Neuroendocrinology of Parturition and Lactation

1. Neuroendocrinology of Parturition and Lactation

2. Parturition What determines its timing? Genetic? Endocrine? Mom? The fetus? It’s about the uterus

3. The uterus shows distinct phases of activity during pregnancy 95%

4. Early on, P comes from the corpus luteum; Later the placenta takes over this role. The pregnant uterus also makes PTHrP, prostacyclin, NO (along with fetal membranes), relaxin, all of which keep the uterus quiet by increasing cAMP and that decreases Ca+2 release.

5. The uterus shows distinct phases of activity during pregnancy

6. Factors controlling activity in parturition CAPs

7. Phase 1 Connexin is induced

8. Phase 1 Connexin is induced by: • Fall in progesterone • Stretch of uterus • E (from DHEA/S made in maternal or fetal adrenal, converted in placenta) inc E:P ratio • May all act in concert

9. Fetal Participation in triggering parturition

11. Negative feedback reduced in fetus: • inactivation of enzyme that converts cortisol to cortisone • decrease # GRs in PVN • increased synthesis of CBG • Increased cortisol: • increases synthesis PGE2 which increases ACTH and cortisol synthesis, inducing a positive feedback response

12. Overall the outcome is induction of CAPs for uterine preparation

13. The functional inc is the result of E. High P enables synthesis but not biding!

14. The uterus shows distinct phases of activity during pregnancy

15. In Stage 2, prostaglandins increase uterine contractility (the ability to show strong contractions) late in pregancy whereas earlier they inhibited contraction. Change in which PG receptors are working (PGE first uses EP1 and EP3 which relax smooth muscle but switch to EP 2 and 4 that contract SM) • PGF2 through FP receptors the PG • increases Ca2 mobilization • decreases cAMP formation • PG metabolism is reduced

16. Oxytocin stimulates contractions.

17. Neuroendocrinology of Lactation a need to understand the mammary gland

18. In the non-pregnant state, only the ducts are present. The glands develop during pregnancy. Estradiol stimulates mammillary duct growth; E+P stimulates aveolar growth (gland proper)

19. In addition, Prolactin, growth hormone, and glucocorticoids induce varying degrees of mammary gland development (depending on species). Prolactin - inc aveolar growth GH stimulates duct development but both hormones are low when the gland shows its most profound growth during pregnancy.

20. During cycling E and P are elevated but at different times. Thus mammary growth is limited. During pregnancy both are elevated. cows

21. Secretory activity of mammary glands is not observed during pregnancy but only after delivery. At that time, suckling increases mammary growth but mechanism unknown. Maintenance of mammary gland cell numbers and secretory activity rely upon neuroendocrine mechanisms determined by the strength and duration of the suckling stimulus. Systems regulating PROLACTIN + ACTH, TSH, GH (depending on the species) maintain or increase milk secretion. PROLACTIN + Glucocorticoidsregulate lactogenesis

22. The major regulator of prolactin secretion is DOPAMINE released by a population of neurons in the arcuate nucleus These tuberoinfundibular dopamine neurons normally INHIBIT prolactin release

23. Blocking prolactin secretion delays/reduces milk production

25. Dopamine l-amino acid decarboxylase l-AADC DOPA Tyrosine Hydroxylase TH Tyrosine

26. If the cells stop firing, dopamine should build up in the median eminence but it doesn’t!

27. Lactating Cycling removed 24 hr

28. How is TH expression regulated by suckling?

31. Milk Ejection Reflex

32. Oxytocin Neuron activity during suckling Action potentials Firing rate intramammary pressure

33. Oxytocin stimulates contractions.

38. Dynorphin neurons heavily innervate dopamine cells