A myriad of symptoms typically arises in a PC patient who undergoes androgen deprivation therapy (ADT). Some of these occur acutely and many may improve over time, but can still be quite troublesome if not aggravating for the patient. Other symptoms develop more gradually and are subtler, but if not treated in a preventative manner, can have a negative impact upon the PC patient’s overall health.

Except for hot flushes and impotency, many ADS symptoms were discounted by physicians and patients as being due to “old age” or other medical problems such as arthritis or heart disease. However, this constellation of clinical and laboratory abnormalities quickly develops in younger men, or older men in otherwise good health, after ADT is initiated. This clearly suggests that these symptoms are not simply attributed to “old age” but are characteristic of what we have termed the Androgen Deprivation Syndrome (ADS).

ADS symptoms are directly or indirectly due to the significant fall in serum testosterone that occurs following orchiectomy or treatment with a LHRH agonist such as Lupron® or Zoladex®. In essence, men who are medically or surgically castrated undergo an accelerated and intensified form of “male menopause” which leads to the same types of symptoms in these men that are seen in women who undergo female menopause. Patients treated with combined ADT (LHRH agonists or orchiectomy plus an anti-androgen such as Eulexin®, Casodex®, or Nilandron®) may have more severe ADS symptoms than those treated with a LHRH agonist or orchiectomy alone. A list the types of acute and chronic ADS symptoms appear in Table 1.

TABLE 1: Commonly Reported Acute & Chronic ADS Symptoms
Acute (symptoms in < 2 months)	Chronic (symptoms in > 6 months)
Hot Flushes	Muscle atrophy in chest, arms & legs
Impotence & loss of libido	Atrophy of testicles
Aches & pains in joints	Decreased muscle strength & endurance
Loss of energy & “feeling weak”	Weight gain due to increased body fat
Short-term memory difficulties	Gynecomastia (breast enlargement)
Mood “swings”	Osteoporosis, progressive on CHB
Emotional changes (tearfulness, etc.)	Chronic fatigue-like syndrome
Anemia unrelated to blood loss, iron deficiency or bone marrow involvement	Difficulty controlling blood pressure, often requiring initiation of changes in drug therapy
Loss of blood sugar control in patients with diabetes mellitus (sugar diabetes)	Alzheimer’s-like symptoms (severe short-term memory difficulties, inability to concentrate, etc.)
Increase in urinary symptoms (? urination or difficulty starting the urinary stream)	Increased serum cholesterol (LDL, or “bad” cholesterol) and/or & triglyceride levels

To assess the significance of common ADS symptoms, we questioned 177 hormone-naïve PC patients consecutively treated with a LHRH agonist and an antiandrogen between 1994 and 1997. We asked patients to grade the frequency and severity of ADS as absent (0), occasional (1), frequent/bothersome (2) or required drug therapy (3). Other than loss of libido and impotence, Figures 1 and 2 depict the most commonly reported acute and chronic symptoms.

Figure 1: Incidence & Severity of Common Acute ADS Symptoms

Figure 2: Incidence & Severity of Common Chronic ADS Symptoms

Several patient and treatment-related factors were found to influence the incidence and severity of ADS symptoms. Figures 3a, 3b and 3c depict hot flushes, anemia and osteoporosis when analyzed with respect to (1) age, (2) choice of ADT and (3) relative duration of ADT, respectively.

Figure 3a: Incidence & Severity of Hot Flushes With Age

Figure 3b: Incidence & Severity of Anemia by ADT Used

Figure 3c: Incidence & Severity of Osteoporosis by ADT Duration


Treatment of certain ADS-related symptoms is important as it can help maintain the patient’s overall health. The decision as to whether or not treatment is indicated must take into account:
• The goals of ADT (neoadjuvant, intermittent or continuous treatment)
• The age and overall general health of the patient (active vs. inactive)
• The degree of tolerance by the patient of the various ADT side-effects.

For example, patients who are candidates for potentially curative local therapies, the duration of neo-adjuvant ADT rarely exceeds 1 year. Therefore, such patients suffer the typical acute ADS symptoms, but will not experience chronic ADS symptoms to any significant extent. However, acute ADS symptoms invariably compromise the lifestyles of healthy and active prostate cancer patients, and mandate that certain changes be made in the patients’ diet, exercise and/or work habits during ADT.

Chronic ADS symptoms are much more prevalent in PC patients treated with ADT than is currently recognized, and some are nearly inevitable in patients treated longer than a year. For such patients, specific treatment strategies must be implemented to minimize or prevent the development of chronic ADS. Left untreated, chronic ADS is progressive with ongoing ADT and often lead to other medical complications.

Summary

In the past, patients who were not candidates for local therapy were typically treated with some form of androgen blockade indefinitely. Armed with our current knowledge of acute and chronic ADS symptoms, we treat such patients with one or more of the therapies listed in Tables 3a and 3b to prevent and/or treat acute ADS (Table 3a) and chronic ADS (Table 3b).1 Another means to avoid chronic ADS is to offer Intermittent Androgen Deprivation (IAD). Depending upon the required duration of ADT individually determined for patients, IAD may be a viable alternative for patients meeting specific response criteria.2

TABLE 2a: Preventative & Active Treatments for Acute ADS
Acute ADS Symptom	Preventive Treatment Strategy
Hot flushes	Soy**, genistein**, Megace®*, Depo-provera®*, DES*, Effexor ®*
Aches & pains in muscles and joints	Acetaminophen, ibuprofen, Fosamax ®*, Aredia ®*, plus calcium, vitamin D, aerobic exercise, walking
Fatigue & feeling weak	Aerobic exercises, muscle stretching
Memory difficulties	Gingko**, Eldepryl ®*, memory execises
Mood & emotional swings	Depo-provera ®*, patience (may improve on its own)
Symptomatic anemia (shortness of breath, dizziness, severe weakness)	Injections of human erythropoietin ( Procrit ®)*
Urinary frequency	Hytrin ®*, Cardura ®*, Flomax ®*
Impotence, loss of libido	Viagra ®*, Muse ®*, Caverject ®*

TABLE 2b: Preventive & Active Treatments for Chronic ADS
Acute ADS Symptom	Preventive Treatment Strategy
Loss of muscle bulk & strength, worse in pectoral, biceps and quadriceps	Regular exercise of pectoral, biceps & quadriceps muscles with light weights, electrical muscle stimulation?
Weight gain and fat redistribution	Low fat diet, regular exercise routine
Chronic fatigue syndrome	Walking, regular exercise, avoid inactivity
Gynecomastia	Breast radiation or Arimidex ® to prevent occurrence; liposuction or surgery to treat severe cases
Osteoporosis	Fosamax ®*, Aredia ®* or Evista ®*, plus calcium & vitamin D, aerobics, walking
Alzheimer’s-like symptoms	Gingko**, Aricept ®*, reading or other mind-stimulating activities
Increased serum cholesterol & triglyceride levels	Low fat diet, regular exercise, if no help, Lipitor ®*, Pravacol ®*, Zocor ®*, Mevacor ®*

Key to Table 2a and 2b Footnotes:
* Doctor’s prescription is required to obtain medication
** Available from nutrition or health food stores

1. Strum SB, Scholz MC & McDermed JE: The Androgen Deprivation Syndrome: the incidence and severity in prostate cancer patients receiving hormone blockade. Proc Amer Soc Clin Oncol. 17: 316A, 1998.
2. Strum SB, and Scholz MC: Intermittent Hormone Blockade: optimal induction duration and predictive factors for prolonged time off hormone blockade. Proc Amer Soc Clin Oncol. 17: 313A, 1998.

Prostate Cancer Research Institute (PCRI)

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