Role Of Intrinsic GnRh Deficiency In Mediating Lowamplitude Lh Secretion

Experiments in the male mouse and rat support an important, but not exclusive, role of GnRH-deficient hypogonadotropism in the hypoandrogenemia of aging (41-44). Evidence to this end includes (1) decreased castration-, naloxone-, and restraint stress-induced LH release in the older rodent (24,42,45-47); (2) diminished in vivo LH pulse amplitude in senescent animals (43,48); (3) reduced in vitro hypothalamic GnRH secretion (49,50); (4) altered GnRH neuronal synaptology (51); (5) preservation of the stimulatory efficacy of GnRH (43,52); and (6) restoration of sexual activity in the impotent animal by fetal hypothalamic neuronal transplantation (53). Although such observations afford important clues for clinical investigation, the regulation of GnRH outflow in the laboratory animal is complex, multifactorial, and incompletely defined.

The intuition that hypothalamic GnRH deficiency subserves relative hypogonadism in elderly men has not been established or refuted (22,26,28,54-57). However, the

Elderly Body Cells

Fig. 1. Simplified schema of the gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH)-testosterone (hypothalamic-pituitary-Leydig cell) axis with feedback (-, inhibitory) and feedforward (+, stimulatory) interactions mediated via specific interface (dose-response) functions. (Unpublished line drawing.)

Fig. 1. Simplified schema of the gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH)-testosterone (hypothalamic-pituitary-Leydig cell) axis with feedback (-, inhibitory) and feedforward (+, stimulatory) interactions mediated via specific interface (dose-response) functions. (Unpublished line drawing.)

Pituitary Leydig Cell Axis
Fig. 2. Primary loci of postulated regulatory failure defects in the gonadotropin-releasing hormone (GnRH)- luteinizing hormone (LH)-testosterone ensemble axis in aging men.

notion is congruent with many clinical observations, as highlighted in Table 1. A necessary, but not sufficient, prediction is that GnRH action on gonadotropes is preserved. A recent prospectively randomized, interventional study used 14 d of pulsatile i.v. infusion of GnRH vs. saline to stimulate LH and testosterone secretion. Older and young men treated with this regimen achieved an equivalent elevation of 24-h LH concentrations (see Fig. 3A) consistent with retention of gonadotrope secretory responsiveness in the older male (28). In young men, the increment in mean LH

Table 1

Indirect Evidence for Impaired Hypothalamic GnRH Drive in Aging Men

Table 1

Indirect Evidence for Impaired Hypothalamic GnRH Drive in Aging Men

References

1. Low-amplitude spontaneous LH pulses

(23,27,28,38,55)

2. Normal or increased (maximal) GnRH efficacy

(28,47,54,97-98)

3. Blunted unleashing of pulsatile LH secretion under

(26,56,57,75,76,123)

negative-feedback withdrawal

4. More disorderly patterns of LH release

(28,30,39,40,76)

5. Asynchrony of central neurohormone outflow; namely, LH, FSH,

(31,32,115)

PRL, sleep stage, and NPT

6. Increased pituitary LH stores postmortem

(24)

7. Neurotransmitter and sex-steroid receptor adaptations in the aged

(77,78)

hypothalamus and pituitary gland

8. Mathematical predictions based on an ensemble concept

(39,40,83)

LH, luteinizing hormone; GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; PRL, prolactin; NPT, nocturnal penile tumescence.

LH, luteinizing hormone; GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; PRL, prolactin; NPT, nocturnal penile tumescence.

concentrations elicited a proportionate rise in testosterone production. On the other hand, the same average increase in LH immunoreactivity in aged individuals failed to augment total (see Fig. 3B), as well as, bioavailable and free-testosterone concentrations equivalently. The latter age-related contrast would point to an abnormal pulsatile LH signal (of equivalent mean concentration only), relatively defective Leydig cell responsiveness, and/or accelerated testosterone metabolism in older men. The last (kinetic) consideration is excluded by the age-related fall in the metabolic clearance rate of testosterone associated with higher SHBG concentrations (34,36,37).

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