Recent studies demonstrate long-term programming of function of specific organ systems resulting from suboptimal environments during fetal life and development up to weaning. Nutrient restriction during pregnancy and lactation impairs overall fetal growth and development. We determined the effects of maternal protein restriction (MPR; 50% normal protein intake) during fetal development and/or lactation in rats on the function and ageing of the reproductive system of female progeny. Rats were fed either a control 20% casein diet (C) or a restricted diet (R) of 10% casein during pregnancy. After delivery mothers received either C or R diet until weaning to provide four groups, CC, RR, CR and RC. We report data on female offspring only. After weaning pups were fed the C diet. MPR increased maternal progesterone, corticosterone, oestradiol and testosterone concentrations at 19 days gestation. Reproductive and somatic phenotype was altered as pup birth weight was decreased, and ano-genital distance was increased by MPR. Pup corticosterone was decreased at 2 days postnatal (PN) life. Vaginal opening and timing of the first oestrus were delayed in RR and CR and these differences were not related to body weight. At 21 days PN oestradiol in RR and CR and progesterone in RR were reduced; at 70 days PN luteinizing hormone (LH) in all restricted groups was reduced in dioestrus while follicle stimulating hormone (FSH) was unchanged. Cycle length increased between 140 days and 1 year in RR and CR but remained unchanged in CC, providing evidence of premature ageing of reproductive function. Fertility rates declined over the same period in the three experimental groups but not CC. MPR in one of the two experimental periods, either pregnancy or lactation, resulted in decreased pup survival compared with CC and RR. These data show that MPR results in delayed sexual maturation and premature ageing of reproductive function.

The present study tested the hypothesis that if polycystic ovary syndrome (PCOS) results from activating the noradrenergic outflow to the ovary, unilaterally sectioning the superior ovarian nerve (SON) will result in ovulation by the denervated ovary, and the restoration of progesterone (P4), testosterone (T) and estradiol (E2) normal serum level. A single 2 mg dose of estradiol valerate (EV) to adult rats results in the development of a syndrome similar to the human PCOS. Ten-day old rats were injected with EV or vehicle solution (Vh) and were submitted to sham surgery, unilateral or bilateral sectioning of the SON at 24-days of age. The animals were sacrificed at 90 to 92 days of age, when they presented vaginal estrus preceded by a pro-estrus smear. In EV-treated animals, unilateral sectioning of the SON restored ovulation by the innervated ovary and unilateral or bilateral sectioning of the SON normalized testosterone and estradiol levels. These results suggest that aside from an increase in ovarian noradrenergic tone in the ovaries, in the pathogenesis of the PCOS participate other neural influences arriving to the ovaries via the SON, regulating spontaneous ovulation. Changes in P4, T and E2 serum levels induced by EV treatment seem to be controlled by neural signals arising from the abdominal wall and other signals arriving to the ovaries through the SON, and presents asymmetry.

In the present study, we analysed and compared the relative in-vitro biological activity of the various intrapituitary human follicle stimulating hormone (FSH) isoforms employing two different bioassay systems. FSH was fractionated by chromatofocusing (pH range 7.10 to < 3.80) and the several isoforms isolated were quantified at multiple dose levels by three highly specific immunoassay systems: radioimmunoassay (RIA), enzyme-immunoassay (EIA) and immunoradiometric assay (IRMA), as well as by two in-vitro bioassays, one that measures the amount of oestrogen produced by rat granulosa cells in culture and the other that determines the amount of cAMP produced by a human fetal cell line (293) expressing the recombinant human FSH receptor. The relative in-vitro biological activity of each FSH isoform, expressed as the bioassay/ immunoassay (B/I) activity ratio (B/RIA, B/EIA and B/IRMA ratios) varied with its elution pH value. Regardless of the immunoassay or bioassay method employed, less acidic FSH isoforms exhibited higher B/I ratios than their more acidic counterparts [B/RIA, B/EIA and B/IRMA ratios for isoforms with elution pH values > 4.5 = 1.05 +/- 0.13, 0.99 +/- 0.10 and 1.15 +/- 0.08 (rat oestrogen bioassay), and 2.75 +/- 0.34, 2.20 +/- 0.25 and 2.96 +/- 0.35 (human cAMP production bioassay) respectively. Ratios for isoforms with pH values < 4.5 = 0.71 +/- 0.06, 0.47 +/- 0.05 and 0.63 +/- 0.06 (rat oestrogen assay), and 1.80 +/- 0.26, 1.10 +/- 0.09 and 1.44 +/- 0.13 (cAMP assay) respectively (P < 0.05 for isoforms with pH < 4.5 compared with those isoforms with pH > 4.5)]. Furthermore, statistically significant direct relationships between the B/RIA, B/EIA and B/IRMA ratios and elution pH value of each isoform was identified by regression analysis [rat assay: r = 0.844, 0.800 and 0.780 (P < 0.01); human assay: r = 0.730, 0.845 and 0.821 (P < 0.01), for their corresponding B/RIA, B/EIA and B/IRMA ratios respectively]. The finding of significant differences in relative in-vitro biological potency among the various intrapituitary FSH isoforms strongly suggests that the shifts towards the production and secretion of more basic or acidic FSH molecules occurring in certain specific physiological conditions (e.g. puberty and menstrual cycle), may represent an important mechanism through which the anterior pituitary regulates gonadal function.

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