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    Hypogonadism: Testosterone Replacement

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    Testosterone is becoming an increasing treatment modality in the United States, particularly by primary care providers.  However, there is conflicting evidence on the benefit of this therapy for an age-related decline in testosterone.

    Like with most things in life, testosterone therapy included, there are bad things that come along with the perceived good.

    Today, we will review the signs and symptoms, evaluation, and treatment of male hypogonadism.

    Testosterone Production

    In the male body, testosterone is made by the Leydig cells in the testes.  This is released, in response to luteinizing hormone, and produced in the pituitary gland.  A decreased production of testosterone, by these cells, is considered hypogonadism.

    It is further broken down into primary (if the testes are not making enough testosterone), secondary (if the pituitary gland is not producing enough LH), or mixed subtypes.

    Causes of Hypogonadism

    Along with age, several other diseases and risk factors, reduce testosterone levels including:

    • Obesity
    • Diabetes
    • Chronic obstructive pulmonary disease
    • Chronic kidney disease
    • HIV
    • Opioid dependence

    There are also pathologic causes of hypogonadism. 

    Primary causes of hypogonadism include:

    • Klinefelter syndrome
    • Androgen receptor defect
    • 5-alpha reductase deficiency
    • Myotonic dystrophy
    • Cryptorchidism
    • Hemochromatosis
    • Mumps orchitis
    • HIV/AIDS

    Secondary causes of hypogonadism include:

    • Kallmann syndrome
    • Prader-Willi syndrome
    • Fertile eunuch syndrome
    • Pituitary disorders
    • HIV/AIDS

    Signs and Symptoms of Hypogonadism

    Signs and symptoms of hypogonadism include a depressed mood, decreased bone density, anemia, reduced energy, sense of vitality, sense of well-being, diminished muscle mass and strength, impaired cognition, increased fatigue, decreased libido, erectile dysfunction, difficulty with orgasm, and decreased penile sensation.

    The most common of these complaints is sexual dysfunction in 31% of males. 

    Diagnosing Hypogonadism

    According to the American Academy of Endocrinology, laboratory values revealing low levels of testosterone, is not enough to establish a diagnosis of hypogonadism. 

    Hypogonadism should only be diagnosed if there are signs and symptoms of the disease accompanying low testosterone levels on at least two separate occasions.

    Testosterone levels vary throughout the day, so serum levels should be drawn in the morning (8 am), or within 2 hours of waking in shift workers. 

    As males age, testosterone levels naturally fall 1%-2% per year, and by age 80 years, over half of men have testosterone level in the hypogonadal range.

    Regarding the laboratory values, there is no set “normal range” for total serum testosterone levels.  The AACE states hypogonadism is present when the total testosterone level is below 200 ng/dL. 

    In patients with a borderline low level, measurement of sex hormone-binding globulin should be performed.

    Remember, before diagnosis is made, the total testosterone should be repeated at least once more to confirm the laboratory value, and the patient must have symptoms of hypogonadism.

    In patients where the diagnosis of hypogonadism is confirmed, LH, FSH, and AM cortisol should be ordered next, to classify if their deficiency (primary or secondary).  Prolactin measurement should be ordered to rule out pituitary adenoma as well. 

    Additionally, I would order an MRI of the brain, with and without contrast, if any of the above (FSH or LH) are low, if a visual field abnormality is present, or if any other neurologic abnormality exists.

    If serum testosterone levels are low, with an elevated LSH and FH (primary hypogonadism), you could consider running chromosomal testing to assess for an underlying etiology, if old age does not fit the clinical picture for diagnosis.

    On physical examination, you should perform a testicular exam, complete neurologic examination, assessment for gynecomastia, evaluation of pubic, body, and scalp hair, and prostate examination to evaluate for any nodules.

    Testosterone Replacement Considerations

    In the appropriate patient, testosterone therapy can provide benefits.  These include increased libido, lean muscle mass, improved cognition, improved mood, increased sense of well-being, increased bone density, muscle strength, and decreased erectile dysfunction.

    However, there are multiple contraindications to testosterone therapy, as well as risks and adverse effects of treatment. 

    Contraindications include:

    • Prostate or breast cancer
    • Severe lower urinary tract symptoms (IPSS score >19)
    • Hematocrit >54% (caution if >50%)
    • Untreated sleep apnea
    • PSA >4.0 or >3.0 in high risk men (African American or men with 1st degree relatives with prostate cancer)
    • Uncontrolled heart failure

    In men over 55 years, it is recommended to use a prostate cancer risk calculator, before starting a patient on testosterone therapy. 

    During treatment, if a new prostate nodule is palpated, if serum PSA levels rise by more than 1.4 ng/mL in a one year period, or if a PSA velocity is greater than 0.4 ng/mL per year for two or more years beginning six months after starting therapy, referral to urology is warranted (Am Fam Physician. 2017 Oct 1;96(7):441-449.).

    Potential risks and adverse effects of testosterone therapy include benign prostate hypertrophy, cardiovascular disease, liver toxicity, polycythemia, virilization, and a possible reduction in sperm count.

    Treating Hypogonadism With Testosterone

    Options for therapy are listed as below:

    hypogonadism testosterone replacement
    Am Fam Physician. 2017 Oct 1;96(7):441-449.

    Oral replacement options are not favored, due to first pass metabolism by the liver, and are associated with hepatic adverse effects.

    With testosterone replacement therapy, benefits are often noted within the first three to six months of treatment.

    Monitoring Patients on Testosterone

    When starting a patient on testosterone replacement therapy, specific laboratory values must be monitored.  In general, the patient should be seen in the office every three to six months following the start of therapy.

    Total serum testosterone should be measured three to six months after initiation of therapy, then annually if stable.  The AACE recommends treating to levels between 400 and 700 ng/dL one week after injection or at any time with other formulations.

    In patients with primary hypogonadism, you can recheck an LH level as well.  Normalization of the LH should be used as a judge on the adequacy of the testosterone dosage.

    Complete blood count should be completed at baseline, and then three to six months after initiation of therapy, then annually if stable.  If the hematocrit level rises above 54%, therapy should be discontinued. 

    Treatment can be restarted at a lower dose, or with a different formulation, once the hematocrit level decreases back towards normal.

    Prostate-specific antigen and digital rectal examination should be performed at baseline and three to six months after initiation of therapy.  Recall, if a PSA level increases by >1.4 ng/mL over 12 months, or there is an abnormality palpated on digital rectal examination, referral to urology is appropriate.

    Bone density should be checked at one to two years after the start of therapy in men with osteoporosis or low trauma fracture history.

    Sources:

    Jared Kocher, MD. Male Testosterone Deficiency and Replacement Lecture. June 21st, 2016.

    Am Fam Physician. Testosterone Therapy: Review of Clinical Applications. 2017 Oct 1;96(7):441-449.

    UpToDate. Testosterone Treatment of Male Hypogonadism.  Accessed November 13th, 2017.

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    Clay Walker
    Clay Walker is a board-certified physician assistant practicing in family medicine and urgent care in rural southern Illinois. He is a graduate of Southern Illinois University School of Medicine Physician Assistant Program - class of 2016. Prior to going to PA school, Clay worked as a histology technician in southern Illinois.  From an early age, he has been interested in medicine. Clay was diagnosed as a type 1 diabetic in the first grade. He began learning about his condition and teaching others about T1DM; since then, he began to have a passion to learn medicine and make a difference in the lives of others. In his free time, Clay enjoys watching sports and going to sporting events, specifically the Chicago Cubs and Philadelphia Eagles.