucidate the biosynthetic mechanisms involved in the changes in hormonal patterns, minces of placentae and corpora lutea (CL) were incubated in vitro with [3H]pregnenolone ([3H]P5) and [3H]androstenedione ([3H]A), and steroid metabolites were isolated and identified by reverse isotope dilution. After a brief rise (corresponding to the approximate time of implantation of the blastocyst), serum P levels declined despite rising serum CG levels and reached a nadir at the time of maximal CG secretion. In contrast, serum androstenedione (A), testosterone (T), estrone (E1), and estradiol (E2) concentrations rose and fell in parallel with CG and reached peak levels near day 24 of pregnancy 2- to 10-fold higher than those during the luteal phase. The CL of early pregnancy produced less than one third as much P from [3H]P5 as did the CL of the cycle, but had a 9-fold greater capacity for estrogen biosynthesis. Total CL aromatase activity did not differ between the nonfertile cycle and early pregnancy. 17-Hydroxylase and C17-20 lyase activities increased in the CL during early pregnancy, since 17-hydroxyprogesterone and A (but not T) syntheses were 3- to 5-fold greater in the CL of early pregnancy than in the CL of the cycle. Although serum E1 and E2 concentrations during early pregnancy were similar, E1 was the predominant estrogen produced from [3H]P5 or [3H] A by luteal tissue in vitro. Placental tissue obtained on days 23-27 of pregnancy produced large amounts of P from [3H]P5, but only trace amounts of estrogens were formed from [3H]A. By day 45 of pregnancy, however, the placenta had acquired substantial amounts of aromatase activity. Neither estrogens nor androgens were formed from [3H]P5 by the placenta.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of Advanced Breast Cancer with Aminoglutethimide: A 14-Year Experience

Abstract: Breast cancer is an endemic disease in the United States with a prevalence rate in excess of 500,000 and an estimate annual reservoir of 300,000 women living with advanced incurable breast cancer. Adrenalectomy, an historical standard treatment used in the control of advanced breast cancer, is an ablative type of hormone-manipulative effort designed to decrease extragonadal circulating estrogens and is variously reported to induce objective tumor remissions from 9 to 12 months in 25 to 50% of patients. However, incidence and duration of response vary with patient selection. Many patients whose clinical features suggest that adrenalectomy would provide a further period of palliation for their disease are often too debilitated to be considered as candidates for surgery for where the therapeutic response rate may be low and the predictability of that response uncertain. Aminoglutethimide, derived from a nonbarbiturate soporific and originally introduced as an anticonvulsant drug, was subsequently discovered to inhibit steroid biosynthesis by interfering with the enzymatic conversion of cholesterol to Δ 5 -pregnenolone. Recently, it has been found to interfere with the aromatization of androstenedione. Schteingart et al. (J. Am. Med. Assoc., 198: 1007–1010, 1966) reported successfully controlling a patient with functional disseminated adrenocortical carcinoma. The wider therapeutic implications of that report prompted this study, designed to exploit the hormone-manipulative property of aminoglutethimide in the treatment of advanced breast cancer. From July 1967 to July 1981, 91 women possessing histologically diagnosed symptomatic measurable advancing metastatic breast cancer refractory to current conventional therapy, including hormonal, were consecutively entered into the treatment study using aminoglutethimide with low-dose dexamethasone (to prevent reflex adrenocorticotropic hormone override) as a “medical adrenalectomizer” in poor-risk patients. No patients possessed solely skin and soft tissue metastases. Preterminal patients were included in this study. Biochemical indices of adrenocortical and gonadal function were obtained pretreatment and periodically thereafter. Response criteria were those established by the Eastern Cooperative Oncology Group. Patients with subjective and stabilization responses were considered nonresponders. Thirty patients (33%) experienced an objective response and survival time varying from 2 to 81 and 3 to 110 months duration, respectively. Median survival time of responding patients was 22 months, compared with 2 months for nonresponding patients. Twenty-five of 73 patients with visceral dominant lesions responded with four compelte visceral responses including two patients with hepatic metastases. Initial patient performance status and dominant metastatic lesion were unrelated to response, but disease-free interval and site of relapse were related to response and survival. There were no deaths related to drug toxicity. Treatment with aminoglutethimide provides effective palliation in poor-risk patients with advanced breast cancer with a response rate and survival time equal to those reported in better-risk patients following surgical adrenalectomy.