Aging in men is accompanied by a progressive, but individually variable decline of serum testosterone production, more than 20% of healthy men over 60 yr of age presenting with serum levels below the range for young men. Albeit the clinical picture of aging in men is reminiscent of that of hypogonadism in young men and decreased testosterone production appears to play a role in part of these clinical changes in at least some elderly men, the clinical relevancy of the age-related decline in sex steroid levels in men has not been unequivocally established. In fact, minimal androgen requirements for elderly men remain poorly defined and are likely to vary between individuals. Consequently, borderline androgen deficiency cannot be reliably diagnosed in the elderly, and strict differentiation between “substitutive” and “pharmacological” androgen administration is not possible. To date, only a few hundred elderly men have received androgen therapy in the setting of a randomized, controlled study, and many of th...

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The decline of androgen levels in elderly men and its clinical and therapeutic implications.

Androgen receptor (AR) is a member of the steroid hormone receptor family of molecules. AR primarily is responsible for mediating the physiologic effects of androgens by binding to specific DNA sequences that influence transcription of androgen-responsive genes. The three-dimensional structure of the AR ligand-binding domain has shown it is similar to other steroid hormone receptors and that ligand binding alters the protein conformation to allow binding of coactivator molecules that amplify the hormone signal and mediate transcriptional initiation. However, AR also undergoes intramolecular interactions that regulate its interactions with coactivators and influence its activity. A large number of naturally occurring mutations of the human AR gene have provided important information about AR molecular structure and intermolecular interactions. AR is also a critical mediator of prostate cancer promotion, conferring growth signals to prostate cancer cells throughout the natural history of the disease. Late-stage prostate cancer, unresponsive to hormonal deprivation, sustains AR signaling through a diverse array of molecular strategies. Variations in the AR gene may also confer genetic predisposition to prostate cancer development and severity. Further understanding of AR action and new strategies to interfere with AR signaling hold promise for improving prostate cancer therapy.

Molecular Biology of the Androgen Receptor

Noninvasive assessment of bone mineral and structure: state of the art.

Background: Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted. Purpose: We conducted a prospective, nested casecontrol study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer. Methods: Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3a-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 °C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided. Results: No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all /> 2.5 ng/mL) were excluded from the analyses. Conclusions: High levels of circulating testosterone and low levels of SHBG—both within normal endogenous ranges—are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor. Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk. [J Natl Cancer Inst 1996;88:1118-26] A longstanding and diverse body of evidence suggests that sex steroids, particularly androgens, play a role in the etiology of prostate cancer. Androgens are essential for normal growth and maintenance of the prostate, stimulate the proliferation of human prostate cancer cells in vitro, and, when given in large amounts, can produce prostate cancer in rodents {12)- In addition, eunuchs rarely develop prostate cancer, and androgen ablation frequently causes prostate tumors to regress (3). In contrast, a reduced risk of prostate cancer has been associated with certain hyperestrogenic states (4), and estrogen therapy has a palliative effect in advanced cases (J). These observations on extreme variations in sex-steroid exposure add credibility to the hypothesis that prostate cancer risk is also related to the smaller contrasts in levels of androgens and estrogens that are found within the normal endogenous range (7). However, studies com

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Prospective Study of Sex Hormone Levels and Risk of Prostate Cancer

Objective: To determine the relation between estrogen replacement therapy and fractures Design: Prospective cohort study Setting: Four clinical centers in Baltimore County, Maryland; Minneapolis,

Estrogen Replacement Therapy and Fractures in Older Women

Serum samples were obtained from 6860 men during their study examination from 1971 to 1975. After a surveillance period of about 14 years, 98 incident cases of prostate cancer were identified. Their stored sera and that of 98 matched controls from the study population were tested for the following: testosterone, dihydrotestosterone, estrone, estradiol, and sex hormone globulin. There was a suggestion that serum dihydrotestosterone levels were lower and the testosterone/dihydrotestosterone ratios were higher in the prostate cancer cases compared with their controls. However, none of these associations or that of the other hormones was strongly significant. Further work is needed to clarify the relationship between sex hormones and prostate cancer risk.

Prediagnostic serum hormones and the risk of prostate cancer.

Prediagnostic Serum Hormones and the Risk of Prostate Cancer

WILLIAMS, JUDITH ANN, JOHN WAGNER, RICHARD WASNICH, and LANCE HEILBRUN. The effect of long-distance running upon appendicular bone mineral content. Med. Sci. Sports Exerc., Vol. 16, No. 3, pp. 223–227, 1984. The bone mineral content (BMC) of the os calcis was measured for a group of 20 male runners at the beginning and the end of a 9-month marathon training program. The participants had no previous running experience. The percent change in bone mineral in the runners was compared with that of a control group of male subjects of the same age range (38–68 yr). The consistent runners showed a significant increase in bone mineral over that of the controls; the increase was not significant for inconsistent runners. The data suggest that those runners with longer, more consistent distances gained more bone mineral than those with shorter, more inconsistent distances.

The effect of long-distance running upon appendicular bone mineral content.

Differential effects of thiazide and estrogen upon bone mineral content and fracture prevalence

Techniques for measuring bone mineral content (BMC) were developed for the purpose of providing an objective and noninvasive indication of bone strength (or lack thereof) and fracture risk, to the extent that strength relates to bone mass. As such, BMC measurements could help to (1) identify those who are most likely to experience nonviolent fractures in the future and who would therefore benefit most from preventive measures, (2) improve their treatment compliance, and (3) monitor the efficacy of treatments intended to reduce bone loss. All these potential uses require that the measurement provide an indication of fracture risk (probability of fractures).



During the past 10–15 years there have been conflicting reports regarding the association of reduced BMC with nonviolent fractures. Some authors have criticized the usefulness of BMC measurements, whereas others have questioned the value of one or more techniques. However, the epidemiology of osteoporosis has only recently been subjected to rigorous study. The use of appropriate statistical methods for relating fracture risk to bone mass may be no more widely practiced in osteoporosis epidemiology today than it was for studying risk factors (e.g., blood pressure) in cardiovascular epidemiology during the 1960s.



The intent of this article is to explore three areas that may have contributed to controversy in the study of bone mass and fracture occurrence: (1) perspective of the investigators, (2) study design, and (3) analytic methodology. Although the focus of this paper is on bone mass, these considerations are equally applicable to some investigations of other risk factors for osteoporotic fractures (e.g., bone architecture, bone turnover and loss rate, or biochemical markers of bone loss).

Lance K. Heilbrun

Papers

Prediagnostic serum hormones and the risk of prostate cancer.

Prediagnostic Serum Hormones and the Risk of Prostate Cancer

The effect of long-distance running upon appendicular bone mineral content.

Differential effects of thiazide and estrogen upon bone mineral content and fracture prevalence

Perspectives: methodologic issues in evaluating risk factors for osteoporotic fractures.