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Effects on Human Males of In Utero Exposure to Exogenous Sex Hormones
Published in Takao Mori, Hiroshi Nagasawa, Toxicity of Hormones in Perinatal Life, 2020
Direct depressive effects of DES on several testicular enzymes involved in testosterone steroidogenesis have been demonstrated in several species. Samuels et al.31 found both in vivo and in vitro suppression of 17α-hydroxylase, 17-20 lyase, and 17β-hydroxysteroid dehydrogenase in rodents (mice and rats) and monkeys. Following 2 weeks of in vivo DES administration to neonatal mice, the activities of these three enzymes were markedly decreased in in vitro assays and the enzyme suppressions persisted for at least 4 months which would be approximately equivalent to 5 years in humans. Hsueh et al.20 and Bartke et al.73 also demonstrated direct inhibitory effects on rodent enzymatic testicular steroidogenesis by DES and E2, with DES being an order of magnitude more potent as an inhibitor.
Diagnostic evaluation
Published in Seema Chopra, Endometriosis, 2020
Neha Agarwal, Seema Chopra, Arshi Syal
For the transition of endometrium from proliferative to luteal phase, progesterone is required. However, in women with endometriosis, there will be increased activation of steroidogenic factor 1 (SF1) and aromatase activity leading to increased production of estradiol. Highly potent estradiol downregulates the expression of progesterone receptors leading to progesterone resistance and further increasing the level of estradiol by lowering the activity of 17β-hydroxysteroid dehydrogenase (17β-HSD) [23].
Hormonal regulation of spermatogenesis
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Pallav Sengupta, Mohamed Arafa, Haitham Elbardisi
LH mediates its action, mostly steroidogenesis to produce testosterone, through its receptors on the plasma membrane of the Leydig cells, which amounts to almost 15,000 in number (27). The occupancy of LH receptors of less than 5% of total receptors reportedly is sufficient for robust steroidogenesis (28). Leydig cells thereby produce testosterone via the LH-dictated pathway. An LH receptor is a single 93 kDa glycoprotein with three functional domains, namely, a glycosylated extracellular LH binding domain, a seven-segmented transmembrane spanning domain and an intracellular message conveying domain (27). These receptors are G-protein-coupled receptors that activate adenylyl cyclase to produce cAMP, which, in turn, leads to the activation of PKA. LH-mediated activated PKA may phosphorylate cholesterol esterase to release cholesterol from the intracellular stores, and/or activate CYP11A1, in order to stimulate steroidogenesis. LH also determines 17β-hydroxysteroid dehydrogenase expression that converts testicular androstenedione to testosterone (29).
The vagina as source and target of androgens: implications for treatment of GSM/VVA, including DHEA
Published in Climacteric, 2023
S. Cipriani, E. Maseroli, S. A. Ravelli, L. Vignozzi
In human distal vaginal tissue samples, the enzymes involved in the reactions upstream of steroidogenesis (steroidogenic acute regulatory protein [STAR], cytochrome P450 11A1 [CYP11A1], CYP17A1) were found to be expressed at much lower levels than in the ovarian tissue [19]. Conversely, the expression of pro-androgenic steroidogenic enzymes such as 17β-hydroxysteroid dehydrogenase type 3 (HSD17β3), 17β-hydroxysteroid dehydrogenase type 5 (HSD17β5) and the three isoforms of 5α-reductase (SRD5A1, SRD5A2 and SRD5A3), implicated in the transformation of testosterone into its most active metabolite, DHT, showed a markedly higher level of expression in the distal vagina than in the ovary [19]. Moreover, mass spectrometry studies revealed a significant increase in androstenedione, testosterone and DHT in the culture medium of hvSMCs, after treatment with increasing concentrations of DHEA, therefore leading to the innovative concept that vaginal muscle cells express the enzymatic machinery necessary to produce the most active metabolites of androgens [19].
Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Maša Sinreih, Rebeka Jójárt, Zoltán Kele, Tomaž Büdefeld, Gábor Paragi, Erzsébet Mernyák, Tea Lanišnik Rižner
Inhibitors against enzymes involved in the regulation of the actions of oestrogens at the pre-receptor level can be designed based on their oestrone substrates. However, one of the major risks of oestrone-based inhibitors is their oestrogenic side-effects. This might be avoided by the use of core-modified synthetic oestrone derivatives that lack hormonal activity. Owing to its modified conformation, 13α-oestrone meets these requirements, in terms of low affinity for nuclear oestrogen receptors21,22. We reported recently on the synthesis and biochemical assessment of oestrone A-ring halogenated derivatives (Figures 1 and 2)23–25. The 2- and 4-halogenated, and the 2,4-bis-halogenated derivatives were subjected to biochemical investigations into their effects on the enzymes involved in oestrogen biosynthesis. Important structure–activity relationships were defined, and certain potent inhibitors of 17β-hydroxysteroid dehydrogenase 1 and steroid sulphatase were identified25.
Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mateusz Daśko, Sebastian Demkowicz, Karol Biernacki, Olga Ciupak, Witold Kozak, Maciej Masłyk, Janusz Rachon
Recently, the other enzyme implicated in the hormone biosynthesis process, 17β-HSD, has reached potential therapeutic importance in the treatment of hormone-dependent diseases. Salah et al.92 reported the first dual inhibitors of STS and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) as promising therapeutics for oestrogen-dependent diseases. The design of dual STS/17β-HSD1 inhibitors was based on combining structural elements, essential for 17β-HSD1 inhibition, with the sulphamate-aryl pharmacophore (crucial in STS inactivation). Among 12 synthesised compounds, derivative 54 (Table 4) demonstrated the most promising biological properties with well-balanced activities against both the STS and 17β-HSD1 enzymes (IC50(STS) value of 15.6 nM and an IC50(17β-HSD1) value of 22.2 nM when evaluated in an assay with T47D cells). Compound 54 did not exhibit cytotoxic properties or oestrogen receptor interference. Moreover, 54 was also able to effectively reverse E1S/E1-stimulated proliferation of T47D cells (at 400 nM). Authors noticed, that the activity towards STS required an additional substituent within the sulphamate-aryl system and EWG substituents turned out to be the most favourable. On the other hand, strong EWGs impaired STS inhibition by reducing the chemical stability of the sulphamate pharmacophore.