In several species, including humans, circulating insulin-like growth factor I (IGF-I) levels increase during the onset of puberty, suggesting that this peptide contributes to attaining sexual maturity. Because IGF-I elicits LHRH release from the median eminence (ME) of immature female rats in vitro, we hypothesized that it may represent one of the peripheral signals suspected to link somatic development to the LHRH-releasing system at puberty. We now present evidence in support of this concept. Quantitation of IGF-I messenger RNA (mRNA) levels by ribonuclease protection assay revealed that expression of the IGF-I gene did not change in the medial basal hypothalamus or preoptic area of female rats during peripubertal development. In contrast, the contents of both IGF-Ia and IGF-Ib mRNA, the two alternatively spliced forms of the IGF-I gene, increased significantly in the liver during the early proestrous phase of puberty. This change was followed by an elevation in serum IGF-I levels during the late proestrous phase of puberty along with a concomitant increase is serum gonadotropin levels. The proestrous change in serum IGF-I levels was accompanied by a selective increase in IGF-I receptor (IGF-IR) mRNA in the ME. Small doses of IGF-I (2-200 ng), administered intraventricularly, effectively induced LH release in both juvenile and peripubertal female rats, an increase prevented by prior immunoneutralization of LHRH actions. Importantly, intraventricular injections of IGF-I (20 ng), administered twice daily in the afternoon to immature animals, significantly advanced puberty. Thus, these results suggest that IGF-I of peripheral origin contributes to the initiation of female puberty by stimulating LHRH release from the hypothalamus, an effect that appears to be amplified by the increased synthesis of IGF-I receptors in the ME during first proestrus.

Alcohol (ALC) use and abuse by adolescents has been rising at an alarming rate. Whether ALC consumption during prepubertal years affects specific hormones and the process of sexual maturation is not known. We used immature female rhesus macaques to assess the effects of ALC on circulating levels of hormones known to be critical for the pubertal process. Ten monkeys averaging 20.3 +/- 0.3 months of age were bled by saphenous vein puncture at 0830 and 2030 h each day for 5 consecutive days to determine baseline levels of GH, insulin-like growth factor I, FSH, LH, estradiol (E2), and leptin. For the next 12 months, each day at 1330 h five monkeys were administered ALC (2 g/kg), and five monkeys were administered an isocaloric sucrose solution via a nasogastric approach. Blood was again collected twice daily on 5 consecutive days at 24, 28, and 32 months for hormone analysis. Food consumption and weight gain were similar for ALC-treated and control animals. The expected night-related increase in serum GH occurred during late juvenile development (28-32 months of age) in control animals, but was suppressed (P < 0.05) in ALC-treated animals. This action was paralleled by a decrease (P < 0.01) in serum insulin-like growth factor I. Serum LH and E2 were also depressed by ALC, with their effects most pronounced at 32 months (LH, P < 0.01; E2, P < 0.001). Serum FSH and leptin were not altered. Although ALC did not affect age at menarche, the interval between subsequent menstruations was lengthened (P < 0.05), thereby showing that ALC affected the development of a regular monthly pattern of menstruation. These results demonstrate the detrimental effects of ALC on the activation of hormone secretion that accompanies puberty in female rhesus monkeys. They also suggest that the subsequent growth spurt and normal timing or progression of puberty may be at risk in human adolescents and teenagers consuming even relatively moderate amounts of ALC on a regular basis.

Evidence exists that testosterone (T) regulates brain aromatase activity in adult rats. It is not known, however, whether the activity and/or its regulation by androgens change during the time of puberty. In the present study, we examined the change in basal aromatase activity associated with puberty in both male and female rats. We also assessed the influence of castration and treatment with a nonaromatizable androgen, dihydrotestosterone (DHT), on the hypothalamic aromatase system during juvenile and peripubertal development of male rats. Aromatase activity was estimated by both quantifying the 3H₂^Oreleased from [ 1 β-³H]T and by isolating the estrogen product(s) by thin-layer chromatography (TLC) after incubations with [1,2,6,7-³H]T. 5α-Reductase activity was determined simultaneously in the male hypothalamus by TLC using [1α-³H]Tas the substrate. Aromatase activity was linear with time of incubation and amount of tissue used. It was detected at similar levels in both tissue fragments and acutely dispersed cell preparations. Expression in the latter, but not the former required the addition of NADPH. Intracellular rates of both aromatase and 5α-reductase activities were highest in the mitochondrial-microsomal fraction. In both males and females the time of puberty was associated with a decrease in hypothalamic aromatase activity. In females, this drop was found to occur between the days of first proestrus and first estrus. In males, it occurred between 48 and 68 days of age (i.e., after the animals had reached puberty, as assessed by the presence of free sperm in the seminiferous tubules). Castration of juvenile (28-day-old), peripubertal (48-day-old), and adult (88-day-old), but not young adult (68-day-old) males decreased aromatase activity. DHT treatment restored the activity in the juvenile-peripubertal animals but, like castration, failed to effect the low levels found in the young adults. 5α-Reductase activity also decreased after puberty, but in contrast to aromatase was not altered, at any age studied, by either castration or DHT. The results indicate that: (a) acquisition of male sexual maturity is accompanied by a (transient) loss in the ability of androgens to upregulate hypothalamic aromatase activity, and (b) in both male and female rats completion of puberty is associated with a decline in this activity, which at least in males occurs even in the absence of the gonads. Since 5α-reductase and aromatase activities decrease with puberty, a reduction in the ability of the hypothalamus to metabolize T to its active metabolites is expected. This may represent a factor determining the decreased sensitivity to steroid negative feedback that accompanies the completion of puberty.

Orchidectomy produced a rise in plasma gonadotropin levels after 16 h, which was completely prevented by an intraperitoneal injection of DL-α-methyltyrosine (α-MT). When α-MT was injected 18 h after castration, a sharp fall in plasma LH, but not of FSH, followed. L-dihydroxyphenylalanine (l-DOPA) and dihydroxyphenylserine (DOPS) were given to restore catecholamine (CA) or norepinephrine (NE) synthesis, respectively. When given intraperitoneally 16 h after α-MT, the precursors did not alter LH levels; however, plasma FSH was significantly increased by either l-DOPA or DOPS. When α-MT was given 8 h after castration and precursors were injected 30 min later, l-DOPA increased both LH and FSH levels significantly 10 h after injections. When α-MT was injected 18 h after castration and precursors were injected 30 min later, DOPS prevented the fall in plasma LH, but l-DOPA was ineffective. The selective blockade of NE synthesis with diethyl dithiocarbamate (DDC) injected intraperitoneally 18 h after castration at two doses, 500 or 250 mg/kg, markedly decreased LH levels but did not alter plasma FSH. l-DOPA or DOPS, injected 30 min later, did not reverse the effect of the higher dose of DDC; however, when DOPS was injected 15 min after the lower dose of DDC, it partially prevented the decrease in plasma LH. Even at a dose of 200 mg/kg l-DOPA was ineffective. The selective blockade of DA receptors with Pimozide did not alter the rise in LH that follows orchidectomy, but partially blocked the rise of plasma

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