Editing Testosterone Deficiency (2018) (section)

=== <span style="color:#ff0000">Second-line: exogenous treatment ===
* '''The term testosterone therapy is preferred''' over testosterone replacement therapy or testosterone supplementation
** '''Testosterone therapy refers to all forms of treatment that are aimed at increasing serum testosterone, including exogenous testosterone as well as alternative strategies, such as selective estrogen receptor modulators (e.g. clomiphene citrate), human chorionic gonadotropin (hCG) or aromatase inhibitors (AIs).'''

==== Indications ====
*'''Campbell’s (8):'''
*# '''Hypopituitarism'''
*# '''Testicular dysgenesis with AD'''
*# '''Delayed puberty (idiopathic, Kallmann syndrome)'''
*# '''Klinefelter syndrome with AD'''
*# '''Adult men with signs and symptoms of AD'''
*# '''Sexual dysfunction with low testosterone'''
*# '''Low bone density with AD'''

==== <span style="color:#ff0000">Contraindications </span> ====
*'''<span style="color:#ff0000">Campbell’s: </span><span style="color:#0000ff">CHEAPS BLUTS</span>'''
*# '''<span style="color:#ff0000">Very high risk of serious adverse outcomes (2):</span>'''
*## '''<span style="color:#ff0000">Metastatic <span style="color:#0000ff">P</span><span style="color:#ff0000">rostate cancer</span>'''
*## '''<span style="color:#0000ff">B</span><span style="color:#ff0000">reast cancer</span>'''
*#'''<span style="color:#ff0000">Moderate to high risk of adverse outcomes (5):</span>'''
*## '''<span style="color:#ff0000">Poorly controlled </span><span style="color:#0000ff">C</span><span style="color:#ff0000">ongestive heart failure</span>'''
*## '''<span style="color:#0000ff">H</span><span style="color:#ff0000">ematocrit > 50%</span>'''
*## '''<span style="color:#0000ff">E</span><span style="color:#ff0000">levated PSA</span>'''
*## '''<span style="color:#0000ff">A</span><span style="color:#ff0000">bnormal DRE</span>'''
*## '''<span style="color:#ff0000">Unevaluated </span><span style="color:#0000ff">S</span><span style="color:#ff0000">leep apnea</span>'''
*## '''<span style="color:#ff0000">Severe </span><span style="color:#0000ff">LUTS</span><span style="color:#ff0000"> associated with benign prostatic hypertrophy</span>''' (IPSS >19)
*'''<span style="color:#ff0000">Testosterone therapy should not be initiated for a period of 3-6 months in patients with a history of cardiovascular events'''

==== Patient Counseling ====

===== Potential Benefits (7) =====
# '''<span style="color:#ff0000">Erectile function'''
# '''<span style="color:#ff0000">Libido'''
# '''<span style="color:#ff0000">Depressive symptoms'''
# '''<span style="color:#ff0000">Anemia'''
# '''<span style="color:#ff0000">Bone mineral density'''
# '''<span style="color:#ff0000">Lean body mass'''
#'''<span style="color:#ff0000">Mitigate the risk of low testosterone on cardiovascular disease'''

====== Testosterone therapy for erectile dysfunction ======
* The role of testosterone therapy as a monotherapy for ED is less clear.
* Combination therapy with phosphodiesterase type 5 inhibitors (PDE5-I) and TT is a highly debated topic. When erection is restored by PDE5-I, the addition of TT does not result in further benefit of erectile function. For ED refractory to PDE5-I, TT has the potential to improve the efficacy of therapy only in men with biochemical AD (<300 ng/dL).
** '''In young men with symptomatic AD, testosterone therapy should be the first-line treatment with high likelihood of improvement in all domains of sexual function, and PDE5-I can be added if necessary.'''
** '''In elderly men with ED, PDE5-I should be first-line therapy with optimization of comorbid conditions.''' In the case of nonresponders, TT should be reserved only in men with biochemical confirmation of AD.

===== Potential Harms (5) =====
# '''<span style="color:#ff0000">Polycythemia'''
# '''<span style="color:#ff0000">Increased prostate size'''
#* Studies have shown a '''significant increase in prostate volume''' during the first 6 months of treatment. However, the increase in prostate volume '''did not translate into worsening LUTS'''.
# '''<span style="color:#ff0000">Sleep apnea'''
# '''<span style="color:#ff0000">Gynecomastia</span>''' '''is a rare complication after TT'''
# '''<span style="color:#ff0000">Infertility'''
#*'''Exogenous testosterone therapy should not be prescribed to men who are currently trying to conceive'''
#**Exogenous testosterone therapy has been shown to interrupt normal spermatogenesis and can put patients in severely oligospermic or azoospermic states
#**While the vast majority of healthy men with normal testosterone levels will recover sperm production after cessation of exogenous testosterone, there are no high-quality reports detailing the recovery of spermatogenesis for either testosterone deficient or infertile males who have used exogenous testosterone.
#**'''For men already on exogenous testosterone who are planning future reproduction, testosterone cessation should occur in advance of initiation of any effort to conceive.''' '''Patients need to be made aware of the highly variable time course to recover sperm in the ejaculate and the variable degree to which spermatogenesis returns after stopping exogenous testosterone.'''
#***'''While two-thirds of males in contraceptive studies recovered sperm in the ejaculate within 6 months of exogenous testosterone therapy cessation, 10% failed to do so until the second year.'''
#***'''Some infertile men may never recover spermatogenesis after use of exogenous testosterone, and this important risk needs to be discussed with patients before starting treatment.'''

===== Inconclusive =====
*'''<span style="color:#ff0000">Cardiovascular events'''
** '''<span style="color:#ff0000">Low testosterone is a risk factor for cardiovascular disease (myocardial infarction, stroke, and possible cardiovascular-related mortality).'''
*** '''It cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events''' (e.g., myocardial infarction, stroke, cardiovascular-related death, all-cause mortality).
****'''<span style="color:#ff00ff">TRAVERSE 2023</span>''' (new since publication of AUA guidelines)
*****'''Population: 5246 males aged 45-80 who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels < 300 ng/dL'''
*****Randomized to daily transdermal testosterone (dose adjusted to maintain normal testosterone levels) or placebo gel
*****'''Outcomes'''
******'''Primary: first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke'''
******Secondary: first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization
*****'''Results'''
******Mean duration of treatment: 27 months
******Mean follow-up: 33 months
******'''No significant difference in primary or secondary outcomes'''
******Higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism in testosterone group
****[https://pubmed.ncbi.nlm.nih.gov/37326322/ Lincoff, A. Michael, et al.] "Cardiovascular Safety of Testosterone-Replacement Therapy." ''New England Journal of Medicine'' (2023).
**'''No definitive evidence linking testosterone therapy to a higher incidence of venothrombolic events'''
* '''Evidence is inconclusive whether testosterone therapy improves cognitive function, energy, fatigue, measures of diabetes, lipid profiles, and quality of life measures'''
** Despite the absence of definitive evidence, the Panel recommends that patients with these symptoms be counseled regarding the possibility of improvement on testosterone therapy.
* '''<span style="color:#ff0000">Prostate cancer''' 
** '''<span style="color:#ff0000">No definitive evidence linking testosterone therapy and prostate cancer risk'''
*** While the FDA retains a warning regarding the potential risk of prostate cancer in patients who are prescribed testosterone products (“patients treated with androgens may be at increased risk for prostate cancer”), there is accumulating evidence against a link between testosterone therapy and prostate cancer development.
** '''<span style="color:#ff0000">Patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy.'''
*** There is no definitive evidence demonstrating that testosterone therapy is not safe for use in prostate cancer patients; the decision to commence testosterone therapy in men with a history of prostate cancer is a negotiated decision based on the perceived potential benefit of treatment.
*** '''Testosterone therapy can be considered in those men who have undergone radical prostatectomy with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively.'''
*** Post-radiation patients (with or without ADT exposure) placed on testosterone therapy do not experience recurrence of prostate cancer'''. A period of time should elapse after RT and before initiating testosterone''' '''therapy to allow adequate time to regain functional endogenous testosterone production'''.
*** '''PSA recurrence in men on testosterone therapy should be evaluated in the same fashion as untreated men. A discussion regarding the benefit of stopping testosterone therapy should include the possibility of a decline in PSA.'''
*** There are limited data in men on active surveillance who are candidates for testosterone therapy.

==== Administration ====
*'''<span style="color:#ff0000">Available formulations (5):</span>'''
*# '''<span style="color:#ff0000">Topical (gel, patch)</span>'''
*#* '''Patients should be informed about the risk of transference</span>'''
*# '''<span style="color:#ff0000">Buccal patch</span>'''
*# '''<span style="color:#ff0000">Nasal gel</span>'''
*#'''<span style="color:#ff0000">Subcutaneous pellets</span>'''
*#'''<span style="color:#ff0000">Intramuscular injections (3 formulations: 2 short-acting, 1 long-acting)</span>'''
*# '''<span style="color:#ff0000">Subcutaneous injections[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293229/ §]</span>'''
* '''Oral'''
** '''Should not be prescribed'''
** '''Methyltestosterone''' is an oral androgen that is rapidly metabolized in the liver; therefore, achieving consistently therapeutic testosterone levels is a challenge. Its use is also '''associated with liver toxicity'''
** '''Testosterone undecanoate is an oral testosterone''' analogue that is '''absorbed via the intestinal lymphatics allowing it to avoid the first pass liver effect'''. It is approved in some countries for treatment of testosterone deficiency but is not currently approved in the US
*'''Native testosterone either orally or parenterally results in absorption by portal circulation and rapid metabolism by the liver, and only a small concentration reaches the systemic circulation.''' Advancement in chemical modification using esterification results in a series of testosterone analogues with improved bioavailability and pharmacokinetics
* '''Commercially manufactured testosterone products should be prescribed rather than compounded testosterone, when possible.'''
*'''The minimal dose necessary of testosterone therapy should be used to achieve a total testosterone level in the normal physiologic range of 450-600 ng/dL''' (in the middle tertile of the normal reference range)
** Treatments success is defined as achievement of therapeutic testosterone levels to the normal physiologic range of 450 -600 ng/dL accompanied by symptom/sign improvement/resolution.

==== Alternatives to testosterone therapy in males desiring fertility ====
* '''<span style="color:#ff0000">Options (as stand-alone or combination) (3):</span>'''
*# '''<span style="color:#ff0000">Selective estrogen receptor modulators (clomiphene citrate, tamoxifen):</span>'''
*#* '''MOA: Inhibit the negative feedback of estrogen on LH production at the level of the hypothalamus and pituitary gland'''
*# '''<span style="color:#ff0000">Aromatase inhibitors (anastrazole):</span>'''
*#* '''MOA: Inhibits conversion of testosterone to estrogen'''
*# '''<span style="color:#ff0000">Human chorionic gonadotropin (hCG):</span>'''
*#* '''MOA: Acts as an LH agonist and stimulates Leydig cell production of testosterone'''
** '''Exogenous testosterone has inhibitory effects on the production of intratesticular testosterone''', which is imperative to maintain normal spermatogenesis. For this reason, alternative therapies, including aromatase inhibitors, hCG, and SERMs (clomiphene citrate), are commonly used to promote the endogenous production of testosterone and maintain intratesticular testosterone levels.
** '''Of these agents, only hCG has been approved by the FDA for use in males''', specifically to treat males with hypogonadotropic hypogonadism. The overall quantity and quality of studies investigating the use of these alternative agents in males are limited.