What is the best course of treatment for primary hypogonadism with testicular atrophy, elevated Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels, and low-normal free testosterone levels?

Primary Hypogonadism with Testicular Atrophy: Treatment Approach

Your elevated FSH (9.9) and LH (7) with testicular atrophy indicate primary (hypergonadotropic) hypogonadism—testicular failure where the pituitary is appropriately trying to stimulate non-responsive testes—and testosterone replacement therapy is the only viable treatment option, as fertility restoration is not possible with primary testicular dysfunction. 1, 2

Understanding Your Diagnosis

Your hormone pattern definitively establishes primary hypogonadism 1, 3:

• Elevated FSH and LH indicate your pituitary is working overtime trying to stimulate failing testes 1, 3
• Total testosterone of 39.9 nmol/L (approximately 1150 ng/dL) appears normal or even high, but this must be interpreted alongside your very high SHBG of 99 nmol/L 2, 3
• Low-normal free testosterone is the critical finding—this is your biologically active testosterone, and SHBG elevation artificially inflates your total testosterone measurement 2, 3
• Testicular atrophy provides physical confirmation of primary testicular failure 1, 4

Critical Treatment Distinction

Primary hypogonadism fundamentally differs from secondary hypogonadism in treatment implications 2, 4:

• In primary hypogonadism, the testes themselves are damaged and cannot respond to hormonal stimulation 1, 5
• Gonadotropin therapy (hCG + FSH) will NOT work because your testes cannot respond—your already-elevated LH and FSH prove this 2, 4
• Fertility preservation is not possible with primary testicular failure 2, 4
• Testosterone replacement is the only option to address symptoms 1, 2

Before Starting Testosterone Therapy

Confirm the Diagnosis

Repeat morning (8-10 AM) testosterone measurements on two separate occasions to establish persistent hypogonadism, as single measurements are insufficient due to diurnal variation 2, 3:

• Measure free testosterone by equilibrium dialysis (the gold standard method) alongside total testosterone 2, 3
• Your high SHBG makes free testosterone the more reliable indicator of true androgen status 2, 3

Identify Underlying Causes of Primary Hypogonadism

Common causes of primary hypogonadism with testicular atrophy include 1:

• Klinefelter syndrome (47,XXY)—most common genetic cause 1
• Mumps orchitis or other viral infections causing testicular damage 1
• Chemotherapy or radiation exposure to testes 1
• Trauma or torsion with testicular injury 1
• Varicocele (you've ruled this out) 1
• Cryptorchidism history (undescended testes) 1
• Autoimmune orchitis 1
• Hemochromatosis causing iron deposition in testes 1, 6

Obtain karyotype testing if no clear cause is identified, as Klinefelter syndrome is frequently undiagnosed until adulthood 1

Address Your Elevated SHBG

Your SHBG of 99 nmol/L is significantly elevated and may be masking more severe testosterone deficiency 1, 2:

Causes of elevated SHBG include 1:

• Hyperthyroidism—check TSH and free T4 1
• Liver disease—check liver function tests 1
• HIV infection—consider testing if risk factors present 1
• Aging 1
• Certain medications (anticonvulsants, estrogens) 1

Testosterone Replacement Therapy Protocol

First-Line Treatment Recommendation

Start with transdermal testosterone gel 1.62% at 40.5 mg daily (two pump actuations) as first-line therapy, applied to clean, dry skin of shoulders/upper arms 2, 7:

• Transdermal preparations provide more stable day-to-day testosterone levels compared to injections 2
• Apply in the morning after showering 7
• Wash hands immediately after application 7
• Cover application site with clothing after gel dries 7
• Wash application site before skin-to-skin contact with others 7

Alternative: Injectable Testosterone

If cost is prohibitive (transdermal costs ~$2,135/year vs. injections ~$156/year), use intramuscular testosterone cypionate or enanthate 50-100 mg every week or 100-200 mg every 2 weeks 2:

• Injectable testosterone has higher risk of erythrocytosis (elevated hematocrit) compared to transdermal 2
• Causes more fluctuation in testosterone levels—peaks at days 2-5, returns to baseline by days 13-14 2
• Measure testosterone levels midway between injections, targeting 500-600 ng/dL 2

Monitoring Schedule

Check testosterone levels 2-3 months after starting therapy or any dose adjustment 2, 7:

• For gel: measure morning testosterone before application 7
• For injections: measure midway between doses 2
• Target total testosterone 500-600 ng/dL (mid-normal range) 2
• Also measure free testosterone given your high SHBG 2

Dose titration based on Day 14,28, and 42 testosterone levels 7:

• If testosterone <350 ng/dL: increase dose by one increment 7
• If testosterone >750 ng/dL: decrease dose by one increment 7
• Available gel doses: 20.25 mg, 40.5 mg, 60.75 mg, 81 mg daily 7

Once stable on a given dose, monitor every 6-12 months 2:

• Total and free testosterone 2
• Hematocrit—withhold treatment if >54% and consider phlebotomy 2
• PSA in men over 40 years 2
• Prostate examination for benign prostatic hyperplasia symptoms 2
• Lipid panel (expect improvements in triglycerides and HDL) 2
• Bone density if long-standing hypogonadism 2

Expected Treatment Outcomes

Set realistic expectations—testosterone therapy provides modest benefits 2:

Sexual Function

• Small but significant improvements in libido and erectile function (standardized mean difference 0.35) 2
• Increased frequency of morning erections 1
• May require combination with PDE5 inhibitors (sildenafil, tadalafil) for optimal erectile function 2

Physical and Metabolic

• Increased lean body mass and decreased body fat 2
• Improved bone mineral density 2
• Improvements in fasting glucose, insulin resistance, and triglycerides 2
• Little to no effect on physical strength or endurance 2

Psychological

• Minimal improvements in energy and fatigue (standardized mean difference 0.17) 2
• Less-than-small improvements in mood (standardized mean difference -0.19) 2
• Small improvements in quality of life, primarily driven by sexual function improvements 2

What Will NOT Improve

• Physical functioning, energy, vitality, or cognition show little to no benefit even with confirmed hypogonadism 2
• Muscle strength gains are minimal 2

Reevaluate at 12 months—if no improvement in sexual function, discontinue therapy to avoid unnecessary long-term exposure to potential risks 2

Absolute Contraindications to Testosterone Therapy

Do not start testosterone if you have 2:

• Active or treated male breast cancer 2
• Active prostate cancer (though evidence is evolving) 2
• Desire for fertility preservation—testosterone will cause azoospermia and permanent infertility in your case 2
• Untreated severe obstructive sleep apnea 2
• Uncontrolled heart failure 2

Potential Risks and Side Effects

Common adverse effects 2:

• Erythrocytosis (elevated red blood cells)—risk up to 44% with injectable testosterone 2
• Fluid retention 2
• Acne or oily skin 2
• Testicular atrophy (further shrinkage beyond current atrophy) 2
• Permanent infertility due to suppression of remaining spermatogenesis 2
• Gynecomastia (breast enlargement) from testosterone aromatization to estradiol 2
• Worsening of benign prostatic hyperplasia 2
• Potential cardiovascular risks (Peto odds ratio 1.22) 2

Critical Pitfalls to Avoid

Never assume you can restore fertility with any treatment 2, 4:

• Primary hypogonadism means testicular failure—gonadotropins cannot help 2, 4
• Testosterone therapy will further suppress any remaining sperm production 2
• If fertility is desired, consider sperm banking BEFORE starting testosterone 2

Do not start testosterone based on symptoms alone without confirming biochemical hypogonadism 2:

• Your free testosterone must be documented as low on repeat testing 2, 3
• Approximately 20-30% of men receiving testosterone never had documented low testosterone 2

Address the elevated SHBG 1, 2:

• High SHBG may indicate underlying thyroid disease or liver dysfunction requiring separate treatment 1
• Treating these conditions may partially improve your testosterone status 1, 8

Do not use testosterone for non-sexual symptoms 2:

• Evidence shows minimal benefit for energy, mood, or physical function 2
• The primary indication is sexual dysfunction with confirmed biochemical hypogonadism 2