Reversibility of Bicalutamide PSMA PET-Positive Gynecomastia With Androgen Deprivation Therapy.

ABSTRACT: A 78-year-old man receiving bicalutamide for prostate cancer was referred for a PSMA PET/CT scan to evaluate his gradually rising prostate-specific antigen level. The PSMA PET/CT revealed gynecomastia with radiotracer uptake in bilateral breast parenchyma, a known but rarely reported effect of bicalutamide monotherapy. This scan also demonstrated metastatic progression of his disease in bone and lymph nodes, and he was started on leuprolide injections. Three months after a decrease in his testosterone level, the radiotracer uptake in his breast tissue had resolved, demonstrating that PSMA-avid bicalutamide-induced gynecomastia is reversible.

Anastrozole as a therapeutic option for gynecomastia in a person receiving antiretroviral therapy: Case report.

A middle-aged Caucasian man living with HIV, clinically stable (viral load <20 copies/mL) on injectable antiretroviral cabotegravir plus rilpivirine every 2 months presented with a 6-month history of bilateral enlargement of the breasts associated with pain. His hormonal profile was normal, and no other underlying cause was identified. He was diagnosed with idiopathic gynecomastia. Tamoxifen is an anti-oestrogen recommended for gynecomastia and has been described in people living with HIV but can potentially induce the activity of cytochrome P450 3A4 (CYP3A4), reducing rilpivirine concentrations, which consequently may cause virological failure and resistance. This is the same for other antiretroviral agents majorly induced by CYP3A4. To date, there have been no reported cases of using anastrozole as a treatment for gynecomastia in people living with HIV or of its co-administration with antiretroviral. We describe the use of an aromatase inhibitor instead of tamoxifen in a person living with HIV, diagnosed with gynecomastia.

Prophylactic Breast Irradiation for Prevention of Bicalutamide-induced Painful Gynecomastia in Patients with Low- and Intermediate-risk Prostate Cancer.

BACKGROUND: Bicalutamide monotherapy (BMT) is an option for androgen deprivation therapy (ADT) in patients with low- and intermediate-risk prostate cancer (LIR-PC). Painful gynecomastia (PG) is a common side effect of BMT. Few therapeutic options are available for preventing BMT-induced PG. OBJECTIVES: To assess the efficacy and side effects of single fraction (SF) prophylactic breast irradiation (PBI) to prevent painful gynecomastia (PG) in patients LIR-PC treated with BMT. METHODS: We reviewed the results of bilateral PBI in a prospective cohort of LIR-PC patients who received 150 mg bicalutamide daily as a first-line treatment for at least 12 months. A single fraction of 8 Gy was administered to both breasts by a stationary field of 10 × 10 cm, using 10-15 MeV electron beam. PBI was commenced on the same day as BMT, but prior to the first dose of bicalutamide. A radiotherapy treatment plan was designed to cover breast tissue by the 90% isodose line. Subsequent monthly physical examinations were scheduled for all patients during the first year of BMT to evaluate any PG symptoms. RESULTS: Seventy-six patients received BMT and PBI, 80% (61/76) showed no signs of PG; 20% (15/76) experienced mild gynecomastia. The main adverse effect of PBI was grade 1 radiation dermatitis. CONCLUSIONS: PBI using a SF of 8 Gy is an effective, safe, and low-cost strategy for the prevention of BMT-induced PG in LIR-PC patients.

A comparative study of the efficacy of tamoxifen and Chinese patented medicine (Pingxiao capsules) in gynecomastia: A retrospective cohort study.

To compare the clinical efficacy of tamoxifen and Chinese patented medicine (Pingxiao capsules) in patients with gynecomastia and discuss the safety of the two treatments. We retrospectively analysed the clinical data of 388 male patients with gynecomastia who were treated in the Outpatient Clinic of our hospital between January 2010 and December 2020. There were 103 patients in the tamoxifen (TAM) group and 103 patients in the Chinese patented medicine group. There were 182 patients in the observation group (non-medication group; age range, 11-75 years; average age, 33.1 years). The natural outcomes were compared between the observation and two medication groups under the same conditions. Disease progression was compared between the observation and two medication groups over the same treatment duration to confirm the efficacy of the medication treatments. Patients with clinical grade 2 gynecomastia accounted for the highest proportion of patients in the TAM group. The percentage of patients with clinical grade 2 gynecomastia was comparable in the Chinese patented medicine and observation groups. The percentage of patients with clinical grades 1 and 3 gynecomastia was the lowest in the TAM group and comparable among the three groups (p = 0.014). The TAM group had the largest number of patients achieving breast shrinkage, and therefore had the best efficacy (p = 0.000). Among the three groups, the surgery rate was the highest in the observation group (p = 0.000). Patients with the greatest glandular tissue thickness achieved better outcomes after medication treatment (p = 0.000). Patients with a higher clinical grade also had a higher surgery rate (p = 0.000). Some patients from the TAM and Chinese patented medicine groups had side effects. TAM results in better outcomes than Chinese patented medicine in gynecomastia patients. The surgery rate is the highest in the observation group. In addition, among some patients with a greater glandular tissue thickness, the higher the clinical grade is, the higher the surgery rate is. Both TAM and Chinese patented medicine cause some side effects and should be used with caution along with continuous follow-up evaluation of patients receiving either treatment.

Comparative Safety and Effectiveness of Aldosterone Antagonists Versus Beta-Blockers as Fourth Agents in Patients With Apparent Resistant Hypertension.

BACKGROUND: Limited evidence exists regarding long-term effectiveness and safety of aldosterone antagonists (AAs) versus beta blockers (BBs) as fourth-line antihypertensive agents in patients with resistant hypertension (RH). We evaluated the comparative effectiveness and safety of aldosterone AA versus BB. METHODS: We conducted a real-world retrospective cohort study using IBM MarketScan commercial claims and Medicare Supplemental claims (2007-2019). Patients with RH entered the cohort (ie, index date) when they newly initiated either AA or BB. The effectiveness outcome was major adverse cardiovascular events. Safety outcomes were hyperkalemia, gynecomastia, and kidney function deterioration. Potential confounding was addressed by adjustment for baseline characteristics via stabilized inverse probability of treatment weighting (SIPTW) based on propensity scores. Cox proportional hazards regression with SIPTWs were used to estimate adjusted hazard ratio (aHR) and 95% CI comparing risk for outcomes between AA and BB groups. RESULTS: We identified 80 598 patients with RH (mean age: 61 years, 51% males), of which 6626 initiated AA and 73 972 initiated BB as the fourth antihypertensive agent. Among patients with RH, initiation of AA as a fourth-line antihypertensive agent did not significantly reduce major adverse cardiovascular event risk relative to BB initiation (aHR, 0.77 [95% CI, 0.50-1.19]) but did substantially increase the risk of hyperkalemia (aHR, 3.86 [95% CI, 2.78-5.34]), gynecomastia (aHR, 9.51 [95% CI, 5.69-15.89]), and kidney function deterioration (aHR, 1.63 [95% CI, 1.34-1.99]). CONCLUSIONS: Long-term clinical trials powered to assess major adverse cardiovascular events are necessary to understand the risk-benefit trade-off of AA as fourth-line therapy for RH.

Association of gynecomastia with antidiabetic medications in older adults: Data mining from different national pharmacovigilance databases.

OBJECTIVE: Gynecomastia is a benign proliferation of the glandular breast tissue in men and is generally caused by a decrease in androgen and an increase in estrogen. Diabetes has been reported to be a risk factor for lowering androgen levels. Moreover, lowered androgen levels are more common in older men. In the present study, we aimed to evaluate the signals for gynecomastia in older men on antidiabetic medications. MATERIALS AND METHODS: A disproportionality analysis was performed to detect the signals for antidiabetic drug-associated gynecomastia in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER), using the reporting odds ratio (ROR) and information component (IC). RESULTS: Among 8 classes of medications for diabetes, a signal was detected only for dipeptidyl peptidase-4 (DPP-4) inhibitors (ROR: 1.90, 95% confidence interval (CI): 1.27 - 2.83; IC: 0.84, 95% CI: 0.26 - 1.42) in the FAERS. Regarding individual drugs, ROR and IC signals were detected for sitagliptin (ROR: 2.37, 95% CI: 1.48 - 3.79; IC: 1.12, 95% CI: 0.44 - 1.79) and vildagliptin (ROR: 3.34, 95% CI: 1.39 - 8.08; IC: 1.26, 95% CI: 0.07 - 2.44) in the FAERS and only for sitagliptin (ROR: 4.84, 95% CI: 1.92 - 12.2; IC: 1.48, 95% CI: 0.24 - 2.73) in the JADER. CONCLUSION: This study showed an association between DPP-4 inhibitor use and gynecomastia in older men with diabetes. Further pharmacoepidemiological studies are warranted to verify this finding.

Pseudogynecomastia: A chance occurrence with acitretin.

Psoriatic involvement of nails manifests in the form of irregular, deep and large pits, splinter hemorrhages, subungual hyperkeratosis, oil drop spot, and onycholysis of the nail bed. Retinoids are one of the treatment modalities for nail psoriasis. Pseudogynecomastia is an uncommonly reported side effect of retinoids. We hereby describe an 11-year-old adolescent who developed pseudogynecomastia posttreatment with acitretin for nail psoriasis.

Drug-induced gynecomastia: A systematic review and meta-analysis of randomized clinical trials.

OBJECTIVE: To review the evidence concerning treatment-related gynecomastia in patients taking spironolactone, antiandrogens, 5 alpha-reductase inhibitors, lipid-lowering and psychotropic drugs. MATERIAL AND METHODS: A search of Medline and EMBASE was performed up to 30 June 2021. We included randomized controlled trials comparing the effects of a drug belonging to these classes versus placebo or versus a drug of the same class. RESULTS: A total of 32 randomized controlled trials were included in the final review. There was an increased odds of gynecomastia in men receiving antiandrogens (OR = 17.38, 95% CI: 11.26 to 26.82; 6 trials, 9599 participants) and 5 alpha-reductase inhibitors compared to controls (OR = 1.77, 95% CI: 1.53 to 2.06; 7 series out of 6 trials, 34860 participants). The use of spironolactone in mixed gender populations was characterized by significantly higher odds of having gynecomastia compared to controls (OR = 8.39, 95% CI: 5.03 to 13.99; 14 trials, 3745 participants). No placebo-controlled trials focusing on the risk of gynecomastia in patients taking antipsychotic drugs was available, although there was a significant difference in the odds of having gynecomastia in a comparison between risperidone and quetiapine (OR = 4.32, 95% CI: 1.31 to 14.27; 3 trials, 343 participants). Limited evidence about the effects of statins on mammary glands was found. CONCLUSIONS: Antiandrogens and to a lesser extent 5 alphareductase inhibitors and spironolactone are associated with an increased risk of developing gynecomastia. Such effect can be explained by a modification of the testosterone to estradiol ratio. Gynecomastia (and galactorrhea) associated to the use of conventional and certain atypical antipsychotics can be related to high prolactin levels.

Possible association between methylphenidate treatment in a child with autism spectrum disorder and subsequent gynecomastia / Lehetséges összefüggés egy autizmusspektrum-zavarban érintett gyermek metilfenidát-kezelése és az azt követoen kialakult gynaecomastia között.

Összefoglaló. Bár a figyelemhiányos hiperaktivitási zavar kezelése során alkalmazott metilfenidát-monoterápiával összefüggésben jelentkezo gynaecomastiáról bizonyos nemkívánatos hatások adatbázisai beszámolnak, a szakirodalom áttekintése alapján ez idáig mindössze 5 esettanulmányt publikáltak a témában. Tanulmányunkban egy autizmusspektrum-zavarral és figyelemhiányos hiperaktivitási zavarral egyaránt diagnosztizált gyermek esetét mutatjuk be, akinél 6 hónapon át tartó, folyamatos metilfenidát-monoterápiájával összefüggésben kétoldali gynaecomastia kialakulását tapasztaltuk. A kezelés azonnali leállítása mellett 10 napos klomifénkezelés történt. A metilfenidát-terápia azonnali leállítását követoen 14 nappal a gynaecomastia mindkét oldalon visszahúzódott. 3 hónapos, gyermekpszichiátriai szempontból gyógyszermentes idoszakot követoen a metilfenidát-terápia újraindítása történt, de 1 hónap elteltével a nem kívánt mellékhatás ismét jelentkezett. A metilfenidát-terápia és a gynaecomastia kialakulása közötti kapcsolat számos mechanizmussal kapcsolatban kérdéseket vet fel. Gyermekpszichiátriai szempontból érdekes kérdés, hogy releváns lehet-e a gyógyszeres terápia következményeként kialakuló nemkívánatos mellékhatás megjelenésében az autizmusspektrum-zavar és a figyelemhiányos hiperaktivitási zavar komorbid fennállása. A jelenség hátterében felmerül továbbá a neuroendokrin-immunológiai rendszer szabályozásának esetleges megváltozása. Esettanulmányunk felhívja a gyakorló orvoskollégák figyelmét a metilfenidát-terápia alkalmazása mellett potenciálisan kialakuló gynaecomastia monitorozására. Orv Hetil. 2021; 162(42): 1703-1708. Summary. Although gynecomastia associated with methylphenidate monotherapy in the treatment of attention deficit hyperactivity disorder has already been reported in some adverse event databases, based on a review of the literature it appears that only five case reports have been published. In our study, we present the case of a child diagnosed with both autism spectrum disorder and attention deficit/hyperactivity disorder, who developed bilateral gynecomastia in association with continuous methylphenidate monotherapy for 6 months. With immediate cessation of methylphenidate therapy, clomiphene treatment was given for 10 days. A total of 14 days after cessation of methylphenidate treatment gynecomastia receded on both sides. After a methylphenidate drug-free period of 3 months, methylphenidate therapy was restarted, but 1 month later the side effect reappeared. The relationship between methylphenidate and the development of gynecomastia raises questions about a number of mechanisms. From a child psychiatrist point of view, it is an interesting question whether the presence of comorbid autism spectrum disorder and attention deficit/hyperactivity disorder may be relevant in the onset of adverse events by medication. The phenomenon may also be caused by altered regulation of the neuroendocrine-immune system. Our case report draws the attention of practicing physicians to monitoring of potential gynecomastia during methylphenidate therapy. Orv Hetil. 2021; 162(42): 1703-1708.

A Threat to Military Combat Power: Dietary Supplements.

BACKGROUND: The use of dietary supplements by young warfighters is pervasive and comes with a readiness cost, especially in the deployed setting. Predatory targeting and marketing by various unscrupulous companies put this population at risk for a higher than baseline risk for adverse events. METHODS: We report on 6 serious adverse events experienced by warfighters while deployed in Kuwait and Afghanistan. Presented is a discussion of current practice gaps and solutions, as well as details regarding how polypharmacy contributes to the seriousness of the threat posed by problematic supplements. RESULTS: The morbidity associated with the 6 cases of dietary supplement adverse events compromised mission readiness and was costly in terms of health and health care expenditures. CONCLUSION: The military dietary supplement issue needs exposure, review, and action at the highest levels of government.

Radiotherapy for prevention or management of gynecomastia recurrence: Future role for general gynecomastia patients in plastic surgery given current role in management of high-risk prostate cancer patients on anti-androgenic therapy.

PURPOSE: Several technologies and innovative approaches continue to emerge for the optimal management of gynecomastia by plastic surgeons; the present study investigates the role of radiation therapy in this context. METHODS: A systematic review was performed to evaluate the utility of radiotherapy for the prevention and treatment of gynecomastia incidence or recurrence by plastic surgeons. RESULTS: Fifteen articles met the inclusion criteria for review. The mean incidence of gynecomastia was 70% in the high-risk population examined representing prostate cancer patients on estrogen or anti-androgen therapy. Radiotherapy was shown to significantly reduce the incidence to a median of 23%, with all six randomized control studies assessed demonstrating a statistically significant decrease in incidence following radiotherapy prophylaxis. Doses examined ranged from 8 to 16 Gy, delivered between 1 and 11 fractions. Complications following radiotherapy were minor and self-limiting in all cases, restricted to minor skin reactions, and associated with larger radiotherapy doses delivered in fewer fractions. The median complication rate was 12.4% with no major complications, such as neoplastic, pulmonary, or adverse cardiac outcomes. While the efficacy of radiation therapy as a treatment modality for gynecomastia was also established, it was shown to be less effective than other available options. CONCLUSIONS: Low-dose radiotherapy to the male breast might be a safe and effective strategy to prevent gynecomastia incidence or recurrence in high-risk patients; further studies are indicated within the common gynecomastia population managed by plastic surgeons to assess the clinical and economical utility of this intervention before a recommendation for its ubiquitous adoption in plastic surgery can be made to continue improving outcomes for high-risk gynecomastia patients.

Peri-areolar double-pedicle technique in the treatment of iatrogenic gynecomastia.

OBJECTIVES: To describe the surgical approach to the treatment of iatrogenic gynecomastia via peri-areolar incision. METHODS: In this study, we describe our experience in the surgical management of iatrogenic hormonal gynecomastia with our technique described for idiopathic gynecomastia. We treated 70 patients with gynecomastia at a plastic surgery unit between 2000 and 2016. Ten of these patients had a painful hypertrophic mammary gland with grade III gynecomastia secondary to hormone therapy after prostate cancer. RESULTS: The presence of a very discreet scar around the areola often has very interesting aesthetic results. Areolar tissue sensation was completely preserved in 40% of patients. No short-term complications were observed; in follow-up, only one case of keloid scars was noted on a patient with dark skin, and only one case of areolar necrosis on a patient with critical breast ptosis. CONCLUSION: This technique is feasible. It restores almost normal anatomy structure with minimal scarring and preserves good regional neurovascular supply, with only 60% altered areolar sensation.

Enzalutamide With Radiation Therapy for Intermediate-Risk Prostate Cancer: A Phase 2 Study.

PURPOSE: Androgen deprivation therapy (ADT) is often used as adjuvant treatment with radiation therapy (RT) for intermediate-risk prostate cancer. ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, antiandrogen monotherapy has been generally better tolerated. This study aimed to assess the effectiveness of enzalutamide (an antiandrogen) monotherapy with RT for the treatment of intermediate-risk prostate cancer. METHODS AND MATERIALS: This trial was an open-label, phase 2 study of 6 months of enzalutamide monotherapy with external beam RT for intermediate-risk prostate cancer. Enzalutamide was initiated 2 months before external beam RT. The primary endpoint was prostate-specific antigen (PSA) response measured at the end of enzalutamide administration at the 6-month timepoint. Secondary endpoints included assessment of toxicity and changes in anthropomorphic body measurement, sexual function, and metabolism. The sample size was 64 patients. The hypothesis was that if ≥60% of the patients did not achieve a PSA nadir of ≤0.2 ng/mL, the study results would be deemed negative. RESULTS: The results met the prespecified endpoint for efficacy in that PSA values ≤0.2 ng/mL were observed in 49 of 64 patients (77%), and 60 of 64 patients (94%) had PSA values ≤0.5ng/mL. The most frequent adverse events were hypertension and gynecomastia. There were no changes in anthropomorphic body measurements and only modest erectile dysfunction. CONCLUSIONS: Using PSA response as an endpoint, enzalutamide monotherapy may be as effective as ADT in combination with external beam RT for patients with intermediate-risk prostate cancer, and it is associated with fewer side effects. Randomized trials comparing enzalutamide with ADT are justified.

Aldosterone antagonists for people with chronic kidney disease requiring dialysis.

BACKGROUND: People with chronic kidney disease (CKD) requiring dialysis are at a particularly high risk of cardiovascular death and morbidity. Several clinical studies suggested that aldosterone antagonists would be a promising treatment option for people undergoing dialysis. However, the clinical efficacy and potential harm of aldosterone antagonists for people with CKD on dialysis has yet to be determined. OBJECTIVES: This review aimed to evaluate the benefits and harms of aldosterone antagonists, both non-selective (spironolactone) and selective (eplerenone), in comparison to control (placebo or standard care) in people with CKD requiring haemodialysis (HD) or peritoneal dialysis (PD). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 5 August 2020 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs), cross-over RCTs, and quasi-RCTs (where group allocation is by a method that is not truly random, such as alternation, assignment based on alternate medical records, date of birth, case record number, or other predictable methods) that compared aldosterone antagonists with placebo or standard care in people with CKD requiring dialysis. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias for included studies. We used a random-effects model meta-analysis to perform a quantitative synthesis of the data. We used the I² statistic to measure heterogeneity among the studies in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes, mean difference (MD) for continuous outcomes, or standardised mean differences (SMD) if different scales were used, with their 95% confidence interval (CI). We assessed the certainty of the evidence for each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. MAIN RESULTS: We included 16 studies (14 parallel RCTs and two cross-over RCTs) involving a total of 1446 participants. Thirteen studies compared spironolactone to placebo or standard care and one study compared eplerenone to a placebo. Most included studies had an unclear or high risk of bias. Compared to control, aldosterone antagonists probably reduced the risk of death (any cause) for people with CKD requiring dialysis (9 studies, 1119 participants: RR 0.45, 95% CI 0.30 to 0.67; I² = 0%; moderate certainty of evidence). Aldosterone antagonist probably decreased the risk of death due to cardiovascular disease (6 studies, 908 participants: RR 0.37, 95% CI 0.22 to 0.64; I² = 0%; moderate certainty of evidence) and cardiovascular and cerebrovascular morbidity (3 studies, 328 participants: RR 0.38, 95% CI 0.18 to 0.76; I² = 0%; moderate certainty of evidence). While aldosterone antagonists probably increased risk of gynaecomastia compared with control (4 studies, 768 participants: RR 5.95, 95% CI 1.93 to 18.3; I² = 0%; moderate certainty of evidence), aldosterone antagonists may make little or no difference to the risk of hyperkalaemia (9 studies, 981 participants: RR 1.41, 95% CI 0.72 to 2.78; I² = 47%; low certainty of evidence). Aldosterone antagonists had a marginal effect on left ventricular mass among participants undergoing dialysis (8 studies, 633 participants: SMD -0.42, 95% CI -0.78 to 0.05; I² = 77%). In people with CKD requiring dialysis received aldosterone antagonists compared to control, there were 72 fewer deaths from all causes per 1000 participants (95% CI 47 to 98) with a number needed to treat for an additional beneficial outcome (NNTB) of 14 (95% CI 10 to 21) and for gynaecomastia were 26 events per 1000 participants (95% CI 15 to 39) with a number need to treat for an additional harmful outcome (NNTH) of 38 (95% CI 26 to 68). AUTHORS' CONCLUSIONS: Based on moderate certainty of the evidence, aldosterone antagonists probably reduces the risk of all-cause and cardiovascular death and probably reduces morbidity due to cardiovascular and cerebrovascular disease in people with CKD requiring dialysis. For the adverse effect of gynaecomastia, the risk was increased compared to control. For this outcome, the absolute risk was lower than the absolute risk of death. It is hoped the three large ongoing studies will provide better certainty of evidence.

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

BACKGROUND: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. METHODS: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 µg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. FINDINGS: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). INTERPRETATION: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. FUNDING: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Positive and negative side effects of androgen abuse. The HAARLEM study: A one-year prospective cohort study in 100 men.

An estimated 4-6% of fitness center visitors uses anabolic-androgenic steroids (AAS). Reliable data about adverse reactions of AAS are scarce. The HAARLEM study aimed to provide insight into the positive and negative effects of AAS use. One hundred men (≥18 years) who intended to start an AAS cycle on short notice were included for follow-up. Clinic visits took place before (T0 ), at the end (T1 ), and three months after the end of the AAS cycle (T2 ), and one year after the start of the cycle (T3 ), and comprised a medical history, physical examination, laboratory analysis, and psychological questionnaires. During the follow-up period, four subjects reported a serious adverse event, that is, congestive heart failure, acute pancreatitis, suicidal ideation, and exacerbation of ulcerative colitis. All subjects reported positive side effects during AAS use, mainly increased strength (100%), and every subject reported at least one negative health effect. Most common were fluid retention (56%) and agitation (36%) during the cycle, and decreased libido (58%) after the cycle. Acne and gynecomastia were observed in 28% and 19%. Mean alanine transaminase (ALT) and creatinine increased 18.7 U/l and 4.7 µmol/L, respectively. AAS dose and cycle duration were not associated with the type and severity of side effects. After one-year follow-up (T3 ), the prevalence of observed effects had returned to baseline. There was no significant change in total scores of questionnaires investigating wellbeing, quality of life, and depression. In conclusion, all subjects experienced positive effects during AAS use. Four subjects experienced a serious adverse event. Other side effects were mostly anticipated, mild, and transient.

Flaxseed oil stimulates gynecomastia.

Flaxseed oil contains lignans, which exhibit anti-inflammatory and antiatherogenic activities. A 70-year-old male patient presented to our office due to hyperlipidaemia and started to take a tablespoon of flaxseed oil daily. Three months later, he reported left breast swelling and pain. Although the echogram revealed a tumour in the left mammary gland, the breast biopsy was compatible with gynecomastia, showing ductal hyperplasia without evidence of malignancy. His breast epithelia were oestrogen receptor-positive. Potential role of phytoestrogens was discussed.