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.

Estrogens, particularly the most active 17β-estradiol (E2), play a crucial role in the initiation and development of breast cancer. Therefore, current treatment strategies are based on interfering with estrogen receptors (ERs) via pure antiestrogens or selective modulators (SERMs) or by inhibiting estrogen synthesis through key enzymes in this pathway. While SERMs are generally effective, resistance often develops. Moreover, they cannot be used to treat triple-negative breast cancers (TNBCs). Three critical enzymes in the estrogen synthesis pathway, namely aromatase, sulfatase, and 17β-hydroxysteroid dehydrogenases, are of particular interest as drug targets. Some, such as aromatase inhibitors, are already used in clinical practice, while the other two remain under intensive investigation. Several comprehensive reviews have been published on ER modulators or individual enzyme inhibitors. This paper attempts to summarize recent data on modulators/inhibitors of both the ER and the major enzymes involved in estrogen biosynthesis and offers a perspective on their further development.

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).

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.

Aromatase, an enzyme that facilitates the last stage in estrogen synthesis (estrogen is identified for a significant impact in the development of breast cancer), has been recognized as a potential target for therapeutic advancements for cancer. Although clinically approved aromatase inhibitors are the cornerstones of estrogen receptor-positive (ER+) breast cancer, their use is often accompanied by adverse side effects and pharmacokinetic limitations, which lead to patient compliance issues and limit therapeutic outcomes. In previous studies, compound 1-(a) was identified for its superior inhibition of aromatase with an IC50 value of 54.0 nM and appreciable tumor growth inhibitory activities. Here, we demonstrated the pharmaceutical capability of 1-(a) while evaluating its various features, including acute toxicity, bioavailability by developing a nanodrug delivery system, and therapeutic efficacy. In vivo acute toxicity studies confirmed the safety of compound 1-(a), with no significant alterations observed. To improve the aqueous solubility and pharmacokinetic profile, a mixed micelle-based delivery system by using Pluronics P123 and F127 was developed, and a 2:1 formulation was optimized for demonstrating excellent drug loading (8.8%) and entrapment efficiency (80%). The micellar formulation significantly enhanced the solubility, stability, % growth inhibition, and cellular uptake of 1-(a) against MCF-7 and MDA-MB-231 cell lines and intestine permeability. An in vitro drug release study performed at pH 1.2, 6.8, and 7.4 indicated the sustained release behavior of 1-(a). Overall, the results of these experiments supported the potential of Pluronics as a drug delivery system for the potent aromatase inhibitor.

Endocrine therapy has stood as a fundamental pillar in addressing hormone receptor-positive breast cancer. Nevertheless, the emergence of resistance to these therapies poses a significant and ongoing clinical hurdle. Of late, there is a growing interest toward investigating the role of steroidal molecules in treatment of endocrine resistant breast cancer. The intricate and fascinating structural framework of the steroidal nucleus has drawn considerable scientific attention globally to devise novel and effective derivatives for combating breast cancer. Apart from its structural appeal, the multi-target oriented steroidal nucleus empowers researchers to design and develop a wide range of compounds for use in the treatment of breast cancer. Steroids remain a cornerstone of breast cancer clinical setting, offering significant advantages over non-steroidal counterparts as they act through multiple mechanisms like irreversibly inactivating the aromatase enzyme, downgrading estrogen receptors and simultaneously reducing estrogen and androgen levels through sulfatase inhibition. It is implied that the development of novel multifunctional steroidal molecules with complementary mechanisms could positively transform hormone-dependent cancer therapy by ensuring prolonged estrogen suppression and reduced resistance risk. This comprehensive review article provides an overview of the underlying complex mechanisms responsible for the development of resistance to endocrine therapies. Furthermore, it aims to explore the potential therapeutic possibilities that steroidal molecules may offer within this resistant context.

To date, there have been no head-to-head randomized controlled trial data comparing cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in patients with HR+/HER2- metastatic breast cancer (mBC), and most prior real-world comparative effectiveness studies have been limited by short follow-up times and small patient sample sizes. In this vodcast, we provide an overview of two recent publications reporting overall survival (OS) and real-world progression-free survival (rwPFS) results from P-VERIFY, a retrospective comparative effectiveness study of CDK4/6 inhibitors plus an aromatase inhibitor (AI) among patients with HR+/HER2- mBC treated in routine clinical practice in the USA. P-VERIFY used the Flatiron Health Analytic Database to identify 9146 patients who initiated first-line (1L) treatment with palbociclib (n = 6831), ribociclib (n = 1279), or abemaciclib (n = 1036), plus an AI, between February 2015 and November 2023. In primary analyses, there were no significant differences in OS and rwPFS between treatment groups after stabilized inverse probability treatment weighting, with hazard ratios ranging from 0.95 to 0.98 across pairwise group comparisons (all P > 0.05). Findings remained generally consistent across sensitivity and subgroup analyses and in a subanalysis of patients who started treatment in 2017 or later, when all three CDK4/6 inhibitors were commercially available. Taken together, results from P-VERIFY, the largest real-world study to date evaluating CDK4/6 inhibitor comparative effectiveness, suggest that there are no significant differences in OS and rwPFS between 1L palbociclib, ribociclib, and abemaciclib, plus an AI, in patients with HR+/HER2- mBC in US routine clinical practice.