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Prolactin Molecular Structure. A single polypeptidecontaining 199 aminoacid residues withmolecular weight22000K.The structureis folded to form aglobular shape, andthe folds areconnected by threedisulfide bonds.. Prolactin Member of somatomammotropin family. Due to the remarkablehomology of theamino acid sequenceamong the moleculesof PRL, GH and PL(40%). It was notuntil 1970 that theprolactine moleculewas identified..
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1. Hyperprolactinemia and Infertility Yung-Chieh Tsai, M.D.
Department of Obstetrics and Gynecology
Chi Mei Foundation Hospital
2. ProlactinMolecular Structure A single polypeptide
containing 199 amino
acid residues with
molecular weight
22000K.The structure
is folded to form a
globular shape, and
the folds are
connected by three
disulfide bonds.
3. ProlactinMember of somatomammotropin family Due to the remarkable
homology of the
amino acid sequence
among the molecules
of PRL, GH and PL
(40%). It was not
until 1970 that the
prolactine molecule
was identified.
4. ProlactinCell of Origin PRL is made by the
pituitary lactotrophs.
The number of
lactotrophs are
similar in number in
both sexs and do not
change significantly
with age.
5. Prolactin Synthesis and metabolism Prolactine is secreted mainly by the lactotroph in the pituitary?
Normal serum level= 10-25 ng/ml, half life =20 minutes
Metabolized in liver and kidney
6. ProlactinIsoforms Little PRL:80-90%, MW 23000K, nonglycosylated monomeric with high receptor binding bioactivity and full immuno-activity
Two glycosylated forms:G1 and G2
7. ProlactinIsoforms Big PRL:8-20%, MW 50000K, mixture of dimeric and trimeric forms of G-PRL
Big-big PRL:1-5%, MW 100000K, polymeric, possibly representing G-PRL coupled covalently with immunoglobulin
8. ProlactinPhysiology Metabolic clearance and production rates
Hormone secretion patterns
Changes in PRL with age
Changes in PRL during menstrual cycle
Changes in PRL levels during pregnancy
Changes in PRL with postpartum lactation
Effects of thyroid hormone status on PRL
9. ProlactinFunction on the breast
on gonadotropin secretion
on the ovary
on the testes
on the adrenal cortex on the bones
on carbohydrate metabolism
on the kidney
on the immune system
10. ProlactinReceptors PRL binds to its
receptor with high
affinity.Half-saturation
of the receptor occurs at
hormone concentration
of 7 ng/ml. Identified receptors in
breast, liver, ovary,
kidney tubules
adrenal cortex
prostate, testes, seminal vesicles, epididymis,
brian, lung,
lymphocyte, myocardium
11. HyperprolactinemiaPathologic conditions Hypothalamic lesions
Craniopharyngioma
Glioma
Granuloma
Stalk transection
Irradiation damage
Pseudocysts
Pituitary tumors
Cushing disease
Acromegaly
Prolactinoma
Reflex causes
Chest wall injury
herpes zoster neuritis
Upper abdominal op
Hypothyroidism
Renal failure
Ectopic pdoduction
Bronchogenic carcinoma
Hypernephroma
12. HyperprolactinemiaPharmacologic conditions Estrogen therapy
Anesthesia
DA receptor blocking agents
Phenothiazones
Haloperidol
Inhibition of DA turnover
Opiates
DA re-uptake blocker
Nomifensine CNS-DA depleting agents
Reserpine
?-methyldopa
MAO inhibitor
Stimulation of serotoninergic system
Amphetamines
Hallucinogens
Histamine H2-receptor antagonists
13. Sleep
Feeding
Exercise
Coitus
Menstrual cycle
Amniotic fluid
If a woman's prolactin level is elevated the first time it is tested,
a second sample should be checked when she is fasting and
non-stressed.
Pregnancy
Puerperium
Nursing
Fetus
Neonate HyperprolactinemiaPhysiologic conditions
14. HyperprolactinemiaEffects on Endocrine-Metabolic Functions Increase lactogenesis
Androgenic effects
Liver:reduced SHBG
Hyperinsulinemia and insuline resistance
Decrease bone density
Hypothalamic-pituitary dysfunction
Impaired Ovarian Steroidogenesis
15. ProlactinNeuroendocrine Regulation A. Dual hypothalamic regulation
1. PRFs: TRH, VIP, PHM
2. PIFs: dopamine is primary–possible role for GAP (GnRH-striated peptide)
3. PIF activity is dominant; PRL is under tonic inhibition by hypothalamus. If the stalk is cut, PRL levels rise whereas other hormone levels fall.
16. ProlactinNeuroendocrine Regulation B. Primary target organ is the breast: suckling stimulates afferent pathways through cord to elicit PRL release in puerperium
C. Metabolic factors: arginine and hypoglycemia stimulate
D. Estrogen stimulates lactotrophs directly
E. PRL is secreted episodically with nocturnal surge
17. HyperprolactinemiaClinical Manifestation A. Galactorrhea indicates elevated PRL in 10% of women and 99% of men
B. Amenorrhea: indicates elevated PRL in 15% of women
C. Galactorrhea plus amenorrhea: indicates elevated PRL in 75%of women
D. Infertility: indicates elevated PRL in up to 33% of women
E. Osteoporosis: increased with elevated PRL--due to estrogen lack. If normal menses are present, osteoporosis does notoccur.
18. HyperprolactinemiaDiagnostic Evaluation A. Basal PRL levels at least twice:
1. PRL >200 ng/mL = prolactinoma or renal failure
2. PRL <200 ng/ml = prolactinoma or any of the other causes
B. Routine history and physical, SMA 20 and TSH excludes almost all above except hypothalamic and pituitary disease
C. CT or MRI to differentiate hypothalamic/ pituitary disease from idiopathic, even with (anything > 25 mg/m!.)
19. Hyperprolactinemia Mechanisms on Reproductive Dysfunction A. Inhibition of pulsatile GnRH secretion
B. Interference with gonadotropin action in ovary
C. Interference with estrogen positive feedback
D. Inhibition of FSH-directed ovarian aromatase
E. Inhibition of progesterone synthesis
F. Impaired follicle development
G. Inhibition of 5-alpha-reductase enzyme in men,
thereby decreasing the conversion of testosterone
to DHT
20. Hyperprolactinemia Inhibition of pulsatile GnRH secretion Hyperprolactinemia
inhibit GnRH activity
by interacting with
hypothalamic DA and
opioidergic system
via the short-loop
feedback mechanism.
21. Hyperprolactinemia Inhibition of pulsatile GnRH secretion
22. Hyperprolactinemia Interference with gonadotropin action in ovary Animal study revealed prolactine can act as a
potent inhibitor of LH-mediated androgen
synthesis.Since androgen serve as substrates
for estrogen production in the ovary,
hypoestrogenism seen with hyperprolactinemic
syndrome may be of ovarian origin.(Endocrinology
111:2001, 1982)
23. HyperprolactinemiaInhibition of FSH-directed ovarian aromatase High affinity prolactine receptors has been demonstrated on the surface of granulosa cells.These cells contain the aromatase enzyme.FSH induces aromatase enzyme activity in vitro and this effect is blocked by coincubation granulosa cells with high levels of prolactine(100 ng/ml).(Fertil Steril 38:182 1982)
24. HyperprolactinemiaInhibition of progesterone synthesis Prolactine is involved in the induction of LH receptors to maintain progesterone synthesis.Prolactine is necessary for complete lutenization.However, very high prolactin level in the early phase of follicular growth inhibit progesterone secretion.(J Endocrinol 64:555, 1975)
25. HyperprolactinemiaImpaired follicle development Samples of follicular fluid obtained from mature follicles contain lower PRL concentration approximating those found in serum,Highest PRL level occurs in the fluid of small follicle, reaching 5-6 fold greater than those in serum.If prolactin exceeds 100 ng/mL, 100% of the follicles are atretic.(Nature 250:653 1974)
26. HyperprolactinemiaTreatment A. Idiopathic hyperprolactinemia bromocriptine is effective in 85%
B. Microprolactinomas
1.Transsphenoidal surgery: initial cure rate 80-85%, with a recurrence rate of 20%. Depends on skill of surgeon
2.Radiotherapy: ineffective and takes a long time
3.Bromocriptine: restores PRL to normal in 80-85%
27. HyperprolactinemiaTreatment 4.Observation only; follow PRL. Repeat CT/MRI if PRL levels rise
C. Macroprolactinomas
1. Surgery: cure rates <50% and very much dependent on size with recurrence rates 20-50%
2. Bromocriptine: size reduction to <50% of original size in 50%, to 50% in 16% and to 10-30% in 33%
28. HyperprolactinemiaTreatment a. First evidence of size reduction may occur after 6 weeks
b. Size reduction does not correlate with basal or nadir PRL or percentage reduction in PRL levels
c. In first 2-3 years, most will reexpand
d. After a few years, few reexpand
29. HyperprolactinemiaIn Men The role of serum prolactine in male infertility is still unclear.Normal PRL serum level have an essential permissive role in testicular and extratesticular physiology. PRL receptors are present on the membrane surfaces of testicular interstitial cells and PRL appear to promote the synthesis of testosterone by increasing the number of LH receptors in Leydig cells..
30. HyperprolactinemiaIn Men Hyperprolactinemia in men is manifested clinically by signs of androgen deficiency and infertility. It may be associated with impotence, loss of libido, and rarely gynecomastia and galactorrhea. Headaches and visual defects occur in patients with large pituitary adenomas.
While some men with apparent hyperprolactinemia are free of symptoms and compliants.
31. HyperprolactinemiaInhibition of 5-alpha-reductase enzyme
32. Hyperprolactinemia in men with asthenozoospermia, oligozoospermia, or azoospermia.Arch Androl 1997 Group PRL<14(ng/ml) PRL>14(ng/ml)
Total(121) 81(66.9%) 40(33.1%)
Oligozoospermia(42) 30(71.4%) 12(28.6%)
Asthenozoospermia(51) 30(58.8%) 21(41.2%)
Azoospermia(28 21(75.0%) 7(25%)
33. Hyperprolactinemia in men with asthenozoospermia, oligozoospermia, or azoospermia.Arch Androl 1997
34. Hyperprolactinemia in men with asthenozoospermia, oligozoospermia, or azoospermia.Arch Androl 1997 Patients with idiopathic oligoasthenozoospermia and hyperprolactinemia were treated with 2.5 mg of bromocriptine daily for 6 months, resulting in a nonmeasurable effect on their sperm analysis.
In conclusion, two-thirds of patients with oligozoospermia, asthenozoospermia, and azoospermia have normal PRL levels. Bromocriptine was of no therapeutic utility.
35. Influence of serum prolactin on semen characteristics and sperm function.Int J Fertil 1991 Serum samples of 204 males were examined during a 1-year period.
No significant correlation of sPRL concentration was found with results of semen analysis, PCT outcome. The functional sperm capacity was better in the groups of patients with sPRL above the median level (P less than .005). No significant difference in pregnancy rate was found between the high (greater than 5 ng/mL) and low (less than or equal to 5 ng/mL) prolactin groups; these were 20% and 26%, respectively
36. Influence of serum prolactin on semen characteristics and sperm function.Int J Fertil 1991 The results suggest that routine screening of asymptomatic male patients during infertility investigation for sPRL concentration is not helpful for assessing fertility prognosis. Prolactin should be preferentially determined in patients with clinical symptoms of hyperprolactinemia to exclude pituitary adenoma.
37. Hyperprolactinemia Differential Diagnosis A.Medications: neuroleptics, metoclopramide, methyldopa, MAO inhibitors,tricyclic
antidepressants,
verapamil
B.Pregnancy
C.Hypothyroidism
D.Renal insufficiency
E.Cirrhosis
F.Neurogenic: breast, chest wall, spinal cord lesions
G.Hypothalamic disease: tumors, sarcoidosis, non-secreting pituitary tumors, neuraxis irradiation, stalk section
H.Empty sella syndrome
I. Acromegaly
38. Hyperprolactinemia Special Considerations A. Tumor fibrosis: primarily a problem for macroadenomas in that it may decrease later surgical cure rate. If tumor shrinks bromocriptine should be continued.
B. Long-term bromocriptine: taper and try to discontinue
C. Growth of tumor while on bromocriptine: noncompliance or possible carcinoma or hemorrhage into tumor
39. Hyperprolactinemia Special Considerations D. Options for patients still hyperprolactinemic after surgery who do not respond to bromocriptine
1.Other dopamine agonists: cabergoline (Dostinex) is well tolerated, once weekly dosing, pergolide (Permax), is once daily
2. Reoperation
3. Irradiation
40. Hyperprolactinemia Special Considerations E. Intolerance to bromocriptine
1. Try intravaginal bromocriptine: no nausea and vomiting
2. Try cabergoline
F. Concomitant estrogen use: safe for almost all patients. Must follow PRL levels to detect the rare patient that may have an estrogen-induced increase in tumor size
41. Hyperprolactinemia in Polycystic Ovaries PRL levels have been found to be elevated in 19-50% of women with polycystic ovaries(PCO). The precise link as to what is causing what is still not firmly established, but it may be the hyperestrogen levels that are occurring in PCO.
Bromocriptine treatment of hyperprolactinemia patients with PCO usually results in a reduction of testosterone and LH levels and resumption of ovulatory cycles.
42. Pregnancy and Prolactinomas A. No teratogenicity or other untoward effects on fetus of bromocriptine in >6,000 pregnancies
B. Risk of symptomatic microadenoma enlargement: 1.6%
C. Risk of symptomatic macroadenoma enlargement: 15.5% if no previous surgery/irradiation but only 4.3 % if previous surgery/irradiation.
43. Pregnancy and Prolactinomas Options:
1. Stop bromocriptine when pregnancy diagnosed and observe. If tumor enlarges, reinstitute bromocriptine----if fails, surgery.
2. Operate on tumor prepregnancy to allow room to enlarge
3. Continue bromocriptine throughout pregnancy