Contribution Of Primary Leydig Cell Steroidogenic Failure

Anatomical studies document an attrition of Leydig cell number in the older male (58). From a functional perspective, pharmacological stimulation with human chorionic gonadotropin (hCG) does not induce maximal young-adult concentrations of testosterone in many elderly men (19,22,59-62). Nonetheless, current hCG paradigms are difficult to interpret on experimental and physiological grounds; for example, (1) unequal concomitant (endogenous) LH concentrations in individuals may confound testicular responses to hCG (12,19,24,61,62); (2) the half-life of circulating hCG is approx 20-30 h, compared with 0.75-1.5 h for LH; indeed, the former kinetics abrogate normal intermittent stimulation of the testis (38,63,64). This distinction is relevant, because each LH pulse normally evokes a prompt burst of testosterone release, as monitored directly in the human spermatic vein (65,66); (3) the nearly irreversible binding of hCG to the gonadal LH receptor downregulates steroidogenesis in vitro and in vivo (67,68); and (4) the magnitude of hCG drive limits clinical evaluation to maximal Leydig cell responsivity. An equivalently sustained and potent lutropic stimulus is never achieved physiologically in vivo, except under maternal hCG exposure in the developing fetus (34,36).

A second means of appraising Leydig cell responsiveness is cross-correlation analysis of LH and (time-delayed) testosterone concentrations in paired hormone time series

Testosterone Levels

Fig. 3. (A) GnRH dose-responsive response stimulation of (2-h mean) serum concentrations of luteinizing hormone (LH) (top), follicle-stimulating hormone (FSH) (middle), and free (uncombined) alpha subunit (bottom) in young men (interrupted lines) and older volunteers (solid lines). Data are the mean ± SEM. Adapted with permission from (96). (B) Relationship between the increment in 24-h mean concentrations of LH (x-axis) and testosterone (y-axis) induced by 14 d of uninterrupted pulsatile i.v. gonadotropin-releasing hormone (GnRH) infusion (100 ng/kg every 90 min) compared with saline in young men (upper interrupted curve and plus signs). There is no correlation in older men (lower continuous line and solid circles). (Adapted from ref. 28.)

Fig. 3. (A) GnRH dose-responsive response stimulation of (2-h mean) serum concentrations of luteinizing hormone (LH) (top), follicle-stimulating hormone (FSH) (middle), and free (uncombined) alpha subunit (bottom) in young men (interrupted lines) and older volunteers (solid lines). Data are the mean ± SEM. Adapted with permission from (96). (B) Relationship between the increment in 24-h mean concentrations of LH (x-axis) and testosterone (y-axis) induced by 14 d of uninterrupted pulsatile i.v. gonadotropin-releasing hormone (GnRH) infusion (100 ng/kg every 90 min) compared with saline in young men (upper interrupted curve and plus signs). There is no correlation in older men (lower continuous line and solid circles). (Adapted from ref. 28.)

Serum Testosterone Serum LH qj

Concentration (ng/dL) Concentration (IU/L)

Optimal Time Lag (min)

1

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z

CO

- II

II

03

Fig. 4. (A) Cross-correlation of 10-min luteinizing hormone (LH) concentrations with (deconvolu-tion-calculated) testosterone secretion rates sampled for 24 h in 11 young and 13 older men. The optimal time lag (upper panel) defines the latency (min) between rising LH concentrations and increasing testosterone secretion rates. The cross-correlation coefficient r (rho) quantitates the strength of feedforward coupling. Data are the mean ± SEM. (B) Infusion of six consecutive rh LH pulses (50 IU i.v. over 6 min every 2 h) in a healthy young man pretreated 12 h earlier with a single sc dose of the selective gonadotropin-releasing hormone (GnRH)-receptor antagonist, ganirelix. Time zero is 2000 h. Blood was withdrawn every 10 min for 2 h before ganirelix injection and for 24 h thereafter. (Unpublished plot from ref. 71.)

(69). Comparisons by age disclose a young adult-like time lag of 30-40 min but significantly reduced feedforward coupling between LH and testosterone in older men. The latter distinction is reflected in a 50% reduction in the cross-correlation coefficient (27,29), as shown in Fig. 4A.

A third experimental strategy to examine Leydig cell steroidogenic capacity is to downregulate gonadotropin secretion with a GnRH analog and then add back pulses of rh LH intravenously to emulate physiological patterns of gonadotropin stimulation. In this paradigm, LH withdrawal enforced by pituitary downregulation impairs testosterone secretory responsiveness profoundly in both age groups, albeit twofold more in elderly men (70).

A fourth interventional scheme is illustrated by a recent pilot analysis in eight young and seven older volunteers. In this approach, a selective GnRH-receptor antagonist (ganirelix) was injected 10 h before infusing successive i.v. pulses of rh LH. Pulsatile injections of rh LH increased testosterone concentrations within 6-8 h from <120 ng/dL to >450 ng/dL in both age cohorts (71). The response in one young subject is illustrated in Fig. 4B. This preliminary study was restricted to 14 h of LH stimulation, measurement of the total testosterone concentration, and a small number of participants. Thus, further investigations will be required to ascertain whether intermittent LH infusion will sustain young-adult production of total, non SHBG-bound, and free testosterone for prolonged intervals in healthy older men.

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