Dihydrotestosterone binding

Testosterone and dihydrotestosterone bind to the intracellular androgen receptor, initiating a series of events similar to those described above for estradiol and progesterone, leading to growth, differentiation, and synthesis of a variety of enzymes and other functional proteins. 

Testosterone or dihydrotestosterone binds to an intracellular protein receptor, and the hormone-receptor complex is attached in the nucleus to specific hormone regulatory... 

Haidar, C. Gupta, D. (1990). Sex- and age-dependent nature of the cytoplasmic 5 alpha-dihydrotestosterone (DHT) binding site/receptor in bovine pineal gland. J. Pineal Res. 8, 289-95. 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

Saw palmetto extract can inhibit the enzyme 5-a-reductase in vitro. This enzyme converts testosterone into dihydrotestosterone (DHT), which in turn contributes to prostatic enlargement. Saw palmetto also appears to have an antiinflammatory effect and can reduce DHT binding to prostatic androgen receptors (antiandrogenic effect). Despite its proposed 5-a-reductase mechanism. 

Testosterone (5.45) is the prototypic androgen sex hormone. Testosterone is synthesized by the testes, and must be reduced to dihydrotestosterone (5.46, DHT) before it will bind to the receptor. Among highly active synthetic testosterone analogs, 7a-methyl-19-nortestosterone (5.47) and oxandrolone (5.48) have about 100 times greater activity than testosterone as androgens. 17a-Methyltestosterone (5.49) is orally active. 

Control of androgen secretion and activity and some sites of action of antiandrogens (1), competitive inhibition of GnRH receptors (2), stimulation (+, pulsatile administration) or inhibition via desensitization of GnRH receptors (-, continuous administration) (3), decreased synthesis of testosterone in the testis (4), decreased synthesis of dihydrotestosterone by inhibition of 5a-reductase (5), competition for binding to cytosol androgen receptors. 

Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H2 antagonists. 

Conversion of testosterone to 5ar-dihydrotestosterone (5a-DHT). Receptor-binding studies indicate that 5a-DHT has a higher affinity for the androgen receptor than testosterone does. 

Saw palmetto relieves urinary symptoms and flow measures associated with an enlarged prostate it does not reduce the enlargement. Saw palmetto is chiefly employed to manage prostatic enlargement or benign prostatic hyperplasia (BPH). A hexane extract inhibits 5-alpha reductase, the enzyme needed for the conversion of testosterone into dihydrotestosterone (DHT). Saw palmetto further antagonizes DHT binding at prostatic receptor sites, which increases the metabolism and excretion of DHT. It is also used to treat BPH-related inflammation (see Chapter 55). 

All classes of steroid hormones bind to specific cytoplasmic receptors in their respective target tissues, and are then translocated to the nucleus. For example, testosterone, a lipid-soluble substance, enters the cell and is enzymatically reduced to dihydrotestosterone by 5-a reductase. Dihydrotestosterone then becomes bound to a specific androgen receptor site located in the cytoplasm. This complex becomes activated and is then translocated to the nucleus, where it binds to the chromatin acceptor site consisting of DNA and nonhistone chromosomal proteins. This interaction results in the transcription of a specific messenger RNA that is then relocated to the cytoplasm and translated on the cytoplasmic ribosomes, resulting in the synthesis of a new protein that sponsors the androgenic functions (Figure 61.6). 

Saw palmetto is most often used in the treatment of benign prostatic hyperplasia. Enzymatic conversion of testosterone to dihydrotestosterone (DHT) by 5a-reductase is inhibited by saw palmetto in vitro. This effect is similar to that of finasteride, which is also used to treat the disorder (Chapter 40 The Gonadal Hormones Inhibitors). In vitro, saw palmetto also inhibits the binding of DHT to androgen receptors. Additional effects that have been observed in vitro include inhibition of prostatic growth factors, blockade of ay-adrenoceptors, and inhibition of inflammatory mediators... 

Xqll-ql3) (17) and dihydrotestosterone syndromes. Impaired response to exogenous testosterone frameshift mutations create receptors with absent or reduced hormone binding, increased lability, and failure of up-regulation (59,60)... 

Abbreviations ABP, androgen-binding protein 5q-DHT. 5a-dihydrotestosterone 5/3-DHT, 5/3-dihy-drotestosterone EGF, epidermal growth factor FSH. folitropin KAP, kidney androgen-induced protein LH, lutropin NGF, nerve growth factor SGF, testis-specific growth factor. 

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