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Alpha-difluoromethylornithine modifies FSH secretion and puberty onset in the female rat
1Laboratorio de Neuroendocrinologia, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina.
Insights
Inhibiting polyamine synthesis with alpha-difluoromethylornithine (DFMO) in newborn female rats delays puberty onset and alters FSH secretion. However, fertility remains normal once puberty is established.
Area of Science:
- Reproductive Endocrinology
- Developmental Neuroscience
- Biochemistry
Background:
- Follicle-stimulating hormone (FSH) secretion is high in immature female rats, crucial for puberty onset.
- Polyamines are vital for tissue growth, brain development, and hormonal action, with highest levels during development.
- Ornithine decarboxylase (ODC) is the key enzyme in polyamine biosynthesis; its inhibition impacts brain development.
Purpose of the Study:
- To investigate the role of polyamines in the brain's reproductive organization.
- To determine the effects of inhibiting ODC with alpha-difluoromethylornithine (DFMO) on reproductive parameters in female rats.
Main Methods:
- DFMO was administered to newborn female rats according to different schedules.
- Effects on pituitary secretion (FSH levels), puberty onset (vaginal opening, first estrus), estrous cyclicity, and fertility were evaluated.
Main Results:
- DFMO administration delayed vaginal opening and first estrus, with variations in body weight at these milestones depending on the treatment schedule.
- Elevated serum FSH levels were observed on postnatal days 10 and 20 in DFMO-treated groups.
- Estrous cyclicity and fertility parameters (litter size, weight) were not significantly affected after puberty onset.
Conclusions:
- Inhibition of ODC during early life affects FSH secretion and delays puberty in female rats.
- Polyamines play a role in the timing of reproductive maturation.
- Normal fertility is achieved once puberty is established, irrespective of early-life DFMO treatment.
Abstract:
FSH secretion is high in immature female rats from Postnatal Day 5 to 18 and decreases thereafter. This is a relatively steroid-independent event of cerebral origin and of importance for puberty onset. Polyamines, a group of ubiquitous amines, play an essential role in tissue growth and differentiation, body weight increment, brain organization, and molecular mechanisms of hormonal action. Polyamine levels as well as the activity of ornithine decarboxylase, the limiting enzyme in polyamines biosynthesis, are highest during development. Inhibition of their synthesis during this period by alpha- difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase, impairs normal brain development. The present study tested the hypothesis that polyamines play a role during brain organization of reproduction. DFMO was administered following different schedules in female newborn rats, and the effect on pituitary secretion, puberty onset, and fertility was evaluated. In three groups (daily injections from Day 1 to 9, or from Day 1 to 6, or injections on alternative days from Day 1 to 9), a delay in vaginal opening and first estrous was observed. When vaginal opening was plotted against body weight, it was evident that in groups daily injected with DFMO vaginal opening occurred at a lower body weight. In the group treated on alternate days, a delay occurred but at a higher body weight than in controls. In this group, serum FSH levels on Day 10 and 20, but not on Day 30, were higher in DFMO rats. In the group treated from Day 1 to 6 daily, DFMO increased serum FSH on Postnatal Day 20. After vaginal opening, estrous cyclicity in control and DFMO injected rats was similar. There was no significant effect of treatment on fertility and litter weight or number of offspring at birth. It is concluded that DFMO, an inhibitor of ornithine decarboxylase, administered during the first week of life in female rats is followed by prolonged high FSH serum levels and delayed puberty, but once puberty occurs, fertility is normal.