Faculty Bibliography

Two long and broad streams of medical literature, from the 1950's to date, have established the existence of two unrelated abnormalities of androgen production in women with breast cancer. One is the genetically determined presence of subnormal production of adrenal androgens (i.e. DHEA and DHEAS) in women with premenopausal breast cancer and their sisters, who are at increased risk for breast cancer. The other is excessive production of testosterone, of ovarian origin, in subsets of women with either premenopausal or postmenopausal breast cancer and women with atypical breast-duct hyperplasia, who are at increased risk for breast cancer; along with the hypertestosteronism, there is frequently chronic anovulation in the premenopausal patients. The combination of ovarian hypertestosteronism and chronic anovulation is characteristic of the polycystic ovary syndrome and is also frequently seen in women with abdominal ("android") obesity; both PCOS and abdominal obesity are known to be characterized by high risk for postmenopausal cancer. The elevated testosterone levels and the increased levels of insulin, IGF-I, and IGF-II that are seen in PCOS and abdominal obesity could favor the development of breast cancer in several ways, all of which have been demonstrated experimentally: binding of testosterone to cancer cells bearing testosterone receptors, with direct stimulation; intratissular aromatization of testosterone to estradiol, with stimulation of estrogen-sensitive cells; stimulation of the production of epithelial growth factor (EGF) by testosterone, with direct mitogenic effect of EGF on cancer cells; stimulation of aromatase by insulin and IGF-I; direct mitogenic stimulation of cancer cells by insulin, IGF-I, and IGF-II; and stimulation by IGF-I and IGF-II of the intratissular reduction of estrone to estradiol. Since PCOS is probably largely genetically determined, and abdominal obesity may also be, the hypertestosteronism of these conditions may represent a second genetically determined hormonal risk factor for breast cancer.

Etiocholanedione (ED), a natural metabolite of dehydroepiandrosterone, has antiobesity effects in animals when given orally and is nontoxic. We carried out a trial of oral ED in obese humans. In a 20-week randomized double-blind crossover study, 14 subjects lost significantly more weight and body fat during treatment with oral ED, 4 gm daily, than during placebo administration. Mean weight loss during ED administration was 2.8 +/- 5.5 kilograms, which was equivalent to 0.53 +/- 0.91 kilograms per week per 100 kilograms of body fat; mean weight change during placebo administration was essentially zero: +0.21 +/- 4.2 kg, or +0.04 +/- 0.74 kg/wk/100 kg body fat. The difference between the weight changes in the two periods was significant: for delta kg, P < 0.05; for delta kg/wk/100 kg body fat, P < 0.03. Densitometric measurement of body fat content showed that the mean weight loss coincided almost exactly with the mean decrease in fat content; thus, over the 10-week period of ED administration, the mean fat loss was about 5% of the initial body fat content. Three of the obese subjects had strikingly greater fat loss, about 18%, 19%, and 25% of the initial body fat content. There were no significant subjective or objective side effects of ED administration.

Studies in our laboratory and elsewhere have demonstrated numerous abnormalities of steroid and polypeptide hormone secretion in obesity: hyperestrogenemia and hypogonadotropic hypogonadism in obese men; diminished SHBG levels in both sexes; elevated free testosterone and free estradiol in obese women; PCOS-like gonadotropin and sex-hormone abnormalities in obese women; elevated serum insulin in both sexes; blunted stimulability of prolactin, growth hormone, and vasopressin in both sexes; and elevated basal levels and blunted stimulability and suppressibility of beta-endorphin in both sexes. All of these abnormalities have been clearly shown to be partly or completely reversible with weight loss, with the exception of the endorphin abnormalities. In that area, four out of the five studies reported show no reversibility with weight loss. Reversibility of nearly all the hormonal abnormalities of obesity (i.e., all but the hyperendorphinemia) by weight loss suggests that none of them is causative of obesity. Nevertheless, some of the reversible abnormalities may secondarily amplify the morbidity associated with obesity: the hyperinsulinemia may be related to the increased risk of hypertension, hyperlipidemia, coronary disease, and Type II diabetes; the elevated levels of free estradiol in obese women may be related to their increased risk of breast and endometrial cancer. The role of hyperendorphinemia in obesity clearly requires further investigation, since it is the only observed hormonal abnormality that appears to be non-reversible by weight loss, and also since there seems to be increased sensitivity to beta-endorphin in obesity. The possibility that endorphin abnormalities may be causal in obesity cannot be ruled out.

The question of whether estrogen therapy increases the risk of breast cancer is reviewed. Despite more than 60 epidemiological studies and several meta-analyses over a five-decade period, there is no consensus about the answer. At present, the majority of investigators agree that short-term or medium-term therapy (less than 10 years) poses no measurable risk; some, but not all, investigators feel that there is a modest risk with long-term therapy (more than 15 years). Even this semi-consensus is clouded by the startling and clear-cut finding of the largest ever epidemiological study, the Nurses Surveillance Study, that a small increase in risk with estrogen therapy occurred only in women who also ingested alcohol, itself a known risk factor for breast cancer; women who did not ingest alcohol were at no increased risk. Because virtually none of the other epidemiological studies has controlled for alcohol ingestion, the conclusions of all of them are placed in doubt. To try to shed light on this problem, the 60-year-old studies of Lacassagne et al. on the induction of breast cancer in mice by estrogens were reviewed. They found that the magnitude and timing of the inducing effect of estrogen depended on the spontaneous breast cancer incidence in the mouse strain studied: in no-incidence strains, no cancer was induced; in high-incidence strains, induction was rapid and universal; in low-incidence strains, only a low percentage of animals had cancer induced, and it required prolonged estrogen administration.(ABSTRACT TRUNCATED AT 250 WORDS)

The measurement called desirable body weight (DBW) was derived by actuaries to indicate that weight which is associated with the lowest mortality. Percent deviation from DBW has become a standard measure of fatness. A different obesity index, body mass index (BMI), is weight in kilograms divided by the square of height in meters. Many workers consider both measures inferior to the measurement of body fat content (BFC). We compared the three measures of fatness in 40 men aged 18-50 and 48 women aged 21-47, ranging from nonobese to extremely obese. Total BFC was determined by isotope dilution of 3H-labeled water. DBWs used were those listed in the US Air Force Examination Manual of 1971; these approximate the midpoint of the range of medium-frame values in the 1959 Metropolitan Life Insurance Tables, but have the advantage of providing a single value for each height. We found nearly perfect correlation (r = 0.99, p < 0.001) between BMI and percent deviation from DBW in both men and women ranging from 14% below to 305% above DBW. Correlations between percent deviation from DBW and total BFC were extremely high: 0.95 (p < 0.001) for the men and 0.94 (p < 0.001) for the women, essentially the same as correlations between BMI and BFC, which were 0.96 (p < 0.001) for the men and 0.95 (p < 0.001) for the women. It appears that the two technically simple weight-height indices, BMI and percent deviation from DBW, give just as accurate a measurement of fatness as the technically complex measurement of total BFC.(ABSTRACT TRUNCATED AT 250 WORDS)

To document the caloric intake of very obese persons and investigate the food choices and dietary composition that maintain severe obesity, we studied the self-selected food intake required to maintain stable weight in two groups of very obese subjects: 11 inpatients with a mean weight 181% above desirable body weight and 35 outpatients with a mean weight 125% above desirable body weight. Qualitative and quantitative food intake were evaluated using records obtained on the hospital metabolic ward for the inpatients and using self-recorded food records for the outpatients. Absolute caloric intake in both groups was greater in proportion to the degree of obesity (deviation from desirable body weight); caloric intake per unit of lean body mass (kilocalories per gram urinary creatinine) was constant regardless of the degree of obesity and was essentially the same as that of normal nonobese persons. Food records indicated that the obese subjects maintained their high caloric intake by consuming mostly foods of high caloric density, with occasional binge eating. They largely avoided foods of low intrinsic energy density and modified-calorie foods, ie, foods with decreased fat, nonnutritive sweeteners, or fillers. By substituting foods of lower caloric density for usual food choices from the same food group, obese persons could decrease caloric intake by 20% and increase potential for notable weight loss.

The consequences of sleep deprivation and stress in residency training have not been quantified. In the course of assembling a control group for other studies, we unexpectedly observed a significant (P less than 0.005) and marked depression of serum testosterone levels in healthy male internal medicine residents (means = 11.8 +/- 1.1 nmol/L, n = 7) compared with other hospital personnel (means = 20.6 +/- 5.3 nmol/L, n = 18). Testosterone concentrations in the two groups were entirely nonoverlapping, while luteinizing hormone levels were not significantly different. We conclude that the stress of residency training leads to a quantifiable depression of gonadal function, and that gonadal steroid concentrations may be useful in evaluating measures intended to reduce that stress.

Because we had observed that smoking has a pronounced effect on serum progesterone levels, we reinvestigated in healthy nonsmokers the relative progesterone levels of men and follicular-phase women. Each of eight women had multiple measurements of serum progesterone during the follicular phase of a menstrual cycle (10 days through 3 days prior to the luteinizing hormone peak of that cycle), and the average of those values was taken to represent the basal progesterone level for that woman. Seven men had blood samples drawn at 20-minute intervals between 6:00 and 9:00 AM, through an indwelling venous catheter, and the average of those values was taken. The mean follicular-phase serum progesterone level in the women was 21.4 +/- 5.4 ng/dl and the mean level in the men was 18.1 +/- 3.1 ng/dl. The difference was not statistically significant. In view of this finding, we conclude that there is essentially no ovarian secretion of progesterone during the follicular phase of the menstrual cycle.