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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
At the molecular level, CPA works by interacting with the AR as a competitive antagonist and a very weak partial agonist. It also interacts at the Progesterone Receptor (PR) and the Pregnane X Receptor (PXR) as an agonist, and at the Glucocorticoid Receptor (GR) as an antagonist. It also inhibits a number of enzymes involved in various steroidal synthesis and metabolic pathways including 3β-hydroxysteroid dehydrogenase, (3β-HSD)21-hydroxylase, 17α-hydroxylase and 17,20-lyase. The 3β-hydroxysteroid dehydrogenase and 21-hydroxylase enzymes are necessary for biosynthesis of the endogenous corticosteroids such as cortisol and aldosterone, and so their levels may be reduced. CPA also has a small direct inhibitory effect on 5α-reductase, which was the rationale for combining it with finasteride (a potent and selective 5α-reductase inhibitor) for the treatment of hirsutism. Finally, CPA has been found to bind nonselectively to opioid receptors (including the μ-, δ-, and κ- subtypes) which could explain the sedation sometimes observed with CPA treatment and/or the effectiveness of CPA in the treatment of cluster headaches.
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
46,XY 3β-Hydroxysteroid dehydrogenase type 2 deficiency (3βHSD). The 3β-hydroxysteroid dehydrogenase converts pregnenolone to progesterone, 17-hydroxypregnenolone to 17-hydroxyprogesterone, and DHEA to androstenedione. The 3βHSD results in decreased aldosterone, cortisol, androgens, and estrogen. This enzymatic deficiency may occur on a spectrum in 46,XY individuals with phenotype variation from typical female genitalia to ambiguous genitalia to typical male genitalia. Regardless of appearance, there is a risk of salt-wasting crisis with this condition. Testing for a mutation of HSD3B2 gene, located on 1p12, may confirm the diagnosis.
Developmental abnormalities of the genitalia: intersex, hypospadias, and cryptorchidism
Published in J Kellogg Parsons, E James Wright, The Brady Urology Manual, 2019
3β-hydroxysteroid dehydrogenase: RareSalt wastingInhibition of synthesis of aldosterone, cortisol, and sex steroidsMay also have ambiguous genitalia in genetic males.3
Curcumin analogues exert potent inhibition on human and rat gonadal 3β-hydroxysteroid dehydrogenases as potential therapeutic agents: structure-activity relationship and in silico docking
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xinyi Qiao, Lei Ye, Jialin Lu, Chengshuang Pan, Qianjin Fei, Yang Zhu, Huitao Li, Han Lin, Ren-shan Ge, Yiyan Wang
Adrenal and gonadal 3β-hydroxysteroid dehydrogenase/Δ5,4-isomerases (3β-HSDs) are hydroxysteroid dehydrogenase subfamily members that play critical role in the second step catalysis for adrenal glucocorticoid and mineralocorticoid and gonadal sex steroid biosynthesis. They catalyse the conversion from pregnenolone (P5) or dehydroepiandrosterone (DHEA) to progesterone (P4) or androstenedione (Figure 1(B)), which are precursors of potent glucocorticoids, mineralocorticoids, androgens, and oestrogens9. Two isoforms of 3β-HSD have been cloned in humans, type 1 3β-HSD1 (h3β-HSD1) and type 2 (h3β-HSD2), and h3β-HSD2 is exclusively present in adrenals and gonads for its function. In the rat model, 4 isoforms have been cloned, rat type 1 (r3β-HSD1) is primarily present in gonadal cells (including testicular Leydig cells)9.
Antioxidant and anti-inflammatory protective effects of rutin and kolaviron against busulfan-induced testicular injuries in rats
Published in Systems Biology in Reproductive Medicine, 2022
Sunny O. Abarikwu, Rex-Clovis C. Njoku, Ifeoma G. John, Benjamin A. Amadi, Chidimma J. Mgbudom-Okah, Chigozie L. Onuah
3β-hydroxysteroid dehydrogenase is a key enzyme in the biosynthesis of all active steroid hormones, and it exerts a regulatory control on the testicular steroid hormone cascade system (Abarikwu et al. 2014; Alamdar et al. 2017). It is believed that the activity of 3β-HSD in the testis is essential for normal steroidogenesis and subsequently for the reproductive capacity of most mammalian animal species (Rasmussen et al. 2013). The finding that 3β-HSD activity was increased in the BUS-treated animals in the present study is consistent with our previous study, and thought to be a compensatory attempt by the testes to drive androgen synthesis (Abarikwu et al. 2020). Interestingly, rutin and kolaviron co-treatment alone or in combination decreased 3β-HSD activity. However, rutin co-treatment (BUS + RUT) had better protective effects on 3β-HSD activity than when kolaviron and rutin were combined (BUS + KV + RUT) or when kolaviron was administered separately (BUS + KV). It may appear that kolaviron and rutin did not exhibit a strong protective effect on 3β-HSD activity in the rat’s testes as a result of the antagonism of both phenolics (Phan et al. 2018b). Considering that these phenolics occur in nature and prevalently in combinations in seeds and fruits, giving them together might not amplify their efficacy against busulfan-induced disturbances in androgen production in animals and clinical models.
Pharmacotherapeutic options for the treatment of menopausal symptoms
Published in Expert Opinion on Pharmacotherapy, 2021
Andrea R. Genazzani, Patrizia Monteleone, Andrea Giannini, Tommaso Simoncini
Upon oral ingestion, tibolone is rapidly metabolized to three active metabolites: a 3α.-OH and a 3β-OH metabolite, and a Δ4-isomer, formed predominantly from the conversion of the 3β-hydroxy metabolite by 3β-hydroxysteroid dehydrogenase [187]. Tibolone is absorbed rapidly and extensively after oral administration [188]. The elimination half-life is 45 hours. Excretion is mainly as sulfated metabolites through the feces, although some excretion occurs via the urine [189]. The elimination of tibolone is independent of renal function. Increasing age does not appear to significantly affect the absorption or metabolism of tibolone [190]. Tibolone metabolites circulate mainly in the sulfated form [177], and the activity of tibolone on various tissues depends on the local expression of sulfatase enzyme, which converts tibolone to its active metabolites.