A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women.

Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer.

Is there visceral adipose tissue (VAT) intracellular hypercortisolism in human obesity?

The fact that obesity is a prominent feature of Cushing's syndrome (systemic hypercortisolism of adrenocortical origin) stimulated a 40-year search for evidence of systemic hypercortisolism in human obesity. That search has failed to find such evidence. For the past 15 years, however, studies have been done to evaluate a possible alternative type of hypercortisolism in obesity, namely visceral adipose tissue (VAT) intracellular hypercortisolism.

Role of androgen excess in the development of estrogen receptor-positive and estrogen receptor-negative breast cancer.

The androgen-excess theory posits a central role of androgens in promoting breast cancer development. At first glance, this appears to contradict the currently accepted central role of estrogens in this process, but as we will show, the apparent contradiction is not a real one. In the present article, we review the mechanisms by which androgen excess may stimulate cancer growth in different subsets of estrogen receptor-positive and estrogen receptor-negative tumors.

Obesity and cortisol status.

The fact, that obesity is a prominent feature of hypercortisolism (Cushing's syndrome) has stimulated investigation on the possible existence of the reverse relationship, namely that hypercortisolism is a feature of obesity. We have reviewed half a century of literature on this question, and have found out the following: (1) Hypercortisolism can exist in two forms: systemic hypercortisolism, in which there is an overall bodily excess of cortisol, and tissue, or intracellular, hypercortisolism, in which there is increased intracellular concentration of cortisol without an overall bodily excess. (2) There are two parameters of systemic hypercortisolism: CPR and plasma cortisol concentration.

Inpatient intervention in an indigent, minority population with uncontrolled diabetes.

Objective: To study whether a program of brief, intensive, inpatient intervention could improve glycemic control in an indigent, minority population with uncontrolled diabetes unresponsive to outpatient treatment.

Methods: Patients with uncontrolled diabetes unresponsive to treatment in our outpatient Diabetes Clinic were admitted to our inpatient Diabetes Unit, where their care was directed by the Diabetes Team (an attending diabetologist, an endocrinology fellow, two nurses, and two nutritionists). Of 108 patients admitted, data were available for 96.

Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone.

Studies from this laboratory have shown that obese men have elevated serum estrogen levels and diminished levels of follicle-stimulating hormone (FSH) and free and total testosterone, all in proportion to their degree of obesity. The decreases in testosterone and FSH constitute a state of hypogonadotropic hypogonadism (HHG), and we have hypothesized that it results from feedback suppression of the pituitary by the elevated estrogen levels. We tested this hypothesis by lowering the serum estrogens of 6 health obese men (body mass index [BMI], 38 to 73) by administering the aromatase inhibitor testolactone (1 g daily for 6 weeks).

Sex difference in the effect of obesity on 24-hour mean serum gonadotropin levels.

To determine the effect of obesity on serum gonadotropin levels and any possible sex difference in the effect, we measured the 24-hour mean serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations in 62 healthy men with Body Mass Index (BMI) ranging from 20 - 94 and 61 healthy, regularly cycling women with BMIs ranging from 19 - 76. We also measured free testosterone (T) and estradiol (E2) in these subjects. There was a significant negative correlation between serum FSH and BMI in men: FSH(IU/L) = 49.

Influence of postmenopausal hormone replacement therapy on an estrogen metabolite biomarker of risk for breast cancer.

Whether postmenopausal hormone-replacement therapy (HRT) increases the risk of breast cancer remains controversial, despite numerous epidemiological studies. We approached the question from a biochemical rather than an epidemiological direction - we hypothesized that if estrogen administration increases the risk of breast cancer, it should also alter a known estrogen biomarker of risk towards what has been observed in patients who already have breast cancer. The specific biomarker we studied was the ratio of the urinary excretion of two principal estradiol metabolites, 2-hydroxyestrone and 16 alpha-hydroxyestrone, which is markedly decreased in women with breast cancer and women with familial risk for breast cancer.

Relationship of endogenous levels of sex hormones to cognition and depression in frail, elderly women.

Neuropsychological evaluations and sex hormone assays for 188 elderly, female nursing home residents (mean age: 87.8 years; standard deviation: 7.0 years) revealed inverse relationships for dehydroepiandrosterone (DHEA) blood levels and cognition scores based on the Mini-Mental State Exam and the Test for Severe Impairment, as well as for scores of the Immediate Recall, Copy, and Recognition tests of the Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R; VR).

Relationships of sex hormone levels to dependence in activities of daily living in the frail elderly.

Objectives: We undertook this nursing home study in order to determine the relationships between dependency in activities of daily living (ADL) and blood levels of estrone, testosterone, androstenedione, and dehydroepiandrosterone (DHEA). Little is known about this issue.

Methods: cross-sectional study of 370 nursing home residents.

Does postmenopausal estrogen administration increase the risk of breast cancer? Contributions of animal, biochemical, and clinical investigative studies to a resolution of the controversy.

Despite nearly six decades of epidemiological studies, meta-analyses, and reviews, there is still considerable controversy in the literature about the question, does postmenopausal estrogen administration increase the risk of breast cancer? In an effort to resolve the controversy, a number of animal, biochemical, and clinical investigative studies in this field have been reviewed. The following summary formulation is proposed: 1. Administration of estrogen is inherently capable of promoting the growth of breast cancer, and therefore of increasing the incidence of clinical breast cancer.

Can (99m)technetium methylene diphosphonate bone scans objectively document costochondritis?

Study Objectives: To determine whether bone imaging with 99mTc methylene diphosphonate is a specific method of making the diagnosis of costochondritis in patients with chest pain who rule out for myocardial infarction.

Design: Nonblinded prospective controlled study in 20 patients and 10 control subjects.

Setting: Inpatient medical service of a tertiary teaching hospital.

Testicular dysfunction in human immunodeficiency virus-infected men.

This review pertains to gonadal function in men with human immunodeficiency virus (HIV) infection, who often exhibit clinical and biochemical evidence of hypogonadism. Hypogonadotropic hypogonadism appears to be the most commonly encountered abnormality, although complete anterior pituitary insufficiency and primary gonadal failure have been reported. Levels of sex hormone-binding globulin (SHBG) are either unchanged or increased.

Impact of endocrine and diabetes team consultation on hospital length of stay for patients with diabetes.

Purpose: To determine whether consultation by an individual endocrinologist or by a multidisciplinary diabetes team (endocrinologist, diabetes nurse educator, and registered dietitian) can impact length of hospital stay of patients with diabetes.

Patients And Methods: Hospital stays of consecutive patients with a principal diagnosis of diabetes were compared. Forty-three patients were seen by an individual endocrine consultant and 27 were managed by the internist alone.

Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women.

The 24-h mean plasma concentration of total testosterone (T) was measured in 33 healthy, regularly cycling, nonobese women between 21 and 51 yr of age. Percent free T was measured in 17 of them. Plasma dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were measured in 24 of them, and the DHEA-to-T and DHEAS-to-T ratios were calculated.

Hormonal profiles in women with breast cancer.

The literature findings on endogenous hormonal profiles in women with breast cancer are reviewed in detail. It is concluded that four sets of findings are valid: (1) diminished adrenal androgen production, probably genetic, in women with premenopausal breast cancer; (2) ovarian dysfunction (luteal inadequacy plus increased testosterone production) in breast cancer at all ages; (3) increased 16 alpha-hydroxylation of estradiol in breast cancer at all ages; and (4) evidence that prolactin is a permissive risk factor for breast cancer, and that the pregnancy-induced decrease in prolactin levels may account for the protective effect of early pregnancy against breast cancer.

The relationship between serum levels of insulin and sex hormone-binding globulin in men: the effect of weight loss.

It is known that there is an inverse relationship between the serum levels of insulin and sex hormone-binding globulin (SHBG) in women, but the relationship in men has not been reported. It is not known whether changes in the one cause changes in the other, or whether they change in opposite directions in response to some third factor. Because obesity raises insulin levels and lowers SHBG levels in both sexes, we proposed to study the cause-effect question by determining whether the relationship between changes in SHBG and insulin levels during active weight loss.

Abnormal production of androgens in women with breast cancer.

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.

A perspective on the hormonal abnormalities of obesity: are they cause or effect?

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.

A randomized double-blind crossover study of the antiobesity effects of etiocholanedione.

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.

Biological and endocrinological insights into the possible breast cancer risk from menopausal estrogen replacement therapy.

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).