23

Integrated Men's Health

Androgen Deficiency, Cardiovascular Risk, and

Metabolic Syndrome

J. Kellogg Parsons; Tung-Chin Hsieh

Questions

Sections 1 and 2

1.Systemic illnesses associated with increased risk for androgen deficiency are:

a.traumatic brain injury.

b.sepsis.

c.chronic obstructive pulmonary disease.

d.rheumatoid arthritis.

e.all of the above.

2.All of the following diseases are associated with primary hypogonadism, EXCEPT:

a.cryptorchidism.

b.Klinefelter syndrome.

c.Pasqualini syndrome.

d.orchitis.

e.Noonan syndrome.

3.All of the following conditions are associated with abnormal sex hormone– binding globulin (SHBG), EXCEPT:

a.diabetes mellitus.

b.coronary heart disease.

c.aging.

d.hepatic cirrhosis.

e.acromegaly.

4.Evaluation for suspected androgen deficiency should include all of the following, EXCEPT:

a.complete history and physical exam.

b.measurement of serum luteinizing hormone (LH) and folliclestimulating hormone (FSH).

c.confirmatory repeat testosterone (T) testing if initial T level is in the mildly hypogonadal range.

d.digital rectal exam and prostate-specific antigen (PSA) testing.

e.scrotal sonography.

5.Which of the following statements regarding the diagnosis of androgen deficiency in aging is TRUE?

a.Screening questionnaires are highly specific.

b.Serum T threshold for symptoms ranges narrowly among individuals.

c.Recurrence of symptoms is highly reproducible for each individual with interruption of therapy.

d.Signs and symptoms of hypogonadism are specific; biochemical support is desirable but not mandatory.

e.Sarcopenia and osteoporosis are fundamental elements for the diagnosis of the condition.

6.For which of the following conditions is T supplemental therapy indicated?

a.Male infertility

b.Inability to concentrate

c.Obesity

d.Sleep disturbance

e.None of the above

7.Which of the following is NOT a contraindication for T supplemental therapy?

a.Polycythemia

b.Congestive heart failure

c.Breast cancer

d.Angina pectoris

e.Gynecomastia

8.T therapy preparations associated with the highest risk of polycythemia are:

a.topical T gels.

b.subcutaneous T implants.

c.intramuscular injectable preparations.

d.oral T undecanoate.

e.T buccal formulation.

9.Recommended follow-up monitoring after initiation of T therapy includes all of the following, EXCEPT:

a.yearly PSA testing.

b.monitoring T level 3 to 6 months after initiation of T therapy.

c.measuring bone mineral density of lumbar spine and/or femoral neck in men with osteoporosis and history of low-trauma fracture.

d.checking baseline hematocrit and then annually.

e.evaluating patients 3 to 6 months after initiation of T therapy, and then

annually to assess symptomatic response and adverse effects.

.Aspects of metabolic syndrome (MetS) are associated with the development of the following urologic diseases, EXCEPT:

a.nephrolithiasis.

b.prostate cancer.

c.benign prostatic hypertrophy.

d.erectile dysfunction.

e.testicular cancer.

Section 3

.According to the National Cholesterol Education Program guidelines, all of the following are components of the metabolic syndrome EXCEPT:

a.elevated serum triglycerides.

b.hypertension.

c.decreased high-density lipoprotein (HDL) cholesterol.

d.abdominal obesity.

e.increased low-density lipoprotein (LDL) cholesterol.

.Which of the following is TRUE of the MetS?

a.It is associated with an increased risk of urinary stones.

b.Definitive guidelines exist regarding the evaluation and treatment of MetS in the context of urologic diseases.

c.It is associated with an increased risk of erectile dysfunction.

d.a and c

e.None of the above

.Regarding obesity:

a. Level 1 evidence indicates that weight loss may improve stress urinary

incontinence in obese women.

b.It is associated with a decreased risk of prostate enlargement.

c.Weight loss will not improve erectile function in obese men.

d.Weight loss will improve fertility in obese men.

e.For the MetS, obesity is measured using body mass index (BMI).

.Which of the following potentially contributes to infertility in the setting of the MetS?

a.Ejaculatory dysfunction

b.Azoospermia

c.Hypogonadism

d.Spermatic DNA damage

e.All of the above

.Which of the following is NOT true of erectile dysfunction (ED)?

a.ED increases the risk of incident cardiovascular disease, including myocardial infarction.

b.For obese men with ED, evidence-based guidelines recommend lifestyle modifications, including weight loss, before initiating pharmacotherapy.

c.ED is as strong a risk factor for cardiovascular disease as smoking and family history.

d.ED is associated with increased risks of insulin resistance and diabetes.

e.Men with hypertension are more likely to develop ED than men without hypertension.

Answers

Sections 1 and 2

1.e. All of the above. Many systemic diseases are associated with increased risk of androgen deficiency. Physicians need to be aware of these disorders when evaluating patients with suspected hypogonadism and offer appropriate screening for at-risk patients. T therapy has been shown to improve outcomes and quality of life in patients with systemic illnesses.

2.c. Pasqualini syndrome. Pasqualini syndrome is a condition characterized by isolated LH deficiency. It is important to differentiate between primary and secondary hypogonadism during the evaluation of suspected patients. In patients with secondary hypogonadism with possible central

nervous system abnormalities, magnetic resonance imaging of the pituitary is indicated.

3.b. Coronary heart disease. Serum total T concentration represents the sum of unbound and protein-bound T in circulation. Most T is bound to SHBG and to albumin; only 0.5% to 3% of circulation T is unbound or "free."

When interpreting biochemical measurements, clinicians need to be aware of conditions associated with alterations in SHBG concentration.

4.e. Scrotal sonography. Guidelines on the evaluation for suspected androgen deficiency are well established. History and physical examination with biochemical testing are required for the initial workup. Although genital and testicular examination is indicated, scrotal imaging is warranted only when an abnormality is found.

5.c. Recurrence of symptoms is highly reproducible for each individual with interruption of therapy. Validated questionnaires are ideal for screening with high sensitivity (~ 80%) but poor specificity (< 50%). There is a wide interpersonal variability among T cutoff for clinical hypogonadal symptoms. However, after adequate response to treatment, discontinuation of T administrations triggers predictable symptom recurrence with reproducible T decline.

6.e. None of the above. T was studied as male contraception and is contraindicated in men desiring future fertility. Although T therapy has been shown to positively impact body composition, obesity alone is not an indication for therapy. Indications for T therapy include delayed puberty, symptomatic hypogonadism, and testicular dysgenesis. Many hypogonadal symptoms are nonspecific, and multiple signs and symptoms before initiating therapy are preferred.

7.d. Angina pectoris. Peripheral aromatization of T to estrogen can stimulate the growth of breast cancer and gynecomastia. Fluid retention is sometimes observed with T therapy and can exacerbate preexisting heart failure. Despite conflicting literature on the cardiovascular risks associated with T therapy, T has been shown to induce coronary vasodilation.

8.c. Intramuscular injectable preparations. Polycythemia is a known complication of T therapy (incidence 5%-30% with elderly men at highest risk). Although the exact mechanism is unknown, both androgen receptor and dihydrotestosterone were implicated. Erythrocytosis is often dose limiting and is the most common reason for treatment

modification/cessation. Injectable formulations are associated with the highest rate of T therapy-related polycythemia.

9.a. Yearly PSA testing. Routine scheduled follow-up is important after initiation of T therapy. Monitoring should include assessment of symptomatic response, adverse events, and biochemical testing (Table 23-1). Although baseline PSA testing and digital rectal exam should be performed before initiation of therapy, prostate cancer screening for men undergoing T therapy is the same as for eugonadal men and should follow the current American Urological Association Guidelines.

Table 23-1

Monitoring after Initiation of Testosterone Therapy: Endocrine Guideline

1.Evaluate the patient every 3-6 months after treatment initiation and then annually to asses symptom response and assess adverse effects.

2.Monitor T level 3-6 months after treatment initiation with goal to raise serum T level into the mid-normal range.

Injectable formulations: measure serum T level midway between injections.

Transdermal patch: assess T level 3-12 hr after application. Transdermal gels: assess T level anytime after 1 wk of treatment. Buccal T: assess T level immediately before or after application. Oral agent: monitor T level 3-5 hr after ingestion.

T pellets: measure T levels at the end of the dosing interval.

3.Check hematocrit at baseline, at 3-6 mo, and then annually.

If Hct > 54%, stop therapy until Hct has decreased to a safe level.

4.Measure bone mineral density of lumbar spine and/or femoral neck after 1-2 yr of T therapy in men with osteoporosis or lowtrauma fracture.

5.Perform digital rectal examination and check PSA before initiation of therapy, at 3-6 mo, and then in accordance with prostate cancer screening guidelines.

6.Additional urologic workup if there is abnormal digital rectal

incontinence in obese women. The Program to Reduce Incontinence by Diet and Exercise (PRIDE) trial demonstrated that overweight or obese women with 10 or more incontinence episodes per week benefited from a behavioral intervention focused on weight loss. Obesity is associated with an increased risk of prostate enlargement. A randomized trial of 110 obese men observed that weight loss significantly improved erectile function, but weight loss trials have as yet not been performed in obese infertile men. For the obesity component of the MetS, abdominal adiposity is measured using waist circumference.

.e. All of the above. Ejaculatory dysfunction, azoospermia, hypogonadism, and spermatic DNA damage are all putative causes of infertility in men with the MetS. Other potential factors include low ejaculate volume and diminished

sperm motility.

.b. For obese men with ED, evidence-based guidelines recommend lifestyle modifications, including weight loss, before initiating pharmacotherapy.

Although level 1 evidence supports the concept that weight loss improves erectile function in obese men, evidence-based guidelines for ED do not as yet formally address the topic of lifestyle interventions. Robust data indicate that ED substantially increases the risk of incident cardiovascular disease and is as strong an independent risk factor as current smoking or family history. Insulin resistance, diabetes, and hypertension are all strongly associated with ED.

Chapter review

1.With aging, there is a change in the gonadal hypothalamic pituitary axis.

2.The number of Leydig cells decrease with aging, and there is a reduction in the diurnal variation of T, suggesting desensitization of Leydig cells to LH with aging.

3.Circulating T is 98% bound to SHBG and albumin. T bound to albumin is more readily unbound than that bound to SHBG. Bioavailable T includes albumin bound and free T.

4.With aging, changes in enzyme receptor function and responsiveness of cells to the balance between T and dihydrotestosterone occur at different rates in individuals, which makes setting an absolute level of hormone deficiency difficult for a particular individual.

5.Metabolism of T takes place mainly in the liver, prostate, and skin; the catabolic products are excreted in the urine.

6.The CAG repeat sequence on the androgen receptor is maximal in humans (about 22 triplets) and is less in other species. There is an increased androgen response of the receptor in men with shorter CAG repeats. The androgen receptor may be activated not only by T but also by protein kinase C and other factors.

7.Hypogonadal men have increased levels of leptin and insulin. They are more likely to be obese. Hypogonadism correlates with elevated serum glucose and triglyceride levels. There is an increase in total body fat mass and fasting insulin resistance index.

8.Administration of T in older men is associated with decreased visceral fat, decreased glucose concentration, and increased sensitivity to insulin.

9.The diagnosis of T deficiency syndrome (TDS) cannot be based on absolute levels of serum T or symptoms and is a matter of judgment. However, among the most prominent symptoms of this syndrome are tiredness, decreased sexual desire, and dysphoria (mood of general dissatisfaction, depression).

10.It appears that bioavailable free T is better correlated with symptoms of TDS than is total T. Measurement of T should be restricted to the morning hours because that is the peak point of secretion. In younger men there is a normal circadian rhythm that is blunted as men age.

11.While men age, growth hormone decreases, which may result in changes in lean muscle mass, bone density, hair distribution, and the pattern of obesity. In addition, there is a reduction in dehydroepiandrosterone (DHEA), melatonin, and thyroxine. Serum leptin levels increase.

12.Hypogonadism is associated with increased mortality in males.

13.Serum T increases bone mineral density. Higher levels of circulating T correlate with a lower cardiovascular risk. Lower levels correlate with hypoactive sexual desire.

14.The presence of prostate or breast cancer is an absolute contraindication for T treatment. There is little evidence to indicate that in the normal male without prostate cancer, supplementation with T for periods of up to 3 years increases prostate growth.

15.Serum PSA thresholds for normal values are less in hypogonadal men.

16.T increases red cell mass (erythrocytosis).

17.Exogenous T suppresses spermatogenesis.

18.Peripheral aromatization of T to estrogen can stimulate the growth of breast cancer and gynecomastia.

19.ED substantially increases the risk of incident cardiovascular disease and is as strong an independent risk factor as current smoking or family history. Insulin resistance, diabetes, and hypertension are all strongly associated with ED.