Prolactin and Oxytocin

Macroprolactinemia and hyperprolactinemia

Heavier (100kD) MW PRL variant is the primary one secreted by the pituitary. Normal menses occurs as this variant has low biological activity

Where is the only place neuroendocrine cells are found?

Hypothalamus

Absolute PRL deficiency

A very rare condition Based on radioimmunoassay, bioassay, and DA antagonist, testing for capacity to induce PRL secretion

OXY mechanism of action

OXY acts on a G-protein coupled receptor. In the myometrium, OXY activates the PLC-IP3-Ca++ pathway and enhances activation of voltage-sensetive Ca++ channels.

Primary hypothyroidism and hyperprolactinemia

20-30% of patients exhibit elevated basal PRL levels due to absence of negative feedback from TRH. Treatmet: T4 daily (100-150micrograms)

Secretion of prolactin

Pulsatile in nature Pituitary output begins during 5th week in utero, blood levels then decline after birth Plasma hormone levels are low in males; elevated in cycling females and increase further during pregnancy and lactation. Sucking will increase release 10-100 fold.

Oxytocin

"Milk letdown factor," After secreted, milk stays in the alveoli. Oxytocin is required to release the milk

Chronic renal faiulre and hyperprolactinemia

20-75% of patients Due to delayed clearance of PRL

Prolactin

Acts upon alveoli stimulating milk production. Structurally related to GH and placental lactogen. 23kD protein with 199 AA. Molecular weight and charge heterogeneity (larger and smaller varieties with differing efficacies. Can become carged through phosphorylation).

Isolated Prolactin Deficiency

Only causes lactational disorders. Narrowly defined as a complete inability of the pituitary to secrete PRL; realistically, includes conditions with diminished PRL secretion.

PRL mechanism of action

PRL receptor encoded by a single gene; alternative splicing of mRNA yields multiple variants including long, short, and intermediate forms (causes cell and tissue specific receptors) COnformational changes recruit and activate JAK kinases, which in turn induce phosphorylation, dimerization, and nuclear translocation of STAT5.

Clinical syndromes of Hyperprolactinemia

Primary hypothyroidism Polycistic ovary syndrome (PCO) Chronic renal failure Idiopathic Macroprolactinemia (large MW PRL) Transient hyperPRL

Stimulation of OXY

Primary stimuli is suckling of breast; dilation of cervix and vagina as well

What is the most common pituitary tumor

Prolactinoma

Long standing hyperprolactinemia

Risk of progression to identifiable tumor is small. Lack of treatment can cause significant reduction of vertebral bone density due to estrogen deficiency

Clinical presentation of prolactinoma

Women: menstrual disorders/infertility Men: Impaired libido/sexual impotency Both: Symptoms of pituitary mass, including headache and visual defects

Target genes for PRL

mild proteins (caseins), keratins, cell-cell communication, and extracellular matrix

Connects 2 separate capillary beds

portal vein

Polycystic ovary syndrome (PCO) and hyperprolactinemia

Elevated PRL due to chronic estrogenization; however, lowering PRL does not induce ovulation. Most common female reproductive disorder: anovulation and increased testosterone secretion.

Thyrotropin-releasing hormone (TRH) action

Increases THyroid stimulating hormone (TSH)

Corticotropin-releasing hormone (CRH) action

Increases adrenocorticotropin (ACTH)

Plasma levels for OXY

Increases in plasma OXY are difficult to detect due to pulsatile nature of secretion adn activity of oxytocinase.

Gonadotropin-releasing hormone (GnRH)

Increases luteinizing hormone (LH) and follicle-stimulating hormone (FSH)

Treatment for PRL deficiency

No specific therapy, such as exogenous PRL, is available. Nonspecific aids, such as bottle feeding, must be used.

Division of the pituitary gland

Anterior is glandular, while the posterioir has a large collection of axon terminals

Assessment for prolactinoma

Basal hormone levels (PRL, T4, TSH, LH, FSH) Dynamic tests of hypothalamic-pituitary axes (TRH, CnRH) CT/MRI imaging

Estrogen and progesterone effect on breast formation

Cause increase and finalization of duct system and alveoli. Make sure enough cells with enough receptors to respond to PRL.

Chemical structure of oxytocin (OXY)

Cyclic nonapeptide chemically related to arginine vasopressin. Most available vasopressin agonists and antagonists have some affinty for OXY receptors. At high doses, may block endogenous effects of OXY

Transient hyperprolactinemia

Cyclic, side effect of estradiol positive-feedback on HT-anterior pituitary axis. Women exhibit normal menstrual cycles, BUT ARE INFERTILE. Cause: a small but significant transitory elevation in PRL coincides with preovulatroy estradiol peak, inhibiting GnRH release. Therapeutic suppression of mild-cylce PRL secretion results in conception within 1-3 months in 40% of patients

Somatastatin action

Decreases Growth hormone

Physiological functions of hormones

Digestion, storage, and utilization of nutrients for energy production in cells Salt and water balance Growth and development Reproduction

What is the main prolactin-releasing factor?

TRH (Throtropin releasing hormone)

Effects of OXY

Uterus: Stimulates frequency and force of uterine contractions in third trimester. Uterine muscle responsiveness to OXY is enhanced by estrogen which increases OXY receptors. Progesterone antagonizes this stimulatory effect of OXY, thereby delaying parturition; development of refratoriness to progesterone action results in initiation of labor. Breast: Stimulates milk let-down by action on myoepithelial cells (epithelial cells that act like muscles). Brain: regulation of trust and autonomic systems controlling fear and anxiety