Testicular Control Of Gonadotropin Secretion

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Gonadotropin secretion, although upregulated by GnRH, is maintained at physiological levels through testicular negative feedback mechanisms summarized in Fig. 5. Accordingly, plasma LH and FSH levels decrease after testosterone or estradiol administration and rise when negative feedback is disrupted by castration.

The process of negative feedback control of LH and FSH by gonadal steroids in males is partly species-specific. There is considerable evidence in primates that androgens suppress LH synthesis and secretion primarily through an action on the GnRH pulse generator. For example, LH pulse frequency and amplitude are elevated in castrated primates, and are suppressed by testosterone replacement (53). Furthermore, when male rhesus monkeys were rendered gonadotropin deficient with radiofrequency lesions and stimulated with GnRH pulses, LH secretion increased little after bilateral orchidectomy, until GnRH pulse frequency was increased (54). In addition, expression of the mRNAs for GnRH (3), as well as pituitary GnRH-recep-tors, and the gonadotropin subunit genes are increased in orchidectomized monkeys (55). Moreover, when pituitary cells from adult male monkeys were stimulated with GnRH pulses, no inhibition of GnRH-induced LH secretion by testosterone or DHT occurred. In pituitary cells from rats, on the other hand, the gonadotroph is a direct site of testosterone-negative feedback control, because GnRH-stimulated LH pulses were suppressed in amplitude by testosterone and a-subunit gene expression was reduced (56).

GnRH-deficient men represent a human model to examine the effects of testicular steroids on the hypothalamus and pituitary. When such patients were treated with fixed

Table 1

Hormone Levels in a Man With a Mutation of the Estrogen Receptora and Two Men Deficient in Aromatase

Table 1

Hormone Levels in a Man With a Mutation of the Estrogen Receptora and Two Men Deficient in Aromatase

Luteinizing

Follicle-Stimulating

Age

Testosterone

Estradiol

Hormone

Hormone

(yr)

(ng/dL)

(pg/mL)

(mIU/mL)

(mIU/mL)

Reference

28

445

119

37 (2.0-20)

33 (2.0-15)

Smith et al. (57)

24

2015

<7

26.1 (2.0-9.9)

28.3 (5.0-9.9)

Morishina et al. (58)

31

523

<10

5.6 (1.4-8.9)

17.1 (1.7-6.9)

Carini et al. (59)

Luteinizing hormone and follicle-stimulating hormone levels in parentheses are the normal ranges reported in those references.

Luteinizing hormone and follicle-stimulating hormone levels in parentheses are the normal ranges reported in those references.

GnRH doses (57), testosterone suppressed LH secretion less than in normal men, implying that testosterone controls GnRH secretion. Moreover, suppression by testosterone was blocked by the aromatase inhibitor testolactone (57), and in separate experiments, dihydrotestosterone had no effect (58). Together, these data imply that the pituitary effect of testosterone to inhibit LH was through bioconversion to estradiol.

Whether it is testosterone and/or the estradiol derived from testosterone by aromatase in the central nervous system or in peripheral tissues that controls LH secretion is of considerable interest. The finding that dihydrotestosterone (DHT), a nonaromatizable androgen, decreases LH pulse frequency strongly supports a role for androgens in the regulation of the GnRH pulse generator. Furthermore, LH pulse frequency is increased in patients with nonfunctional androgen receptors (AR) in the complete androgen insensitivity syndrome, indicating that AR signaling regulates GnRH pulse frequency (59).

Estradiol also plays an important physiological role in the negative feedback control of gonadotropin secretion in men. This control mechanism was suggested by pharmacological studies using the estrogen antagonist clomiphene (60) or the aromatase inhibitor testolactone (61). When those drugs were administered to normal men, circulating LH and FSH levels rose, together with plasma testosterone concentrations. More recently, as shown in Table 1, gonadotropin and testosterone levels increased in a man with an inactivating mutation of the estrogen receptor-a (62) and in two men with mutations in the aromatase gene (63,64). In these models, even though androgen levels were increased, estrogen blockade or deficiency was associated with increased gonadotropin secretion. Moreover, in one man with aromatase deficiency, estrogen treatment suppressed serum gonadotropin levels. The finding that clomiphene increased LH pulse frequency (60) indicated that the negative feedback action of estradiol was partly at the level of the GnRH pulse generator. This finding was recently confirmed and extended using the aromatase inhibitors anastra-zole (65). Estradiol treatment also decreases the LH response to GnRH stimulation in men (66) and in primate pituitary cells perifused with GnRH pulses, (56) indicating an additional direct negative effect on the pituitary gland.

GnRH neurons appear by autoradiography and immunocytochemistry to lack both androgen and estrogen receptors. Thus, the mechanism for their effect on GnRH neurons is believed to involve transsynaptic or neuronal-glial interactions or nongenomic membrane effects.

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Responses

  • ville-veik koivula
    How is testosterone a negative feedback process?
    7 years ago

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