A further advance was made in 1952 when it was shown (14) that the administration of cortisone to patients in relapse after conventional anti-androgenic measures can cause some regression of the disease; adrenalectomy was not performed in these men. Such relief of symptoms is brief, being measurable in a few months only.

The level of 17-ketosteroids (46) in the urine of patients with cancer of the prostate is well below that for normal males of a younger age. Castration causes a prompt decrease in the excretion of androgenic substances, as determined by biological methods (10), and an increase of urinary gonado-trophins (10, 46).

Birke, Franksson, and Plantin (2) studied the urinary excretion of steroids in cancer of the prostate in two patients prior to orchiectomy and in ten patients after this intervention. Oral administration of cortisone acetate produced diminution of the urinary excretion of androsterone and etio-cholanolone in the patients with intact testes. Cortisone therapy after orchiectomy resulted in complete disappearance of these compounds from the urine in nine cases, while in a tenth case these metabolites persisted although in greatly decreased amount.

Mammary Cancer Ovariectomy

Beatson (1) discovered that mammary cancer can be forced to regress by excision of the ovaries. The working hypothesis arose from reflection on the mechanism of lactation in farm animals and the similarity between "fatty degeneration" in a tumor and the formation of milk by the mammary gland. Beatson stated, "We must look in the female to the ovaries as the seat of the existing cause of carcinoma, certainly of the mamma, in all probability of the female generative organs generally, and possibly of the rest of the body."

The regression of mammary cancer can be profound; remission occurs in approximately 20 per cent of mammary cancers.1

Orchiectomy

While engaged in a study of induced hormonal imbalance on the course of advanced mammary cancer in clinical cases, Farrow and Adair (6) observed that orchiectomy was followed by regression of the neoplasm in a male, age 72 years. Beneficial results of great magnitude have followed orchiectomy (28, 50, 51).

Adrenalectomy

The hypothesis leading to adrenalectomy in mammary cancer is that the human adrenal gland can secrete sufficient quantities of growth-promoting steroids to maintain dependent neoplasms. Here are the basic theoretical considerations which led to the introduction (16, 26) of adrenalectomy: (a) Steroids which promote growth of the secondary sex structures are elaborated by the adrenal cortex in patients with tumors or hyperplasias of this structure. (6) Steroids of this kind are produced in certain women after the menopause, (c) Orchiectomy, in patients with cancer of the prostate, generally induces a rise (46) in the amount of 17-ketosteroids excreted in the urine, (d) Woolley el al. (53) discovered that gonadectomy performed at an early age in susceptible strains of mice leads to hyperplasias and neoplasms of the adrenal cortex and that these lesions often secrete steroids which induce growth in the mammary gland, (e) In force-fed ovariectomized rats, adrenalectomy retards (30) the growth of Walker carcinoma 256.

Maintained adequately with steroid substitution therapy, the adrenalectomized patients have a healthy appearance, are not incapacitated, and are able to engage in all their usual activities. When the patient is on an adequate hormonal maintenance, the glucose tolerance test (17), insulin tolerance test, and water diuresis test are normal and similar to those in the pre-operative period. In postmenopausal women, adrenalectomy frequently is followed by the recrudescence of menopausal symptoms which had been dormant for some years; the hot flushes have persisted more than 5 years in patients who originally had widespread active mammary cancer. In such patients after adrenalectomy there is a pronounced rise in titer of gonadotrophins in the urine above pre-adrenalectomy levels.

1 The statistical effects of treatments of advanced mammary cancer have been presented elsewhere (15).

It is certain that bilateral adrenalectomy without the removal of the ovaries can induce profound and prolonged regression (12, 17, 19) of disseminated mammary cancer. The first woman to be subjected to this operation, a women in the terminal stage of mammary cancer, is in good health after 5 years. Cade (4) states: "In a proportion of cases both subjective and objective improvement has been achieved which has never been accomplished before by any other method of treatment." It cannot be denied that hormones from either the ovaries or the adrenals can sustain mammary cancer in the human. Adrenalectomy has also caused regression of cancer of the breast in the human male (17).

However, the combined removal of the ovaries and the adrenals does not always lead to the complete atrophy of the human mammary gland. The formation of milk, in any amount, by the breast is the criterion of functional maturity of mammary epithelium, and this can be tested in intact persons. The administration of lactogenic hormone for 7 days induced the secretion of milk in certain patients (20) with mammary cancer; the induction of lactation is especially impressive in aged nullip-arous women, and indicates that a potential secretory capacity can be retained by the human mammary gland in senility. In some of these women lactation, so induced, ceased abruptly following removal of the ovaries and adrenals, while in others it persisted for many months despite these operations. It is apparent that the human mammary gland can remain in a mature functional state in the absence of the principal steroid-producing glands.

Hypophysectomy

The pituitary gland was removed (47) from a man with malignant melanoma, but regression of the tumor did not occur.

Hypophysectomy was introduced as a therapeutic measure in mammary cancer by Luft, Olivecro-na, and Sjogren (37). The perspicacity, tenacity of purpose, and the skill of the Stockholm workers are admirable in their approach to this problem. The rationale for this procedure in mammary cancer is the profound atrophy of the accessory sex structures which follows removal of the pituitary; in the rat (22) and dog (25) this atrophy is more profound than that following adrenalectomy and ovariectomy. These animals deprived of the pituitary require no substitution therapy. Hypophysec-tomized man develops adrenal insufficiency (43) unless treated with appropriate steroids, and myxedema usually appears in a few weeks after hypophysectomy.

It is certain that remission of mammary cancer follows hypophysectomy in some cases (86, 45). Hypophysectomy induced objective remissions in 21 of 41 patients with advanced cancer (43). Pearson et al. (43) have reported that certain women, who had undergone castration and adrenalectomy earlier, received additional objective improvement in the form of regression of the carcinoma from hypophysectomy which was performed later.

Pearson et al. (44) have presented evidence to indicate that beef pituitary growth hormone caused an increased excretion of calcium in the urine of an hypophysectomized woman with breast cancer; but it is not yet certain that breast cancers are directly dependent on protein hormones.