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Current Medicinal Chemistry 2016This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate... (Review)
Review
This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Androgens; Dihydrotestosterone; Drug Discovery; Humans; Male; Molecular Conformation; Prostatic Hyperplasia; Prostatic Neoplasms; Structure-Activity Relationship
PubMed: 26861003
DOI: 10.2174/0929867323666160210125642 -
Frontiers in Endocrinology 2023The mechanisms by which male hormones affect the development of ovaries and follicles has been studied by injecting exogenous androgens into sows. This may provide a... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The mechanisms by which male hormones affect the development of ovaries and follicles has been studied by injecting exogenous androgens into sows. This may provide a reference for human polycystic ovary syndrome (PCOS), and can also provide guidance for improving the litter size of sows.
METHODS
We present a meta-analysis of studies published in the past 30 years on the effect of androgens on the ovulation rate of sows. A total of 517 papers were analyzed.
RESULTS
The results showed that both testosterone (T) and dihydrotestosterone (DHT) injected into sows were positively related to the ovulation rate. T did not have a relevant effect on swine in vivo blastocyst survival rate. DHT had a negative phase with respect to blastocyst survival rate. Pig T-androgen receiver affinity was higher than the analogous affinity for DHT; this is different in humans. This suggests that sows are not suitable as human PCOS experimental animal models.
DISCUSSION
To improve the litter size of sows, future research should focus on the mixed use of T and DHT, and the timing of use should be consistent with the periodic changes in androgen levels in sows. In addition, the welfare of experimental sows should be considered with reference to the clinical symptoms of PCOS.
Topics: Female; Male; Animals; Swine; Humans; Androgens; Polycystic Ovary Syndrome; Dihydrotestosterone; Ovulation
PubMed: 36843577
DOI: 10.3389/fendo.2023.1094466 -
Bioprocess and Biosystems Engineering May 2021Polycystic ovary syndrome (PCOS) is associated with gut microbiota disturbance. Emerging evidence has shown that gut microbiota plays a major role in the development of...
Polycystic ovary syndrome (PCOS) is associated with gut microbiota disturbance. Emerging evidence has shown that gut microbiota plays a major role in the development of PCOS. To better understand how the gut microbiota contributes to the development of PCOS, we investigated the influences of high-fat diet and hyperandrogenism, independently or synergistically, have on the gut microbiota in rats. Furthermore, we explored the associations between gut microbiota and hyperandrogenism or other hallmarks of PCOS. Twenty female SD rats were randomized at aged 3 weeks into 4 groups (n = 5, each); HA: PCOS rats fed with ordinary diet; HF: rats with high-fat diet (HFD); HA-HF: PCOS rats fed with HFD; and C: control rats with ordinary diet. PCOS rat model was induced by 5α-dihydrotestosterone (DHT) injection for 6 weeks. The fasting blood glucose (FBG), plasma insulin, testosterone, free testosterone, TNF-α, MDA, SOD, LPS, TLR4, TG, TC, HDL-C, and LDL-C levels were measured. The molecular ecology of the fecal gut microbiota was analyzed by 16S rDNA high-throughput sequencing. The results showed that rats in the HA and HA-HF group displayed abnormal estrous cycles with increasing androgen level and exhibited multiple large cysts with diminished granulosa layers in ovarian tissues. Compare with the C group, relative abundance of the Bacteroidetes phylum decreased significantly in the other groups (P < 0.05). The Chao1 was the highest in the group C and significantly higher than the HA-HF group (P < 0.05). T, FT, insulin, MDA, LPS, and TNF-α levels had the negative correlation with the richness of community (Chao1 index) in the gut. The rats in the HF and HA-HF groups tended to have lower Shannon and Simpson indices than the C group (P < 0.01, respectively). However, there were no significant differences between C group and the HA group in the Shannon and Simpson values. Beta diversity analysis was then performed based on a weighted UniFrac analysis. The PCoA plots showed a clear separation of the C group from the other groups. ANOSIM analysis of variance confirmed that there were statistically significant separations between the C group and the HA, HA-HF, and HF groups (P < 0.01, respectively). These results showed that DHT with HFD could lower diversity of the gut microbial community. Both HFD and DHT could shift the overall gut microbial composition and change the composition of the microbial community in gut. Furthermore, our analyses demonstrated that the levels of TG, MDA, TNF-α, LPS, TLR4, T, FT, FINS, and HDL-C were correlated with the changes of in the gut microbiome. HFD and DHT were associated with the development and pathology of PCOS by shaping gut microbial communities.
Topics: Animals; Diet, High-Fat; Dihydrotestosterone; Female; Gastrointestinal Microbiome; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley
PubMed: 32157446
DOI: 10.1007/s00449-020-02320-w -
European Journal of Endocrinology Oct 2021The two major androgens in humans are testosterone (T) and dihydrotestosterone (DHT). DHT is produced via the classical, backdoor, and alternative steroidogenic...
INTRODUCTION
The two major androgens in humans are testosterone (T) and dihydrotestosterone (DHT). DHT is produced via the classical, backdoor, and alternative steroidogenic pathways. In addition, recent studies have identified C11-oxy C19 steroids as novel human androgens. Although the placenta is known to be involved in steroid metabolism, androgen levels in full-term placentas have poorly been investigated.
SUBJECTS AND METHODS
Ten placentas of healthy full-term neonates (five males and five females) were examined. We quantified progesterone, androstenedione (A4), T, allopregnanolone, androsterone, and estradiol, as well as four C11-oxy androgens (11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketoandrostenedione (11KA4), and 11-ketotestosterone (11KT)), using liquid chromatography-tandem mass spectrometry.
RESULTS
In all samples, levels of the ten steroids were above the detection limit. Progesterone was by far most abundant, while levels of T and androsterone were relatively low. Levels of 11KT and 11KA4 were higher than those of T and A4, respectively. There were no differences in steroid levels between male and female samples.
DISCUSSION
This study demonstrates that full-term placentas contain several steroids in the classical, backdoor, and alternative pathways. Placentas are likely to function as the supplier of progesterone to other steroidogenic tissues. More importantly, we found that placentas comprise relatively large amounts of 11KA4 and 11KT, which may be produced through steroid transfer from the adrenal gland or from the maternal circulation. These results indicate that the placenta participates in a feto-maternal multi-organ network for androgen biosynthesis.
Topics: Adult; Androgens; Dihydrotestosterone; Female; Humans; Infant, Newborn; Limit of Detection; Male; Placenta; Pregnancy; Progesterone; Reproducibility of Results; Steroids; Tandem Mass Spectrometry; Testosterone
PubMed: 34379603
DOI: 10.1530/EJE-21-0312 -
Journal of Cosmetic Dermatology Mar 2024Hair loss occurs due to various biological and environmental causes, which can have psychosocial consequences. The Wnt/β-catenin signaling is well-known for its role in...
BACKGROUND
Hair loss occurs due to various biological and environmental causes, which can have psychosocial consequences. The Wnt/β-catenin signaling is well-known for its role in hair growth and regeneration, as it induces the proliferation and differentiation of hair cells. When the leucine-rich G protein-coupled receptor 5 (Lgr5) interacts with the R-spondins, the frizzled receptor (FZD), a Wnt receptor, becomes stabilized, resulting in an increased β-catenin activity.
AIM
We investigated whether the octapeptide that binds to Lgr5 enhances proliferation and differentiation of human primary hair cells through the activation of Wnt/β-catenin signaling.
METHODS
The binding affinity of the octapeptide to Lgr5 was evaluated using surface plasmon resonance (SPR). We confirmed changes in proliferation and related factors like β-catenin activation and growth factors (GFs) expression in human hair follicle dermal papilla cells (HHFDPCs). Additionally, we observed the proliferation and the expression of differentiation markers in human hair follicle outer root sheath cells (HHFORSCs), human hair follicle germinal matrix cells (HHFGMCs), and human hair follicle stem cells (HHFSCs). We used three-dimensional HHFDPC spheroid culture treated with dihydrotestosterone (DHT) to create in vitro conditions that mimic androgenetic alopecia, and we studied the effects of octapeptide on Wnt expression and HHFSC differentiation.
RESULTS
The binding of the octapeptide to Lgr5 was confirmed using SPR analysis. In HHFDPCs, treatment with octapeptide resulted in a concentration-dependent increase in proliferation. We also observed increased nuclear translocation of β-catenin and increased expression of its downstream targets. HHFDPCs treated with octapeptide exhibited increased expression of growth factors and phosphorylation of Akt and ERK. In addition, we confirmed that octapeptide increased proliferation and induced differentiation in HHFORSCs, HHFGMCs, and HHFSCs. Under the HHFDPC spheroid culture conditions, we found that octapeptide restored the inhibition of Wnt-5a and Wnt-10b expressions by DHT. In HHFSCs treated with HHFDPC spheroid culture media, we observed that octapeptide recovered the inhibition of differentiation by DHT.
CONCLUSION
We found that octapeptides activated the Wnt/β-catenin signaling and induced the proliferation and differentiation of human primary hair cells by acting as an exogenous ligand for Lgr5. In addition, octapeptides recovered inhibited hair regeneration characters by DHT in androgenetic alopecia-mimic in vitro model. These findings suggest that octapeptides may be a promising therapeutic option for treating hair loss.
Topics: Humans; beta Catenin; Hair Follicle; Hair; Receptors, G-Protein-Coupled; Wnt Signaling Pathway; Dihydrotestosterone; Alopecia; Intercellular Signaling Peptides and Proteins; Cell Proliferation
PubMed: 37905348
DOI: 10.1111/jocd.16036 -
Reproductive Sciences (Thousand Oaks,... Jan 2020Prenatal testosterone (T) excess, partly via androgenic programming, enhances follicular recruitment/persistence in sheep as in women with polycystic ovarian syndrome...
Prenatal testosterone (T) excess, partly via androgenic programming, enhances follicular recruitment/persistence in sheep as in women with polycystic ovarian syndrome (PCOS). Decreased anti-Mullerian hormone (AMH) in early growing and increased AMH in antral follicles may underlie enhanced recruitment and persistence, respectively. Changes in AMH may be mediated by steroidogenic factor 1 (SF1), an enhancer of AMH, and dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1), that antagonizes SF1. Another mediator could be forkhead box 03 (FOXO3) which regulates follicular recruitment/atresia. To test if androgen-programmed changes in SF1, DAX1, and FOXO3 proteins contribute to follicular defects in prenatal T-treated sheep, ovaries from control, prenatal T-, and dihydrotestosterone (DHT)-treated (days 30-90 of gestation) animals at fetal day (FD) 90, FD140, and 1 and 2 years-of-age were studied. Prenatal T increased DAX1 in granulosa cells of primordial through large preantral and theca cells of large preantral follicles at FD140 and increased SF1 in the granulosa cells of preantral and antral and theca cells of large preantral follicle at 2 years-of-age. Prenatal T increased FOXO3 only in theca cells of preantral (FD140) and antral (2 years-of-age) follicles. Prenatal DHT increased DAX1 in granulosa cells from small preantral follicles at FD140 while increasing SF1 in granulosa cells from antral follicles at 1 year-of-age. These age-dependent changes in DAX1/SF1 partly via androgen-programming are consistent with changes in AMH and may contribute to the enhanced follicular recruitment/persistence, and multifollicular phenotype of prenatal T-treated females and may be of translational relevance to PCOS.
Topics: Androgens; Animals; DAX-1 Orphan Nuclear Receptor; Dihydrotestosterone; Female; Forkhead Box Protein O3; Ovary; Pregnancy; Prenatal Exposure Delayed Effects; Sheep; Steroidogenic Factor 1; Testosterone
PubMed: 32046386
DOI: 10.1007/s43032-019-00029-0 -
International Journal of Environmental... Sep 2022The potential role of testosterone and dihydrotestosterone in the pathogenesis of depression in older subjects is poorly recognized and understood. The current study...
Relationships between Plasma Concentrations of Testosterone and Dihydrotestosterone and Geriatric Depression Scale Scores in Men and Women Aged 60-65 Years-A Multivariate Approach with the Use of Quade's Test.
The potential role of testosterone and dihydrotestosterone in the pathogenesis of depression in older subjects is poorly recognized and understood. The current study examines the symptoms of depression in males and females at the age of 60-65 using a short version (15 questions) of the Geriatric Depression Scale (GDS) questionnaire. Blood plasma levels of androgens were estimated by LC/MS/MS. Total GDS score calculated for males were not found to be significantly associated with plasma levels of testosterone or dihydrotestosterone. Older men with higher plasma testosteronemia were more likely to report being in good spirits most of the time, but more willing to stay at home than undertake outside activities. The men with higher plasma levels of dihydrotestosterone also perceived themselves as being in good spirits most of the time. Older men with higher testosterone were more likely to report having more problems with their memory than others. No significant associations were found between plasma levels of androgens and GDS scores in older women; however, some tendencies suggest that testosterone and dihydrotestosterone may act as antidepressants in older women.
Topics: Aged; Androgens; Depression; Dihydrotestosterone; Female; Humans; Male; Tandem Mass Spectrometry; Testosterone
PubMed: 36231806
DOI: 10.3390/ijerph191912507 -
Reproduction in Domestic Animals =... Feb 2021Steroid hormones and receptors play important roles in female reproduction, and their expression patterns affect follicular growth and development. To examine the...
Steroid hormones and receptors play important roles in female reproduction, and their expression patterns affect follicular growth and development. To examine the expression of dihydrotestosterone (DHT) synthases (5α-reductases (5α-red1 and 5α-red2)) and androgen receptor (AR) during follicular development, and the regulation of DHT signalling by follicle-stimulating hormone (FSH) and luteinizing hormone (LH), we have used enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, immunohistochemical staining and Western blotting to examine DHT synthesis in small (≤2 mm), medium (2-5 mm) and large (≥5 mm) sheep follicles. Expression of 5α-red1, 5α-red2 and AR was observed in ovine ovaries, and with the development of follicles, the expressions of 5α-red1 and 5α-red2 mRNA and protein increased, but the levels of AR mRNA, protein and DHT level decreased. In addition, granulosa cells were treated with FSH (0.01, 0.1 and 1 international unit (IU)/ml), LH (0.01, 0.1 and 1 IU/ml) and testosterone (T, 10 M) to evaluate the effects of FSH and LH on DHT and oestradiol (E2) synthesis and 5α-red1, 5α-red2 and AR expression. We found that FSH and LH upregulated 5α-red1 and 5α-red2 in sheep granulosa cells, but downregulated the concentration of DHT and expression of AR. Meanwhile, FSH and LH significantly upregulated the expression of aromatase (P450arom) and secretion of E2. This result indicates that although FSH and LH promote the expression of 5α-red1 and 5α-red2, T is not transformed into DHT, but E2. This study reveals the reason why DHT concentration is downregulated in large follicles and lays a foundation for further exploring the synthesis mechanism of DHT during follicular development.
Topics: Animals; Dihydrotestosterone; Female; Follicle Stimulating Hormone; Granulosa Cells; Luteinizing Hormone; Ovarian Follicle; Oxidoreductases; Receptors, Androgen; Sheep, Domestic
PubMed: 33001490
DOI: 10.1111/rda.13837 -
Journal of Neuroendocrinology Feb 2022Sex steroids, such as estradiol (E ) and dihydrotestosterone (DHT), regulate hippocampal plasticity and memory in a sex-dependent manner. Because the activity-regulated...
Sex steroids, such as estradiol (E ) and dihydrotestosterone (DHT), regulate hippocampal plasticity and memory in a sex-dependent manner. Because the activity-regulated cytoskeleton protein Arc/Arg3.1 is essential for long-term memory formation and synaptic plasticity, we investigated the expression of Arc/Arg3.1 with respect to its responsiveness to E and DHT in male and female hippocampal neurons. For the first time, we show that, in hippocampal neurons, Arc/Arg3.1 expression is sex-dependently regulated by sex steroids. No difference in the expression between sexes was observed under control conditions. Using a quantitative real-time polymerase chain reaction, western blot analysis and quantitative immunoreactivity, upregulation of Arc/Arg3.1 protein expression was observed in specifically female hippocampal neurons after application of E to the cultures. Conversely, upregulation of Arc/Arg3.1 was seen in specifically male neurons after application of DHT. A quantitative real-time PCR revealed that the sex-dependency was most pronounced on the mRNA level. Most importantly, the effects of E in cultures of female animals were abolished when neuron-derived E synthesis was inhibited. Our results point to a potentially important role of Arc/Arg3.1 regarding sex-dependency in sex steroid-induced synaptic plasticity in the hippocampus.
Topics: Animals; Cytoskeletal Proteins; Dihydrotestosterone; Estradiol; Female; Hippocampus; Male; Nerve Tissue Proteins; Neuronal Plasticity; Neurons; Neurosteroids
PubMed: 35081672
DOI: 10.1111/jne.13090 -
Annals of Nuclear Medicine Jan 20177α-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized...
OBJECTIVE
7α-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized fluoropropyl derivatives of 7α-(3-[F]fluoropropyl)-testosterone ([F]7) and 7α-(3-[F]fluoropropyl)-dihydrotestosterone ([F]15), and characterized their in vitro binding, in vivo biodistribution, and performed blocking studies in mature androgen deprived male rats.
METHODS
We synthesized [F]7 and [F]15. In vitro binding to recombinant rat AR ligand binding domain protein was determined using a competitive radiometric ligand-binding assay with the high-affinity synthetic androgen [17α-methyl-H]-methyltrienolone ([H]R1881). In vivo biodistribution was performed in mature male rats treated with diethylstilbestrol (chemical castration). A blocking study was performed by co-administration of dihydrotestosterone (36 µg/animal).
RESULTS
7α-(3-Fluoropropyl)-testosterone (7) and 7α-(3-fluoropropyl)-dihydrotestosterone (15) showed competitive binding to recombinant rat AR ligand binding domain protein. The IC value of 15 (13.0 ± 3.3 nM) was higher than 7 (47.8 ± 10.0 nM). In contrast to the AR binding affinity, the ventral prostate uptake of [F]7 and [F]15 at 2 h post-injection was similar (0.07 % injected dose/g of tissue). A blocking study indicated that specific binding of [F]15 is observed in the ventral prostate. [F]7 and [F]15 showed moderate levels of bone uptake, which indicates moderate metabolic de-fluorination in rodents.
CONCLUSION
[F]15 is better than [F]7 in terms of radiochemical yield, in vitro binding affinity, prostate specific binding and stability against in vivo metabolic de-fluorination. However, the net uptake level of [F]15 in prostate might be insufficient for in vivo visualization. Although [F]7 and [F]15 improved in vivo stability against de-fluorination, other basic characterization data in rodents were not superior to the current standard tracer 16β-[F]fluoro-5α-dihydrotestosterone. It is also revealed that the shorter side chain length of 7α-[F]fluoromethyl-dihydrotestosterone is superior to the longer three carbon chain in [F]15, in terms of net prostate uptake and in vivo metabolic stability.
Topics: Androgens; Animals; Chemistry Techniques, Synthetic; Dihydrotestosterone; Male; Radiochemistry; Rats; Receptors, Androgen; Testosterone; Tissue Distribution
PubMed: 27680022
DOI: 10.1007/s12149-016-1130-7