Journal of Steroid Biochemistry and Molecular Biology最新文献

Prostate cancer (PC) is a common and widespread cancer that affects men globally. A complicated interaction of hormonal variables influences its development. Sex hormone-binding globulin (SHBG) is a crucial element in controlling the availability of sex hormones, especially androgens, which have a notable impact on the development and progression of PC. SHBG controls the levels of free, active androgens in the body, which helps regulate androgen-dependent processes associated with PC. The equilibrium between SHBG and androgens plays a critical role in maintaining the stability of the prostate. When this balance is disrupted, it is associated with the development and advancement of PC. The processes responsible for SHBG's role in PC are complex and have multiple aspects. SHBG primarily binds to androgens, preventing them from interacting with androgen receptors (ARs) in prostate cells. It reduces the activation of androgen signaling pathways essential for tumor development and survival. In addition, SHBG can directly affect prostate cells by interacting with specific receptors on the cell surface. This review thoroughly examines the role of SHBG in PC, including its physiological activities, methods of action, and clinical consequences.

Breast cancer (BC) is a highly heterogeneous tumor that has surpassed lung cancer as the most frequently diagnosed cancer in women. In clinical practice,the primary approach for treating estrogen receptor alpha (ERα)-positive BC is through endocrine therapy, which involves targeting the ERα using medications like tamoxifen and fulvestrant. However, the problem of de novo or acquired resistance poses a significant clinical challenge, emphasizing the critical need for the development of novel therapeutic strategies. In this regard, we have successfully designed and developed a novel selective estrogen receptor degrader (SERD) called OBHSA, which specifically targets and degrades ERα, demonstrating remarkable efficacy. Our findings revealed the effectiveness of OBHSA in inhibiting the proliferation of various BC cells, including both tamoxifen-sensitive and tamoxifen-resistant BC cells, indicating its great potential to overcome endocrine resistance. In terms of mechanism, we discovered that OBHSA overcame tamoxifen resistance through two distinct pathways. Firstly, OBHSA degraded cyclin D1 in an ERα-dependent manner, thereby blocking the cell cycle. Secondly, OBHSA induced an elevation in intracellular reactive oxygen species, triggering an excessive activation of the unfolded protein response (UPR) and ultimately leading to apoptotic cell death. In summary, our finding demonstrated that OBHSA exerts anti-tumor effects by inducing cell cycle arrest and UPR-mediated apoptosis. These findings hold promise for the development of novel therapeutic drugs targeting endocrine-resistant BC.

This research aimed to develop novel selective secosteroids that are highly active against hormone-dependent breast cancer. A simple and convenient approach to N′-acylated 13,17-secoestra-1,3,5(10)-trien-17-oic acid hydrazides was disclosed and these novel types of secosteroids were screened for cytotoxicity against the hormone-dependent human breast cancer cell line MCF7. Most secosteroid N′-benzoyl hydrazides have demonstrated high cytotoxicity against MCF7 cells with IC₅₀ values below 5 μM, which are superior to that of the reference drug cisplatin. Hit compounds 2c, 2e and 2i were characterized by high cytotoxicity (IC₅₀ = 1.6–1.9 μM) and very good selectivity towards MCF7 breast cancer cells. The lead secosteroids 2c, 2e and 2i also exhibit antiestrogenic effects and alter the expression of cell cycle regulating proteins. The effect of selected compounds on PARP (poly(ADP-ribose) polymerase) and Bcl-2 (B-cell CLL/lymphoma 2) indicates their proapoptotic potential. The synthesized secosteroids may be considered as new promising anti-breast cancer agents targeting ERα and apoptosis pathways.

Transgender is a term for people whose gender identity or expression differs from their natal sex. These individuals often seek cross-hormonal therapy to simulate the individual´s desired gender. However, the use of estrogens and testosterone has side effects such as a higher propensity to cancer, weight changes and cardiovascular diseases. Testosterone has also been linked with hypertension. Still, little is known about the outcomes and prevalence of metabolic perturbations in the trans community. Here we aim to analyze if cross-administering sexual hormones affects heart mitochondrial function. Mitochondria produces the ATP needed for heart function. In fact, different studies show that mitochondrial dysfunction precedes cardiac damage. In this work we used either female rats castrated and injected with testosterone or male rats castrated and injected with estrogens for 4 months. We performed an electrocardiogram, and then we isolated heart mitochondria to measure the rate of oxygen consumption, calcium fluxes, membrane potential, superoxide dismutase activity, lipoperoxidation and cytokines. We detected wide modifications in all parameters associated to cross-hormonal administration.

Since steroids are crucial for diagnosing endocrine disorders, the lack of research on factors that affect hormone levels makes interpreting the results difficult. Our study aims to assess the stability of the pre-analytical procedure and the impact of hormonal physiological fluctuations using real-world data. The datasets were created using 12,418 records from individuals whose steroid hormone measurements were taken in our laboratory between September 2019 and March 2024. 22 steroid hormones in plasma by a well-validated liquid chromatography tandem mass spectrometry method were measured. After normalization transformation, outlier removal, and z-score normalization, generalized additive models were constructed to evaluate preanalytic stability and age, sex, and sample time-dependent hormonal fluctuations. Most hormones exhibit significant variability with age, particularly steroid hormone precursors, sex hormones, and certain corticosteroids such as aldosterone. 18-hydroxycortisol, 18-oxocortisol. Sex hormones varied between males and females. Levels of certain hormones, including cortisol, cortisone, 11-deoxycortisol, 18-hydroxycortisol, 18-oxocortisol, corticosterone, aldosterone, estrone, testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, 11-ketotestosterone, and 11-hydroxytestosterone, fluctuated with sampling time. Moreover, levels of pregnenolone and progesterone decreased within 1 hour of sampling, with pregnenolone becoming unstable with storage time at 4 degrees after centrifugation, while other hormone levels remained relatively stable for a short period of time without or after centrifugation of the sample. This is the first instance real-world data has been used to assess the pre-analytic stability of plasma hormones and to evaluate the impact of physiological factors on steroid hormones.

The distribution of CYP11B2-positive or aldosterone producing adrenocortical cells in human fetuses and children and their age-dependent changes has not been studied. We aimed to explore the changes of aldosterone biosynthesis and age-related histological alterations of the zona glomerulosa in human adrenal gland during fetal and pediatric periods. We first reviewed 125 fetal and pediatric autopsy cases and retrieved 78 adrenals from 70 cases. CYP11B2 immunohistochemistry and quantitative image analysis of its results were performed in all adrenal glands. The ratio of the definitive zone (DZ) or zona glomerulosa (ZG) / the whole adrenocortical areas started to increase in the 2nd trimester, subsequently decreased in the 3rd, increased after birth, peaked in infancy, and then gradually decreased. The ratio of CYP11B2-positive / whole adrenocortical areas remained low during the fetal period but increased after birth, peaked at infancy, and then decreased. The ratio of CYP11B2-positive / DZ or ZG areas and CYP11B2-positive areas / depth of DZ or ZG demonstrated a distinctive bimodal pattern, with one peak in the fetal period and another in the neonatal period to infancy. This is the first study to perform quantitative analysis of the distribution of CYP11B2-positive cells, the histological DZ or ZG, and the development of aldosterone biosynthesis in human adrenal glands during fetal and pediatric periods.

The estrogen receptor (ER), a ligand-dependent transcription factor, is critical for vertebrate reproduction. However, its role in bivalves is not well understood, with ongoing debates regarding its function in regulating reproduction similarly to vertebrates. To investigate ER's function, we conducted a 21-day RNA interference experiment focusing on its role in gonadal development in bivalves. Histological analyses revealed that ER inhibition significantly suppressed ovarian development in females and, conversely, promoted gonadal development in males. Additionally, levels of 17β-estrogen (E2) were markedly reduced in the gonads of both sexes following ER suppression. Transcriptomic analysis from RNA-seq of testes and ovaries after ER interference showed changes in the expression of key genes such as Vtg, CYP17, 3β-HSD, and 17β-HSD. These genes are involved in the estrogen signaling pathway and steroid hormone biosynthesis. Furthermore, ER suppression significantly affected the expression of genes linked to gametogenesis and the reproductive cycle. Our findings highlight ER's crucial, yet complex and sex-specific roles in gonadal development in bivalves, emphasizing the need for further detailed studies.

Steroid hormone imbalance is believed to increase the odds of developing PE. Bisphenol A (BPA) and its substitutes (e.g., bisphenol S (BPS) and bisphenol F (BPF)) have estrogen-like effects, and its exposure may be related to the development of preeclampsia (PE). To explore the effects of bisphenol exposure on maternal serum steroid hormones and the potential mediating role of steroid hormones in the association between bisphenol exposure and developing PE, concentrations of bisphenols and steroid hormones in serum samples of 383 pregnant women were examined before delivery (including 160 PE cases and 223 control cases). Multivariable logistic and linear models were used to explore the associations of maternal serum bisphenols concentrations with both maternal steroid hormones and PE risk. Mediation modeling was employed to evaluate the mediating role of steroid hormones in the association between bisphenols and PE. Results showed that maternal serum BPS concentrations were positively associated with testosterone (T) concentrations. The mediation analyses suggested that approximately 10.17 % of the associations between BPS concentrations and the development of PE might be mediated by maternal T. In conclusion, maternal exposure to BPS during pregnancy is linked to higher maternal T concentrations, which might increase the odds of developing PE. T might mediate the association between BPS exposure and the development of PE.

20-hydroxyprogesterone (20-DHP) is a natural metabolite of progesterone which occurs with two diastereoisomers: 20α-DHP and 20β-DHP. They have drawn attention for their progesterone-like activity since the middle of the 20th century. However, the literature from that era bears witness to a lack of consensus regarding their specific effects. Considered that their stereoisomerism differences, it is essential to investigate their biological activities in vivo separately. In this study, we presented a chemical synthesis technique that yielded highly pure samples of 20α-DHP and 20β-DHP, and performed simultaneous content analysis. Subsequently, we examined and contrasted the progesterone-like properties of 20α-DHP, 20β-DHP, and a 1:1 mixture of 20α-DHP and 20β-DHP. The Morphological observations of the endometrium were conducted via Haematoxylin–eosin staining. Serum hormone levels were measured using enzyme-linked immunosorbent assays. Furthermore, real-time fluorescence quantitative polymerase chain reaction and immunohistochemistry were employed to analyse the relevant mRNA and protein expression, respectively. Our comparison revealed that 20α-DHP and P4 share identical progesterone-like actions, while 20β-DHP exhibits partial similarity. The progesterone activity varied when the two were combined in a 1:1 ratio.