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...

https://www.hormonebalance.org/images/documents/Kauffman%2005%20TDS%20REVIEW%20ER.pdf

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

Publisher Summary This chapter discusses the serum transport of steroid hormones Steroid hormones are extensively bound to plasma proteins including albumin, corticosteroid binding globulin (CBG), and sex hormone binding globulin (SHBG) Because of its high concentration, albumin binding is important in determining the magnitude of the nonprotein bound or free fraction of a steroid in plasma The generally accepted model of steroid hormone action suggests that free steroid (in equilibrium with circulating binding proteins) diffuses passively through target cell membranes and binds to a soluble intracellular receptor The steroid-receptor complex apparently moves into the nucleus where it modifies the chromatin transcriptional activity which results in, among other things, altered levels of protein synthesis CBG has been differentiated from the intracellular glucocorticoid and progesterone receptors by its inability to bind synthetic glucocorticoids and progestins

The serum transport of steroid hormones.

Sex hormone-binding globulin (SHBG) production in humans has been thought to be stimulated by estrogens and thyroid hormone and inhibited by androgens. However, recent data indicate that SHBG production in vitro is stimulated by both androgens and estrogens. This study was designed to determine what other hormonal factors regulate SHBG production. Since hyperinsulinemia and hyperprolactinemia both occur in disease states in which low serum SHBG levels are found, the effects of insulin and PRL were compared to and/or studied in combination with estradiol (E2), T4, and testosterone (T) in a human hepatoma cell line (Hep G2). Hep G2 cells were grown to near confluence in medium including 10% fetal calf serum, and then 72-h experimental incubations were carried out which used only fetal calf serum-free medium. Compared to control incubations, both insulin (10(-8) mol/L) and PRL (10(-8) mol/L) decreased SHBG production from 65.0 +/- 0.6 (+/- SE) to 46.8 +/- 1.1 and 46.8 +/- 1.2 nmol/10(6) cells, respectively (P less than 0.01). Insulin also inhibited both E2 and T4-stimulated SHBG production. T stimulated SHBG production to the same degree as E2. Finally, both E2 and insulin significantly increased cell number, an important consideration when expressing the effect of a hormone on SHBG production in cultured cells. We conclude that insulin and PRL inhibit SHBG production and confirm that T4, T, and E2 stimulate SHBG production in vitro. These findings suggest that insulin and PRL may be important factors in the regulation of SHBG production in vivo.

Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin.

This study examined the prevalence of both basal and glucose-stimulated hyperinsulinemia and acanthosis nigricans (AN) as well as the relationship between insulin and androgen levels in hyperandrogenic women. Sixty-two women who had an elevation of 1 or more plasma androgen levels were studied. The results in these women, grouped for analysis on the basis of obesity and ovulatory status, were compared to those in 36 control women of similar ages and weights. The anovulatory hyperandrogenic women had the clinical and biochemical features of the polycystic ovary syndrome (PCO). Oral glucose tolerance tests were performed with measurement of glucose, insulin, sex hormone-binding globulin (SHBG), and total and non-SHBG-bound sex steroid levels. AN was present in 29% of the hyperandrogenic women, the majority of them obese. Fifty percent of obese PCO women had AN, but they did not otherwise differ from PCO women lacking this dermatological change. Only women with PCO had significant hyperinsulinemia independent of obesity, and obese PCO women with AN had the highest serum insulin levels. Plasma glucose values during the oral glucose tolerance test were significantly increased in obese PCO women independent of the presence of AN, and 20% of these women had frank impairment of glucose tolerance. Ovulatory hyperandrogenic women had normal insulin levels and glucose tolerance. Obese and nonobese women had different relationships between sex steroid and insulin levels; obese women had significant correlations between insulin and non-SHBG testosterone levels (r = 0.30; P less than 0.05), whereas nonobese women had significant correlations between insulin and FSH (r = 0.40; P less than 0.01), dehydroepiandrosterone sulfate (r = 0.33; P less than 0.05), and SHBG (r = 0.37; P less than 0.05) levels, suggesting that the mechanisms underlying the association between sex steroid and insulin levels are complex. These findings suggest that 1) only women with PCO have hyperinsulinemia independent of obesity; hyperinsulinemia is not a feature of hyperandrogenic states in general; 2) AN is a common finding in obese hyperandrogenic women, particularly those with PCO; 3) only obese PCO women are at risk for impairment of glucose tolerance, independent of the presence of AN, suggesting that the negative impact of PCO and obesity on insulin action is additive; and 4) PCO women with AN can be considered as a subgroup of PCO and do not appear to have a distinct endocrine disorder.

Characterization of Groups of Hyperaiidrogenic Women with Acanthosis Nigricans, Impaired Glucose Tolerance, and/or Hyperinsulinemia

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.

/pdf/androgen-receptor-structure-role-in-prostate-cancer-and-drug-4hfptgb67m.pdf

Androgen receptor: structure, role in prostate cancer and drug discovery

We examined the influence of numerous substances on the secretion of corticosteroid-binding globulin (CBG) and testosterone-estradiol binding globulin (TeBG) by a human hepatoma-derived cell line. Thyroxine, at physiologic concentrations, resulted in an increased secretion of TeBG but not CBG. Estrogens, antiestrogens, and androgens were without effect on either of these binding proteins.

Hormonal influences on the secretion of steroid-binding proteins by a human hepatoma-derived cell line.

Sex hormone-binding globulin: anatomy and physiology of a new regulatory system.

We isolated testosterone-estradiol-binding globulin (TeBG) from human pregnancy plasma and used the isolated protein to obtain a rabbit antiserum to it. Using immunochemical techniques, the antiserum was demonstrated to be both monospecific and to have the ability to remove TeBG-binding activity from human serum. This antiserum was used to develop a RIA for human TeBG. The sensitivity is such that TeBG can be determined in as little as 0.005 µl serum or plasma, although we routinely use 0.5-1.0 µl. The correlation between the RIA and an established binding assay, using 63 different specimens, was 0.995.

Radioimmunoassay for human testosterone-estradiol-binding globulin.

I n plasma, most steroid hormones are largely bound and transported by two specific steroid-hormone-binding proteins, corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG) (Siiteri et al, 1982; Englebienne, 1984; Westphal, 1986; Rosner, 1986; Brien, 1981; Mercier-Bodard et al, 1981). Although it is an oversimplification (see Mendel, 1989), it is fair to state that the prevailing view of the function of these proteins is to bind steroids and thus trap them in the plasma compartment. Only a small fraction of free steroids are available to diffuse passively out of the capillary bed and across cell membranes to initiate hormonal effects. The best evidence supports this notion of how steroid hormones exit the vascular space and enter cells. In the past few years, however, there is undeniable evidence of additional functions for the steroidbinding proteins. The major lines of evidence that led to this conclusion are reviewed here.

Sex hormone-binding globulin. Binding to cell membranes and generation of a second messenger.

We have studied the concentration and properties of a protein which binds coitisol in human milk in samples obtained from women during the first 100 days after delivery. A filter disk assay was developed both for the measurement of plasma corticosteroid-binding globulin (CBG) and for the cortisol-binding protein in milk. The concentration of CBG in milk, expressed as its capacity to bind coitisol, is highest on the day of delivery, ca. 0.80 μg/dl, falls over the next 10 days to ca. 0.25 μg/dl, and remains at that level thereafter. If the concentration of CBG is expressed relative to the concentration of serum albumin in milk, it increases from day 1 to day 3 and then remains constant. A detailed comparison of CBG derived from milk and plasma showed that the two proteins co-migrated on Sephadex, sucrose gradient ultiacentrifugation, and polyacrylamide gel electrophoresis. The two proteins had the same affinity for coitisol, progesterone, 17-OH-progesterone, and dexamethasone. Furthermore, the bind...

M. Saeed Khan

Papers

Hormonal influences on the secretion of steroid-binding proteins by a human hepatoma-derived cell line.

Sex hormone-binding globulin: anatomy and physiology of a new regulatory system.

Radioimmunoassay for human testosterone-estradiol-binding globulin.

Sex hormone-binding globulin. Binding to cell membranes and generation of a second messenger.

Identification of Corticosteroid-Binding Globulin in Human Milk: Measurement with a Filter Disk Assay