Non-obstructive azoospermia (NOA) is the most severe phenotype of male-factor infertility and reflects impaired spermatogenesis rather than ductal obstruction. Microdissection testicular sperm extraction (micro-TESE) is the primary sperm retrieval method, but sperm retrieval rates remain at approximately 40-60% and vary with etiology, genetics, histopathology, surgical expertise, and endocrine phenotype. This narrative review synthesizes major international and regional guidelines and contemporary evidence on preoperative hormonal optimization, with particular emphasis on endogenous testosterone dynamics. Exogenous testosterone is contraindicated in fertility-seeking men because it suppresses gonadotropins and intratesticular testosterone. By contrast, selective estrogen receptor modulators, aromatase inhibitors, human chorionic gonadotropin, and follicle-stimulating hormone aim to preserve or augment endogenous Leydig- and Sertoli-cell function. Low-certainty, predominantly observational evidence suggests an association between hormonal pretreatment and higher sperm retrieval in selected normogonadotropic or hypogonadal men, but not consistently in hypergonadotropic NOA. A larger testosterone rise during stimulation has been positively associated with retrieval and may reflect residual Leydig-cell reserve, although causality and transferable thresholds remain unproven. Preoperative endocrine therapy should therefore remain individualized, phenotype-guided, off-label, closely monitored, and preferably investigated within clinical trials; the testosterone response is best regarded as a candidate prognostic biomarker rather than a validated therapeutic target or decision rule.

Breast cancer (BC) is the most incidental cancer in women. Patients' living conditions and survival rates have significantly improved with the success of two first-line endocrine therapies of selective estrogen-receptor modulators (SERMs from 1977) and aromatase inhibitors (AIs from 1995). Unfortunately, both therapies have produced significant resistance. AI resistance reaches 50% in metastatic estrogen-dependent BC cases, leading oncologists to seek a substitute for current therapies. We target the reductive 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), which stimulates the synthesis of the active estrogen estradiol (E2) and reduces the potent androgen dihydrotestosterone (DHT) simultaneously, triggering negative feedback on 17β-HSD7 expression. INH7(464), an improved 17β-HSD7 inhibitor, efficiently blocks estrogen conversion at an IC50 of 92 ± 8 nM. INH7(464) inhibited cell proliferation by decreasing E2 levels and restoring DHT, successively arresting the cell cycle in G0/G1 phase. In vivo, INH7(464) reduced tumor size by 49% on Day 22 in BC xenografts with T47D. INH7(464) reduced E2 levels in mouse blood circulation and xenograft tumor tissue. There is no demonstrated cytotoxicity or cardiotoxicity of INH7(464) on cellular levels and mouse models under the experimental conditions. 17β-HSD7 is a potential target for estrogen-dependent BC therapy, while INH7(464) is promising for a preclinical lead compound (PCT/CA2022/050966).

Cardiac fibrosis plays a crucial role in heart failure, but research in this field remains challenging due to heterogeneity of cardiac fibroblast populations. In the past years, several Cre-drivers have been proposed for cardiac fibroblast-specific deletion of floxed genes in adult mouse research models. Here, we evaluated whether Tcf21-iCre, a tamoxifen-inducible Cre recombinase (iCre) under the endogenous Tcf21 promoter, was able to successfully target two floxed loci (Hypoxia inducible factor 1a (Hif1a) and the fluorescent reporter locus mTmG) after intraperitoneal tamoxifen injections. Six-week-old mice received intraperitoneal tamoxifen injections on five consecutive days to induce Cre activity, and the recombination efficiency was measured in isolated fibroblasts via qPCR, Western Blot and fluorescence microscopy. Recombination efficiency was very low, with minimal reduction in expression of Hif1a. For the mTmG locus, both bi-allelic and mono-allelic recombination was detected, with mono-allelic events suggesting low Cre activity even within Tcf21-expressing fibroblasts. The addition of experimental models of heart failure with reduced or preserved ejection fraction as pro-fibrotic stimuli or an inclusion of an additional round or higher doses of tamoxifen injections did not improve recombination efficiency of the targeted alleles. Thus, Tcf21-iCre targets only a small proportion of fibrogenic fibroblasts following i.p. tamoxifen injection, limiting its usability in loss-of-function studies that require broad fibroblast coverage and highlighting the need for alternative Cre-drivers or delivery strategies to facilitate antifibrotic therapy development.

Cervical cancer (CxCa) remains a major global gynecological malignancy causally linked to high-risk human papillomavirus (HPV) infection. However, HPV alone is insufficient for carcinogenesis; sex hormones and their receptors serve as essential cofactors. This review aims to synthesize current knowledge on the role of cervical histoarchitecture and hormonal microenvironments in ectocervical squamous cell carcinoma (SCC), and to explore how receptor-mediated signals contribute to malignant transformation and metastatic spread. The review examines the expression patterns of estrogen receptor α (ERα) and progesterone receptor (PR) in the uterine cervix, which is a hormone-responsive tissue. It discusses how these receptors fluctuate throughout the menstrual cycle and evaluates evidence from HPV-transgenic mouse models and human tissue analyses. The findings converge on a compelling model: stromal ERα drives pro-carcinogenic paracrine signaling, epithelial PR suppresses neoplastic transformation, and stromal PRB confers antimetastatic protection. These insights highlight the complex interplay between hormonal signals and SCC development in the ectocervix. Future therapeutic exploitation of these mechanistic insights-including selective estrogen receptor modulators, selective progesterone receptor modulators, and PR status-guided chemoprevention-holds considerable promise. This review provides a coherent framework for translating laboratory findings into clinical diagnostics and targeted interventions.

Globally, breast cancer stands as one of the primary causes of cancer related deaths. Among the types of breast cancer, estrogen receptor- positive (ER+) breast cancer accounts for the highest incidence and mortality worldwide. The present study emphasizes the design, synthesis, and biological evaluation of a series of novel triphenylethylene (TPE) based selective estrogen receptor modulators (SERMs) for their antiproliferative activity against ER+ breast cancer. All the synthesized compounds were well characterized using spectroscopic and chromatographic techniques. Favorable druglike properties indicating acceptable permeability through membrane and oral bioavailability were observed in in-silico physicochemical, ADME, and toxicity profiling. Further, biological evaluation of the synthesized compounds against MCF-7 breast cancer cells demonstrated significant antiproliferative nature of the synthesized compounds. Compounds 5g and 5o showed antiproliferative activity comparable to the standard metabolite 4-hydroxytamoxifen (4-OH TAM) and the IC50 of compounds 5g and 5o were found to be 4.350 ± 0.373 and 3.562 ± 0.466 μM respectively. Subsequently, the cell death pathway was revealed through caspase-3/7 assay and immunoblotting analysis and the compounds were found to cause cell death through activation of apoptosis-related proteins such as cleaved PARP and cleaved caspase-7. The molecular docking studies on the target protein ERα (PDB ID: 3ERT) exhibited favorable docking interactions between the compounds 5g and 5o with key amino acid residues such as Asp351, Thr347, Leu346, and His524. Similar interactions with amino acid residues were observed in the case of 4-OH TAM. Comprehensively, the results of the study highlight the promising anticancer potential of the synthesized compounds 5g and 5o as TPE-based SERM for selective ER+ breast cancer.

Preclinical studies suggest that tamoxifen (TAM) may interact with the efflux transporter P-glycoprotein (P-gp); however, its effect on intestinal P-gp activity in vivo remains poorly characterized. This study evaluated intestinal P-gp activity in women receiving tamoxifen therapy using fexofenadine (FEXO) as a probe substrate. Sixteen women receiving tamoxifen (20 mg/day for ≥80 days) and 12 healthy women were enrolled. All participants received a single oral dose of fexofenadine (120 mg), and serial plasma samples were collected over 12 h. Pharmacokinetic parameters were determined by noncompartmental analysis, and plasma fexofenadine concentrations were quantified by LC-MS/MS. Systemic exposure to fexofenadine was lower in women receiving tamoxifen than in healthy women. Geometric mean (95% confidence interval [CI]) AUC0-12h was 646.55 ng.h/mL (523.50-798.52) in the tamoxifen group and 994.77 ng.h/mL (832.21-1189.07) in healthy women, whereas AUC0-∞ was 715.40 ng.h/mL (588.92-869.05) and 1123.66 ng.h/mL (919.98-1372.43), respectively (P < .05). Apparent oral clearance (CL/F) was higher in women receiving tamoxifen (167.74 vs 106.79 L/h; P < .05), whereas elimination half-life was unchanged between groups. The observed pharmacokinetic profile is consistent with reduced oral bioavailability and suggests modulation of intestinal transporter-mediated drug disposition during tamoxifen therapy. These findings may have implications for the disposition of concomitantly administered orally administered P-gp substrates and warrant further investigation in dedicated clinical pharmacology studies.

Endometriosis is a chronic inflammatory and estrogen-dependent disease in which pain remains the leading cause of impaired quality of life. Hormonal therapies constitute the cornerstone of medical management and include progestins, combined estrogen-progestin contraceptives, gonadotropin-releasing hormone (GnRH) agonists and antagonists, selective estrogen and progesterone receptor modulators, and aromatase inhibitors. Although these treatments effectively suppress ovarian function and reduce estrogen-dependent lesion activity, their clinical benefits are frequently limited by adverse effects, contraceptive implications, and symptom recurrence after treatment discontinuation. Increasing evidence indicates that the persistence of endometriosis-associated pain cannot be explained solely by hormonal dysregulation. A sustained inflammatory microenvironment, characterized by innate immune cell activation, pro-inflammatory cytokine production, and neuroimmune interactions, contributes to peripheral and central sensitization, thereby limiting the effectiveness of therapies targeting endocrine pathways alone. These disease-driven mechanisms provide a biological explanation for the heterogeneous response to hormonal treatment observed in clinical practice. This review summarizes the mechanisms of action, clinical efficacy, safety profile and limitations of current hormonal therapies for endometriosis-associated pain. In addition, it discusses the inflammatory and neuroimmune mechanisms underlying persistent pain and highlights the rationale for combining endocrine therapies with emerging anti-inflammatory and immunomodulatory strategies. Such integrated approaches may improve long-term pain control, reduce recurrence, and contribute to more personalized management of endometriosis.

Tamoxifen-induced retinopathy is well recognized and frequently reported in clinical practice. By contrast, ocular adverse events associated with the structurally similar agent toremifene remain rarely described. We present a case of bilateral visual impairment in a patient receiving long-term oral toremifene citrate for secondary prevention after breast cancer surgery. Ophthalmic evaluation showed yellowish-white crystalline deposits within the macular retinal layers in both eyes. Optical coherence tomography (OCT) revealed cystic vacuolization in the bilateral foveal regions, with features closely resembling tamoxifen-induced retinopathy. A clinical diagnosis of toremifene-associated retinopathy was established. This case may provide reference for clinicians when judging the appropriate timing of toremifene withdrawal. Should drug cessation be considered, a joint assessment by ophthalmologists and oncologists should be performed to balance the risks of tumor progression and ocular damage before reaching a clinical decision. In addition, this case supplements available evidence regarding toremifene-related ocular toxicity and raises clinical awareness of this condition.

Breast cancer is often treated with tamoxifen, a drug that can cause ocular side effects, including toxic retinopathy. Multimodal imaging, particularly optical coherence tomography (OCT), has improved the detection of early lesions such as foveal pseudocysts, thus increasing the prevalence of this complication. We present a case of tamoxifen-induced retinopathy in a patient treated for four years who developed decreased visual acuity with irreversible retinal lesions in the right eye despite discontinuation of the treatment. OCT was essential in characterizing the lesions. The pathophysiology remains poorly understood, but involvement of Müller cells and glutamate accumulation in the retinal pigment epithelium are suspected. Toxicity depends on cumulative dose, duration of treatment, and individual factors. Initial ophthalmologic screening and regular OCT monitoring are recommended to detect retinal damage early. In case of lesions, substitution with an aromatase inhibitor is often considered to limit lesion progression and preserve vision.