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Hyperprolactinemia and Infertility

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									Hyperprolactinemia and Infertility


       Yung-Chieh Tsai, M.D.

 Department of Obstetrics and Gynecology
      Chi Mei Foundation Hospital
Prolactin
Molecular 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.
Prolactin
Member 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.
Prolactin
Cell 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.
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
Prolactin
Isoforms
• Little PRL:80-90%,
  MW 23000K,
  nonglycosylated
  monomeric with high
  receptor binding
  bioactivity and full
  immuno-activity
• Two glycosylated
  forms:G1 and G2
Prolactin
Isoforms
• 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
Prolactin
Physiology
‧   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
Prolactin
Function
‧ on the breast     ‧ on the bones
‧ on gonadotropin   ‧ on carbohydrate
  secretion           metabolism
‧ on the ovary      ‧ on the kidney
‧ on the testes     ‧ on the immune
‧ on the adrenal      system
  cortex
 Prolactin
 Receptors
                          Identified receptors in
PRL binds to its
                          ‧ breast, liver, ovary,
receptor with high
                          ‧ kidney tubules
affinity.Half-saturation
                          ‧ adrenal cortex
of the receptor occurs at ‧ prostate, testes,
hormone concentration       seminal vesicles,
of 7 ng/ml.                 epididymis,
                          ‧ brian, lung,
                          ‧ lymphocyte,
                            myocardium
Hyperprolactinemia
Pathologic conditions
• Hypothalamic lesions   • Reflex causes
Craniopharyngioma        Chest wall injury
Glioma                   herpes zoster neuritis
Granuloma                Upper abdominal op
Stalk transection        • Hypothyroidism
Irradiation damage       • Renal failure
Pseudocysts
                         • Ectopic pdoduction
• Pituitary tumors       Bronchogenic carcinoma
Cushing disease          Hypernephroma
Acromegaly
Prolactinoma
Hyperprolactinemia
Pharmacologic conditions
• Estrogen therapy       • CNS-DA depleting
• Anesthesia               agents
• DA receptor blocking     Reserpine
  agents                   -methyldopa
  Phenothiazones           MAO inhibitor
  Haloperidol            • Stimulation of
• Inhibition of DA         serotoninergic system
  turnover                 Amphetamines
  Opiates                  Hallucinogens
• DA re-uptake blocker   • Histamine H2-receptor
  Nomifensine              antagonists
Hyperprolactinemia
Physiologic conditions
    – Sleep                            – Pregnancy
    – Feeding                          – Puerperium
    – Exercise                         – Nursing
    – Coitus                           – Fetus
    – Menstrual cycle                  – Neonate
    – 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.
Hyperprolactinemia
Effects on Endocrine-Metabolic Functions

•   Increase lactogenesis
•   Androgenic effects
•   Liver:reduced SHBG
•   Hyperinsulinemia and insuline resistance
•   Decrease bone density
•   Hypothalamic-pituitary dysfunction
•   Impaired Ovarian Steroidogenesis
Prolactin
Neuroendocrine 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.
Prolactin
Neuroendocrine 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
Hyperprolactinemia
Clinical 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.
Hyperprolactinemia
Diagnostic 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!.)
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
Hyperprolactinemia
Inhibition of pulsatile GnRH secretion

Hyperprolactinemia
inhibit GnRH activity
by interacting with
hypothalamic DA and
opioidergic system
via the short-loop
feedback mechanism.
Hyperprolactinemia
Inhibition of pulsatile GnRH secretion
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)
Hyperprolactinemia
Inhibition 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)
Hyperprolactinemia
Inhibition 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)
Hyperprolactinemia
Impaired 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)
Hyperprolactinemia
Treatment
• 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%
Hyperprolactinemia
Treatment
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%
Hyperprolactinemia
Treatment
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
Hyperprolactinemia
In 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..
Hyperprolactinemia
In 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.
Hyperprolactinemia
Inhibition of 5-alpha-reductase enzyme
       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%)
            Hyperprolactinemia in men with
        asthenozoospermia, oligozoospermia, or
            azoospermia.Arch Androl 1997

Group          PRL(ng/ml) T(ng/ml)     E2(pg/ml)    LH(mIU/ml) FSH(mIU/ml
                                                               )
Normozoosp     7.3(2.1)     4.9(1.5)   25.9(8.9)    4.7(3.6)   4.7(3.6)
ermia(46)
Oligozoosper   12.6(7.8)*   5.1(1.5)   31.9(15.3)   4.8(3.1)     6.4(5.8)
mia(42)
Asthenozoos    13.9(6.6)*   5.2(1.4)   34.9(33.0)   4.1(3.3)     4.7(4.0)
permia(51)
Azoospermia    10.9(4.8)*   4.5(1.8)   26.2(16.0)   10.3(8.6)*   12.1(9.1)*
(28)
       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.
    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
    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.
 Hyperprolactinemia
 Differential Diagnosis

A.Medications:           F.Neurogenic: breast,
  neuroleptics,            chest wall, spinal cord
  metoclopramide,          lesions
  methyldopa, MAO        G.Hypothalamic disease:
  inhibitors,tricyclic     tumors, sarcoidosis,
  antidepressants,         non-secreting pituitary
  verapamil                tumors, neuraxis
B.Pregnancy                irradiation, stalk section
C.Hypothyroidism         H.Empty sella syndrome
D.Renal insufficiency    I. Acromegaly
E.Cirrhosis
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
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
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
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.
   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.
   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

								
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