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
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‧
‧
‧
‧
‧
‧
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 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
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,
epididymis,
of 7 ng/ml.
‧ brian, lung,
‧ lymphocyte,
myocardium
Hyperprolactinemia
Pathologic 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
Hyperprolactinemia
Pharmacologic 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
Hyperprolactinemia
Physiologic conditions
– Sleep
– Feeding
– Exercise
– Coitus
– Menstrual cycle
– Amniotic fluid
– Pregnancy
– Puerperium
– Nursing
– Fetus
– Neonate
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 8085%, 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 8085%
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 2050%
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)
Total(121)
81(66.9%)
Oligozoospermia(42)
30(71.4%)
Asthenozoospermia(51) 30(58.8%)
Azoospermia(28
21(75.0%)
PRL>14(ng/ml)
40(33.1%)
12(28.6%)
21(41.2%)
7(25%)
Hyperprolactinemia in men with
asthenozoospermia, oligozoospermia, or
azoospermia.Arch Androl 1997
Group
PRL(ng/ml) T(ng/ml)
E2(pg/ml)
Normozoosp
ermia(46)
Oligozoosper
mia(42)
Asthenozoos
permia(51)
Azoospermia
(28)
7.3(2.1)
4.9(1.5)
25.9(8.9)
LH(mIU/ml) FSH(mIU/ml
)
4.7(3.6)
4.7(3.6)
12.6(7.8)*
5.1(1.5)
31.9(15.3)
4.8(3.1)
6.4(5.8)
13.9(6.6)*
5.2(1.4)
34.9(33.0)
4.1(3.3)
4.7(4.0)
10.9(4.8)*
4.5(1.8)
26.2(16.0)
10.3(8.6)*
12.1(9.1)*
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:
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
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 estrogeninduced 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