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Background: The co-treatment of androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) with the fetal estrogen estetrol (E4) may further inhibit endocrine PCa tumor stimulators. We previously reported the suppression of follicle-stimulating hormone (FSH), total and free testosterone, and prostate-specific antigen by ADT+E4. Here, we provide more detailed data on FSH suppression by E4 and present new findings on the effect of ADT+E4 on insulin-like growth factor-1 (IGF-1). Methods: A Phase II, double-blind, randomized, placebo-controlled study (the PCombi study) was conducted in advanced PCa patients treated with ADT. The study assessed the effect of E4 co-treatment with LHRH agonist ADT on tumor stimulators, including FSH and IGF-1. Patients starting ADT were randomized 2:1 to receive either 40 mg E4 ( n = 41) or placebo ( n = 21) for 24 weeks. Non-parametric analyses were performed on the per-protocol population (PP) and individual changes were visualized. Results: The PP included 57 patients (37 ADT+E4; 20 ADT+placebo). ADT+E4 almost completely suppressed FSH in all patients (98% versus 37%; p < 0.0001). IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo ( p < 0.0001). Conclusions: The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA.

The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical consequences of E2 deficiency in men and discuss the effects of restoration of levels of this reproductive steroid hormone. In men with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT), E2 is suppressed along with testosterone, leading to side effects affecting the quality of life. These include hot flashes, arthralgia, fatigue, mood changes, cognition problems, weight gain, bone loss, and increased risk of cardiovascular disease. Transdermal E2 alone for ADT has shown equivalent testosterone suppression compared to gonadotropin-releasing hormone (GnRH) agonists while also preventing estrogen-deficiency side effects, including hot flashes and bone loss. Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Finasteride and dutasteride, synthetic 5α-reductase inhibitors (5ARIs) are recommended in many guidelines for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms and alopecia despite a variety of side effects like sexual, neurological, psychiatric, endocrinological, metabolic and ophthalmological dysfunctions and the increased incidence of high grade prostate cancer. The sexual side effects are common during the use of the drug but in a small subgroup of patients, they can persist after stopping the drug. This so-called post-finasteride syndrome has serious implications for the quality of life without a clear etiology or therapy. Three types of 5α-reductases are present in many organs in- and outside the brain where they can be blocked by the two 5ARIs. There is increasing evidence that 5ARIs not only inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT) in the prostate and the scalp but also in many other tissues. The lipophilic 5ARIs can pass the blood-brain barrier and might block many other neurosteroids in the brain with changes in the neurochemistry and impaired neurogenesis. Further research and therapeutic innovations are urgently needed that might cure or relieve these side effects. More awareness is needed for physicians to outweigh these health risks against the benefits of 5ARIs., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Compared to females, males experience severe acute respiratory syndrome due to COVID-19 (SARS-CoV-2) more often, and also die more frequently from COVID-19. Testosterone has inhibitory and estrogens have favorable effects on the immune system. Both ACE2 and TMPRSS2 are specific host-cellular proteins stimulating viral entry in cells and SARS-CoV-2. Both proteins can be suppressed by inhibition of testosterone levels and by stimulation of estrogen levels. Therefore, both androgen-deprivation therapy (ADT) and estrogen therapy (ET) may decrease COVID-19 virus cell entry. Literature was searched for evidence of COVID-19 treatment benefits with estrogens, progesterone, androgen deprivation, and anti-androgens. Data supporting the effect of ADT on SARS-CoV-2 are sparse and inconsistent. The benefit of anti-androgen therapy is inconsistent. Data on the effect of ET were not found. Indirect estrogen data related to menopausal hormone therapy and hormonal contraception are favorable. In a small study, progesterone had some beneficial effects. The combination of ADT and ET (ADET) has never been studied as a treatment option for SARS-CoV-2. Based on the mode of action of the combination, it is hypothesized that ADET may be an effective and safe treatment of SARS-CoV-2, to be confirmed in a clinical trial., Competing Interests: The authors declare the following conflict of interests: Dr. Coelingh Bennink is president and shareholder of Pantarhei Oncology, an affiliate of Pantarhei Bioscience BV, Zeist, The Netherlands. He has submitted a patent application for the ADET treatment concept. Mr Egberts declares no conflict of interest. Dr Debruyne is Medical Director of Andros Men’s Health Institutes, the Netherlands, and is consultant for Pantarhei Oncology BV, the company developing ADET for the treatment of advanced prostate cancer., (© 2022 The Author(s).)

The purpose of androgen deprivation therapy (ADT) in prostate cancer (PCa), using luteinizing hormone-releasing hormone agonists (LHRHa) or gonadotrophin-releasing hormone antagonists, is to suppress the levels of testosterone. Since testosterone is the precursor of estradiol (E2), one of the major undesired effects of ADT is the concomitant loss of E2, causing among others an increased bone turnover and bone loss and an increased risk of osteoporosis and fractures. Therefore, the guidelines for ADT indicate to combine ADT routinely with bone-sparing agents such as bisphosphonates, denosumab or selective estrogen receptor modulators. However, these compounds may have side effects and some require inconvenient parenteral administration. Co-treatment with estrogens is an alternative approach to prevent bone loss and at the same time, to avoid other side effects caused by the loss of estrogens, which is the topic explored in the present narrative review. Estrogens investigated in PCa patients include parenteral or transdermal E2, diethylstilbestrol (DES), and ethinylestradiol (EE) as monotherapy, or high-dose estetrol (HDE4) combined with ADT. Cardiovascular adverse events have been reported with parenteral E2, DES and EE. Encouraging effects on bone parameters have been obtained with transdermal E2 (tE2) and HDE4, in the tE2 development program (PATCH study), and in the LHRHa/HDE4 co-treatment study (PCombi), respectively. Confirmation of the beneficial effects of estrogen therapy with tE2 or HDE4 on bone health in patients with advanced PCa is needed, with special emphasis on bone mass and fracture rate.

Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is accompanied by side effects affecting health-related quality of life (HRQL)., Objective: To assess the effects of the fetal estrogen estetrol (E4) on symptoms related to estrogen and androgen deficiency, and on HRQL measured using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire., Design Setting and Participants: This was a phase 2, double-blind, randomized, placebo-controlled study in patients with advanced PCa., Intervention: Patients receiving ADT were randomly assigned at a 2:1 ratio to daily treatment with a high dose of E4 (HDE4; n  = 41) or placebo ( n  = 21) for 24 wk., Outcome Measurements and Statistical Analysis: The primary outcome was the effect of HDE4 cotreatment on hot flushes (HFs). Secondary outcomes were the Q-Man questionnaire for evaluation of the effect on estrogen and androgen deficiency symptoms, and the FACT-P questionnaire for evaluating HRQL., Results and Limitations: At 24 wk, the number of patients experiencing HFs was significantly lower in the HDE4 group than in the placebo group (14.3% vs 60.0%; p  < 0.001). HDE4 treatment was associated with lower incidence of night sweats, arthralgia, and fatigue, but more nipple tenderness and gynecomastia. At 24 wk, the mean HRQL score favored HDE4 over placebo for the FACT-P total score (122.2 ± 12.3 vs 118.7 ± 19.7) and for several other FACT subscales., Conclusions: Daily HDE4 coadministration almost completely prevented HFs in patients with advanced PCa treated with ADT. HDE4 also had positive effects on HRQL and counteracted other estrogen deficiency symptoms caused by ADT. These data support the dual efficacy concept of ADT and HDE4 to improve HRQL and increase the antitumor effect of ADT., Patient Summary: For patients on androgen deprivation therapy for advanced prostate cancer, cotreatment with a high dose of estetrol almost completely prevents the occurrence of hot flushes and improves quality of life and well-being, but nipple sensitivity and an increase in breast size may occur., (© 2022 The Author(s).)

Background: Androgen deprivation therapy (ADT) for prostate cancer with luteinizing hormone-releasing hormone (LHRH) agonists can be improved., Objective: To assess safety, the frequency and severity of hot flushes (HFs), bone health, and antitumor effects of high-dose estetrol (HDE4) when combined with ADT., Design Setting and Participants: A phase II, double-blind, randomized, placebo-controlled study was conducted in advanced prostate cancer patients requiring ADT (the PCombi study)., Intervention: Patients receiving LHRH agonist treatment were randomized 2:1 to 40 mg HDE4 ( n  = 41) or placebo ( n  = 21) cotreatment for 24 wk., Outcome Measurements and Statistical Analysis: Coprimary endpoints were frequency/severity of HFs and levels of total and free testosterone (T). Secondary endpoints included assessments of bone metabolism (osteocalcin and type I collagen telopeptide [CTX1]), prostate-specific antigen (PSA), and follicle-stimulating hormone (FSH). Efficacy analysis was based on the selected per-protocol (PP) population., Results and Limitations: Of 62 patients included in the study, 57 were suitable for a PP analysis (37 HDE4; 20 placebo). No E4-related serious cardiovascular adverse events occurred at 24 wk. Weekly HFs were reported by 13.5% of patients with HDE4 and 60.0% with placebo ( p  < 0.001). Daily HFs occurred in 5.9% versus 55%. Bone turnover parameters decreased significantly with HDE4 ( p  < 0.0001). Total and free T decreased earlier ( p  < 0.05), and free T was suppressed further ( p  < 0.05). PSA suppression was more profound and earlier ( p  < 0.005). FSH levels were suppressed by 98% versus 57% ( p  < 0.0001). Estrogenic side effects were nipple sensitivity (34%) and gynecomastia (17%)., Conclusions: HDE4 cotreatment of ADT patients with advanced prostate cancer was well tolerated, and no treatment-related cardiovascular adverse events were observed at 24 wk. HFs and bone turnover were substantially reduced. Suppression of free T, PSA, and FSH was more rapid and profound, suggesting enhanced disease control by HDE4 cotreatment. Larger and longer-lasting studies are needed to confirm the results of the study reported here., Patient Summary: Cotreatment of androgen deprivation therapy with high-dose estetrol in advanced prostate cancer patients results in fewer occurrences of hot flushes, bone protection, and other antitumor benefits. Nipple sensitivity and gynecomastia may occur as side effects., (© 2021 The Authors.)

Background: Androgen deprivation therapy (ADT) is foundational in the management of advanced prostate cancer (PCa) and has benefitted from a recent explosion in scientific advances. These include approval of new therapies that suppress testosterone (T) levels or inactivate its function, improvements in diagnostic and assay technologies, identification of lower therapeutic targets for T, discovery of the relevance of germline genetic mutations and identification of the benefits of sequential and combination therapies., Methods: This review discusses the clinical profiles of the most up-to-date options for ADT, best practices for managing patients with advanced PCa and future directions in therapy., Results and Conclusions: Modern assay technologies reveal that bilateral orchiectomy results in a serum T level of approximately 15 ng/dL as compared to the historical definition of castration of T < 50 ng/dL. Evidence shows that lowering T levels to <20 ng/dL improves patient survival and delays disease progression. Routine monitoring of T in addition to prostate-specific antigen throughout treatment is important to ensure continuing efficacy of T suppression. New drugs that inhibit androgen signaling in combination with traditional ADT suppress T activity to near zero and have significantly improved patient survival. When personalizing ADT regimens physicians should consider a number of factors including initiation and duration of ADT, monitoring of T levels and PSA, the possibility of switching monotherapies if a patient does not achieve adequate T suppression, and consideration of intermittent vs. continuous ADT according to patients' lifestyles, comorbidities, risk factors and tolerance to treatment.

Context: Luteinizing hormone-releasing hormone (LHRH) agonists have replaced estrogens for endocrine treatment of advanced prostate cancer (PC) because of cardiovascular side effects. The fetal estrogen estetrol (E4) may be safer for PC treatment and is expected to decrease testosterone (T) and prevent estrogen deficiency., Objective: To investigate the safety and T-suppressive effect of E4 in healthy men., Design: Double-blind, randomized, placebo-controlled, dose-escalating study., Setting: The study was conducted at a phase I clinical unit (QPS, Netherlands)., Participants: Healthy male volunteers aged 40 to 70 years., Intervention(s): Three treatment cohorts of 15 volunteers with placebo (n = 5) and E4 (n = 10). Estetrol doses tested were 20, 40, and 60 mg/d. Subjects were treated for 4 weeks., Main Outcome Measures: Subjective side effects, pharmacodynamic effects on hemostatic variables, lipids, glucose, bone parameters, and endocrine parameters related to T metabolism., Results: Total and free T decreased dose-dependently and significantly. Nipple tenderness occurred in 40% and decrease of libido occurred in 30% of E4-treated men. The unwanted estrogenic effects on hemostasis were small, dose dependent, and in some cases significant. Lipid and bone parameters showed a favorable trend., Conclusion: The effect of E4 on testosterone levels is insufficient for standalone PC treatment. Taking all clinical and pharmacodynamic variables into consideration, a daily dose of 40 mg E4 seems safe for further evaluation of endocrine PC treatment in combination with LHRH analogs.

Background: The benefits and risks of long-term testosterone administration have been a topic of much scientific and regulatory interest in recent years., Aim: To assess long-term quality of life (QOL) and sexual function benefits of testosterone replacement therapy (TRT) prospectively in a diverse, multinational cohort of men with hypogonadism., Methods: A multinational patient registry was used to assess long-term changes associated with TRT in middle-age and older men with hypogonadism. Comprehensive evaluations were conducted at 6, 12, 24, and 36 months after enrollment into the registry., Outcomes: QOL and sexual function were evaluated by validated measures, including the Aging Males' Symptom (AMS) Scale and the International Index of Erectile Function (IIEF)., Results: A total of 999 previously untreated men with hypogonadism were enrolled at 25 European centers, 750 of whom received TRT at at least one visit during the period of observation. Patients on TRT reported rapid and sustained improvements in QOL, with fewer sexual, psychological, and somatic symptoms. Modest improvements in QOL and sexual function, including erectile function, also were noted in RHYME patients not on TRT, although treated patients showed consistently greater benefit over time in all symptom domains compared with untreated patients. AMS total scores for patients on TRT were 32.8 (95% confidence interval = 31.3-34.4) compared with 36.6 (95% confidence interval = 34.8-38.5) for untreated patients (P < .001). Small but significant improvements in IIEF scores over time also were noted with TRT. Approximately 25% of treated and untreated men also used phosphodiesterase type 5 inhibitors, with notable differences in the frequency of phosphodiesterase type 5 inhibitor prescription use according to physician specialty and geographic site location., Clinical Implications: TRT-related benefits in QOL and sexual function are well maintained for up to 36 months after initiation of treatment., Strengths and Limitations: The major strengths are the large, diverse patient population being treated in multidisciplinary clinical settings. The major limitation is the frequency of switching from one formulation to another., Conclusion: Overall, we confirmed the broad and sustained benefits of TRT across major QOL dimensions, including sexual, somatic, and psychological health, which were sustained over 36 months in our treatment cohort. Rosen RC, Wu F, Behre H, et al. Quality of Life and Sexual Function Benefits Effects of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). J Sex Med 2017;14:1104-1115., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

The landscape of the surgical management of urologic malignancies has dramatically changed over the past 20 years. On one side, better diagnostic and prognostic tools allowed better patient selection and more reliable surgical planning. On the other hand, the implementation of minimally invasive techniques and technologies, such as robot-assisted laparoscopy surgery and image-guided surgery, allowed minimizing surgical morbidity. Ultimately, these advances have translated into a more tailored approach to the management of urologic cancer patients. Following the paradigm of "precision medicine", contemporary urologic surgery has entered a technology-driven era of "precision surgery", which entails a range of surgical procedures tailored to combine maximal treatment efficacy with minimal impact on patient function and health related quality of life. Aim of this non-systematic review is to provide a critical analysis of the most recent advances in the field of surgical uro-oncology, and to define the current and future role of "precision surgery" in the management of genitourinary cancers., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)