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r. R, 49, presents to his primary care provider’s offi ce and indicates he has had increased fatigue for 1 year, with new onset of low libido and erectile

dysfunction for the last 3 months. He recently saw a magazine advertisement about “low T” and asks to be prescribed testosterone to help him feel more energetic.

Male hypogonadism is defi ned by the Endocrine Soci- ety as failure of the testes to produce suffi cient amounts of testosterone (androgen deficiency) and a normal level of spermatozoa due to hypothalamic-pituitary-gonadal (HPG) axis dysfunction.1 Hypogonadism is characterized by a decreased concentration of testosterone, an essential hormone that influences sexual and cognitive physiology as well as physical function and development1,2 It is associated with comorbidities such as diabetes mellitus, osteoporosis, hypertension, metabolic syndrome, dyslipidemia, sexual dysfunction, and depression.1,3 Recently, consumer-targeted therapy has heightened awareness of male hypogonadism, encouraging patients to broach the subject of low testosterone with their healthcare providers. Male patients may present to healthcare providers with non-specifi c symptoms, including fatigue, low libido, depression, or erectile dysfunction; they may also simply request screening if asymptomatic.4 As a result, healthcare providers may encounter patients who expect prescriptions for testosterone replacement for hypogonadism without a comprehensive workup to establish the correct diagnosis.4Advanced practice registered nurses (APRNs) are

in an excellent position to offer appropriate testing and follow up care if hypogonadism is suspected. APRNs can also help ensure that hypogonadism is accurately diagnosed and managed.

■ Physiology Male reproductive physiology is based on the hypothalamic- pituitary-gonadal (HPG) axis. The male sex hormones are androgens, essential for the maintenance of sexual function in men. In normal male physiology, the hypothalamus secretes gonadotropin-releasing hormone, which is trans- ported to the pituitary gland, stimulating the synthesis and secretion of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). FSH promotes spermatogenesis by acting on Sertoli cells; LH acts on the Leydig cells of the testes and regulates testosterone secretion. Prolactin is secreted from the pituitary gland and helps support testosterone biosynthesis.5,6 (See Hypothalamic- pituitary-target cell feedback mechanism.)

Testosterone is the primary male sex hormone and is the major steroid produced by the testes. Testosterone circulates primarily in bound form; only 1% to 2% circulates freely in the blood. The remaining 98% of testosterone binds to either albumin (approximately 38%) or sex hormone binding globulin (SHBG; 60%).5-7 Testosterone that binds to SHBG is tightly bound and is less biologically available than testosterone that binds to albumin, which is weakly

Evaluation and treatment of male hypogonadism in primary care

By Kim Anne Pickett, MS, APRN, BC-ADM, CDE

Abstract: Male hypogonadism is increasing in prevalence, particularly in the older male

population. Signs and symptoms associated with hypogonadism are often nonspecifi c and

may be diffi cult to categorize. This article discusses parameters for screening patients at risk,

reviews how to establish the diagnosis of primary or secondary male hypogonadism, and

offers important considerations for treatment of patients with hypogonadism.

Keywords: androgen defi ciency, hypogonadism, low testosterone, testosterone replacement

Evaluation and treatment of male hypogonadism in primary care

bound. The 2% of testosterone that remains unbound is free to enter cells to facilitate metabolic processes.6,7

Total serum testosterone levels are affected by variances in both the SHBG and albumin levels. Therefore, “free” testosterone is a more accurate indicator of true testosterone status, although some clinicians assert that “bioavailable” testosterone (testosterone bound to albumin plus free testosterone) should be considered as the more accurate indicator of active hormone levels.7

SHBG levels are decreased in obese patients or those with type 2 diabetes mellitus (T2DM), which decreases total serum testosterone levels. SHBG levels are also decreased in patients with comorbidities, such as hypothyroidism, acromegaly, and nephrotic syndrome, or in patients who use glucocorticoids, androgenic steroids, or progestins. SHBG levels are commonly increased in older patients; men with hyperthyroidism, hepatic cirrhosis, or HIV infection; and men who use antiepileptic drugs.1

■ Hypogonadism: Primary vs. secondary Hypogonadism is categorized into primary, secondary, or mixed. Primary hypogonadism (also referred to as “hypergonadotropic hypogonadism”) results from a failure or disease of the testes and is characterized by low serum testosterone and high LH and FSH concentrations. Primary hypogonadism results from conditions such as testicular injury or trauma, radiation or chemotherapy, orchitis secondary to mumps, or genetic conditions, such as Klinefelter syndrome.5,8

Secondary hypogonadism (also referred to as “hypo- gonadotropic hypogonadism”) results from a hypothalamus or pituitary disorder, causing low testosterone levels due to insuffi cient stimulation of the Leydig cells, which produce testosterone. Secondary hypogonadism is characterized by low serum testosterone and low or low-normal FSH and LH levels.5 (If testosterone levels are low and FSH and LH are within normal range, the FSH and LH may be considered “inappropriately normal” in the context of the HPG axis’ negative feedback mechanism; further investigation is warranted.) Secondary hypogonadism can be caused by pituitary tumors, hyperprolactinemia, cranial trauma, medications, or radiation as well as genetic conditions, such as Kallmann syndrome and Prader-Willi syndrome.5,7,8

The term “mixed hypogonadism” is also noted in the Endocrine Society guidelines but is less common. Mixed hypogonadism indicates dual defects in the HPG axis at the testicular level as well as the hypothalamus and/or pituitary level (usually as a result of genetic DAX-1 mutations, aging, alcohol abuse, sickle cell disease, thalassemia, glucocorticoid

CNS

Hypothalamus

Posterior pituitary (oxytocin and ADH)

Anterior pituitary

Growth hormone

TSH

FSH LH

ACTH

Thyroid (thyroid

hormones)

Adrenal gland (glucocorticoids)

Ovaries (estrogen and progesterone)

Testes

(testosterone)

Hypothalamic-pituitary-target cell

feedback mechanism

Control of hormone production is regulated by the hypothalamic- pituitary-target cell feedback mechanism. Hormone levels from the target glands regulate the release of hormones from the anterior pituitary through a negative feedback system. The dashed lines represent feedback control.

ADH = antidiuretic hormone, ACTH = adrenocorticotropic hormone, CNS = central nervous system, FSH = follicle-stimulating hormone, LH = luteinizing hormone, TSH = thyroid-stimulating hormone.

Source: Porth CM. Essentials of Pathophysiology Concepts of Altered Health States. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015:763.

Evaluation and treatment of male hypogonadism in primary care

treatment, hemochromatosis, or systemic disease).1 It should be noted that the term “mixed hypogonadism” is often not used in clinical practice in the United States and is considered a subset of secondary hypogonadism.5

■ The role of testosterone in the body Testosterone and other androgens have a crucial role in male physiology. Testosterone assists in the development of male secondary characteristics, promoting bone growth and hemoglobin synthesis while suppressing adipose tissue for- mation. It may also be associated with positive effects on mood and cognitive function.5

Testosterone levels increase from puberty to adulthood, with a decline starting at the fourth or fi fth decade of life.9 Signs of low testosterone may include low bone mineral density, reduced muscle strength, and anemia.10 Symptoms are also nonspecific and may include decreased libido, fatigue, infertility, mood disturbances, increased body fat, sleep disturbances, and decreased physical or work performance.1

■ Who should be screened? Although instruments for routine hypogonadism screening, such as the Androgen Deficiency in the Aging Male questionnaire, are not recommended by the Endocrine Society, their use may help the APRN establish dialogue with a reluctant patient.1,5 The Endocrine Society guidelines support the consideration of screening for patients who are at higher risk for androgen defi ciency as compared to the general population; these patients include those with T2DM, HIV-associated weight loss, infertility, osteoporosis, moderate-to-severe chronic obstructive pulmonary disease, or a history of sellar mass or radiation; obese patients; and patients who have had treatment with medications that affect testosterone production, such as glucocorticoids, keto- conazole, or opioids.1

■ Establishing the diagnosis of hypogonadism Signs and symptoms of hypogonadism are often broad and may be attributable to other medical conditions. Signs and symptoms most commonly associated with hypogonadism include low libido, reduced muscle mass, depression, fatigue, sexual dysfunction not alleviated by medications, or low bone density.5 Other signs and symptoms may include decreased erections, loss of body hair, infertility, poor mem- ory, sleep disturbances, anemia, hot fl ushes, sweating, or incomplete sexual development.5

The Endocrine Society guidelines recommend estab- lishing a diagnosis of androgen defi ciency only in men with

signs and symptoms of androgen defi ciency who also have unequivocally low morning testosterone levels of less than 300 ng/dL on two separate occasions.1

When a patient presents to the clinic with symptoms and requests that a testosterone level be checked, start with a thorough history and medication review; a complete physical exam should be performed. Medication lists, including over-the-counter supplements, should be reviewed. Pertinent lab work, such as a complete blood cell count, thyroid-stimulating hormone (TSH) level, and com- prehensive metabolic panel, may also be included.1

Issues such as sleep apnea or depression should also be investigated and treated. If there is no apparent cause for the symptoms after a preliminary workup and history/physical, a more extensive workup (including serum testosterone levels) may be assessed.1

■ Measurement of testosterone levels Testosterone levels follow a diurnal variation in most men, although night-shift workers may express different patterns. Levels at 8:00 a.m. are usually highest.1,7 Testosterone levels may be affected by acute exacerbations of chronic illnesses, such as uncontrolled diabetes mellitus and heart failure; therefore, measurements obtained when the patient is ill should be repeated when health status is improved.1,7 Males with suspected hypogonadism should have a complete physical exam and medication history, as certain medica- tions (such as glucocorticoids, opioids, and recreational drugs) can lower testosterone levels transiently.1,7

The Endocrine Society recommends 300 ng/dL (10.4 nmol/L) as an appropriate level to consider as a low normal testosterone level.1 The measurement of an 8:00 a.m. morning total testosterone is recommended as the initial test for the diagnosis of androgen defi ciency in males.1 If an 8:00 a.m. testosterone level is low, repeat a confi rmatory total testosterone (and in some patients, with measurement of a free or bioavailable testosterone) within the next few weeks, also at 8:00 a.m. All levels should be performed by a reliable lab assay. If both sets of 8:00 a.m. levels are low, further evaluation should be conducted.1

It is crucial to establish whether the patient has primary (testicular) or secondary (pituitary-hypothalamic) hypogo- nadism by measuring FSH and LH levels. Prescribing testosterone replacement in a patient with an unknown hypogonadism etiology has potentially dangerous effects.4

Although testosterone therapy can be considered relatively early in the course of primary hypogonadism, the causes for secondary hypogonadism (such as a pituitary tumor) must be evaluated before any further treatment is considered.4

Evaluation and treatment of male hypogonadism in primary care

Elevation in serum LH and FSH levels with a low testosterone level indicates primary hypogonadism, whereas low or low-normal LH and FSH levels with a low testosterone level are consistent with secondary hypogonadism.1,7

In men with secondary hypogonadism, further evaluation is warranted to determine the etiology of the pituitary and/or hypothalamic dysfunction. The evaluation may include prolactin levels to rule out prolactinoma, iron saturation levels, screening for hemochromatosis, and/or pituitary function testing.1 If a very low total testosterone concentration (less than 150 ng/mL) is evident, pituitary imaging studies are recommended.1 Further workup and referral to an endocrinologist or other appropriate specialist are warranted if the diagnosis is diffi cult or unclear.

■ Treatment of hypogonadism After evaluation of the patient is completed and the diag- nosis is established, the underlying causes for testosterone defi ciency should be treated. Patients with hyperprolac- tinemia, panhypopituitarism, or fertility issues will require treatment for these conditions and will benefi t from a spe- cialist. Underlying conditions associated with hypogonad- ism, such as obesity, obstructive sleep apnea, and T2DM, should be treated with intense targeted therapies, such as weight loss, adequate diet, and exercise.7

If the provider and patient elect to consider testosterone replacement therapy (TRT) after the diagnosis is estab- lished, the risks, adverse reactions, and benefi ts of TRT should be discussed. Testosterone is a controlled substance in the United States and should be prescribed using careful consideration. Benefi ts of TRT include improvement of

sexual function and libido, improvement in energy, increased muscle strength, increased bone mineral density, improved mood, and improvement in fatigue symp- toms.1,11,12

Adverse reactions of TRT include acne, erythrocytosis (the erythropoietic stimulating effect of testosterone may cause polycythemia, which manifests as an increase in the hemoglobin, hematocrit, or red blood cell count), metastatic prostate cancer growth, and reduced sperm production.1,5 There are also formulation-specifi c adverse reactions, such as risk of transmission to other individuals in close skin contact with the patient using transdermal gel due to secondary expo- sure. In addition, erythrocytosis (resulting in a hematocrit level greater than 50%) can occur—particularly with patients receiving I.M. testosterone injections.1,13

Before proceeding with treatment, it is important to review conditions in which testosterone therapy is not rec- ommended. Patients with the following conditions generally should not receive testosterone therapy: • metastatic prostate cancer • breast cancer • palpable prostate nodules or induration • unexplained prostate-specifi c antigen (PSA) elevation • erythrocytosis (defi ned by a serum hematocrit of greater

than 50%) • severe symptoms of benign prostatic hyperplasia

(American Urological Association/International Prostate Symptom Score greater than 19)

• untreated obstructive sleep apnea • unstable severe heart failure (New York Heart Association

Stage III/IV).1

TRT option s1,5,11

Formulation Advantages Disadvantages

Injectable testosterone (enan- thate testosterone, cypionate)

• Cost effective • Administered in office or home • Flexibility of dosing

• Mood, sexual function fluctuations due to peaks and valleys of testosterone

• Requires I.M. injection; lab monitoring must be done at midpoint of injection cycle

Oral testosterone (buccal tablets) Low adverse reaction profile Potential for local irritation

Transdermal patches • Ease of use • Less increase in hemoglobin

than injectable medications

Potential for local irritation

Testosterone gel • Flexibility of dosing • Generally well tolerated on skin • Ease of application

Risk of cutaneous transfer

Testosterone pellets (subcutaneous implant)

Convenient for patients who do not wish to apply daily gel or undergo regular injections

• Require surgical incision • Pellets may extrude

Evaluation and treatment of male hypogonadism in primary care

Cardiovascular health and the impact of TRT remains a major consideration. Recent studies have highlighted con- cerns about the long-term safety of TRT in males, particu- larly those with cardiovascular disease. Although testos terone defi ciency is associated with increased cardiovascular and metabolic disease, the FDA warns of the possible risks asso- ciated with TRT, including increased incidence of myocar- dial infarction, stroke, and venous thrombosis; the FDA cautions that TRT is only indicated in males with an estab- lished diagnosis of hypogonadism.14,15 However, there is a growing body of evidence indicating TRT for men with hypogonadism is believe to be safe and may actually decrease cardiovascular risk and all-cause mortality. Further research is underway.12,13 Healthcare providers should exercise cau- tion when prescribing TRT and offer treatment only after considering treatment risks versus benefi ts while providing ongoing monitoring if the patient elects treatment.10,13 (See TRT options.)

■ Use of “testosterone boosters” and herbal supplements Patients may also rely on readily available, over-the-counter (OTC) herbal or nonherbal supplements or performance- enhancing drugs (including pharmaceutical analogues) to provide “testosterone boosting” effects or to enhance profes- sional or recreational performance.16,17 Nutritional supple- ment use is increasing in the United States. Over half of U.S. adults report having taken at least one dietary supplement in the last 30 days.18

Unlike prescription medications, which are closely reg- ulated by the FDA, dietary supplements are not required to undergo the same extensive testing and approval before being sold to consumers.16 Under the current system, the FDA often only learns about the supplements after they have caused harm.16 Although some OTC nutritional supple- ments are initially assumed to be safe by consumers, they often have deleterious effects. One popular testosterone

supplement was found to be responsible for several cases of acute hepatitis and liver failure; it ultimately caused 97 inci- dents, including 47 hospitalizations, 3 liver transplants, and 1 death before it was recalled in 2013.16

Herbal ingredients are also purported by manufactur- ers to increase circulating testosterone levels in the body. Herbal supplements include astragalus root, Chinese yam, fenugreek (Greek hay), barrenwort, Longjack root, vel- vet bean, ginkgo biloba, and ginseng.19 Therefore, most herbal supplements have not been shown to be effective and have not been studied in human clinical trials. Further- more, there is no strong evidence to support their use routinely.19,20

Nonherbal dietary supplements (including D-aspartic acid and N-methyl-d-aspartate) are widely utilized, alth- ough studies in humans are scarce.19 Until stricter laws are in place regulating all supplements, including required test- ing before marketing, it would be diffi cult to confi dently and safely recommend the use of any OTC testosterone supplement to patients seeking alternative therapies. (See Helpful websites.)

■ Clinical monitoring The goal of treatment is to restore physiologic target levels of testosterone, generally in the midnormal range from 350 to 750 ng/dL.1 In the 2010 guidelines, the Endocrine Society recommends that testosterone levels should be monitored 2 to 3 months after treatment starts. If a patient is taking injectable testosterone, serum testosterone levels should be done midpoint between injections.1

Hematocrit should be checked at baseline, at 3 months, and then annually. Therapy should be discontinued if hema- tocrit exceeds 50%; the patient should be evaluated for hypoxia and sleep apnea, and the therapy can be resumed at a reduced dosage when hematocrit returns to normal.1,9

A physical exam, including digital rectal exam (DRE) with PSA level, should be completed before initiating treat- ment, at 3 months, and then as needed according to guide- lines for the patient’s age and ethnicity.1 Urologic referral should be obtained if there is an abnormal fi nding on DRE, a serum PSA concentration of greater than 4.0 ng/mL or greater than 3.0 ng/mL in men at high risk for prostate can- cer, or an increased serum PSA concentration greater than 1.4 ng/mL within any 12-month period of TRT.1

The concept of PSA velocity is also an important con- sideration. Any PSA velocity of greater than 0.4 ng/mL per year using the PSA level after 6 months of TRT as the refer- ence is significant. At least 2 years of measurements are needed to gauge velocity.1

Helpful websites

FDA

www.fda.gov/Food/DietarySupplements/Report AdverseEvent/default.htm

Safety Reporting Portal

www.safetyreporting.hhs.gov

National Institutes of Health: Offi ce of Dietary Supplements

https://ods.od.nih.gov

U.S. Anti-Doping Agency

www.usada.org and www.supplement411.org

Evaluation and treatment of male hypogonadism in primary care

■ Clinical implications APRNs are in an excellent position to help recognize, diag- nose, and treat patients with hypogonadism. Patients may initially present with nonspecific signs and symptoms. Conducting a detailed history and physical exam will help guide the provider toward a medically appropriate and cost- effective workup. It is essential to distinguish between pri- mary and secondary hypogonadism in order to facilitate proper medical care.

The provider should be familiar with risks, benefi ts, and adverse reactions of TRT and should be aware of the recom- mended monitoring of the patient on TRT in order to pro- vide safe and effective care.

REFERENCES 1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with

androgen defi ciency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metabolism. 2010;95(6):2536-2559.

2. Kumar P, Kumar N, Thakur DS, Patidar A. Male hypogonadism: symptoms and treatment. J Adv Pharm Technol Res Jul. 2010;1(3):297-301.

3. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762-769.

4. Gentry J, Price DJ, Peiris AN. Hypogonadism in primary care: the lowdown on low testosterone. Southern Med J. 2013;106(9):492.

5. Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64(6):682-696.

6. McCance KL, Huether SE. Pathophysiology : The Biologic Basis for Disease in Adults and Children. 7th ed. Maryland Heights, MO: Mosby Elsevier; 2013.

7. Pantalone KM, Faiman C. Male hypogonadism: more than just a low testosterone. Cleveland Clinic J Med. 2012;79(10):717-725.

8. Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update. Endocr Pract. 2002;8(6):440-456.

9. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005;26(6): 833-876.

10. Rivas AM, Mulkey Z, Lado-Abeal J, Yarbrough S. Diagnosing and managing low serum testosterone. Proceedings (Baylor University Medical Center). 2014;27(4):321-324.

11. Nieschlag E. Current topics in testosterone replacement of hypogonadal men. Best Pract Res Clin Endocrinol Metabolism. 2015;29:77-90.

12. Corona G, Vignozzi L, Sforza A, Maggi M. Risks and benefi ts of late onset hypogonadism treatment: an expert opinion. World J Mens Health. 2013; 31(2):103-125.

13. Grech A, Breck J, Heidelbaugh J. Adverse effects of testosterone replacement therapy: an update on the evidence and controversy. Ther Adv Drug Saf. 2014;5(5):190-200.

14. U.S. Food and Drug Administration. Testosterone information. 2015. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor PatientsandProviders/ucm161874.htm.

15. U.S. Food and drug Administration. Testosterone products: drug safety communication. 2015. www.fda.gov/Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm436280.htm.

16. Cohen PA. Hazards of hindsight: monitoring the safety of nutritional supplements. NEJM. 2014;370(14):1277-1280.

17. Pope HG, Wood RI, Rogol A, Nyberg F, Bowers L, Bhasin S. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientifi c statement. Endocr Rev. 35(3):341-375.

18. Gahche J, Bailey R, Burt V, et al. Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994). NCHS Data Brief. 2011;61:1-8.

19. Gunnels TA, Bloommer RJ. Increasing circulating testosterone: impact of herbal dietary supplements. J Plant Biochem Physiol. 2014;2(2):130.

20. Hackett G. An update on the role of testosterone replacement therapy in the management of hypogonadism. Ther Adv Urol. 2016;8(2):147-160.

Kim Anne Pickett is a family NP at the Medical Group of the Carolinas Center for Family Medicine Residency Program, Spartanburg, S.C.

With appreciation to Elaine Sunderlin, MD, for her review of this article.

The author has disclosed that she has no fi nancial relationships related to this article.

DOI-10.1097/01.NPR.0000488713.97938.0f

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/ENU (Use these settings to create PDF's if you are not downloading low Res ads from AdSpring.) >> >> setdistillerparams << /HWResolution [2400 2400] /PageSize [612.000 792.000] >> setpagedevice