Hormonal Regulation Prostate

The prostate gland is a solid, rounded, heart-shaped organ positioned between the neck of the bladder and the urogenital diaphragm (Fig. 92-1). The normal prostate is composed of acinar secretory cells arranged in a radial shape and surrounded by a foundation of supporting tissue. The size, shape, or presence of acini is almost always altered in the gland that has been invaded by prostatic carcinoma. Adenocarcinoma, the major

22 23

pathologic cell type, accounts for more than 95% of prostate cancer cases. ' Much rarer tumor types include small-cell neuroendocrine cancers, sarcomas, and transitional cell carcinomas.

Prostate cancer can be graded systematically according to the histologic appearance of the malignant cell and then grouped into well, moderately, or poorly differen-23 24

tiated grades. ' Gland architecture is examined and then rated on a scale of 1 (well differentiated) to 5 (poorly differentiated). Two different specimens are examined, and the score for each specimen is added. Groupings for total Gleason score are 2 to 4 for well-differentiated, 5 or 6 for moderately differentiated, and 7 to 10 for poorly differentiated tumors. Poorly differentiated tumors grow rapidly (poor prognosis), while well-differentiated tumors grow slowly (better prognosis).

Lymphatic Drainage Prostate
FIGURE 92-1. The prostate gland. (From DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill, 2005: 1856.)

Metastatic spread can occur by local extension, lymphatic drainage, or hematogen-


ous dissemination. ' Lymph node metastases are more common in patients with large, undifferentiated tumors that invade the seminal vesicles. The pelvic and abdominal lymph node groups are the most common sites of lymph node involvement (Fig. 92-1). Skeletal metastases from hematogenous spread are the most common sites of distant spread. Typically, the bone lesions are osteoblastic or a combination of os-teoblastic and osteolytic. The most common site of bone involvement is the lumbar spine. Other sites of bone involvement include the proximal femurs, pelvis, thoracic spine, ribs, sternum, skull, and humerus. The lung, liver, brain, and adrenal glands are the most common sites of visceral involvement, although these organs usually are not involved initially. About 25% to 35% of patients will have evidence of lymphangitic or nodular pulmonary infiltrates at autopsy. The prostate is rarely a site for metastatic involvement from other solid tumors.

Normal growth and differentiation of the prostate depends on the presence of androgens, specifically DHT.25,26 The testes and the adrenal glands are the major sources of circulating androgens. Hormonal regulation of androgen synthesis is me diated through a series of biochemical interactions between the hypothalamus, pituitary, adrenal glands, and testes (Fig. 92-2). Luteinizing hormone-releasing hormone (LHRH) released from the hypothalamus stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. LH complexes with receptors on the Leydig cell testicular membrane and stimulates the production of testosterone and small amounts of estrogen. FSH acts on the Sertoli cells within the testes to promote the maturation of LH receptors and to produce an androgen-binding protein. Circulating testosterone and estradiol influence the synthesis of LHRH, LH, and FSH by a negative feedback loop operating at the hypo-

thalamic and pituitary level. Prolactin, growth hormone, and estradiol appear to be important accessory regulators for prostatic tissue permeability, receptor binding, and testosterone synthesis.

Hormone Found The Prostate Gland

FIGURE 92-2. Hormonal regulation of the prostate gland. ACTH, adrenocorticotropic hormone; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; PROL, prolactin; R, receptor. (From DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill, 2005: 1856.)

FIGURE 92-2. Hormonal regulation of the prostate gland. ACTH, adrenocorticotropic hormone; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; PROL, prolactin; R, receptor. (From DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill, 2005: 1856.)

Testosterone, the major androgenic hormone, accounts for 95% of the androgen concentration. The primary source of testosterone is the testes; however, 3% to 5%

of the testosterone concentration is derived from direct adrenal cortical secretion of

OA O/i testosterone or C19 steroids such as androstenedione. -

In early stage prostate cancers, aberrant tumor cell proliferation is promoted by the presence of androgens. For these tumors, blockade of androgens induces tumor regression in most patients. Hormonal manipulations to ablate or reduce circulating androgens can occur through several mechanisms25,26 (Table 92-2). The organs responsible for androgen production can be removed surgically (orchiectomy, hypo-physectomy, or adrenalectomy). Hormonal pathways that modulate prostatic growth can be interrupted at several steps (see Fig. 92-2). Interference with LHRH or LH (by estrogens, LHRH agonists, progesterones, and cyproterone acetate) can reduce testosterone secretion by the testes. Estrogen administration reduces androgens by directly inhibiting LH release, by acting directly on the prostate cell, or by decreasing free androgens by increasing steroid-binding globulin levels.24-26

Table 92-2 Hormonal Manipulations in Prostate Cancer

Hormonal Manipulations in Prostate Cancer

Androgen source ablation Orchiectomy Adrenalectomy Hypo phy sec LOriny LHRH or LH inhibition Estrogens LHRH agon ¬°its Progesterone^' Cyp rote rone acetate'1 Gonadotropin receptor antagonists Abarelix DegaVelix Androgen synthesis inhibition Aminogiutethirnido Ketocgnazole Progeste rones5

111, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone.

,JM1noi mechanisms of action, investigational compounds of use.

Isolation of the naturally occurring hypothalamic decapeptide hormone LHRH has provided another group of effective agents for advanced prostate cancer treatment. The physiologic response to LHRH depends on both the dose and the mode of administration. Intermittent pulsed LHRH administration, which mimics the endogenous release pattern, causes sustained release of both LH and FSH, whereas high dose or continuous IV administration of LHRH inhibits gonadotropin release due to receptor downregulation.19 Structural modification of the naturally occurring LHRH and

Antlandrogens Rutamide Bicalutamide Niiutamide Cyproterone acetate'5 Progesterones 5-a-reductase inhibition Finasteride Dutasteride"

innovative delivery have produced a series of LHRH agonists that cause a similar

downregulation of pituitary receptors and a decrease in testosterone production.

Androgen synthesis can also be inhibited in the testes or adrenal gland. Aminoglu-tethimide inhibits the desmolase-enzyme complex in the adrenal gland, thereby preventing the conversion of cholesterol to pregnenolone. Pregnenolone is the precursor substrate for all adrenal-derived steroids, including androgens, glucocorticoids, and mineralo corticoids. Ketoconazole, an imidazole antifungal agent, causes a dose-related reversible reduction in serum cortisol and testosterone concentration by inhib-

iting both adrenal andtesticular steroidogenesis. Megestrol is a synthetic derivative of progesterone that exhibits a secondary mechanism of action by inhibiting the synthesis of androgens. This inhibition appears to occur at the adrenal level, but circulating levels of testosterone also are reduced, suggesting that inhibition at the testicular level also may occur.28

Antiandrogens inhibit the formation of the DHT-receptor complex and thereby in-

terfere with androgen-mediated action at the cellular level. Megestrol acetate, a pro-

gestational agent, also is available and has antiandrogen actions. Finally, the con-

version of testosterone to DHT may be inhibited by 5-a-reductase inhibitors.

In advanced stages of the disease, prostate cancer cells may be able to survive and proliferate without the signals normally provided by circulating androgens.29 When this occurs, the tumors are no longer sensitive to therapies that are dependent on androgen blockade. These tumors are often referred to as hormone refractory or androgen independent.

clinical presentation and diagnosis

Prior to the implementation of routine screening, prostate cancers were frequently identified on the investigation of symptoms including urinary hesitancy, retention, painful urination, hematuria, and erectile dysfunction. With the introduction of screening techniques, most prostate cancers are now identified prior to the development of symptoms. 0

The information obtained from the diagnostic tests is used to stage the patient. There are two commonly recognized staging classification systems (Table 92-3). The formal international classification system (tumor, node, metastases; TNM), adopted by the International Union Against Cancer in 1974, was last updated in 2002. The AUA classification is the most commonly used staging system in the United States (Table 92-4). Patients are assigned to stages A through D and corresponding sub-

categories based on the size of the tumor (T), local or regional extension, presence of involved lymph node groups (N), and presence of metastases (M). Some studies

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