The aims of this study were to determine which hormones may have a role in the expression of maternal undernutrition effects on reproductive function, in both the developing fetus and the adult offspring. This was undertaken by measuring the effects of long-term maternal undernutrition on metabolic hormone profiles and pituitary responses to single doses of GnRH and GH-releasing factor (GRF) in fetal sheep. From mating, groups of ewes were fed rations providing either 100% (HIGH) or 50% (LOW) of estimated metabolisable energy requirements for pregnancy throughout the experiment until slaughter at approximately 119 days of gestation. Fetal and maternal blood samples were collected from 113 until 119 days of gestation, via carotid and jugular catheters respectively, and assayed for insulin, IGF-I, GH, thyroxine and triiodothyronine (T(3)). Undernutrition had no effects on fetal weight, fetal gonad weight of either sex, fetal insulin or IGF-I concentrations. Male LOW fetuses exhibited a significantly attenuated response (P<0.05) to a bolus challenge of GnRH compared with HIGH fetuses. Basal fetal GH concentrations and the response to exogenous GRF were similar in both treatment groups, although LOW fetuses exhibited more secretory episodes (P<0.01). Mean T(3) concentrations were significantly lower in both the maternal (P<0.01) and fetal (P<0.05) plasma of LOW animals compared with HIGH animals. It is concluded that pituitary function was altered in fetal males and could influence male reproductive development. On the other hand, in female sheep, fetal gonadal abnormalities and reductions in reproductive capacity in adult life which are associated with fetal undernutrition are unlikely to be attributable to altered pituitary function. Additionally, these studies raise the possibility that thyroid hormones may have a role in the expression of maternal undernutrition effects on fetal development.

Body reserves (long-term) and food intake (short-term) both contribute nutritional feedback to the hypothalamus. Reproductive neuroendocrine output (GnRH/LH) is stimulated by increased food intake and not by high adiposity in sheep, but it is unknown whether appetite-regulating hypothalamic neurons show this differential response. Castrated male sheep (Scottish Blackface) with oestradiol implants were studied in two 4 week experiments. In Experiment 1, sheep were fed to maintain the initial body condition (BC) score of 2.0+/-0.00 (lower BC (LBC), n=7) or 2.9+/-0.09 (higher BC (HBC), n=9), and liveweight of 43+/-1.1 and 59+/-1.6 kg respectively. LBC and HBC sheep had similar mean plasma LH concentration, pulse frequency and amplitude, but HBC animals had higher mean plasma concentrations of insulin (P<0.01), leptin (P<0.01) and glucose (P<0.01). Gene expression (measured by in situ hybridisation) in the hypothalamic arcuate nucleus (ARC) was higher in LBC than HBC sheep for neuropeptide Y (NPY; 486% of HBC, P<0.01), agouti-related peptide (AGRP; 467%, P<0.05) and leptin receptor (OB-Rb; 141%, P<0.05), but lower for cocaine- and amphetamine-regulated transcript (CART; 92%, P<0.05) and similar between groups for pro-opiomelanocortin (POMC). In Experiment 2, sheep with initial mean BC score 2.4+/-0.03 and liveweight 55+/-0.8 kg were fed a liveweight-maintenance ration (low intake, LI, n=7) while sheep with initial mean BC score 2.0+/-0.03 and liveweight 43+/-1.4 kg were fed freely so that BC score increased to 2.5+/-0.00 and liveweight increased to 54+/-1.4 kg (high intake, HI, n=9). Compared with LI, HI sheep had higher mean plasma LH (P<0.05), baseline LH (P<0.01) and pulse amplitude (P<0.01) and showed a trend towards higher pulse frequency. Although there were no differences in final mean plasma concentrations, there were significant increases over time in mean concentrations of insulin (P<0.001), leptin (P<0.05) and glucose (P<0.001) in HI sheep. Gene expression for AGRP in the ARC was higher in HI than LI animals (453% of LI; P<0.05), but expression levels were similar for NPY, OB-Rb, CART and POMC. Thus, the hypothalamus shows differential responses to steady-state adiposity as opposed to an increase in food intake, in terms of both reproductive neuroendocrine activity and hypothalamic appetite-regulating pathways. Differences in hypothalamic gene expression were largely consistent with contemporary levels of systemic leptin and insulin feedback; however, increased nutritional feedback was stimulatory to GnRH/LH whereas constant high feedback was not. The hypothalamus therefore has the ability to retain a nutritional memory that can influence subsequent responses.