Are You Sure the Patient Has Hypogonadism?

Male hypogonadism is a clinical syndrome resulting from inadequate testosterone and/or sperm production from the testis. The presence and severity of the clinical manifestations of hypogonadism depend on the degree, duration, and timing of onset. A careful history, medication review, physical examination, and laboratory evaluation are essential to establish the diagnosis and underlying cause(s).

Symptoms (in order of specificity)

Unique to pre-pubertal onset

  • Delayed puberty

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  • Absent or minimal facial/body hair

Any age of onset

  • Reduced frequency of shaving, decreased axillary hair

  • Height loss, fracture with minimal trauma

  • Infertility

  • Reduction in ejaculate volume

  • Poor libido

  • Erectile dysfunction

Less specific

  • Reduced strength and endurance

  • Increased body fat

  • Depressed mood and/or irritability

  • Poor concentration

  • Fatigue

Signs (in order of specificity)

Unique to pre-pubertal onset

  • Unilateral or bilateral cryptorchidism

  • Small testes (<4 cc), prostate and phallus

  • Absence of secondary sex-characteristics

    Voice deepening

    Adult body and pubic hair distribution and density

  • Eunuchoid proportions (Arm span >5cm longer than total height, floor-to-pubis height >2cm taller than pubis-to-crown height)

  • Mild normocytic anemia

Any age of onset

  • Testicular volume loss (<2 cc)

  • Gynecomastia

  • Oligospermia, azoosperma

  • Low bone mineral density (BMD), fragility fracture

The prevalence of hypogonadism is enriched in certain populations. A high index of suspicion is prudent regardless of symptoms if the following conditions are present:

End-stage renal disease requiring peritoneal dialysis or hemodialysis

Type 2 diabetes mellitus

Severe chronic obstructive pulmonary disease

Human immunodeficiency virus (HIV)-associated wasting syndrome or lipodystrophy

Pituitary disease or prior sellar radiation/surgery

High risk medications, especially if use is prolonged (e.g., long-acting opioids, high-dose glucocorticoids)

Infertility

Fragility fracture, low BMD

Etiologies of Hypogonadism

Causes of hypogonadism may be separated into diseases of the testis (primary), and diseases of the hypothalamic-pituitary axis (secondary). Diseases of the testis may be further subdivided into combined defects in hormone production and spermatogenesis, and isolated defects in spermatogenesis.

Causes of primary hypogonadism

  • Combined defects in hormone production and spermatogenesis

    Congenital/developmental disorders

    Klinefelter syndrome (XXY karyotype, most common cause of primary hypogonadism)

    Anorchia

    Down syndrome

    Myotonic dystrophy

    Defects in testosterone synthesis

    Luteinizing hormone (LH) receptor resistance

    Autoimmune polyglandular syndrome

    Acquired causes

    Orchitis

    Medications/drugs: chemotherapy, ketoconazole, spironolactone, alcohol, chemical toxins

    Testicular cancer

    Testicular trauma, torsion, surgery, radiation

  • Isolated defects in spermatogenesis

    Y-chromosome microdeletions

    Varicocoele

    Cryptorchidism

Causes of secondary hypogonadism

  • Pituitary disease

    Benign or malignant sellar/suprasellar tumors

    Hyperprolactinemia

    Cysts or congenital malformations

    Apoplexy

    Infiltrative/deposition diseases (e.g., hemochromatosis (HH) or transfusion-related iron overload, amyloidosis)

    Inflammatory conditions (e.g., granulomatosis with polyangiitis, Langerhans cell histiocytosis, hypophysitis)

    Infection

    Head trauma, or pituitary radiation and/or surgery

  • Genetic diseases including Idiopathic Hypogonadotropic Hypogonadism (IHH), Kallmann syndrome (IHH and anosmia), etc.

  • Medications: exogenous androgens (or estrogens/progestins), GnRH analogs, high-dose glucocorticoids, opiates or opioids (especially long-acting formulations)

  • Obesity

  • Obstructive sleep apnea (OSA)

Either acute or chronic systemic illness including HIV, diabetes mellitus, cirrhosis, chronic renal, heart, and liver failure, chronic lung disease, anorexia nervosa, rheumatologic diseases, sickle cell disease, advanced cancer, protein-calorie malnutrition, alcoholism, etc., can cause both primary and secondary hypogonadism by multiple mechanisms.

Aging is not a cause of hypogonadism per se. Although serum testosterone levels decline with age, the decline is typically within the normal range. The increased incidence of hypogonadism in older men is largely attributed to the increased incidence of medical comorbidities.

What Else Could the Patient Have?

The differential diagnosis of hypogonadism includes other disorders that may cause sexual dysfunction (poor libido, erectile dysfunction, disorders of orgasm or ejaculation) or infertility. Because many of the symptoms of hypogonadism are nonspecific, and many of these disorders can directly cause sexual dysfunction along with hypogonadism, a careful history is essential.

  • Stress or performance anxiety

  • Depression or other psychiatric illness

  • Significant medical comorbidities (e.g., heart, renal, liver, or respiratory failure)

  • Neurodegenerative disorders (e.g., Parkinson’s, Alzheimer’s dementia)

  • Spinal cord and peripheral nerve disorders (e.g., trauma, stenosis, tumor, myelitis)

  • Peripheral vascular disease

  • Medications/drugs: diuretics, β-blockers, calcium-channel blockers, first generation antihistamines, antidepressants, neuroleptics, alcohol, opiates/opioids

  • Primary disorders of the penis (e.g., Peyronie’s disease, micropenis, priapism, trauma)

  • Pelvic surgery and/or radiation therapy

Diagnosis of Hypogonadism: Key Laboratory and Imaging Tests

The diagnosis of hypogonadism requires consistent clinical signs and symptoms of testosterone deficiency in the setting of an unequivocally low fasting morning (ideally, 8-9 a.m.) serum total testosterone by a reliable assay. Specific attention should be paid to the normative ranges since they differ considerably amongst assays. Low testosterone levels should be confirmed with repeat fasting morning measurements due to the following observations:

The prevalence of low testosterone levels alone without symptoms or signs is much higher than the prevalence of the clinical syndrome,

Glucose administration and meals suppress serum testosterone levels,

Serum testosterone levels exhibit a circadian rhythm and the normal ranges of most assays were generated from morning values. Levels may decline as much as 25% by 8 p.m., although this decline is less prominent as men age,

15% of young healthy men may have a sub-normal testosterone level over the course of a day, and

Up to 35% of men with a mildly low serum testosterone level will have a normal level on repeat testing.

Diagnosis of hypogonadism is challenging since there is no universally accepted threshold serum testosterone level below which symptoms and increased morbidity/mortality have been consistently demonstrated. It’s likely that various target tissues have unique thresholds for manifesting symptoms of androgen deficiency, with inter-individual variability due to varying androgen receptor sensitivity and modifying factors such as age-of-onset, duration, and comorbidities. This uncertainty is magnified by variability in assay methodology.

The majority of circulating testosterone is bound to sex-hormone binding globulin (SHBG) and albumin, with <3% of the total in circulation as free testosterone. Although bound-testosterone has traditionally been thought to be inactive, recent data suggest certain tissues may respond to SHBG-bound testosterone, and the relationship between each testosterone compartment is sufficiently complex and dynamic to require caution in interpreting ex vivo specimens that reflect a single point in time.

In men with borderline total testosterone values, or where a derangement of protein quantity or binding is suspected, measurement of free testosterone should be considered. Quantitative or qualitative abnormalities in protein binding may be seen in the following conditions:

Increased SHBG

Advancing age

Hepatitis, cirrhosis

Hyperthyroidism

HIV infection

Drugs, including anticonvulsants, estrogens

Decreased SHBG

Obesity

Diabetes

Hypothyroidism

Nephrotic syndrome or protein-losing enteropathy

Acromegaly

Drugs, including glucocorticoids, progestins, androgens

Although automated total testosterone assays are widely available and acceptably accurate, free testosterone assays are less reliable and are best performed at a reference laboratory using equilibrium dialysis methods (gold standard). Most local laboratories use testosterone analog-based immunoassays that do not accurately detect free testosterone. Free testosterone may also be calculated using total testosterone, SHBG, and albumin concentrations, however the accuracy of the calculation is dependent upon the quality of the individual assays. “Bioavailable” testosterone refers to the sum of free testosterone and testosterone bound to albumin (less tightly bound compared to SHBG) which is theoretically available after disassociation to bind to target tissues. Bioavailable testosterone may be directly measured by ammonium sulfate precipitation at a reference laboratory, or calculated similarly to free testosterone with acceptable accuracy.

Serum testosterone levels should not be measured during acute illness since transient secondary (and occasionally, primary) hypogonadism are frequently observed in this setting along with derangements in protein binding; the degree of hypogonadism is directly related to the severity of illness.

After confirming low morning serum total testosterone levels, laboratory evaluation with pituitary gonadotropins should be sought to establish the level of pathology in the hypothalamic-pituitary-testicular axis. LH and follicle-stimulating hormone (FSH) are elevated in primary (hypergonadotropic) hypogonadism, and are low or inappropriately normal in secondary (hypogonadotropic) hypogonadism. Isolated FSH elevations may be seen in isolated defects of spermatogenesis due to the loss of feedback inhibition from inhibin B, an important product of Sertoli cells in the seminiferous tubules. A careful history and physical examination can provide clues to the underlying cause and help guide additional testing.

In men with primary hypogonadism, further evaluation should include:

Karyotype analysis – Karyotype of peripheral leukocytes will evaluate for Klinefelter syndrome and other less common chromosomal abnormalities. Suspicion for Klinefelter syndrome should be particularly high in men with small (especially <6 cc) testes, gynecomastia, learning disorders or behavioral problems, although mosaic Klinefelter syndrome may have much subtler clinical manifestations.

In men with secondary hypogonadism, further evaluation should include:

Prolactin – Hyperprolactinemia suppresses the hypothalamic-pituitary-testicular axis and may be found in the setting of prolactin-secreting pituitary adenomas, primary hypothyroidism, renal and/or hepatic failure, chest wall trauma, medications (particularly dopamine antagonists), hypophysitis, pituitary stalk compression, etc.

Transferrin saturation and ferritin – Hypogonadism is the most common endocrine abnormality in men with HH and may be reversible if identified and treated at an early age. The presence of unexplained liver function abnormalities, cardiac dysfunction, diabetes mellitus, and skin hyperpigmentation (in addition to hypogonadism) should raise suspicion for HH.

In men with secondary hypogonadism, further evaluation may include:

Pituitary function testing – If the history and physical exam suggest hypothyroidism or adrenal insufficiency, then a TSH and free T4, and 8 a.m. cortisol (or cosyntropin stimulation testing), should be obtained, respectively.

Pituitary-protocol MRI – Reserved for men with severe testosterone deficiency (e.g., serum total testosterone <50 ng/dL), symptoms or signs of potential tumor or mass effect (e.g., headache, visual loss or field defects, hyperprolactinemia), or evidence of other pituitary hormone loss or excess, especially if there is no obvious cause (e.g., morbid obesity, common offending medications).

Additional studies that are useful in both primary and secondary hypogonadism may include:

Semen analysis – For men interested in fertility. Semen analysis should ideally be collected within 1 hour of ejaculation and after 48-72 hours of abstinence. Given significant intraindividual variability, repeated analyses are frequently needed.

Dual-energy X-ray absorptiometry (DXA) – For men who have sustained fragility fractures, have radiographic osteopenia, or have severely low testosterone levels.

Approach to Treatment of Hypogonadism

Who should be treated?

We recommend treating boys with constitutional delay of puberty, and adult men with consistent signs of symptoms in the presence of overtly low serum testosterone levels. Androgen replacement therapy remains controversial for aging men without classical syndromes, as well as for those with low testosterone levels associated with chronic disease. There is growing data to support the use of androgen replacement in men with HIV and glucocorticoid-induced secondary hypogonadism. Recent data has demonstrated improvement in sexual function in symptomatic older men >65 years of age with mildly low serum testosterone levels, although whether the benefits of treatment outweigh the risks remains unclear.

Testosterone is the most commonly prescribed androgen and directly raises serum testosterone levels, effecting target tissue signaling through binding to the androgen receptor. Additional tissue-specific effects are mediated after conversion to dihydrotestosterone by 5α reductase (e.g., prostate, testes, penis, androgen-sensitive hair) or to estradiol by aromatase (e.g., bone, adipose tissue, brain).

Over the preceding decade, there has been a nearly four-fold increase in the number of testosterone prescriptions written in the United States, attributed to increased ease of administration coupled with direct-to-consumer advertising. Disturbingly, many of these prescriptions were provided to men with normal testosterone levels, or without prior biochemical evaluation. We strongly recommend against the use of androgen replacement therapy in healthy men with nonspecific symptoms and mild, or single but not consistently low serum testosterone levels. Men who have normal serum testosterone concentrations should not be treated, regardless of symptoms.

In men with secondary hypogonadism who desire fertility, injectable human chorionic gonadotropin (hCG) may be used for induction or maintenance of spermatogenesis and normalization of serum testosterone levels. hCG has the same biologic activity as LH but with the benefit of a longer half-life due to heavier glycosylation, and stimulates testicular Leydig cells to secrete testosterone. Pre-pubertal boys often require administration of both hCG and FSH therapy to restore spermatogenesis; post-pubertal men usually do not require supplemental FSH injections.

Goal of therapy and expected benefits

The goal of androgen replacement therapy is to raise serum testosterone levels to the mid-normal range for young healthy men, and to alleviate symptoms and signs of hypogonadism. Androgen replacement therapy of hypogonadal men has been shown to improve:

Sexual libido

Frequency/duration of spontaneous erections

Hair growth in androgen-sensitive body areas

Muscle mass

Body fat percentage

Muscle strength

BMD

There is suggestion of a benefit of androgen replacement therapy on mood. It is not clear if treatment improves cognition.

Potential adverse effects and contraindications of therapy

  • Growth of subclinical or metastatic hormone-responsive cancer of the prostate or breast – avoid in men with active prostate or breast cancer, or those with an unevaluated prostate nodule, asymmetric induration, or prostate specific antigen (PSA) >4 ng/L (or >3 ng/L in high risk populations).

  • Prostate growth and worsening lower urinary tract symptoms (LUTS) – avoid in men with untreated severe LUTS (International Prostate Symptom Score [IPSS] >19).

  • Erythrocytosis – avoid if pre-existing erythrocytosis is present (e.g., hematocrit >50%).

  • Worsening or precipitation of insipient OSA – avoid in men with uncontrolled or untreated severe OSA.

  • Reduction in sperm quantity and fertility – avoid in men desiring fertility.

  • Uncontrolled congestive heart failure.

  • Acne, oily skin.

  • Male pattern balding.

  • Gynecomastia.

  • Drug-drug interactions. Testosterone can enhance the effect of vitamin K antagonists and insulin. Testosterone can also enhance the hepatotoxic effect of systemic cyclosporine, mineralocorticoid effect of systemic corticosteroids, and thrombogenic effect of conestat alfa.

See below for adverse effects specific to each androgen replacement formulation.

Checklist prior to starting therapy

  • Perform a digital prostate exam in men >40 years of age to exclude nodules or asymmetry, and measure a baseline PSA level. In men >55 years of age, we also recommend use of a prostate cancer risk calculator to estimate risk.

  • Assess for LUTS (we recommend using the IPSS to quantify symptoms, if the review of systems is positive).

  • Measure a complete blood count (CBC) to exclude erythrocytosis (hematocrit >50%).

  • Assess for OSA.

  • Perform a complete medication reconciliation.

Treatment Regimens and Monitoring

General principles of monitoring

Men treated with androgen replacement should be monitored regularly to ensure target serum testosterone levels and clinical goals are met, and to perform surveillance for adverse effects of therapy. The timing of serum testosterone measurements varies with each specific formulation. The goal serum testosterone level is typically the mid-normal range (>350 ng/dL, <700 ng/dL for most assays).

We suggest the following timeline of clinical monitoring:

Baseline: pre-therapy checklist, listed above.

3 months:

Reassess symptoms, weight, blood pressure, presence of gynecomastia.

Check serum testosterone level (see formulation-specific instructions for timing of testosterone level).

Evaluate for adverse effects of testosterone therapy.

Check hematocrit; if it increases to >54%, stop therapy until hematocrit decreases into the normal range. Evaluate for OSA or other conditions associated with secondary erythrocytosis. Resume therapy at a lower dose.

Perform digital rectal examination, check PSA, and assess for LUTS.

Obtain urologic consultation for palpable prostate abnormalities, PSA >4 ng/L (or >3 ng/L in high risk populations), or IPSS >19.

Assess for adverse effects specific to each testosterone formulation, listed below. If present, consider switching to alternative formulation.

1 year and annually thereafter (or according to national guidelines or local custom):

Reassess symptoms, weight, blood pressure, presence of gynecomastia.

Check serum testosterone level (see formulation-specific instructions for timing of testosterone level).

Evaluate for adverse effects of testosterone or the testosterone formulation.

Check hematocrit; if it increases to >54%, stop therapy until hematocrit decreases into the normal range. Evaluate for OSA or other conditions associated with secondary erythrocytosis. Resume therapy at a lower dose.

Perform digital rectal examination and check PSA.

Obtain urologic consultation for new prostate abnormalities, an increase in serum PSA of >1.4 ng/mL over a 12-month period, PSA >4 ng/L (or >3 ng/L in high risk populations), or IPSS >19.

Assess for adverse effects specific to each testosterone formulation, listed below.

Biannually:

If low bone density or prior fragility fracture are documented, recheck bone density with DXA.

Testosterone therapy

We recommend starting with transdermal testosterone formulations due to their convenience, ease of use, and effectiveness in restoring serum testosterone levels into the normal range. Specific formulations should be chosen based on patient preference, insurance coverage, cost, patient comorbidities, and risks associated with each formulation. We suggest switching to an alternative formulation if the goal serum testosterone level is not obtained despite dose titration, or if adverse effects particular to the formulation occur. In general, intramuscular testosterone ester preparations have the lowest out-of-pocket cost.

Transdermal formulations

Gels

Instructions: Follow manufacturer instructions. Androgel®, Testim®, Vogelxo® are applied in the morning to the shoulder and upper arms. Fortesta® is applied to the thighs.

Counseling: Wash hands thoroughly and cover application site with clothing immediately after application.

Monitoring: Serum total testosterone level drawn any time after patient has been on a stable dose for at least two weeks. Most manufacturers vary in their recommendations of the timing of serum testosterone draws in relation to gel application. There is high intra-individual variability of serum testosterone measurements in men treated with gels; at least two values should be obtained before titrating gel doses.

Goal testosterone level: Mid-normal range.

Troubleshooting: For patients who have suboptimal responses to gels, assess for daily adherence and proper application to a sufficiently large surface area. Some patients absorb transdermal gels poorly and should be switched to an alternative formulation if goal serum testosterone levels are not met despite titration to the maximum daily dose.

Adverse effects: Potential risk for transfer to partner or other people in close contact (e.g., children), skin irritation.

N.B. For each gel formulation, the dosage of testosterone is expressed in milligrams while the dosage of the gel carrier is expressed in grams.

  • 1% alcohol-based gels

    Formulations:

    AndroGel®: 25 mg/2.5 g packets, 50 mg/5 g packets

    Testim®: 50 mg/5 g packets

    Vogelxo®: 75 g pump bottle (12.5 mg/1.25 g per actuation), 50 mg/5 g packets

    Generic: 25mg /2.5 g packets, 50 mg/5 g packets

    Starting dose: 50 mg (5 g gel) daily

    Titration: 25 mg/ 2.5 g increments to a maximum daily dose of 100 mg/10 g

  • 1.62% alcohol-based gels

    Formulations:

    AndroGel®: 75g pump bottle (20.25 mg/1.25 g per actuation), 20.25 mg/1.25 g packets, 40.5 mg/2.5 g packets

    Starting dose: 40.5 mg (2.5 g gel) daily

    Titration: 20.25 mg/1.25 g increments to a maximum daily dose of 81 mg/5 g

  • 2% alcohol-based gels

    Formulations:

    Fortesta®: 60 g pump bottle (10 mg/0.5 g per actuation)

    Generic: 60 g pump bottle (10 mg/0.5 g per actuation)

    Starting dose: 40 mg (2 g gel) daily

    Titration: 10 mg/0.5 g gel increments to a maximum daily dose of 70 mg/3.5 g

Patches

Instructions: Follow manufacturer instructions. Applied to back, stomach, upper arms, or thighs only. Bony prominences, and areas that are oily or covered with hair should be avoided.

Counseling: May contain conducting metal; remove prior to MRI. Patch may be worn while showering or swimming.

Monitoring: Serum total testosterone level drawn from three to twelve hours after placement, after patient has been on a stable dose for at least two weeks. Examine skin at each appointment.

Goal testosterone level: Mid-normal range.

Adverse effects: Skin irritation at the application site is common.

  • Adhesive patches

    Formulations:

    Androderm®: 2 mg/day patch, 4 mg/day patch

    Starting dose: 4 mg/day patch

    Titration: decrease to 2 mg/day patch, or increase to 4 mg/day + 2 mg/day patches. Do not use two 2 mg/day or 4 mg/day patches.

Solutions (alcohol-based)

Instructions: Follow manufacturer instructions. Applied to the axilla via applicator cup.

Counseling: Wash hands thoroughly and cover application site with clothing immediately after solution has dried. Use has not been established in men with a body mass index (BMI) >35 kg/m2.

Monitoring: Serum total testosterone level drawn two to eight hours after application after patient has been on a stable dose for at least 2 weeks.

Goal testosterone level: Mid-normal range.

Adverse effects: Potential risk for transfer to partner or other people in close contact (e.g., children), skin irritation.

  • Axillary alcohol-based solutions

    Formulations:

    Axiron®: 90 cc bottle (30 mg/1.5 cc per actuation)

    Starting dose: 60 mg (3 cc) daily

    Titration: 30 mg/3 cc increments to a maximum daily dose of 120 mg/12 cc

Injectable formulations

Intramuscular solutions

Instructions: Patient should be taught to draw up medication, clean the injection site at the vastus lateralis or upper outer quadrant of the gluteus maximus muscles, and inject into the muscle while avoiding vascular structures.

Also requires: 1-5 mL syringe, 18-gauge needle for drawing, 22-gauge 1.5″ needle for injecting.

Monitoring: Serum total testosterone level drawn midway between injections (target mid-normal range), or just prior to next dose.

Goal testosterone level: Mid-normal range (if drawn midway between injections), or low-normal range (if drawn as a trough, just prior to next dose)

Adverse effects: Pain, infection, or bleeding at injection site, peak and nadir of mood and/or libido, cough immediately following injection (pathophysiology unclear, but attributed to oil microembolism). Intramuscular testosterone is more likely than other routes to cause erythrocytosis and should be used with caution in men with high-normal hemoglobin values.

N.B. Testosterone enanthate availability has declined in the United States. However, testosterone cypionate is widely available and has similar pharmacokinetics.

  • Intermediate-acting testosterone esters

    Formulations:

    Depot-Testosterone® (testosterone cypionate): 10 mL vial (100 mg/mL), 1 and 10 mL vials (200 mg/mL)

    Generic testosterone cypionate: 10 mL vial (100 mg/mL), 1 and 10 mL vials (200 mg/mL)

    Generic testosterone enanthate: 5 mL vial (200 mg/mL)

    Starting dose: 50 mg to 100 mg every week, 150 mg to 200 mg every two weeks

    Titration: 50 mg increments

  • Long-acting testosterone esters

    Formulations:

    Aveed® (testosterone undecanoate): 3 mL vial (750 mg/3 mL)

    Starting dose: 750 mg followed by an additional 750 mg four weeks later, followed by an additional 750 mg 10 weeks later and every 10 weeks thereafter

    Titration: Adjust dosing interval rather than dose

    Warning: Testosterone undecanoate has a United States boxed warning for serious pulmonary oil microembolism and anaphylaxis). Prescribing must be done through the Aveed® risk management (REMS) program. Patients should receive injections under observation and be monitored for at least 30 minutes after injections.

Pellets

Instructions: Surgically inserted into the subcutaneous tissue by a health-care provider.

Monitoring: Serum total testosterone level drawn at the end of the dosing interval. Examine pellet insertion site at each appointment.

Goal testosterone level: Mid-normal range.

Adverse effects: Scarring/fibrosis, infection, pellet extrusion (highest risk in physical laborers).

Implantable pellets

Formulations:

Testopel®: 75 mg pellets

Generic: 12.5 mg, 25 mg, 37.5 mg, or 50 mg pellets

Starting dose: 150 mg every three to six months

Titration: Adjust number of pellets (in 12.5-75 mg increments) and/or dosing interval

Mucosal formulations

Buccal

Instructions: Apply to the gum area above either incisor.

Monitoring: Serum total testosterone level drawn after at least four weeks of therapy. Examine gums at each appointment.

Goal testosterone level: Mid-normal range.

Adverse effects: Gum irritation, alteration in taste, headache.

Mucoadhesive buccal tablets

Formulations:

Striant®: 30 mg tablets

Starting dose: 30 mg twice daily

Titration: None; discontinue if serum testosterone levels are outside the goal range

Nasal

Instructions: Follow manufacturer’s instructions.

Contraindications: Not recommended for men with sinus disease, mucosal inflammatory disorders, a history of nasal or sinus surgery, recent nasal fracture, or any nasal fracture leading to deformity of the nasal septum. Use has not been established in men with a BMI >35 kg/m2.

Monitoring: Serum total testosterone level drawn after at least four weeks of therapy.

Goal testosterone level: Mid-normal range.

Adverse effects: Local nasal irritation (rhinorrhea, sneezing, epistaxis, mucosal erosion or dryness), sinus infection, upper respiratory infections, pharyngitis, headache.

  • Nasal gel

    Formulations:

    NatestoTM: 11 g metered-dose pump bottle (5.5 mg/0.122 g per actuation, total of 60 actuations per pump bottle)

    Starting dose: 33 mg (six pump actuations) split into 11 mg (two actuations: one per nostril) thrice daily dosing

    Titration: None; discontinue if serum testosterone levels are outside the goal range

Chorionic gonadotropin therapy

N.B. There are several acceptable hCG administration regimens. The following instructions, starting dose, and titration guidelines are our personal recommendation and represent common practice at our institution.

Instructions: Patient should be taught to inject 10 cc of sterile saline into the hCG vial to yield a 1,000 units/mL suspension.

Also requires: 1 mL syringe, 18-gauge needle for drawing/mixing, 22-gauge 1.5″ needle (for intramuscular route) or 25 g 5/8″ needle (for subcutaneous route; not FDA approved), sterile saline.

Monitoring: Serum total testosterone level drawn in the morning before administration (trough level) after the patient has been on a stable dose for one month. Estradiol should also be measured if breast tenderness or overt gynecomastia occurs, or if the serum testosterone level is higher than expected.

Goal testosterone level: Trough level in the low-normal range.

Adverse effects: Pain, infection, or bleeding at injection site. Gynecomastia may occur, particularly if the serum testosterone trough levels are higher than the low-normal range.

Formulations:

hCG: 10,000 units/vial (powder)

Starting dose: 1,000 units subcutaneously every other day

Titration: 500 unit increments; amount of diluent may be reduced to avoid pain from high volume administration

What’s the Evidence?/References

Finkelstein, JS, Lee, H, Burnett-Bowie, SM, Pallais, JC. “Gonadal steroids and body composition, strength, and sexual function in men”. N Engl J Med. vol. 369. 2013. pp. 1011-1022. (Elegant study of the role of testosterone vs. estrogen in mediating androgen effects on bone, strength, body composition, and sexual function.)

Bhasin, S. “Approach to the infertile man”. J Clin Endocrinol Metab. vol. 92. 2007. pp. 1995-2004. (Thoughtful review of male-factor infertility and the role of diagnosing and treating hypogonadism.)

Wikström, AM, Dunkel, L. “Klinefelter syndrome”. Best Pract Res Clin Endocrinol Metab. vol. 25. 2011. pp. 239-250. (Comprehensive review of Klinefelter's syndrome.)

Rosner, W, Auchus, RJ, Azziz, R, Sluss, PM. “Utility, limitations, and pitfalls in measuring testosterone: An Endocrine Society position statement”. J Clin Endocrinol Metab. vol. 92. 2007. pp. 405-413. (Endocrine Society position statement on the performance of testosterone assays.)

Layton, JB, Li, D, Meier, CR, Sharpless, JL. “Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011”. J Clin Endocrinol Metab. vol. 99. 2014. pp. 835-842. (Epidemiologic study of the testosterone prescribing "epidemic".)

Snyder, PJ, Peachey, H, Berlin, JA, Hannoush, P. “Effects of testosterone replacement in hypogonadal men”. J Clin Endocrinol Metab. vol. 85. 2000. pp. 2670-2677. (Longitudinal study of the magnitude and timing of benefits from physiological testosterone replacement over three years in a small group of adult men with hypogonadism.)

Bhasin, S, Cunningham, GR, Hayes, FJ, Matsumoto, AM. “Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 2536-2559. (Endocrine Society clinical practice guideline on the diagnosis and treatment of androgen deficiency in men.)

Cunningham, GR, Toma, SM. “Clinical review: Why is androgen replacement in males controversial?”. J Clin Endocrinol Metab. vol. 96. 2011. pp. 38-52. (Thoughtful commentary on the controversies surrounding androgen replacement in men.)

Wu, FC, Tajar, A, Beynon, JM, Pye, SR. “EMAS Group. Identification of late-onset hypogonadism in middle-aged and elderly men”. N Engl J Med. vol. 363. 2010. pp. 123-135. (Large European survey to clinically define hypogonadism in middle-aged and elderly men.)

Basaria, S, Coviello, AD, Travison, TG, Storer, TW. “Adverse events associated with testosterone administration”. N Engl J Med. vol. 363. 2010. pp. 109-122. (Landmark randomized control trial to assess the adverse effects of testosterone replacement in older men with multiple medical comorbidities.)

Snyder, PJ, Bhasin, S, Cunningham, GR, Matsumoto, AM. “Testosterone Trials Investigators. Effects of Testosterone Treatment in Older Men”. N Engl J Med. vol. 374. 2016. pp. 611-624. (Recent randomized controlled trial on the effects of testosterone treatment in men >65 years of age.)

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