17β-Hydroxysteroid dehydrogenase 3 deficiency: Three case reports and a systematic review

Yang, Zuwei; Ye, Lei; Wang, Wei; Zhao, Yu; Wang, Wencui; Jia, Huiying; Dong, Zhiya; Chen, Yuhong; Wang, Weiqing; Ning, Guang; Sun, Shouyue

doi:10.1016/j.jsbmb.2017.08.012

Cited by 33 publications

(32 citation statements)

References 14 publications

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“…Numerous studies have investigated the potency of 17b-HSD3 inhibitors in the last decade (Kenmogne et al, 2016;Bacsa et al, 2017;Pourbasheer et al, 2017;Yang et al, 2017;Yazawa et al, 2019), however, none of these inhibitors are currently under investigation in clinical trials (Barbosa et al, 2015). Inhibitors of 17b-HSD3 can either work at the gene level, targeting the mRNA expression of the 17b-HSD3 gene, or inhibit the activity of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3

Cheng

Yang

et al. 2020

Front. Pharmacol.

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The 17b-hydroxysteroid dehydrogenase type 3 (17b-HSD3) enzyme is a potential therapeutic target for hormone-dependent prostate cancer, as it is the key enzyme in the last step of testosterone (T) biosynthesis. A curcumin analog, H10, was optimized for inhibiting T production in LC540 cells that stably overexpressed 17b-HSD3 enzyme (LC540 [17b-HSD3]) (P < 0.01), without affecting progesterone (P) synthesis. H10 downregulated the production of T in the microsomal fraction of rat testes containing the 17b-HSD3 enzyme from 100 to 78.41 ± 7.41%, 51.86 ± 10.03%, and 45.14 ± 8.49% at doses of 10, 20, and 40 mM, respectively. There were no significant differences among the groups with respect to the protein expression levels of 17b-HSD3, 3bHSD1, CYP17a1, CYP11a1, and STAR, which participate in 17b-HSD3-mediated conversion of androgens to T (P > 0.05). This indicated that H10 only inhibited the enzymatic activity of 17b-HSD3 in vitro. Furthermore, H10 inhibited the adione-stimulated growth of xenografts established from LNCaP cells in nude mice in vivo. We conclude that H10 could serve as an effective inhibitor of 17b-HSD3, which in turn would inhibit the biosynthesis of androgens and progression of prostate cancer.

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Section: Introductionmentioning

confidence: 99%

The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3

Cheng

Yang

et al. 2020

Front. Pharmacol.

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“…Similarly, there are only isolated reports on germ cell malignancies among HSD17B3 deficient patients; one report where histological findings of spermatogonia were consistent with testicular malignancy, one report of 30‐years‐old patient with metastatic teratocarcinoma‐seminoma and reports of 16‐years‐ and 4‐years‐old patients with OCT4 staining positive germ cell neoplasia in situ (GCNIS) . In contrast, Leydig cell hyperplasia is a common finding in patients with HSD17B3 mutations . In HSD17B3KO mouse testis, the Leydig cell number was not changed, and furthermore, we did not observe any malignant changes in the testes of the HSD17B3KO males at the age of 3 or 10 months, suggesting that HSD17B3 mutations per se do not cause malignant changes in the testis.…”

Section: Discussionmentioning

confidence: 54%

“…Several inactivating HSD17B3 mutations have been discovered in humans. They cause a rare 46, XY disorder of sex development (DSD) resulting from homozygous or compound heterozygous mutations in the HSD17B3 gene . Due to the rarity of the condition, the worldwide prevalence is unknown, but the estimated incidences vary from 1:147 000 in The Netherlands to 1:100‐150 in the Arab population of the Gaza strip .…”

Section: Introductionmentioning

confidence: 99%

The lack of HSD17B3 in male mice results in disturbed Leydig cell maturation and endocrine imbalance akin to humans with HSD17B3 deficiency

et al. 2020

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Hydroxysteroid (17β) dehydrogenase type 3 (HSD17B3) deficiency causes a disorder of sex development in humans, where affected males are born with female-appearing external genitalia, but are virilized during puberty. The hormonal disturbances observed in the Hsd17b3 knockout mice (HSD17B3KO), generated in the present study, mimic those found in patients with HSD17B3 mutations. Identical to affected humans, serum T in the adult HSD17B3KO mice was within the normal range, while a striking increase was detected in serum A-dione concentration. This resulted in a marked reduction of the serum T/A-dione ratio, a diagnostic hallmark for the patients with HSD17B3 deficiency. However, unlike humans, male HSD17B3KO mice were born with normally virilized phenotype, but presenting with delayed puberty. In contrast to the current belief, data from HSD17B3KO mice show that the circulating T largely originates from the testes, indicating a strong compensatory mechanism in the absence of HSD17B3. The lack of testicular malignancies in HSD17B3KO mice supports the view that testis tumors in human patients are due to associated cryptorchidism. The HSD17B3KO mice presented also with impaired Leydig cell maturation and signs of undermasculinization in adulthood. The identical hormonal disturbances between HSD17B3 deficient knockout mice and human patients make the current mouse model valuable for understanding the mechanism of the patient phenotypes, as well as endocrinopathies and compensatory steroidogenic mechanisms in HSD17B3 deficiency. K E Y W O R D S disorder of sex development, HSD17B3, Leydig cell maturation 6112 | SIPILÄ et aL. | 6115 SIPILÄ et aL.to the circumference of seminiferous tubules. Two testis crosssections were analyzed from each male.

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“…AAV-mediated gene delivery is an accurate etiological treatment that is ideal for genetic diseases 13,17 . Based on the therapeutic effects of AAV8-Lhcgr on Lhcgr-de cient LCF mice, it is rational to hypothesize that AAV-mediated gene therapy exhibits strong potential to exert favorable effects on other types of genetic LCF, such as 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2) de ciency 38 , cytochrome P450 oxidoreductase (POR) de ciency 39 , CYP17A1 de ciency 40 , or 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) de ciency 41 . Although further studies are needed to thoroughly assess whether these types of LCF can be addressed by AAV8-mediated gene therapy, the present study shed new light on the novel treatment of LCF, which can potentially be expanded to more than 70 forms of genetic gonadal failure in an individualized manner 42 .…”

Section: Discussionmentioning

confidence: 99%

AAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure

Xia

Wang

Lai

et al. 2021

Preprint

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Leydig cell failure (LCF) caused by gene mutation results in testosterone deficiency and infertility. Serum testosterone levels can be recovered via testosterone replacement; however, established therapies have shown limited success in restoring fertility. Here, we used a luteinizing hormone/choriogonadotrophin receptor (Lhcgr)-deficient mouse model of genetic LCF to investigate the feasibility of gene therapy for restoring testosterone production and fertility. We screened several adeno-associated virus (AAV) serotypes and identified AAV8 as an efficient vector to drive exogenous Lhcgr expression in progenitor Leydig cells through interstitial injection. We observed considerable testosterone recovery and Leydig cell maturation after AAV8-Lhcgr treatment in pubertal Lhcgr−/− mice. This gene therapy substantially recovered sexual development, partially restored spermatogenesis and effectively produced fertile offspring. Furthermore, these favorable effects could be reproduced in adult Lhcgr−/− mice. Our proof-of-concept experiments in this mouse model demonstrate that AAV-mediated gene therapy may represent a promising therapeutic approach for patients with genetic LCF.

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17β-Hydroxysteroid dehydrogenase 3 deficiency: Three case reports and a systematic review

Cited by 33 publications

References 14 publications

The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3

The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3

The lack of HSD17B3 in male mice results in disturbed Leydig cell maturation and endocrine imbalance akin to humans with HSD17B3 deficiency

AAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure

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