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Hyperprolactinemia
Bruce Tjaden, DO
Reproductive Endocrinology
The Department of Obstetrics and Gynecology
University of Kansas School of Medicine – Wichita
Hypothalamus
• A small region located within the base of the brain
• Controls many bodily functions, – eating and drinking,
– sexual functions and behaviors,
– blood pressure and heart rate,
– body temperature maintenance,
– sleep-wake cycle,
– emotional states (e.g., fear, pain, anger, and pleasure).
• Hypothalamic hormones play pivotal roles in the
regulation of many of those functions.
• Hypothalamus is part of the central nervous system
& as such hypothalamic hormones are produced by
nerve cells (i.e., neurons).
Hyperprolactinemia
• Hypothalamus
• Hypophysis (aka, pituitary gland)
Hypophysis
• Anterior pituitary gland = adenohypophysis
• Posterior pituitary gland = neurohypophysis
Hypophysal fossa
Pituitary gland
Pituitary gland
Pituitary
• The anterior pituitary produces several important hormones
that either stimulate target glands (e.g., the adrenal glands,
gonads, or thyroid gland) to produce target gland hormones
or directly affect target organs.
• The anterior pituitary hormones include:
• adreno-corticotropic hormone (ACTH)
• gonadotropins (FSH, LH)
• thyroid-stimulating hormone (TSH), aka, thyrotropin
• growth hormone (GH)
• prolactin (PRL)
Pituitary
• ACTH, gonadotropins, and TSH act on other glands.
– ACTH stimulates the adrenal cortex to produce corticosteroid
hormones (primarily cortisol) as well as small amounts of
female and male sex hormones.
– Gonadotropins comprise two molecules, luteinizing hormone
(LH) and follicle-stimulating hormone (FSH) regulate the
production of sex hormones in the gonads, as well as the
production of germ cells
– TSH stimulates the thyroid gland to produce and release
thyroid hormone.
• GH and prolactin, directly affect their target organs.
Pituitary gland
• It is believed that specific cells in the
pituitary gland generally release only certain
hormones
– Lactotrophs release prolactin
– Gonadotrophs release FSH and LH
– Thyrotrophs release TSH
Pituitary gland
Control of prolactin secretion
PIF PRF
DA
GABA
TRH
VIP
Angiotensin II
lactotrope
receptors
PRL release
tonic
pulsatile
estradiolprogesterone
• complex hypothalamic dual
regulatory system
• involves both inhibitory &
stimulatory substances
• paracrine and autocrine
mechanisms
• peripheral hormones exert
marked effect
Control of prolactin secretion
• Lactotrophs are programed to continually
release prolactin
• Prolactin is under TONIC INHIBITION from
dopamine
• This is UNLIKE any of the other pituitary
hormones
Control of Prolactin Secretion
In contrast to what is seen with all the other
pituitary hormones, the hypothalamus tonically
suppresses prolactin secretion from the
pituitary. In other words, there is usually a
hypothalamic "brake" set on the lactotroph, and
prolactin is secreted only when the brake is
released.
If the pituitary stalk is severed, prolactin secretion
increases, while secretion of all the other pituitary
hormones fall dramatically due to loss of
hypothalamic releasing hormones.
Prolactin inhibiting factor
tyrosine
dihydroxyphenylalanine
dopamine
portal circulation
binds to lactotropes
Dopamine is the hypothalamic brake
that inhibits prolactin release
Heterogeneity of prolactin
• multiple isoforms of PRL have been identified in plasma and the
pituitary
• “little” PRL - m.w. ~ 23,000 non-glycosylated form with high
receptor binding, bioactivity and full immunoactivity
• glycosylated forms m.w. ~ 25,000 (G1 and G2) with reduced
immunoreactivity and G1 25% of the bioactivity of G2
• “big” PRL - m.w. ~ 50,000, dimeric and trimeric forms of
glycosylated PRL
• “big-big” PRL (macroprolactin)- m.w. ~ 100,000, possibly
representing G-PRL covalently bound to immunoglobulins
x
NH2 COOH
Growth hormone
xNH2
COOHx
Prolactin
Prolactin secretion
• Diurnal secretion
• Lowest in early AM
• Increased after meals (especially high protein)
• Increases in response to stress
• Increases with estrogen intake
Pituitary gland
• Enlarges during pregnancy
– Lactotroph hyperplasia
– (increases ~ 50% in size)
• Prolactin levels are elevated during pregnancy
– End of the 1st trimester up to 40 ng/mL
– End of the 2nd trimester up to 150 ng/mL
– End of the 3rd trimester up to 400 ng/mL
Serum prolactin concentrations basally and in response to suckling as a function of time after delivery. Within the first week after delivery, the basal value is high relative to the nonpregnant state, and there may be a further increase in response to suckling. Several weeks after delivery, the basal value is close to that of the nonpregnant state, but there is still a pronounced increase in response to suckling. Three months after delivery, the basal value is similar to that of the nonpregnant state, and there is a minimal response to suckling, if any.Data from Tyson JE, Ito P, Guyda H, et al. Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 1972; 113:14.
HPO dysfunction in patients with hyperPRL
• Hypo-estrogenic
• DO NOT have vasomotor hot flushes
• Greater changes in pulsatile LH secretion than FSH secretion
• Decreased bone density has been demonstrated in women with normal estrogen levels
• Increased androgen secretion
• Hyper-insulinemia and insulin resistance
Amenorrhea associated with hyperprolactinemia
• is secondary to PRL inhibition of the pulsatile
release of GnRH (i.e., a decrease in GnRH)
• this inhibition is mediated by increased opiod
activity
Hyperprolactinemia• 1/3 of women with no obvious cause of amenorrhea
• 1/3 of women with hyperprolactinemia will have
galactorrhea
• 1/3 of women with galactorrhea will have normal menses
• 1/3 of women with galactorrhea will have pituitary tumor
• ~2/3 of women with amenorrhea and galactorrhea will
have pituitary tumor
• Though classically associated with hyperprolactinemia
galactorrhea is a late clinical symptom
Clinical spectrum of hyperprolactinemia
• asymptomatic
• luteal phase defect
• ovulatory dysfunction
• amenorrhea
galactorrhea
Causes of hyperprolactinemia
• Prolactinoma
• Medications: estrogen, methyl-dopa, metoclopramide,
narcotics, phenothiazine derivatives, reserpine, tricyclic
antidepressants
• Compression of the pituitary stalk
• Infiltrative disorders of the pituitary
• Hypothyroidism (centrally mediated)
• Chronic renal failure
• Cirrhosis
• Stimulation of the intercostal nerve
• Idiopathic
Causes of hyperprolactinemia
idiopathic: elevated prolactin levels
but no demonstrable
pituitary pathology
(“tumor”) noted on
radiographic imaging
microadenoma: pituitary tumor less than
10 mm in greatest
diameter
macroadenoma: pituitary tumor greater
than than 10 mm in any
diameter
Prolactin secreting adenomas
• Most common pituitary tumor
• ~ 50% of all pituitary adenoma found at autopsy
• In autopsy series 9-27% of cases have pituitary
tumor …. equal sex distribution
• Clinical manifestations are more common in women
…. probably secondary to the influence of estrogen
Treatment of hyperprolactinemia
• Medical
vs
• Surgical
Treatment of hyperprolactinemia
1. Medical therapy
2. Medical therapy
3. Medical therapy
4. Medical therapy
5. Surgery
Prolactinomas: surgical treatment
• complete resolution– microadenomas : 80%
– macroadenomas : 40%
• recurrence rates– microadenomas : 70%
– macroadenomas : 10%
• complications– panhypopituitarism ~ 10%
following surgical resection of
a macroadenoma
– others
Hyperprolactinemia: medical therapy
• Because dopamine is the major PRL inhibitory factor
• Dopamine agonist are the mainstay of medical
therapy
Hyperprolactinemia: medical therapy
• Bromocriptine (Parlodel)
• Cabergoline (Dostinex)
• Pergolide – no longer available
• Quinagolide (CV 205-502) – no longer available
Hyperprolactinemia: medical therapy
• Bromocriptine (Parlodel)
– oral: 2.5 mg tabs daily 2.5 to 10 mg
– vaginal:2.5 mg tabs daily 2.5 to 10 mg (?)
– depot: 50 mg /mL monthly 50-75 mg
• Cabergoline (Dostinex)
– oral 0.5 mg tabs twice weekly
– vaginal:0.5 mg tabs daily 2.5 to 10 mg (?)
Dopamine, bromocriptine & cabergoline
dopamine
N
HN Br
CH
C
O
N
H
O
O
N
O
N
CH2CH(CH3)2
CH
CH(CH3)2
bromocriptine
N
N - CH2- CH = CH2
H
H
H
CO - N - CONH- CH2 CH3
CH2 CH2 CH2 N - CH3
CH3
cabergoline
Dopamine agonists – Side Effects
• Nasal congestion
• Headaches
• Dizziness (postural hypotension)
• Nausea
Hyperprolactinemia: treatment
The most important question:
IS THE PATIENT SYMPTOMATIC ?
If yes, what are the symptoms?
galactorrhea
amenorrhea
infertility
CNS symptoms
What are the patients goals (desires) ?
reassurance
elimination of galactorrhea
menstrual regulation
fertility
relief of other symptoms
prevention of osteoporosis
Hyperprolactinemia: treatment
• Conservative / expectant management
• Not all elevated PRL are secondary to pituitary disease
(eg, PCOS)
• Oral contraceptives
• Dopamine agonists
– Parlodel (bromocriptine)
– Dostinex (cabergoline)
• Surgery (?)
issues of concern relating to treatment
• osteoporosis
• estrogen effect on the pituitary
• natural history of adenomas
Hyperprolactinemia: treatment
• Parlodel or Dostinex
• 2.5 mg qd vs 0.5 mg q3-4d
• start at hs
• warn patients about symptoms
• repeat PRL in 2 weeks,
– if level is decreasing repeat again in 2 weeks
– if level is not decreasing, increase dose
• consider stopping therapy at one year to re-
evaluate PRL level and radiographic imaging
Resolution of galactorrhea is
much slower than resumption of
ovulation and normalization of
menstruation!
HyperPRL and pregnancy
• Discontinue dopamine agonist with (+) pregnancy test
• Follow the patients clinically
• Clinical evidence of tumor enlargement should prompt
radiographic studies
• Re-start dopamine agonist therapy if indicated…… no
evidence of adverse effects in mother or baby
• ~ 5% of micro-adenoma “recur” or enlarge w/ pregnancy
• ~ 15% of macro-adenomas “recur” or enlarge w/ pregnancy
SP 28 yo p0000 referred from PCP for amenorrhea and galactorrhea
Prolactin 370 ng/mL TSH 2.0 uIU/mL FSH 2.5 mIU/mL
LH 3.0 mIU/mL AMH 1.9 ng/mL
MRI - 9 mm homogenous mass
Parlodel 2.5 mg po qd
3 wks later PRL 345 ng/mL
Parlodel 5 mg po qd
Calls one week later can’t tolerate the medication
Change to vaginal administration, if tolerates medication, repeat
PRL in 2-3 weeks
3 wks later PRL 190 ng/mL
+2.5 wks later PRL 50 ng/mL
+3 wks later PRL 15 ng/mL
PC 2 wks later spontaneous menses
Das Ende
Nausea
Vomiting
Constipation
Headaches
Dizziness / vertigo
Abd. pain / dyspepsia
Fatigue / weakness
Breast pain
Depression
Hot flushes
BRC
n = 231
115 (50)
22 (10)
21 (9)
68 (29)
59 (26)
45 (20)
41 (18)
12 (5)
4 (2)
5 (2)
CAB
n = 221
68 (31)
10 (4)
15 (7)
66 (30)
55 (25)
34 (15)
29 (13)
10 (4)
7 (3)
7 (3)
A comparison of cabergoline and bromocriptine in the treatment of
hyperprolactinemic amenorrhea. N Engl J Med 331:904-9, 1994
Adverse effects of treatment with BRC and CAB in
women with hyperprolactinemic amenorrhea
Cabergoline vs bromocriptine:
drug safety
adverse side effects
BRC 78%
CAB 68%
A comparison of cabergoline and bromocriptine in the treatment of
hyperprolactinemic amenorrhea. N Engl J Med 331:904-9, 1994
Two thirds of women reporting side effects from either
medication the side effects developed within two weeks of
starting the medications
Overall adverse side effects were less frequent and less severe with
CAB (14% vs 20%)
Discontinued therapy
CAB 7%
BRC 12%
Kletzky
Falsetti
Moriondo
Archer
No.
19
35
36
17
Reduced PRL (%)
[% to normal]
100 [74]
89
100 [22]
94
Kletzky
Falsetti
Moriondo
Archer
21
23
-
-
100
96
-
-
NL menses
(%)
100
94
-
94
100
100
-
-
Microadenomas
Idiopathic hyperprolactinemia
adapted from Katz et al, Contemp Ob/Gyn March 1992
Bromocriptine therapy
Cost of medications for hyperprolactinemia
• Bromocriptine Parlodel 2.5 mg #30 / $55
• Cabergoline Dostinex 0.5 mg #8 / $200
• Pergolide Permax not available in the US
• Quinagolide Norprolac not available in the US
Cost of medications for hyperprolactinemia
• Parlodel 2.5 mg bid 60 tabs /mo $110
• Dostinex 0.5 mg q3-4d 8 tabs / mo $200
Around the clock prolactin concentrations in 8 normal women.
Acute elevations of PRL occurs shortly after the onset of sleep &
begins to decline shortly before awakening.
(adapted Reproductive Endocrinology, Yen & Jaffe, 1991)
0
10
20
30
40
50
800 1600 2400 800
lunch
dinner
sleep
6
8
10
12
14
16
clock hours
PR
L
ng
/mL
lunch
6
8
10
12
14
16
clock hours
PR
L
ng
/mL
sham lunch
Serum PRL levels in seven normal fasting volunteers before
and after the ingestion of a regular mixed meal or sham meal
(seeing and chewing only) at 1200 hours.
(adapted from Reproductive Endocrinology, Yen & Jaffe, 1991)
0
20
40
60
80
100
120
140
160
0 3 6
hours
PR
L n
g/m
L
Acute release of PRL in response to anesthesia and surgical
stress in women undergoing laparotomy. Arrows indicate pre-
medication, hatched bars represent anesthesia and black bars
represent the time of surgery.
(adapted from Reproductive Endocrinology, Yen & Jaffe, 1991)
0
20
40
60
80
100
120
140
160
0 1 2 3 4 5 6 7 8
hours
PR
L n
g/m
L
0
50
100
150
200
250
300
350
400
450
1 2 3 4 5 6 7
days
Se
rum
PR
L %
in
cre
ase
Changes in serum PRL concentrations determined at 0800 &
2000 each day before and during treatment with EE.
(adapted from Reproductive Endocrinology, Yen & Jaffe, 1991)
EE - 100 ug q6h
Clinical features of women presenting
with PRL-secreting adenomas
symptoms
galactorrhea (389)
headache (259)
visual complaints (264)
infertility (56)
2o amenorrhea, median number
of months (389)
microadenoma
91.9
57.3
10.5
34.5
24
macroadenoma
91.9
57.3
10.5
34.5
24
Transsphenoidal pituitary resection for preoperative diagnosis of
prolactin secreting pituitary adenoma in women: long term follow-up.
Feigenbaum et al , J Clin Endocrinol Metab 81: 1711-19, 1996
The effect of L-dopa on showing an acute inhibition of prolactin
secretion by the pituitary.
(adapted from Reproductive Endocrinology, Yen & Jaffe, 1991)
-50
-40
-30
-20
-10
0
10
20
30
40
2 4 6 8
Hours
pe
rce
nt
ch
an
ge
L-Dopa
0.5 mg po
PRL
Around the clock prolactin concentrations in 8 normal women.
Acute elevations of PRL occurs shortly after the onset of sleep &
begins to decline shortly before awakening.
(adapted Reproductive Endocrinology, Yen & Jaffe, 1991)
0
10
20
30
40
50
800 1600 2400 800
lunch
dinner
sleep
6
8
10
12
14
16
clock hours
PR
L
ng
/mL
lunch
6
8
10
12
14
16
clock hours
PR
L
ng
/mL
sham lunch
Serum PRL levels in seven normal fasting volunteers before
and after the ingestion of a regular mixed meal or sham meal
(seeing and chewing only) at 1200 hours.
(adapted from Reproductive Endocrinology, Yen & Jaffe, 1991)
0
20
40
60
80
100
120
140
160
0 3 6
hours
PR
L n
g/m
L
Acute release of PRL in response to anesthesia and surgical
stress in women undergoing laparotomy. Arrows indicate pre-
medication, hatched bars represent anesthesia and black bars
represent the time of surgery.
(adapted from Reproductive Endocrinology, Yen & Jaffe, 1991)
0
20
40
60
80
100
120
140
160
0 1 2 3 4 5 6 7 8
hours
PR
L n
g/m
L
0
50
100
150
200
250
300
350
400
450
1 2 3 4 5 6 7
days
Se
rum
PR
L %
in
cre
ase
Changes in serum PRL concentrations determined at 0800 &
2000 each day before and during treatment with EE.
(adapted from Reproductive Endocrinology, Yen & Jaffe, 1991)
EE - 100 ug q6h
The effect of L-dopa on showing an acute inhibition of prolactin
secretion by the pituitary.
(adapted from Reproductive Endocrinology, Yen & Jaffe, 1991)
-50
-40
-30
-20
-10
0
10
20
30
40
2 4 6 8
Hours
pe
rce
nt
ch
an
ge
L-Dopa
0.5 mg po
PRL
Surgical treatment for prolactinomas
Wilson
Randall
Thompson
Saitoh
Serri
Parl
No.
40
54
61
50
28
NR
Remission
93
88
75
54
85
13
Recurrence
0
NR
NR
NR
50
31
No.
87
46
8
48
16
NR
Remission
54
35
50
19
47
NR
Recurrence
4.3
NR
NR
NR
80
91
Microadenomas Macroadenomas
NR = not reported
adapted from Katz et al, Contemp Ob/Gyn March 1992
Percentage of women with hyperprolactinemic
amenorrhea treated with CAB or BRC who
reported adverse effects
A comparison of cabergoline and bromocriptine in the treatment of
hyperprolactinemic amenorrhea. N Engl J Med 331:904-9, 1994
0
10
20
30
40
50
60
0 2 4 6 8 10 12 14 16 18 30 22 24
weeks of treatment
ad
vers
e e
ffects
(%
of
wo
me
n)
BRC
CAB
0
20
40
60
80
100
120
140
160
180
200
0 2 4 6 8 10 12
BCR-oral
BCR-vaginal
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12
PRL-oral
PRL-vaginal
Circulating levels of bromocriptine (BRC) and prolactin (PRL)
after intra-vaginal and oral administration of a 2.5-mg tablet.
(adapted from Katz et al , Fertil Steril 55: 822, 1991)
Bromocriptine therapy: macroadenomas
Corenblum
Spark
Wass
Wollesen
Weiss
Zarate
Johnston
Warfield
Molitch
Liuzzi
van’t Verlatt
Sieck
No.
8
10
18
4
19
12
15
6
27
38
12
24
Reduced PRL (%)
[% to normal]
100
100 [80]
100 [38]
100
100
100 [83]
100 [93]
100 [50]
100 [66]
97 [78]
100 [83]
96 [63]
NL menses
(%)
100
90
61
100
53
33
67
67
100
76
100
96
adapted from Katz et al, Contemp Ob/Gyn March 1992
Plasma prolactin levels in 12 individuals patients with
macroadenomas after withdrawal of bromocriptine.
2 4 6 8 10 12
weeks
Adapted from van’t Verlaat Clin Endocrinol 34:175-178, 1991
normal
3 patients
Distribution of women with hyperprolactinemia
amenorrhea according to the final dose of
bromocriptine or cabergoline
2.5 5 7.5 100
25
50
75
100
125
150
175
2.5 5 7.5 10 0.5 1 1.5 20.5 1 1.5 2
Bromocriptine
total daily dose
Cabergoline
total daily dose
Red bars represent those
completing 24 weeks of
therapy
White bars represent
those discontinuing
treatment early
A comparison of cabergoline and bromocriptine in the treatment of
hyperprolactinemic amenorrhea. N Engl J Med 331:904-9, 1994