Health and Prostate

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The response of prostate cancer to androgen ablation is among the most reproducible, durable, and profound of any systemic therapy for a solid tumor. The early and frequent descriptions of the immediate relief of bone pain from metastatic prostate cancer after castration do not diminish the marvel of observing this phenomenon firsthand. As is the case with many paradigm-shifting observations, endocrine therapy was based on a simple hypothesis. Described as a “biological syllogism” (Huggins, 1947), the idea had a major premise: In many instances a malignant prostatic tumor is an overgrowth of adult epithelial cells; a minor premise: All known types of adult prostatic epithelium undergo atrophy when androgen hormones are greatly reduced in amount; and a conclusion: Therefore, significant improvements should occur in the clinical condition of patients with far advanced prostate cancer subjected to castration.

It had been known for at least a century that prostatic epithelium undergoes atrophy after castration (Hunter, 1840). The breakthrough in Huggins’ hypothesis was the recognition that benign prostatic epithelium and prostate carcinoma are biochemically analogous and respond in a similar fashion to androgen ablation. With emphasis on the importance of basic observations — “The evidence for the facts which represent the premises was obtained entirely in the laboratory” (Huggins, 1944) — studies on acid phosphatase provided the crucial link between benign and malignant prostate cells. Large amounts of acid phosphatase were found in the prostate glands of men and monkeys (Kutscher and Benjamin, 1935), in primary and metastatic prostate cancer (Gutman et al, 1936), and the levels increased with androgen administration (Gutman and Gutman, 1938). Serum levels of acid phosphatase were increased in men with disseminated prostate cancer (Gutman and Gutman, 1938; Barringer and Woodard, 1938). With localization of the enzyme to prostatic epithelial cells and primary and metastatic prostatic cancer cells (Gomori, 1939), the stage was set for Charles Huggins, R. E. Stevens, and Clarence V. Hodges to test the hypothesis in men with prostate cancer.

Despite negative results of castration in two men with prostate cancer reported by Young (1936), a series of 21 consecutive patients with locally advanced or metastatic prostate cancer underwent surgical castration at the University of Chicago. “A noticeable improvement occurred in the clinical status of all but three patients,” with weight gain, resolution of anemia, and improvement in pain (Huggins et al, 1941). Other reported consequences of castration, a large appetite for food, loss of sexual desire and penile erections, and hot flashes, remain the common side effect profile of androgen ablation therapy today. Although this report was the first to describe the benefits of androgen ablation in the treatment of prostate cancer, it also created a new disease state, androgen-refractory prostate cancer.

In considering these “failure cases” (Huggins, 1942), it was found that those with small testes at time of castration had a poor prognosis, the first description of a more ominous prostate cancer arising in the hypogonadal man. After castration, rises in the levels of urinary 17-ketosteroids, a major metabolite of the adrenal gland, led to the hypothesis that adrenal androgens contributed to subsequent disease progression. The first reports of bilateral adrenalectomies for the treatment of hormone-refractory disease (Huggins and Scott, 1945) are described later in a somewhat defensive manner (Scott, 1954), perhaps because of the lack of response and high perioperative mortality. Hypophysectomy and pituitary irradiation (Murphy and Schwippert, 1951) were also investigated. Unfortunately, the benefits of surgical castration were soon equaled by the tenacity and inevitable progression of androgen independence, a state still synonymous with the lethal form of the disease. Even in accepting the Nobel Prize (1966) for this work, Charles Huggins admitted, “Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.”

Direct ablation of the source of androgen, like surgical castration, is only one of the perturbations of the hypothalamic-pituitary-gonadal axis developed to treat prostate cancer. The first central inhibition of the axis exploited the potent negative feedback of estrogen on luteinizing hormone (LH) secretion. It is now known that estradiol is a thousand-fold more potent at suppressing LH and follicle-stimulating hormone (FSH) secretion by the pituitary compared with testosterone (Swerdloff and Walsh, 1973). The effects of estrogen on the male phenotype, namely, regression of androgen-sensitive tissues, have been exploited, historically, to produce the effects of castration without surgical removal of the testes. For example, capons (neutered roosters) were produced by placement of estrogen pellets in the neck of the bird rather than by castration (Scott, 1954). Among the various estrogenic compounds, diethylstilbestrol (DES) has been most widely studied and used. Early studies indicating improved survival in men treated with both surgical castration and continuous DES (Nesbit and Baum, 1951) have not held up under further scrutiny, but the equivalence of DES compared with castration has. Indeed, given the effectiveness of the considerably less expensive estrogenic compounds, it is unfortunate that the associated cardiovascular toxicity has limited their widespread use.

The first isolation of luteinizing hormone–releasing hormone (LHRH) by Andrew Schally and colleagues (1971) required the hypothalami of 165,000 pigs to obtain 800 μg of the 10–amino acid peptide. This Nobel Prize (1977) – winning work led to the development of synthetic LHRH analogs, peptides generated by substituting d–amino acid residues at certain locations in the natural compound, creating both LHRH agonists and LHRH antagonists. After an initial surge in LH release (and testosterone levels) in response to LHRH agonists, the loss of phasic pituitary stimulation results in plummeting LH levels. In the absence of LH, Leydig cell production of testosterone drops to castrate levels. Initially, the clinical utility of these agents was hampered by their short half-life, requiring daily injections to maintain suppression of the hypothalamic-pituitary axis. The generation of long-acting depot preparations, lasting several months, has established LHRH agonists as the dominant treatment in hormone therapy for prostate cancer. Recently, direct LHRH antagonists have been developed for clinical use. Lacking agonist action, these agents do not produce the surge in LH and testosterone. It is interesting that both classes of compounds were developed within a few years of the discovery of LHRH, and yet it took decades to develop clinically useful agents.

Moving beyond strategies targeting the hypothalamicpituitary axis, interruption of ligand-receptor interaction with antiandrogenic compounds is another way to reduce androgen action in prostate cancer. All antiandrogens inhibit androgen action by binding to the androgen receptor in a competitive fashion and are classified as steroidal or nonsteroidal. The steroidal antiandrogen cyproterone acetate is a derivative of 17-hydroxyprogesterone and suppresses LH release (and testosterone production) through its central progestational inhibitory effects. Therefore, steroidal antiandrogens block androgen action at the cellular level and also reduce circulating testosterone levels, leading to the classic side effects of hypogonadal state, such as loss of libido and erectile dysfunction. On the other hand, the nonsteroidal antiandrogens have no antigonadotropic effects and simply block androgen receptors, including those in the hypothalamic-pituitary axis. By blocking the normal inhibiting feedback of testosterone, the antiandrogens produce a paradoxical increase in LH and testosterone. Although this maintenance of testosterone can preserve potency, the peripheral conversion of this excessive testosterone to estrogen can lead to painful gynecomastia.

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