Case Scenarios in Androgen Deficiency

THE AGING MALE Case Scenarios in Androgen Deficiency Andrew McCullough, MD New York University School of Medicine, New York, NY Deciding whether to choose androgen replacement for a particular patient is one of the many tasks facing the urologist. Factors including androgen levels, medical history, symptom profile, current medications, and prostate cancer risk all need to be considered when making this decision. However, the role each of these factors plays in arguing for or against androgen replacement remains controversial and more research is needed in many of these areas before the outstanding issues can be resolved. This article presents three cases involving patients who may require androgen supplementation. The cases describe (1) partial androgen deficiency syndrome, (2) testosterone deficiency in an anorchic man after bilateral orchiectomy for seminoma, and (3) a patient with sildenafilrefractory erectile dysfunction following treatment of localized prostate cancer with radiation therapy and androgen ablation. These cases illustrate some of the dilemmas and controversies surrounding androgen replacement that face the practicing urologist. [Rev Urol. 2003;5(suppl 1):S41–S48] © 2003 MedReviews, LLC Key words: Androgen replacement • Partial androgen deficiency • Erectile dysfunction • Hypogonadism • Prostate cancer art of the urologist's responsibility is to identify the patient for whom androgen replacement is an appropriate therapy. The cases presented in this article describe three candidates for androgen replacement. • Case 1: Partial androgen deficiency syndrome • Case 2: Testosterone deficiency in anorchic man after bilateral orchiectomy for seminoma • Case 3: Patient with sildenafil-refractory erectile dysfunction (ED) following treatment of localized prostate cancer with radiation therapy and androgen ablation P VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY S41 Case Scenarios in Androgen Deficiency continued Table 1 Case 1: Patient Profile Past Medical History Medical illnesses Medications Hypercholesterolemia 10 yrs Hypertension 15 yrs Depression 5 yrs Lipitor 20 mgs Accupril 20 mgs Paxil 40 mgs Hospitalizations None Surgeries Left varicocelectomy Social History Professional Retired previous year Successful upper-management hotel executive Family 1 child (it took the couple a long time to conceive because of patient's low sperm count) Review of Symptoms Urinary frequency Nocturia (2 times/night) Physical Examination Height: 5'9" Weight: 260 lbs Blood pressure: 130/85 Normal male escutcheon and normal penis size Persistent large left varicocele with ipsilateral testicular hypotrophy Rectal exam: 35 smooth benign prostate Laboratory Results Hematocrit 49 Testosterone 195 ng/dL, 200 Free testosterone 48 and 49 Cholesterol 140 LDL 36 PSA 3.3 Summary Erectile dysfunction Lack of libido Hypertension (treated) Hypercholesterolemia (treated) Depression (treated) Clinical and biochemical hypogonadism LDL indicates low-density lipoprotein; PSA, prostate-specific antigen. S42 VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY These patients typify those that a urologist might see in his or her practice, and their cases illustrate some of the dilemmas and controversies that face the practicing urologist. Case 1 A 66-year-old male makes an appointment to discuss his ED and lack of sex drive. During the office visit, he reports that he has had some mostly mild ED for 10 years. “I was fine 10 years ago. We were having sex twice a week," he states. He has been married for 30 years and is attracted to his wife. His sex drive has, nonetheless, always been lower than that of his wife, and she was the motivating force behind his making the appointment. He is now intermittently unable to achieve and maintain an erection satisfactory for sexual intercourse. He reports that he doesn't get “turned on" and “can take it or leave it." He was last sexually active 6 months ago. He has not tried sildenafil. His energy level has decreased over the past 5 years; he has difficulty getting up in the morning and suffers from lack of motivation. He reports “I’m always tired." He does not exercise regularly and has gained 10 pounds over the past 5 years. He is currently seeing a psychopharmacologist for treatment of his chronic, low-level depression. Other relevant information is presented in Table 1. This patient presents with androgen levels and symptoms consistent with partial androgen deficiency of the aging male (PADAM). This syndrome is described in Table 2. Theoretically, the patient would be a candidate for androgen replacement. The benefits of androgen replacement in symptomatic hypogonadal men are documented in the literature, and yet treatment of PADAM does not always reverse the symptoms, despite normalization of androgen levels.1 Many of this Case Scenarios in Androgen Deficiency patient’s symptoms are consistent with aging-related changes, and were it not for the decreased androgen levels, this patient might simply be treated with an erectogenic agent. Several historical points are important. 1. It is probably significant to the patient's diagnosis that his wife motivated him to make the appointment. Many men with true hypogonadism are not particularly bothered by their symptoms, and their partners will frequently encourage them to see the doctor. 2. This patient’s history suggests longstanding hypogonadism. Specifically, his infertility (low sperm count) may have been related to low androgen levels, his libido has always been lower than that of his partner, and he has suffered from chronic depression. 3. The patient is on statins. Erectile dysfunction has been associated with statin use2-5 but is also a consequence of hyperlipidemia. The mechanism of drug-induced dysfunction is unclear. Plasma lipoproteins are a major source of cholesterol for steroid-hormone synthesis. 3-Hydroxy-3-methylglu- Table 2 Partial Androgen Deficiency of the Aging Male: Syndrome Description ■ Testosterone level below 3 ng/mL (300 ng/dL or 12 nmol/L) (Normal range 10-40 nmol/mL) ■ Diminished sexual desire and erectile capacity ■ Decrease in intellectual activity ■ Fatigue ■ Depression ■ Decrease in lean body mass ■ Skin alterations ■ Decrease in body hair ■ Decrease in bone mineral density that results in osteoporosis ■ Increase in visceral fat, obesity From Ludwig.43 mone (LH) levels and no changes in sex hormone binding globulin were seen. All men underwent human chorionic gonadotropin stimulation testing to assess gonadal hormone secretion potential using pooled serum samples taken 15 minutes apart, and no differences were seen between the placebo and treatment groups. A significant decrease in bioavailable testosterone was observed, Many men with true hypogonadism are not particularly bothered by their symptoms, and their partners will frequently encourage them to see the doctor. taryl-coenzyme-A reductase inhibitors, which reduce both intracellular cholesterol synthesis and serum cholesterol levels, thus have a potential negative impact on steroidogenesis (Figure 1). In a placebo-controlled trial of 81 men on simvastatin, the simvastatin-treated group showed small declines in pooled total, free, and bioavailable testosterone after 12 weeks, although no compensatory increase in serum follicle-stimulating hormone (FSH) or luteinizing hor- but absolute levels remained in the normal range.6 These results have been seen in other studies as well.7 Whether a more significant detrimental impact on serum androgen levels might occur in hypogonadal men remains to be determined. In addition, a number of questions arise with regard to this patient: 1. In a patient with a known propensity for elevated cholesterol, does administering testosterone pose any danger with respect to his lipoprotein profile? Numerous studies have demonstrated no detrimental effect of exogenous-testosterone administration on serum lipoproteins.8-11 In a 1-year study of transdermal testosterone in 44 older men (mean age 77), total cholesterol, triglyceride, and lowdensity lipoprotein (LDL) cholesterol levels did not significantly change during the year of therapy in the men receiving testosterone supplementation, whereas high-density lipoprotein (HDL) levels and HDL (2) subfraction decreased.12 In order for testosterone to have an effect on cholesterol, there would have to be a reversal of the metabolic pathway, which might occur if supraphysiological levels of testosterone were present. The effect of testosterone on men who have elevated cholesterol levels or who take statins has not been evaluated. 2. Several questions relate to the dilemma that the prostate-specific antigen (PSA) level presents for the urologist. • In a hypogonadal man, is a PSA level of 3.3 worrisome? • Should this man have a prostate VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY S43 Case Scenarios in Androgen Deficiency continued Figure 1. Overall synthesis and metabolism of testosterone in four body compartments. Reproduced, with permission, from Coffey DS. The molecular biology, endocrinology, and physiology of the prostate and seminal vesicles. In: Campbell MF, Walsh PC, eds. Campbell’s Urology, 6e. Philadelphia, PA: WB Saunders Company; 1992:233. ADRENAL SYNTHESIS CH3 CH3 C=O C=O OH HO O O HO HO PREGNENOLONE 17 – HYDROXY PREGNENOLONE HSO4 DEHYDROEPIANDROSTERONE CH3 CH3 C=O C=O OH DEHYDROEPIANDROSTERONE SULFATE O O O OH CH2 O O O O PROGESTERONE 17 – HYDROXY PROGESTERONE ANDROSTENEDIONE OH OH 17 – KETOSTEROIDS HO H LIVER PERIPHERAL CONVERSIONS TO ESTROGENS OH 19 – HYDROXYTESTOSTERONE HO 17 – ESTRADIOL 5 REDUCTION O ANDROSTERONE OH O O SERUM TESTOSTERONE HO ESTRONE CH2 TESTICULAR SYNTHESIS O HO 19 – HYDROXYANDROSTENEDIONE O O H H EPIANDROSTERONE DIHYDROTESTOSTERONE 5 REDUCTION O HO OH OH HO H HO H ETIOCHOLANOLONE 3 ANDROSTANEDIOL H 3ß PROSTATE biopsy prior to androgen supplementation? • Is there a PSA-to-androgen ratio that might indicate higher risk of cancer? • Does androgen replacement to “normal" levels increase the risk of prostate cancer? • How long can exogenous testosterone be administered to men “at risk" for prostate cancer? • If the patient's androgen level increases on treatment, should treatment be discontinued irrespective of the biopsy result? • Is the cancer in a hypogonadal man biologically different from that in a non-hypogonadal man? These questions have not yet been answered and deserve further largescale prospective studies. Though the S44 VOL. 5 SUPPL. 1 2003 administration of exogenous testosterone is theoretically contraindicated in men with prostate cancer, current evidence does not support the view that appropriate treatment with androgens of hypogonadal elderly men causes prostate cancer.13 Li and colleagues found no increase in term (< 36 months) studies have found no significant increase in PSA levels with physiologic, exogenous replacement.15-17 Long-term studies are lacking. Guay and colleagues found that PSA levels may well increase after 3 months of treatment and that prostate cancer can be found in men Current evidence does not support the view that appropriate treatment with androgens of hypogonadal elderly men causes prostate cancer. PSA levels in 86 men treated with oral testosterone undecanoate for 2 months.8 In a 6-month, placebocontrolled study of transdermal dihydrotestosterone (DHT), Kunelius found no increase in prostate volumes or PSA levels.14 Numerous short REVIEWS IN UROLOGY with increased PSA levels.18 It is highly improbable that a 3-month course of exogenous testosterone caused the cancer. The study authors believed that the low androgen levels artificially lowered the PSA levels and that a PSA elevation after treatment Case Scenarios in Androgen Deficiency would warrant a biopsy. Finally, there appears to be no difference in testosterone levels in men without, or subsequently diagnosed with, prostate cancer.19 The last question that begs to be answered pertains to the significance of a high end of the normal range PSA in a hypoandrogenic state. One study suggests that disease in hypogonadal men may be more aggressive.20 Since androgen levels depend on body mass index (BMI), should a PSAtestosterone-BMI nomogram be developed that defines the risk of prostate cancer in hypoandrogenic men? 3. Can we anticipate that the patient will experience a progression of his lower urinary tract symptoms (LUTS)? The prostate and seminal vesicles are exquisitely sensitive to androgens levels. Treatment of LUTS with 5-alpha-reductase inhibitors or androgen deprivation invariably results in a decrease in prostate size.21,22 One would intuitively think that hypoandrogenic men would have fewer LUTS. Yet LUTS have been reported in as many as 20% of hypogonadal men. Does restoration of testosterone to physiologic levels result in an increase in prostate size and, more potentially devastating, an increase in LUTS? In a 1-year study of 29 men on a nonscrotal transdermal permeation system, no patients developed LUTS.24 In a study of 54 hypoandrogenic men on long-term androgen replacement (median duration of therapy, 32 months), though they started out with lower prostate volume than did age-matched controls, there was no significant size change of any prostate zone, as measured by transrectal ultrasound during the observation period.16 The potential adverse effects of longterm androgen replacement in men with LUTS have not been studied. 4. Testosterone replacement is associated with an increase in hema- tocrit. Of what order is this increase and how long must we be concerned about it? In their 6-month DHT trial, Kunelius and colleagues found a significant increase in hematocrit concentration, from 43.5 to 45.8.14 Snyder and colleagues found a comparable increase that stabilized at 3 months; no further increase occurred over the observation period of between 12 and 36 months. It appears that the increase stabilizes at between 5% and 13%.9 5. How much is the androgen deficiency contributing to the patient's ED? In the early part of the 20th century, androgen deficiency was believed to be the predominant form of organic ED. Men commonly underwent androgen replacement despite androgen levels in the low end of the “normal" range. As we began to understand the vascular basis of ED, the primary use of androgen replacement in the treatment of ED was abandoned. Though a longitudinal study of testosterone level in aging men suggests that sexually active men have higher testosterone levels, age more than testosterone level affects sexual function.25 Both the Massachusetts Male Aging Study (MMAS) and the Baltimore Longitudinal Study of Aging reported declines in testosterone that were greater than those found in crosssectional studies.26,27 Are men with larger declines in their testosterone levels more prone to sexual dysfunction? Are hypogonadal men with ED refractory to hormone replacement unable to respond because they have been androgen-deprived for too long? Though this situation is not seen in the hypogonadotropic hypogonadal patients, those patients are usually younger. 6. Because the symptoms of PADAM are so vague and nonspecific, the treatment paradigm is likewise con- fusing. How long does it take to see treatment effect? When does one determine that treatment is effective or ineffective? Does one continue administering testosterone if no clinical improvement is observed in the patient's PADAM symptoms, despite the normalization of androgen levels? Most studies suggest that beneficial drug effects should be evident by 3 months, and that, in the absence of improvement, continuing treatment beyond 3 months is of no benefit. 7. Does one treat the hypoandrogenic state before starting erectogenic therapy? From an academic standpoint, it might be useful to know if the androgen replacement or the phosphodiesterase type 5 (PDE-5) inhibition (from erectogenic medication) is responsible for any improvement in erectile function. Practically speaking, with such effective erectogenic medication such as sildenafil, it is hard to justify delaying such treatment. Sildenafil has been shown to be effective in hypoandrogenic men. Evidence is lacking in humans that PDE-5 inhibitors work any better in a corrected androgenic state. 8. How much is the erectile dysfunction, and not the hypoandrogenism, contributing to the patient's depression and lack of libido? A review of the MMAS testosterone data failed to show a clear correlation between testosterone levels and depression.28 Case 2 The patient is a 42-year-old status post bilateral orchiectomy for metachronous seminoma (3 years apart). He underwent radiation therapy (RT) after the second cancer and has no evidence of disease at 7 years. He is a philosophy professor who is divorced and dating. He has one child, conceived with cryopreserved sperm. He receives injectable testosterone every 3 weeks and reports feeling “low" VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY S45 Case Scenarios in Androgen Deficiency continued Table 3 Case 2: Results of Physical Examination and Laboratory Tests Physical Examination Height: 5'11" Weight: 220 lbs Blood pressure: 130/90 Anorchic Small prostate Laboratory Results Testosterone peak nadir 1200 5 Total cholesterol 220 LDL 100 PSA 1.5 Bone density scan measurement slightly low LDL indicates low-density lipoprotein; PSA, prostate-specific antigen. after 2 weeks. He is experiencing mild ED and uses sildenafil before a date because of anxiety. Results of this patient's physical examination and laboratory tests are shown in Table 3. 1. Before now, the replacement of androgens in anorchic men has been problematic, as the only available therapy involved painful intramuscular injections for life. In a Scandinavian study of patients on injection therapy after bilateral orchiectomy, 17 of 31 evaluable patients had subnormal testosterone levels. Hypogonadal levels were observed more often in patients receiving injections at intervals of at least 3 weeks than in patients receiving injections more frequently. Eleven patients reported symptomatic hot flashes, yet the hypogonadal patients’ quality of life was similar to that of a control group.29 Patients appear to strike a balance between injection frequency and their hypogonadal symptoms, frequently preferring the symptoms to more frequent injections. S46 VOL. 5 SUPPL. 1 2003 Androgen replacement in these acutely hypogonadal men offers dramatic therapeutic benefit, whereas this benefit is not realized in men with waning androgen levels where the drop is gradual occurring at 1% per year.26 In a placebo-controlled study of androgen replacement in borderline hypogonadal men after cytotoxic chemotherapy, testosterone-treated men showed a significant reduction in physical fatigue, a borderline cycles may be blunted in elderly men, they remain quite pronounced in the age range of the young men whom we would be treating for simultaneous testis cancer.31 Transdermal formulations allow for more physiological replacement.32 3. Hormonally deprived men with prostate cancer experience bone mineral density loss of 3% to 5% yearly in the first few years of androgen deprivation therapy and an increase in osteoporotic fracture incidence.33 Testosterone does not appear to be the determining hormone for bone loss. Numerous studies have now demonstrated the importance of estrogen in the maintenance of bone density.34,35 Estradiol levels below 40 pmol/L may well be the major cause of bone loss in elderly men.36 Presumably, satisfactory levels of estrogen will be achieved with adequate testosterone replacement. 4. Most patients respond to 5 to 10 grams of the 1% testosterone gel. To achieve comparable levels with injection therapy, most men will require 200 mg every 2 weeks. The peaks and nadirs of testosterone that result from intermittent injection therapy are intolerable to many young men. These men frequently experience supraphysiologic and Patients appear to strike a balance between injection frequency and their hypogonadal symptoms, frequently preferring the symptoms to more frequent injections. improvement in activity score, and a small reduction in LDL cholesterol. There were no significant effects of treatment on mood, sexual function, bone mineral density, body composition, or lipids.30 2. With the advent of effective topical agents, a more natural circadian rhythm of testosterone levels can be achieved. Though the circadian REVIEWS IN UROLOGY subtherapeutic testosterone level in the interval between treatments. Though the symptoms of excessive testosterone are not well described, during the treatment nadir men frequently report loss of nocturnal erections, vasomotor flushing, and difficulty achieving orgasms. Normalization of testosterone levels results in improvement in mood, sexual Case Scenarios in Androgen Deficiency Table 4 Case 3: Results of Physical Examination and Laboratory Tests Physical Examination Prostate nonpalpable Laboratory Results PSA current preradiation 0.1 5.2 Testosterone 50 ng/dL FSH 1 LH 2 PSA indicates prostate-specific antigen; FSH, follicle-stimulating hormone; and LH, luteinizing hormone. desire, orgasmic function, and erectile function.24 Case 3 The patient is a 58-year-old businessman 5 years status post combined external and interstitial RT and 2 years of neoadjuvant androgen ablation for Gleason grade 7, localized prostate cancer. He had no ED prior to his RT. He now complains vociferously about his ED, which is refractory to sildenafil and injection therapy; his lack of libido; and his inability to have orgasms. He is otherwise completely healthy and takes no medications. Results of his physical examination and laboratory tests appear in Table 4. Few cases will result in as much controversy as this one. Is there any reason not to “normalize" this patient's androgen levels? When do androgens return to normal after neoadjuvant treatment? Is androgen replacement uniformly and unequivocally contraindicated in men with clinically localized prostate cancer, for whom androgen ablation is not usually part of the therapeutic regimen? If it is, why are all men diagnosed with prostrate cancer not what little reported evidence exists for and against the view that androgen replacement is associated with a risk of prostate cancer. They concluded that no conclusive evidence exists that levels of circulating testosterone in individuals developing prostate cancer are higher than those in individuals who do not subsequently develop the disease.37 Clearly, large prospective studies are needed. 2. RT can be associated with decrease in testosterone. In a study of 666 patients receiving external beam RT, serum testosterone and PSA levels were measured before therapy and at 3 and 6 months. At a median nadir time of 6 months, testosterone level decreased to a mean of 83% of that measured at baseline. A decrease of more than 50% was observed in 7.5% of patients. Ninety-seven percent of those with normal initial testosterone Will normalization of the patient's androgen status result in improved erectile function? chemically castrated? Will normalization of the patient's androgen status result in improved erectile function? 1. The potential risk of the development of prostate cancer with the use of hormone replacement is highly controversial. In a review article on the topic, Slater and Olive examined levels recovered to at least normal levels, but only 60% recovered to their pretreatment level. Patients with lower pre-intervention testosterone levels and larger radiation volumes had lower testosterone nadirs. Initial testosterone level, degree of decrease, and absolute testosterone nadir had no effect on Main Points • The availability of good androgen replacement therapy has prompted a re-examination of some of the “accepted dogma." • Better longitudinal epidemiological data are necessary on testosterone levels and clinical symptoms. • Research is needed to examine the role of androgen replacement in the treatment of men with hyperlipidemia. • The influence and significance of hypogonadism and prostate-specific antigen levels with regard to prostate cancer need further scrutiny. Hormonal status may need to be incorporated into the decision-making process surrounding when to perform a biopsy of the prostate. • Guidelines are needed in the treatment of men with partial androgen deficiency of the aging male and erectile dysfunction. VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY S47 Case Scenarios in Androgen Deficiency continued biochemical control rates. PSA doubling times in patients with relapse were no different than in those with a smaller or larger testosterone decrease, suggesting that testosterone levels had no impact on biochemical recurrences.38 3. Neoadjuvant androgen ablation is increasingly used in early-stage prostate cancer, before both radical surgery and RT. The therapeutic benefit of neoadjuvant hormonal therapy in early stage low grade prostate cancer is not yet generally accepted.39-41 The duration of hypogonadism after androgen suppression may be longer than generally recognized. In a study of men on 3-month depot lupron, the median period of castrate level was 6 months. A significant association was observed between an increasing duration of castration after luteinizing hormone–releasing hormone agonist injection and both advancing patient age and increasing duration of hormonal therapy.42 Men who have had antiandrogen therapy and are complaining of PADAM symptoms should have their androgen levels checked; in addition, replacement therapy for these men should be considered carefully. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. References 1. 2. 3. 4. 5. 6. S48 Lund BC, Bever-Stille KA, Perry PJ. Testosterone and andropause: the feasibility of testosterone replacement therapy in elderly men. Pharmacotherapy. 1999;19:951–956. Rizvi K, Hampson JP, Harvey JN. Do lipid-lowering drugs cause erectile dysfunction? A systematic review. Fam Pract. 2002;19:95–98. Schachter M. Erectile dysfunction and lipid disorders. Curr Med Res Opin. 2000;16 (suppl 1):S9–S12. Buajordet I, Madsen S, Olsen H. 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