Testosterone Deficiency (2018)

See Original Guideline

See Video Review of 2018 AUA Guidelines on Testosterone Deficiency

Androgen deficiency (AD)

• The term androgen/testosterone deficiency is preferred over hypogonadism
• Unlike female menopause, which is a universal process associated with aging, the exact rate of testosterone decline and presenting symptoms are highly variable in males

Epidemiology

• True prevalence of AD in the adult male is unknown as a result of inconsistent definitions used in the literature; population-based studies suggest prevalence 2-39%

Pathophysiology

Classification

• Causes classified as primary vs. secondary
  • Primary: caused by testicular failure
  • Secondary: caused by the disruption at the hypothalamic–pituitary–gonadal (HPG) axis level

Primary hypogonadism

• Primary (hypergonadotropic hypogonadism) causes (5):
  1. Congenital causes (DUNKY XX):
     1. Down syndrone
     2. Undescended testis
     3. Noonan’s syndrome
     4. Kleinfelters syndrome
     5. Y-microdeletions
     6. XX-male
  2. Iatrogenic causes (e.g., bilateral orchiectomy, testicular radiation, chemotherapy)
  3. Testicular trauma
  4. Infection (orchitis)
  5. Auto-immune

Secondary hypogonadism

• Secondary (hypogonadotropic hypogonadism) causes (8):
  1. Congenital causes (e.g. Kallman syndrome (congenital deficiency of GnRH))
  2. Pituitary or suprasellar tumors
  3. Pituitary infiltrative disorders (e.g., hemochromatosis, tuberculosis, sarcoidosis, histiocytosis)
  4. Pituitary apoplexy
  5. Medications (i.e. chronic opioid exposure)
  6. Hyperprolactinemia
  7. Severe chronic illness
  8. Systemic illnesses associated with AD:
     • Diabetes
     • Obesity
     • HIV
     • Myocardial infarction
     • Stroke
     • COPD
     • Respiratory illness
     • Cancer
     • Sepsis
     • Chronic liver disease
     • Chronic kidney disease; renal transplantation appears to reverse the hormonal abnormalities associated with ESRD
     • Rheumatoid arthritis
     • Burn injury
     • Traumatic brain injury
     • Surgical stress

Diagnosis and Evaluation

• Clinical diagnosis of testosterone deficiency requires BOTH:
  1. Low testosterone levels combined WITH
  2. Symptoms or signs that are associated with low serum total testosterone.
  • A patient is considered testosterone deficient and a candidate for testosterone therapy only when he meets both criteria

UrologySchool.com summary

• Recommended (2):
  1. History and Physical exam
  2. Laboratory confirmation of low testosterone
     1. Total morning testosterone < 300 ng/dL on 2 separate occasions
  • Questionnaire not recommended

History and Physical Exam

History

• Signs and symptoms
  • Categories (3):
    1. Physical
       • Loss of body hair, reduced lean muscle mass, gynecomastia
       • Fatigue
       • Visual field changes (bitemporal hemianopsia), anosmia (loss of smell)
    2. Cognitive
       • Depression
       • Cognitive dysfunction, poor concentration, poor memory
       • Irritability
    3. Sexual
       • 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.
• Risk factors for AD (see above)
  • Past medical history
  • Past surgical history
  • Medications

Physical exam

1. General
   1. Body habitus (BMI or waist circumference)
   2. Virilization status (body hair patterns and amounts in androgen dependent areas)
   3. Presence of gynecomastia
      • 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):
          1. Pharmacological (risperidone, anti-androgens, marijuana, clomiphene)
          2. Physiological (neonatal period and at puberty)
          3. Pathological (testicular tumours, Klinefelter syndrome, cirrhosis)
        • With any enlargement of the male breast, the possibility of carcinoma should be considered.
2. Genitals
   • 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

1. Confirmation of low testosterone
   • Morning total testosterone level < 300 ng/dL 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.
     • Free testosterone measurements are not recommended as the primary diagnostic method for testosterone deficiency
       • 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
   • 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
     • 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
   • 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):
     1. Diabetes
     2. Obesity (BMI ≥30) or who have increased waist circumference (>40 inches)
     3. HIV/AIDS
     4. Male infertility
     5. Exposure to chemotherapy
     6. Exposure to testicular radiation
     7. Chronic narcotic use
     8. Chronic corticosteroid use
     9. Pituitary dysfunction
     10. Unexplained anemia
     11. Bone density loss

Other

Validated Questionnaires

• Examples
  • ADAM
  • Quantitative ADAM
  • Aging Male Survey (AMS)
  • MMAS
  • ANDROTEST
• The use of validated questionnaires is NOT currently recommended 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

• Initial Evaluation (1):
  1. LH
     • Helps determine etiology of testosterone deficiency
     • If low, obtain Prolactin (screen for hyperprolactinemia)
• Recommended prior to initiating treatment (4):
  1. Hematocrit (all patients, risk of polycythemia)
  2. Estradiol (in patients who present with breast symptoms or gynecomastia)
  3. Testicular exam and FSH (in patients interested in fertility)
  4. PSA (if history of prostate cancer, men >40 years, or younger with risk factors)

Initial Evaluation

• Serum luteinizing hormone (LH)
  • Should be measured in all patients with low testosterone
    • 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 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
    • Age-related changes
      • LH does not decline as males age, suggesting that reduced testosterone results from testicular hypofunction rather than changes at the hypothalamic-pituitary levels.
      • The number of Leydig cells per testis has been shown to remain unchanged, suggesting that changes in the steroidogenic machinery of the individual cells and not their reduced number are responsible for the declining serum testosterone concentrations.
• Serum prolactin
  • Should be measured in patients with low testosterone levels AND low or low/normal luteinizing hormone levels (hypogonadotropic hypogonadism) to screen for hyperprolactinemia.
  • Hyperprolactinemia
    • Prolactin is a hormone that is synthesized and secreted from the pituitary gland
    • Cause of secondary (central) testosterone deficiency and can lead to (4):
      1. Infertility
      2. Decreased libido
      3. Sexual dysfunction
      4. Gynecomastia
    • The mechanism of action of prolactin may be through inhibition of dopaminergic activity in the medial preoptic area and decreased testosterone. In addition, prolactin may have a direct effect on the penis through its contractile effect on the cavernous smooth muscle
    • Causes:§
      1. Medications (7):
         1. Dopamine antagonists (most commonly)
         2. Anti-psychotics
         3. Selective serotonin reuptake inhibitors
         4. Proton pump inhibitors
         5. Calcium channel blockers
         6. Anti-emetics
         7. Opiates
      2. Chronic medical conditions (3):
         1. Hypothyroidism
         2. Renal failure
         3. Cirrhosis
         4. Stress
      3. Tumors
         1. Pituitary tumor
            • Persistently elevated prolactin levels can indicate the presence of pituitary tumors such as prolactinomas. Pituitary prolactinomas are benign tumors that can be effectively managed using medications, such as bromocriptine or carbergoline
         2. Prolactin producing tumors
         3. Non-lactotroph adenomas (GH, ACTH, chromophobe)
         4. Cystic adenomas
         5. 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
      4. Other
         1. Elevated estrogen levels
         2. Chest wall injuries
    • Diagnosis and Evaluation
      • 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★
        • False positive elevated prolactin levels can occur with a stressful blood draw. Consider this if it is only slightly elevated
      • For persistently elevated prolactin levels above the normal value without an exogenous etiology, MRI is indicated.★
      • 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.
      • Patients should be referred to an endocrinologist for further evaluation if the etiology for hyperprolactinemia cannot be established.
    • Management§§
      • 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

• Hemoglobin and hematocrit
  • Should be measured planning on initiating treatment and patients should be informed regarding the increased risk of polycythemia
    • Elevation of Hb/Hct is the most frequent adverse event related to testosterone therapy.
      • Androgens have a stimulating effect on erythropoiesis
      • Polycythemia, sometimes called erythrocytosis, is defined as a hematocrit (Hct) >52%
      • Trials have indicated that injectable testosterone is associated with the greatest treatment-induced increases in Hb/Hct
    • 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.
    • While on testosterone therapy, a Hct ≥54% warrants intervention:
      • In males with elevated Hct and
        • High on-treatment testosterone levels, dose adjustment should be attempted as first-line management
        • 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.
• Serum estradiol
  • Should be measured in patients who present with breast symptoms or gynecomastia
    • 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
• Reproductive health evaluation (testicular exam and serum FSH)
  • Should be evaluated in men who are interested in fertility
    • Testicular exam
      • 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.
    • Serum FSH
      • 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
        • 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.
• PSA
  • Should be measured in men (3):
    1. Age > 40
    2. Younger males with risk factors for prostate cancer
    3. History of prostate cancer
    • The rise of PSA levels in patients on testosterone therapy is primarily dependent upon baseline total testosterone levels; 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.

Management

First-line: lifestyle modifications

• Weight loss (maintaining weight within the recommended range) and increasing physical activity may increase total testosterone levels and/or reduce signs and symptoms associated with testosterone deficiency
• Clinicians should counsel patients that lifestyle modifications should be undertaken for the benefit of their overall health and that improvements in total testosterone levels might not be clinically meaningful. Significant improvements in testosterone levels do not occur until a patient loses 5-10% of his body weight

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):
  1. Hypopituitarism
  2. Testicular dysgenesis with AD
  3. Delayed puberty (idiopathic, Kallmann syndrome)
  4. Klinefelter syndrome with AD
  5. Adult men with signs and symptoms of AD
  6. Sexual dysfunction with low testosterone
  7. Low bone density with AD

Contraindications

• Campbell’s: CHEAPS BLUTS
  1. Very high risk of serious adverse outcomes (2):
     1. Metastatic Prostate cancer
     2. Breast cancer
  2. Moderate to high risk of adverse outcomes (5):
     1. Poorly controlled Congestive heart failure
     2. Hematocrit > 50%
     3. Elevated PSA
     4. Abnormal DRE
     5. Unevaluated Sleep apnea
     6. Severe LUTS associated with benign prostatic hypertrophy (IPSS >19)
• 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)

1. Erectile function
2. Libido
3. Depressive symptoms
4. Anemia
5. Bone mineral density
6. Lean body mass
7. 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)

1. Polycythemia
2. 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.
3. Sleep apnea
4. Gynecomastia is a rare complication after TT
5. 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

• Cardiovascular events
  • 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).
      • TRAVERSE 2023 (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
      • 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.
• Prostate cancer
  • 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.
  • 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

• Available formulations (5):
  1. Topical (gel, patch)
     • Patients should be informed about the risk of transference
  2. Buccal patch
  3. Nasal gel
  4. Subcutaneous pellets
  5. Intramuscular injections (3 formulations: 2 short-acting, 1 long-acting)
  6. Subcutaneous injections§
• 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

• Options (as stand-alone or combination) (3):
  1. Selective estrogen receptor modulators (clomiphene citrate, tamoxifen):
     • MOA: Inhibit the negative feedback of estrogen on LH production at the level of the hypothalamus and pituitary gland
  2. Aromatase inhibitors (anastrazole):
     • MOA: Inhibits conversion of testosterone to estrogen
  3. Human chorionic gonadotropin (hCG):
     • 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.

Follow-up of Men on Testosterone Therapy

• Initial follow-up total testosterone level after an appropriate interval (depends on the method of administration) to ensure that target testosterone levels have been achieved
  • Patients on topical gels, patches, and intranasal formulations should have their testosterone checked between 2-4 weeks after commencement of therapy.
  • Patients on short-acting IM or short-acting SQ pellets (testosterone cypionate or enanthate) should have their testosterone measured after several cycles such that testosterone level equilibration has been achieved.
    • Endocrine Society Clinical Practice Guidelines recommend measuring serum T levels midway between injections for IM testosterone enanthate or testosterone cypionate and at the end of the dosing interval prior to the subsequent injection for IM testosterone undecanoate, adjusting dose or frequency to target the low‐mid physiological range (12.1–20.8 nmol/L, or 350–600 ng/dl).§
  • Given the mechanisms of action of anastrozole, clomiphene citrate, and hCG, patients using these medications should wait a longer period before follow-up blood work is performed.
• Symptoms/signs should be re-evaluated within 3 months after the commencement of treatment to determine if dosing adjustments are necessary
  • While some patients may continue to experience symptom/sign relief after this time point, the majority of men have meaningful improvements within the first 3 months of therapy
  • For men who remain testosterone deficient in the setting of symptom/sign improvement, testosterone therapy should be stopped
  • For men with on-treatment testosterone levels that fall below the suggested target range but who:
    • Have some on-treatment amelioration of symptoms, up-titration may be considered in an effort to achieve symptom abolition.
    • Experience complete resolution of symptoms, there is no need to titrate dosing.
  • For men who experience normalization of total testosterone levels but fail to achieve symptom or sign improvement, cessation of testosterone therapy 3-6 months after commencement of treatment should be discussed
    • An exception can be made if patients do not have symptoms but have documented BMD loss
    • Similarly, in the event patients have unexplained anemia that improves on testosterone therapy, continuation can be considered even in the absence of other symptom improvement.
• Total testosterone levels should be measured every 6-12 months while on testosterone therapy
• Hematocrit/hemoglobin should be measured every 6-12 months or sooner depending on prior values to maintain hematocrit levels < 54%
• PSA
  • In men without a history of prostate cancer, testing should be conducted utilizing a shared decision-making approach, in accordance with the AUA Early Detection of Prostate Cancer Guideline
  • Prostate cancer patients on testosterone therapy should have their PSA levels monitored on the same schedule as men without AD; however, clinicians may choose to increase the frequency of testing
• If baseline DEXA demonstrate bone density loss, imaging should be repeated 1-2 years after testosterone initiation. DEXA should be repeated sooner should any LTBF occur. If normalized, subsequent serial imaging can be performed in 2-5 years.

Questions

1. List systemic illnesses associated with testosterone deficiency
2. List causes of primary and secondary androgen deficiency
3. What are the recommended initial investigations in someone suspected of having AD
4. Describe your history and physical exam
5. What is required for a diagnosis of AD?
6. After confirming diagnosis of AD, what tests are required? What tests are required prior to initiating treatment?
7. What are the signs and symptoms of hyperprolactinemia? What are causes of hyperprolactinemia?
8. What are the treatment options for AD in patients who want to preserve fertility?

Answers

1. List systemic illnesses associated with testosterone deficiency
2. List causes of primary and secondary androgen deficiency
3. What are the recommended initial investigations in someone suspected of having AD
4. Describe your history and physical exam
5. What is required for a diagnosis of AD?
6. After confirming diagnosis of AD, what tests are required? What tests are required prior to initiating treatment?
7. What are the signs and symptoms of hyperprolactinemia? What are causes of hyperprolactinemia?
8. What are the treatment options for AD in patients who want to preserve fertility?

References

• Mulhall, John P., et al. "Evaluation and management of testosterone deficiency: AUA guideline." The Journal of urology 200.2 (2018): 423-432.