NC.com

Diagnosis

Definitions

• Testosterone deficiency: low production + signs/symptoms
• Lab cutoff: < 300ng/dL
• Testosterone therapy: replacement therapies and therapies that stimulate endogenous testosterone production
• Success: improved levels to 450-600ng/dL + improvement/resolution of signs/symptoms

History/Physical

• Symptoms: fatigue, reduced energy/endurance, depression, poor concentration/memory, irritability, reduced sex drive, erectile dysfunction, history infertility, visual field changes, anosmia
• Signs: body habitus, body hair patterns, gynecomastia, decreased muscle mass
• Associated conditions: obesity (BMI > 40), anemia, low bone density, DM, testis/pelvic XRT, HIV, infertility, pituitary dysfunction
• Medications: spironolactone, ketoconazole, ADT, marijuana, steroids, opioids, chemotherapy
• Questionnaires: currently none exist that are proven to be beneficial

Causes of hypogonadism

• Primary testicular failure: Klinefelter syndrome, Noonan syndrome, absent testes, poorly functioning testes
• Secondary testicular failure: Kallmann syndorme, exogenous androgen, hyperprolactinemia, hemochormatosis, opioid use, pituitary/hypothalamic injury, Prader-Willi syndrome, Laurence-Moon-Bardet-Biedl syndrome (hypogonadism + polydactly + retinitis pigmentosa)

Labs

• Tips: confirm low T on 2+ tests on separate occasions, draw lab between 3-8AM (if sleep cycle 10PM-6AM), illness can cause decreased testosterone, draw albumin and SHBG to assess bioavailable T
• If proven low T: draw LH (hypogonadotropic hypogonadism)
• If low T + low LH: draw prolactin (prolactinoma)
• If gynecomastia or other breast symptoms: check estrogen (may worsen symptoms)
• Other tests: check baseline CBC, PSA if > 40yo, and consider DEXA, FSH, HbA1c, karyotype in individually indicated patients

Hyperprolactinemia

• Evaluation: check prolactin levels x2 (can be randomly elevated)
• Non-prolactinoma causes: renal failure, liver failure, hypothyroid, estrogen use, stress, medications
• Workup: check brain MRI to assess for prolactinoma
• Bromocriptine: dopamine agonist, can improve libido and erections
• Prolactinoma: most commonly presents with reduced libido and ED, can try bromocriptine, otherwise XRT/surgery, testosterone may not normalize after treatment

Serum Hormone Binding Globulin

• Effect: increased levels decrease free and bioavailable testosterone (tightly binds, does not exert biological effect)
• Decreased SHBG: hypothyroid, obesity, nephrotic syndrome, DM, acromegaly, steroids
• Increased SHBG: liver disease, estrogen use, hyperthyroid, HIV, seizure meds, smoking, aging

Management

Counseling

• Lifestyle modifications: weight loss, exercise, diet, can improve symptoms and increase levels without treatment
• Expected improvements: anemia, libido, erections, bone density, lean body mass, depressive symptoms
• Polycythemia: do not start testosterone if Hct > 50%, requires management if rises > 54%
• Cardiovascular risk: low T may increase risk for major cardiac event (MI/stroke), replacement may decrease risk, do not give in patients with event within past 3-6mo
• VTE: no evidence that therapy increases risk for events, but counsel patients
• Infertility: replacement therapy worsens fertility, consider using HCG, aromatase inhibitors, SERM
• Gynecomastia: unknown probability of development, can consider aromatase inhibitors or SERMs
• Prostate risk: check PSA if > 40yo, not proven to cause prostate cancer or risk to worsen localized or adequately treated prostate cancer, lower baseline PSA will see greater relative rise after starting T, not recommended for locally advanced or metastatic disease (especially if on ADT), no clear effects on BPH
• Source: method of administration depends on patient factors and preference, use manufactured products over compounded products to maintain less variation
• Contraindications: prostate cancer, breast cancer, hematocrit level > 54%, untreated OSA, uncontrolled congestive heart failure, severe liver dysfunction, severe dyslipidemia, untreated BPH, desire to preserve fertility
• Side effects: breast cancer and prostate cancer growth, worsening BPH, OSA, hepatitis, acne, weight gain, dyslipidemia, polycythemia, infertility, priapism, behavioral changes, gynecomastia, DVT risk, theoretical cardiac risk, hypoglycemia in DM

Testosterone replacement options

Application	Advantages	Disadvantages	Drug	Dosing
Intramuscular	Low cost	Fluctuating T levels Multiple injections Pain at injection site	Enthanate	250mg q2-3wk
			Cypionate	200mg q2-3wk
			Propionate	100mg q2d
			Undecanoate	1000mg q10-14wk
SubQ	3-4 treatments per year	Invasive placement Extrusion risk Infection risk	Native T	4-6 200mg, last ≤ 6mo
Buccal	Mimics physiologic range	Oral irritation BID administration Unpleasant taste	Native T	30mg BID
Transdermal	Simple administration Mimics circadian rhythm Maintains normal range	Skin irritation Risk for transfer during contact Daily administration	T patch	5-10mg daily
			T gel 1-2%	5-10g daily
			T nasal gel	33mg daily
			T solution	60-120mg daily
Oral	Oral convenience Modifiable dosing	Take with meals Potential hepatotoxicity	Undecanoate	120-240mg BID-TID
			Methyl-T	20-50mg BID-TID
			Mesterolone	100-150mg BID-TID

Non-replacement therapy options

Class	Drug	Dosing	Side Effects
Selective Endrogen Receptor Modulator (SERMs)	Clomiphene citrate	25-50mg PO q1-2d	Visual symptoms, flushing, headache, GI distress
	Tamoxifen	20mg PO QD	Hepatitis, transaminitis, cataracts, VTE/stroke
Aromatase inhibitor	Anastrozole	0.05-1mg q1-3d	Hot flashes, HTN, nausea, bone pain, dyspnea, edema
Human Chorionic Gonadotropin (HCG)		500-4000IU SQ/IM 2-3x weekly	Headache, irritability, depression, fatigue, gynecomastia, injection site pain

Follow up

• Labs: check T, CBC, PSA, LFT, lipids
• Timing: check 2-4wks after starting treatment, then at 3mo, then q6-12mo
• SERM labs: monitor LH levels
• When to stop therapy: if no improvement in symptoms despite normalization of testosterone