Bruce Tjaden, DO Reproductive Endocrinology The Department of … · 2019-08-14 · Pituitary •...

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

• 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


• Bromocriptine (Parlodel)

• Cabergoline (Dostinex)

• Pergolide – no longer available

• Quinagolide (CV 205-502) – no longer available


• 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


• 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


• 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%



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.


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.


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.


-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.


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.


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.


EE - 100 ug q6h

The effect of L-dopa on showing an acute inhibition of prolactin

secretion by the pituitary.


-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


Percentage of women with hyperprolactinemic

amenorrhea treated with CAB or BRC who

reported adverse effects



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


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



Bruce Tjaden, DO Reproductive Endocrinology The Department of … · 2019-08-14 · Pituitary •...

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Transcript of Bruce Tjaden, DO Reproductive Endocrinology The Department of … · 2019-08-14 · Pituitary •...