Editing Hormonal Therapy (section)

== Complications of Androgen Ablation ==

* '''COACH Wants BDSM From Montreal (16):'''

# '''Cardiovascular disease'''
# '''Osteoporosis'''
# '''Anemia'''
# '''Cognitive dysfunction'''
# '''Hot Flashes'''
# '''Weight gain and fat % mass increase'''
# '''Breast events'''
# '''Diabetes'''
# '''Sexual dysfunction'''
# '''Muscle % body mass decrease'''
# '''Fatigue'''
# '''Metabolic (5):'''
## '''Insulin resistance'''
## '''Glucose intolerance'''
## '''Increased triglycerides and total cholesterol levels'''
## '''Worsened glycemic control in men with a pre-existing diagnosis'''
## '''Increased risk of metabolic syndrome'''

=== Cardiovascular disease ===

* '''Conflicting findings between observational studies and secondary analyses of randomized trials'''; '''overall, sufficient evidence to suggest a link between use of ADT and CVD'''
** Cardiovascular mortality§
*** Meta-analyses of observational studies found significant increased risk
**** Observational studies limited by confounding
*** Meta-analyses of randomized trials found no significant association
**** Secondary analyses of randomized trials limited by power
** Nonfatal cardiovascular disease§
*** Meta-analyses of observational studies found significant increased risk
*** Meta-analyses of randomized trials found significant increased risk
** Myocardial infarction§
*** 1 meta-analysis of observational studies found significant increased risk, 1 found no significant association
*** Meta-analysis of randomized trials found no significant association
** Stroke§
*** Some meta-analyses of observational studies found significant increased risk, others did not
*** Meta-analysis of randomized trials found no significant association
** Venous thromboembolism
*** 2021 CUA Guidelines on ADT Adverse Events: Insufficient evidence to recommend routine use of venous thromboembolism prophylaxis in men receiving ADT.
* '''Pre-existing heart disease is significant risk factor for development of major adverse cardiac events (MACE) in men receiving ADT.'''
** MACE is defined as myocardial infarction, coronary revascularization, stroke, and hospitalization because of heart failure.
** '''Nanda et al. JAMA 2009'''
*** Population: 5077 males with localized or locally advanced prostate cancer treated with or without neoadjuvant ADT followed by RT
**** Median duration ADT 4 months
*** Primary outcome: all-cause mortality
*** Results:
**** No significantly increased risk of all-cause mortality in males with no comorbidity or a single coronary artery disease risk factor
**** Significantly increased risk of all-cause mortality in males with coronary artery disease–induced congestive heart failure or myocardial infarction
*** Nanda, Akash, et al."Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease–induced congestive heart failure or myocardial infarction." ''Jama'' 302.8 (2009): 866-873.
* '''GnRH agonist vs. antagonist'''
** Animal studies suggest that GnRH agonists, but not antagonists, may induce plaque instability and rupture
** Meta-analysis of randomized trials found that GnRH antagonists were associated with lower risk of cardiovascular events than GnRH agonists (HR 0.44 (95% CI 0.26 – 0.74)§
** HERO trial (see above) found that MACE occurs in 3% of patients randomized to relugolix compared to 6% of patients randomized to leuprolide§
** '''2021 CUA Guidelines on ADT Adverse Events: in males with a prior history of MI or stroke, consider use of a gonadotropin-releasing hormone (GnRH) antagonist'''
* '''Enzalutamide'''§
** Meta-analysis of observational studies found no significant increased risk of cardiac events
** Meta-analysis of randomized trials found no significant increased risk of cardiac events
** Significantly increased risk of hypertension
* '''Abiraterone'''§
** Meta-analysis of randomized trials found significant increased risk of cardiac events
** Pharmacovigilance study found significant increased risk of atrial tachyarrhythmia and heat failure§
* Trials underway to address cardiac outcomes in men receiving ADT
** PRONOUNCE
*** Population: males with advanced prostate cancer
*** Randomized to degarelix (GnRH antagonist) vs. leuprolide (GnRH agonist)
*** Primary outcome: time from randomization to MACE
** RADICAL-PC: RAndomizeD Intervention for Cardiovascular and Lifestyle Risk Factors in Prostate Cancer
*** Population: males with a new diagnosis of prostate cancer or recently initiated/about to initiate ADT
*** Randomized to systematic cardiovascular and lifestyle risk factor modification strategy vs. usual care
*** Primary outcome: time from randomization to MACE

=== Osteoporosis ===

* Prostate cancer occurs mostly in older men, who are at increased risk for osteoporosis, even in the absence of ADT
* '''ADT associated with (3):'''
** '''Decreased bone mineral density (BMD)'''
*** BMD loss occurs at a maximum rate during the first year of therapy, however, continues to decline with prolonged use of ADT
** '''Osteoporosis'''
*** Osteoporosis is defined as BMD of 2.5 or more standard deviations below the peak bone mass for young adults (i.e., T-score ≤-2.5).
*** Osteopenia (low bone mass) is defined as BMD more than 1.0 but less than 2.5 standard deviations below the peak bone mass for young adults (i.e., T-score <-1 and >-2.5).
*** '''4 years of ADT will place the average man in the osteopenia''' (precursor of osteoporosis) '''range'''.
** '''Increased risk for clinical fractures'''
*** '''Shahinian et al. NEJM 2005'''
**** Population: 50,613 males from SEER with a diagnosis of prostate cancer
**** Comparison: patients treated with or without ADT
**** Primary outcomes: occurrence of any fracture and pccurrence of a fracture resulting in hospitalization
**** Results:
***** Risk of facture within 5 years of prostate cancer diagnosis: 19% with ADT vs. 13% without ADT
***** Risk of facture requiring hospitalization within 5 years of prostate cancer diagnosis: 5.2% with ADT vs. 2.4% without ADT
***** Risk of fracture increased with increasing number of ADT doses
**** Shahinian, Vahakn B., et al. "Risk of fracture after androgen deprivation for prostate cancer." New England Journal of Medicine 352.2 (2005): 154-164.

=== Anemia ===

* '''Very common'''
* '''Thought to be secondary to lack of testosterone stimulation of erythroid precursors and a decrease in erythropoietin production'''
* '''Usually normochromic, normocytic'''
* Hemoglobin levels decrease by 1–2 ng/dL from baseline
** 90% of men receiving combined androgen blockade experienced declines in hemoglobin concentration of at least 10%

=== Cognitive dysfunction ===

* '''ADT in men with PCa may be associated with (3):'''
*# '''Changes in cognition''' (concentration, memory)
*# '''Depression'''
*# '''Dementia'''
** '''Evidence related to causality remains weak and further prospective data are needed'''
** Changes in cognition
*** Conflicting findings
**** Some studies find reduced cognition
**** Self-reported changes in concentration, information processing, verbal fluency, visual information processing, visuospatial function, memory, and executive function, neuro-fatigue and apathy
**** Objective changes in verbal memory, spatial abilities and attention
**** Some studies find no change in cognition
**** One study reported improvement in episodic memory and delayed recall§
** Depression
*** Meta-analysis of 6 studies comprising 226,871 patients found significantly increased risk (HR 1.51 (95% CI 1.34 – 1.69))§
** Dementia
*** Meta-analysis of 9 studies comprising 442,665 patients found significantly increased risk (HR 1.21 (95% CI 1.11 – 1.33))§
** Alzheimer’s disease
*** Meta-analysis of 8 studies comprising 1,597,546 patients found significantly increased risk (HR 1.16 (95% CI 1.09 – 1.24))§

=== Hot flashes ===

* '''Common and bothersome side effect of ADT'''
** '''Among the most common adverse events associated with androgen ablation''', affecting between 50-80% of patients
** If bothersome, they can lead to a deterioration in quality of life and may decrease compliance to ADT
* Described as a subjective feeling of warmth in the upper torso and head followed by objective perspiration.
* '''Generally decrease in both frequency and intensity over time but often persist in some men'''

=== Weight gain and fat % mass increase ===

* Largely due to an accumulation of subcutaneous fat, rather than intraabdominal adipose tissue
* Thought to occur soon after initiating therapy, sometimes as early as 1 month following treatment
* '''Weight increases on average by 2.1%''' and % fat mass increases on average by 8%§
** Longer duration of therapy appears to increase weight gain and percentage fat mass
* Changes may persist up to 2 years beyond treatment cessation

=== Breast events ===

* '''Breast events include gynecomastia (increased amount of breast tissue) and mastodynia (breast tenderness).'''
** May occur concurrently or separately
** '''Gynecomastia'''
*** Occurs as a result of peripheral conversion of testosterone to estradiol, which increases the ratio of estrogen to androgen activity
*** '''Occurs most commonly with androgen-receptor antagonist monotherapy'''
*** '''Rare complication of LHRH monotherapy or combined androgen blockade'''

=== Diabetes ===

* '''Alibhai et al. JCO 2009'''
** Population: matched cohort study 38,158 males aged 66 or older with prostate cancer
** Comparison: males given continuous ADT for at least 6 months or underwent bilateral orchiectomy vs. those without
** Primary outcomes: acute myocardial infarction, sudden cardiac death, diabetes
** '''Results:'''
*** '''Significantly increased risk of incident diabetes''' (hazard ratio 1.16 (95% CI 1.11 - 1.21))
** Alibhai, Shabbir MH, et al."Impact of androgen deprivation therapy on cardiovascular disease and diabetes." ''Journal of clinical oncology: official journal of the American Society of Clinical Oncology'' 27.21 (2009): 3452.

=== Sexual dysfunction ===

* '''Impacts multiple domains of sexual function, including'''
*# '''Loss of libido''' (in up to 90% of men)
*# '''Erectile dysfunction'''
*# '''Decreased sensitivity to sexual stimulation'''
*# '''Decreased penile and testicular size'''
*# '''Body image'''
* A study of 39 males with non-metastatic prostate cancer initiating ADT found that stretched penile length decreased from an average of 10.76 cm to 8.05 cm after 15 months of ADT and plateaued thereafter.§
* Only up to 20% of men on ADT are able to maintain some sexual activity. Libido is more severely compromised, with ≈5% of men maintaining a high level of sexual interest with ADT

=== Muscle mass % decrease ===

* A decrease in muscle mass causes a decrease in grip strength, absolute muscular strength, and gait speed.
* ADT also results in detrimental changes to multiple other physical parameters, including aerobic fitness and overall physical function

=== Fatigue ===

* Noticeable side effect of ADT
* Underlying cause is often multifactorial

=== Metabolic (5): ===

# '''Insulin resistance'''
# '''Glucose intolerance'''
# '''Worsened glycemic control in men with a pre-existing diabetes'''
# '''Increased triglycerides, low-density lipoprotein (LDL), and total cholesterol levels'''
# '''Increased risk of metabolic syndrome'''

* '''Braga-Basaria et al. JCO 2006'''
** Population: Cross-sectional study of 58 males from 3 groups
**PCa who were undergoing ADT (for recurrent or metastatic disease) for at least 12 months before the onset of the study and were in clinical and biochemical remission (ADT group)
** Age-matched men with nonmetastatic PCa who had undergone prostatectomy and/or radiotherapy and were recently found to have an increasing prostate-specific antigen (PSA) level but had not received ADT and were eugonadal (non-ADT group)
** Age-matched healthy eugonadal men with a normal PSA (control group)
** Results
*** ADT group had significantly higher body mass index, prevelanece of metabolic syndrome, abdominal obesity, and hyperglycemia
*** ADT group had significantly lower total and free testosterone levels.
** Braga-Basaria, Milena, et al."Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy." Journal of clinical oncology 24.24 (2006): 3979-3983.