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Variation of sex differentiation
Published in Joseph S. Sanfilippo, Eduardo Lara-Torre, Veronica Gomez-Lobo, Sanfilippo's Textbook of Pediatric and Adolescent GynecologySecond Edition, 2019
Anne-Marie Amies Oelschlager, Margarett Shnorhavorian
17α-Hydroxylase/17.20 lyase deficiency is caused by a mutation in the cytochrome P450c17 gene (CYP17A1). The gene is located at 10q24.32. The CYP17A1 enzyme converts pregnenolone to 17-hydroxypregnenolone and progesterone to 17-hydroxyprogesterone by hydroxylation. Also, 17,20 lyase activity converts 17-hydroxypregnenolone to DHEA (Figure 7.1). A genetic mutation may result in deficiency in hydroxylation and/or lyase reactions. This results in low androgen and estrogen levels. Affected 46,XY individuals appear phenotypically female with absent Müllerian structures and typical external female genitalia. Individuals not identified at birth may present with pubertal delay. Cortisol synthesis is blocked, but due to elevated ACTH, there is an increase in aldosterone with resultant hypokalemia and hypertension. Glucocorticoid treatment addresses the ACTH overproduction and, therefore, suppresses corticosterone overproduction. Sex steroid hormonal induction and maintenance are necessary at puberty.
Disorders of sexual differentiation
Published in Brice Antao, S Irish Michael, Anthony Lander, S Rothenberg MD Steven, Succeeding in Paediatric Surgery Examinations, 2017
Sarah M Lambert, Howard M Snyder III
A child with 11β-hydroxylase deficiency can be differentiated from other forms of CAH by having elevated levels of deoxycorticosterone and 11-deoxycortisol. The diagnosis of 21-hydroxylase deficiency is confirmed by the identification of increased serum levels of 17-hydroxyprogesterone. The diagnosis of 3β-hydroxysteroid dehydrogenase deficiency is confirmed by the identification of increased serum levels of 17-hydroxypregnenolone and dehydroepiandrosterone. The evaluation of a teenage girl with primary amenorrhoea and normal external genitalia should include a pelvic ultrasound to assess for the presence or absence of gonads and müllerian structures and a karyotype. A laparoscopic abdominal exploration can be performed to confirm a vanishing testis in a boy with a unilateral non-palpable testis. During the exploration a viable testis or blind-ending vas deferens and gonadal vessels can be located.
Evaluating the Transdermal Permeability of Chemicals
Published in Richard H. Guy, Jonathan Hadgraft, Transdermal Drug Delivery, 2002
Brent E. Vecchia, Annette L. Bunge
The appendix lists experimental permeability coefficient values included in the Flynn database along with MW, log Kow, the temperature at which the permeability coefficient was determined, the fraction of the penetrating compound that is in its nonionized form, and the permeability coefficient as predicted by Model 15. Two sets of log Kow values are listed (Set A and Set B). The Set A values of log Kow, most of which were tabulated by Flynn (1) and reprinted exactly by the USEPA (13), were used in developing several of the permeability coefficient equations based on the Flynn database. Flynn (1) did not list log Kow values for four chemicals (chlorpheniramine, diethylcarbamazine, N-nitrosodiethanolamine, and ouabain), and so Set B values were used for these chemicals in analyses described later, unless specified otherwise. To indicate that these values were not provided in the original Flynn database we enclose the log Kowvalues for these four chemicals in parentheses [e.g., for chlorpheniramine (3.39)]. The Set B log Kow values are recommended star (★) values from Hansch et al. (26) unless contained in brackets (e.g., for chloroxylenol [3.48]), in which case they were calculated using Daylight (27). According to Hansch et al., the star designates preferred measurements of log as or converted to the neutral (nonionized) form of compounds (26). Neither a star value nor a calculated value were available for 17-hydroxypregnenolone.
Effect of dexamethasone on labour induction and cervical ripening in term pregnancies: a systematic review and meta-analysis
Published in Journal of Obstetrics and Gynaecology, 2022
Shahla Hemmatzadeh, Parivash Ahmadpoor, Sevda Kamrani, Mojgan Mirghafourvand
The role of corticosteroid hormones in the mechanisms responsible for parturition in mammalian species has been a subject of intensive investigation. There is evidence supporting the role of glucocorticosteroid receptors in the foetal membranes at the beginning of the labour process. In pregnant sheep the sequence of events leading to parturition includes activation of the foetal hypothalamic-pituitary adrenal axis with the production of corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol. Cortisol, produced by the foetal adrenal gland, is presumed to induce the expression of P-450 17-20 lyase by the placenta. This enzyme catalyses the transformation of pregnenolone to 17a-hydroxypregnenolone, which is a source of androgens (dehydroepiandrosterone, androstenedione) that are subsequently aromatised to oestrogens. The net effect of the activity of P450 17-20 lyase is to decrease the production of progesterone (‘progesterone withdrawal’) and to increase the bioavailability of oestrogens (Campbell et al. 1987; Meyer et al. 2016). Maternal cortisol acts on the developing foetus either directly by passing through the placenta, or indirectly via its effects on placental production of corticotrophin-releasing hormone (CRH) (Mastorakos and Ilias 2003; Entringer et al. 2011).
A rare cause of delayed puberty in two cases with 46,XX and 46,XY karyotype: 17 α-hydroxylase deficiency due to a novel variant in CYP17A1 gene
Published in Gynecological Endocrinology, 2020
Edip Unal, Ruken Yıldırım, Funda Feryal Taş, Suat Tekin, Serdar Ceylaner, Yusuf Kenan Haspolat
Cytochrome P450 17α-hydroxylase deficiency (P450c17) is rarely seen and constitutes approximately 1% of all CAH cases. P450c17 enzyme is encoded by CYP17A1 gene, which is located on chromosome 10q24.3, and plays an important role in steroid hormone biosynthesis. P450c17 catalyzes 2 different reactions. The first reaction occurs with 17α-hydroxylase activity which provides the transformation of pregnenolone and progesterone to 17α-hydroxypregnenolone and 17α-hydroxyprogesterone respectively. The second reaction occurs with 17,20-lyase activity, which transforms the created 17α-hydroxysteroids to dihydroepiandrosterone and androstenedione [5,6]. P450c17 enzyme is expressed both in the adrenal cortex and in the gonads [7]. Therefore, in cases of 17α-hydroxylase deficiency, both adrenal and gonadal steroid synthesis is impaired, and clinically primary amenorrhea and sexual infantilism are seen in girls (46,XX) and disorders of sex development are seen in boys (46,XY). Excessive ACTH production occurs to compensate for reduced cortisol synthesis. Increased ACTH leads to an excessive amount of 11-deoxycorticosterone (DOC) production, which in turn results in hypertension and hypokalemia. The presentations of both cases to our attention were similar. Both cases had female phenotype and hypertension, hypokalemia, delayed puberty and hypergonadotropic hypogonadism were present. However, in the karyotype analysis, ıt was found that the first case had a 46,XY karyotype and the second case had 46,XX. The lack of virilization in the first case is associated with impaired gonadal and adrenal androgen production.
Abiraterone acetate in combination with prednisone in the treatment of prostate cancer: safety and efficacy
Published in Expert Review of Anticancer Therapy, 2020
Cécile Manceau, Loic Mourey, Damien Pouessel, Guillaume Ploussard
CYP17A1 is an enzyme expressed in steroidogenic tissue like testes and adrenal cortex. It’s also expressed in prostatic tumor tissue. This enzyme is involved in the conversion of cholesterol to the androgen precursor and steroid hormone synthesis. The generation of glucocorticoid such as cortisol requires 17 α-hydroxylase as it converts pregnenolone and progesterone to 17-hydroxypregnenolone and 17-hydroxyprogesterone. So, 17 α-hydroxylase deficiency impairs glucocorticoids production, pregnenolone, and progesterone increase. The decrease in cortisol levels includes a compensatory increase in adrenocorticotropic hormone (ACTH) and the increase in pregnenolone and progesterone is treated to form mineralocorticoids [6]. Prednisone is associated to compensate cortisol reduction due to 17 α-hydroxylase inhibition, therefore, decreasing the mineralocorticoid excess [6] (Figure 1).