Editing Testosterone Deficiency (2018) (section)

== Diagnosis and Evaluation ==

* '''<span style="color:#ff0000">Clinical diagnosis of testosterone deficiency requires BOTH:</span>'''
*# '''<span style="color:#ff0000">Low testosterone levels combined WITH</span>'''
*# '''<span style="color:#ff0000">Symptoms or signs that are associated with low serum total testosterone.</span>'''
** A patient is considered testosterone deficient and a candidate for testosterone therapy only when he meets both criteria

=== UrologySchool.com summary ===
* '''<span style="color:#ff0000">Recommended (2):</span>'''
*# '''<span style="color:#ff0000">History and Physical exam</span>'''
*# '''<span style="color:#ff0000">Laboratory confirmation of low testosterone</span>'''
*## '''<span style="color:#ff0000">Total morning testosterone < 300 ng/dL on 2 separate occasions</span>'''
** '''Questionnaire not recommended'''

=== History and Physical Exam ===

==== History ====
* '''<span style="color:#ff0000">Signs and symptoms</span>'''
**'''<span style="color:#ff0000">Categories (3):</span>'''
**# '''<span style="color:#ff0000">Physical</span>'''
**#* '''Loss of body hair, reduced lean muscle mass, gynecomastia'''
**#* '''Fatigue'''
**#* '''Visual field changes (bitemporal hemianopsia), anosmia (loss of smell)'''
**# '''<span style="color:#ff0000">Cognitive</span>'''
**#* '''Depression'''
**#* '''Cognitive dysfunction, poor concentration, poor memory'''
**#* '''Irritability'''
**# '''<span style="color:#ff0000">Sexual</span>'''
**#* '''Erectile dysfunction, decreased libido'''
**#* '''Infertility/difficulty conceiving'''
**'''Many of the symptoms are non-specific (e.g. fatigue) and might be related to conditions other than low testosterone.'''
* '''<span style="color:#ff0000">Risk factors for AD (see above)</span>'''
**'''Past medical history'''
**'''Past surgical history'''
**'''Medications'''

==== Physical exam ====
# '''<span style="color:#ff0000">General</span>''' 
##'''<span style="color:#ff0000">Body habitus</span>''' (BMI or waist circumference)
## '''<span style="color:#ff0000">Virilization status</span>''' (body hair patterns and amounts in androgen dependent areas)
## '''<span style="color:#ff0000">Presence of gynecomastia</span>'''
##* Gynecomastia is a benign enlargement of the male breast tissue that can occur at times of male androgen/estrogen change (alteration in testosterone/estradiol [E2] ratio) such as infancy, adolescence, or old age, and may also be a sign of low serum testosterone.
##** '''Male breast growth can be classified as (3):'''
##**# '''Pharmacological''' (risperidone, anti-androgens, marijuana, clomiphene)
##**# '''Physiological (neonatal period and at puberty)'''
##**# '''Pathological (testicular tumours, Klinefelter syndrome, cirrhosis)'''
##** '''With any enlargement of the male breast, the possibility of carcinoma should be considered.'''
# '''<span style="color:#ff0000">Genitals</span>'''
#* '''Testicular size, consistency'''
#*'''Presence of varicoceles'''
#**'''No definitive evidence that varicocele is a cause of low testosterone, however, varicocele ligation surgery might increase serum testosterone levels'''

=== Laboratory ===
# '''<span style="color:#ff0000">Confirmation of low testosterone</span>'''
#* '''<span style="color:#ff0000">Morning total testosterone level < 300 ng/dL</span> is considered low'''
#** '''Total testosterone can be measured by 3 methods:''' 
#***'''Liquid chromatography/tandem mass spectrometry (preferred, when possible)'''
#***'''Radioimmunoassay'''
#***'''Immunometric assay'''
#**** Significant variations among assay techniques and among different laboratories.
#**** The same laboratory with the same method/instrumentation should be used for serial total testosterone measurement.
#** '''<span style="color:#ff0000">Free testosterone measurements are not recommended as the primary diagnostic method for testosterone deficiency</span>'''
#*** Some have advocated that free testosterone should be the primary measure used to define testosterone deficiency since the free testosterone fraction is believed to be the most biologically active component. However''', direct measurement of free testosterone is unreliable, time-consuming and labour intensive'''. '''Indirect measurement''' (calculation-derived) of free testosterone is more commonly used, however there is '''considerable variation''' in total testosterone assays as well as the clinical conditions that affect serum albumin and SHBG, all of which impact this measurement.
#*** '''Free testosterone may have a place in the diagnosis of testosterone deficiency in highly symptomatic patients with total testosterone levels in the low/normal or equivocal range'''
#** While a cut-off of total testosterone < 300 ng/dL is considered low, in clinical practice, there are men with levels >300 ng/dL who are highly symptomatic and who have experienced improvement with testosterone therapy
#* '''<span style="color:#ff0000">Diagnosis of low testosterone should be made only after 2 total testosterone measurements are taken on separate occasions with both tests being conducted in an early morning</span>'''
#** Serum testosterone levels peak in the morning and vary significantly as a result of circadian and circannual rhythm
#** No evidence indicating what the optimal time interval should be between the separate tests
#** If a patient’s first test is <300 ng/dL and the second test is normal, the clinician should use his or her judgment to determine if a third test is to be used as a control
#** Fasting is not needed prior to testosterone testing
#* '''<span style="color:#ff0000">Due to associations with low testosterone, even in the absence of symptoms or signs associated with testosterone deficiency, consider measuring total testosterone in patients with a history of (11):</span>'''
#*# '''<span style="color:#ff0000">Diabetes</span>'''
#*# '''<span style="color:#ff0000">Obesity</span>''' (BMI ≥30) or who have increased waist circumference (>40 inches)
#*# '''<span style="color:#ff0000">HIV/AIDS</span>'''
#*# '''<span style="color:#ff0000">Male infertility</span>'''
#*# '''<span style="color:#ff0000">Exposure to chemotherapy</span>'''
#*# '''<span style="color:#ff0000">Exposure to testicular radiation</span>'''
#*# '''<span style="color:#ff0000">Chronic narcotic use</span>'''
#*# '''<span style="color:#ff0000">Chronic corticosteroid use</span>'''
#*# '''<span style="color:#ff0000">Pituitary dysfunction</span>'''
#*# '''<span style="color:#ff0000">Unexplained anemia</span>'''
#*# '''<span style="color:#ff0000">Bone density loss</span>'''

=== Other ===

==== Validated Questionnaires ====
* Examples
**ADAM
**Quantitative ADAM
**Aging Male Survey (AMS)
**MMAS
**ANDROTEST
*'''<span style="color:#ff0000">The use of validated questionnaires is NOT currently recommended</span> to either define which patients are candidates for testosterone therapy or monitor symptom response in patients on testosterone therapy'''
** Questionnaires are highly sensitive (≈80%) but not specific (<50%)

=== Adjunctive Testing in Patients with Testosterone Deficiency ===

==== UrologySchool.com Summary ====
* '''<span style="color:#ff0000">Initial Evaluation (1)</span>''':
*# '''<span style="color:#ff0000">LH</span>''' 
*#* '''<span style="color:#ff0000">Helps determine etiology of testosterone deficiency</span>'''
*#*'''<span style="color:#ff0000">If low, obtain Prolactin (screen for hyperprolactinemia)</span>'''
* '''<span style="color:#ff0000">Recommended prior to initiating treatment (4):</span>'''
*# '''<span style="color:#ff0000">Hematocrit (all patients, risk of polycythemia)</span>'''
*# '''<span style="color:#ff0000">Estradiol (in patients who present with breast symptoms or gynecomastia)</span>'''
*# '''<span style="color:#ff0000">Testicular exam and FSH (in patients interested in fertility)</span>'''
*# '''<span style="color:#ff0000">PSA (if history of prostate cancer, men >40 years, or younger with risk factors)</span>'''

==== Initial Evaluation ====
* '''<span style="color:#ff0000">Serum luteinizing hormone (LH)</span>'''
**'''<span style="color:#ff0000">Should be measured in all patients with low testosterone</span>'''
*** '''Low or low/normal LH level is consistent with a secondary (central) hypothalamic-pituitary defect, (hypogonadotropic hypogonadism)'''
***'''High LH indicates a primary testicular defect (hypergonadotropic hypogonadism)'''
**** In some cases, the etiology is obvious (e.g. iatrogenic causes), in others, a karyotype may be warranted to establish a diagnosis of Klinefelter syndrome (47, XXY). In other cases, it may not be possible to establish a definitive etiology
***** '''Klinefelter syndrome'''
****** '''See [https://test.urologyschool.com/index.php/Disorders_of_Sexual_Differentiation#Klinefelter_syndrome Klinefelter Syndrome Section] in [[Disorders of Sexual Differentiation]] Chapter Notes'''
******'''Characterized by hypergonadotropic hypogonadism (very high LH and FSH, low testosterone)'''
****** '''Management'''
*******'''Exogenous testosterone to treat signs and symptoms associated with low testosterone'''
*** '''<span style="color:#ff0000">Age-related changes</span>'''
**** '''<span style="color:#ff0000">LH does not decline as males age</span>, suggesting that reduced testosterone results from testicular hypofunction rather than changes at the hypothalamic-pituitary levels.'''
**** '''<span style="color:#ff0000">The number of Leydig cells per testis has been shown to remain unchanged,</span> suggesting that changes in the steroidogenic machinery of the individual cells and not their reduced number are responsible for the declining serum testosterone concentrations.'''
* '''<span style="color:#ff0000">Serum prolactin</span>''' 
**'''<span style="color:#ff0000">Should be measured in patients with low testosterone levels AND low or low/normal luteinizing hormone levels (hypogonadotropic hypogonadism) to screen for hyperprolactinemia.</span>'''
** '''<span style="color:#ff0000">Hyperprolactinemia</span>''' 
***Prolactin is a hormone that is synthesized and secreted from the pituitary gland
***'''<span style="color:#ff0000">Cause of secondary (central) testosterone deficiency and can lead to (4):</span>'''
***# '''<span style="color:#ff0000">Infertility</span>'''
***# '''<span style="color:#ff0000">Decreased libido</span>'''
***# '''<span style="color:#ff0000">Sexual dysfunction</span>'''
***# '''<span style="color:#ff0000">Gynecomastia</span>'''
*** '''<span style="color:#ff0000">The mechanism of action of prolactin may be through inhibition of dopaminergic activity in the medial preoptic area and decreased testosterone.</span> In addition, prolactin may have a direct effect on the penis through its contractile effect on the cavernous smooth muscle'''
*** '''<span style="color:#ff0000">Causes:[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]</span>'''
***# '''<span style="color:#ff0000">Medications (7):</span>'''
***## '''<span style="color:#ff0000">Dopamine antagonists (most commonly)</span>'''
***## '''<span style="color:#ff0000">Anti-psychotics</span>'''
***## '''<span style="color:#ff0000">Selective serotonin reuptake inhibitors</span>'''
***## '''<span style="color:#ff0000">Proton pump inhibitors</span>'''
***## '''<span style="color:#ff0000">Calcium channel blockers</span>'''
***## '''<span style="color:#ff0000">Anti-emetics</span>'''
***## '''<span style="color:#ff0000">Opiates</span>'''
***# '''<span style="color:#ff0000">Chronic medical conditions (3):</span>'''
***## '''<span style="color:#ff0000">Hypothyroidism</span>'''
***## '''<span style="color:#ff0000">Renal failure</span>'''
***## '''<span style="color:#ff0000">Cirrhosis</span>'''
***##'''<span style="color:#ff0000">Stress</span>'''
***# '''<span style="color:#ff0000">Tumors</span>'''
***##'''<span style="color:#ff0000">Pituitary tumor</span>'''
***##* Persistently elevated prolactin levels can indicate the presence of pituitary tumors such as prolactinomas. '''<span style="color:#ff0000">Pituitary prolactinomas are benign tumors that can be effectively managed using medications, such as bromocriptine or carbergoline</span>'''
***##'''<span style="color:#ff0000">Prolactin producing tumors</span>'''
***##Non-lactotroph adenomas (GH, ACTH, chromophobe)
***##Cystic adenomas
***##Tumors near the hypothalamus or pituitary that interfere with the secretion of dopamine or its delivery to the hypothalamus (e.g.,craniopharyngiomas) infiltrative diseases (e.g., sarcoidosis, hemochromatosis, TB), and malignant tumors that arise within or near the sella or metastasize to these areas
***#Other
***##Elevated estrogen levels
***##Chest wall injuries
*** '''<span style="color:#ff0000">Diagnosis and Evaluation</span>'''
****'''<span style="color:#ff0000">If prolactin is mildly elevated (≤1.5 times the upper limit of normal), a repeat fasting prolactin should be drawn to rule out a spurious elevation[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]</span>'''
***** '''<span style="color:#ff0000">False positive elevated prolactin levels can occur with a stressful blood draw.</span> Consider this if it is only slightly elevated'''
**** '''For persistently elevated prolactin levels above the normal value without an exogenous etiology, MRI is indicated.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
****'''<span style="color:#ff0000">If total testosterone levels <150 ng/dL with a low or low/normal LH, patients should undergo a pituitary MRI regardless of prolactin levels, as non-secreting adenomas may be identified.</span>'''
**** '''Patients should be referred to an endocrinologist for further evaluation if the etiology for hyperprolactinemia cannot be established.'''
***'''Management<span style="color:#ff0000">[https://pubmed.ncbi.nlm.nih.gov/33295257/ §][https://www.ncbi.nlm.nih.gov/books/NBK459347/ §]</span>'''
****'''Depends on the etiology of the hyperprolactinemia'''
****'''If pituitary prolactinoma'''
*****'''Options (2):'''
******'''Dopamine agonists (first-line)'''
******'''Transsphenoidal surgery''' 
*******'''Surgery may be considered when dopamine agonist treatment is unsuccessful or if the patient prefers surgery to life-long therapy'''
****If hyperprolactinemia without, management should focus on treatment of the underlying condition or factor causing the elevated prolactin (e.g., treatment of hypothyroidism, medication changes for drugs associated with elevated prolactin levels).

==== Prior to initiating treatment ====
* '''<span style="color:#ff0000">Hemoglobin and hematocrit</span>''' 
**'''<span style="color:#ff0000">Should be measured planning on initiating treatment and patients should be informed regarding the increased risk of polycythemia</span>'''
*** '''<span style="color:#ff0000">Elevation of Hb/Hct is the most frequent adverse event related to testosterone therapy.</span>'''
**** '''Androgens have a stimulating effect on erythropoiesis'''
**** '''<span style="color:#ff0000">Polycythemia,</span>''' sometimes called erythrocytosis, '''<span style="color:#ff0000">is defined as a hematocrit (Hct) >52%</span>'''
**** Trials have indicated that '''<span style="color:#ff0000">injectable testosterone is associated with the greatest treatment-induced increases in Hb/Hct</span>'''
*** '''Increased blood viscosity can aggravate vascular disease in the coronary, cerebrovascular, or peripheral vascular circulation, particularly in the elderly with pre-existing conditions'''
*** '''If the baseline Hct exceeds 50%, clinicians should consider withholding testosterone therapy until the etiology of the high Hct is explained'''
*** '''During testosterone therapy, levels of Hb/Hct generally rise for the first 6 months, and then tend to plateau'''.
*** '''<span style="color:#ff0000">While on testosterone therapy, a Hct ≥54% warrants intervention:</span>'''
**** '''<span style="color:#ff0000">In males with elevated Hct and</span>'''
***** '''<span style="color:#ff0000">High on-treatment testosterone levels, dose adjustment should be attempted as first-line management</span>'''
***** Low/normal on-treatment testosterone levels, measuring a SHBG level and a free testosterone level using a reliable assay is suggested.
****** '''Low/normal on-treatment testosterone levels with high free testosterone''' and low SHBG [i.e. low proportion of tightly-bound testosterone]: '''dose adjustment of the testosterone therapy should be considered.'''
****** Low/normal on-treatment testosterone levels with low/normal free testosterone: refer to a hematologist for further evaluation and possible coordination of phlebotomy.
* '''<span style="color:#ff0000">Serum estradiol</span>''' 
**'''<span style="color:#ff0000">Should be measured in patients who present with breast symptoms or gynecomastia</span>'''
*** Given the enzymatic conversion of testosterone to E2 by aromatase, '''it is not uncommon for''' '''E2 levels to increase while patients are on testosterone therapy'''.
*** Men who present with breast symptoms should have their E2 measured and those with elevated E2 measurements (>40 pg/mL), should be referred to an endocrinologist.
*** '''Symptomatic gynecomastia or other breast symptoms are an uncommon side effect of testosterone therapy'''
* '''<span style="color:#ff0000">Reproductive health evaluation (testicular exam and serum FSH)</span>''' 
**'''<span style="color:#ff0000">Should be evaluated in men who are interested in fertility</span>'''
*** '''<span style="color:#ff0000">Testicular exam</span>'''
**** Evaluate testicular size, consistency, and descent; most of the testis is composed of reproductive tissue, such as germ cells and Sertoli cells, and it is common for men with reduced testicular volume to also have impaired sperm production.
*** '''<span style="color:#ff0000">Serum FSH'''
**** '''<span style="color:#ff0000">Elevated FSH levels in the setting of testosterone deficiency (hypergonadatropic hypogonadism) is typically indicative of impaired spermatogenesis, and in such patients, clinicians should consider fertility testing, such as semen analysis.'''
***** FSH, a pituitary gonadotropin, targets the Sertoli cells within the testes and is a key regulator of spermatogenesis. '''Normal spermatogenesis is typically associated with an FSH level in the low/normal range'''
***** '''<span style="color:#ff0000">Patients who have elevated FSH with azoospermia or severe oligospermia (sperm concentration <5 million sperm per mL) should be offered reproductive genetics testing consisting of karyotype testing and Y-chromosome analysis for microdeletions'''
****** 2015 CUA Azoospermia Guidelines recommend karyotype and Y-chromosome microdeletion in patients with testicular failure.
* '''<span style="color:#ff0000">PSA</span>''' 
**'''<span style="color:#ff0000">Should be measured in men (3):</span>'''
**# '''<span style="color:#ff0000">Age > 40</span>'''
**# '''<span style="color:#ff0000">Younger males with risk factors for prostate cancer</span>'''
**# '''<span style="color:#ff0000">History of prostate cancer</span>'''
*** '''The rise of PSA levels in patients on testosterone therapy is primarily dependent upon baseline total testosterone levels; <span style="color:#ff0000">males with lower baseline testosterone levels are more likely to experience PSA level increases'''.
*** For patients who have an elevated PSA at baseline, a second PSA test is recommended to rule out a spurious elevation. In patients who have two PSA levels at baseline that raise suspicion for the presence of prostate cancer, a more formal evaluation to rule out prostate cancer (4K, phi, prostate biopsy with/without MRI, etc.) should be considered before initiating testosterone therapy.
#