Management Of Prolactinomas During Pregnancy

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• Management Of Prolactinomas During Pregnancy
• Dr. Majeed Mustafa , FRCP (Ed.)
• Consultant Endocrinologist Diabetologist
• GDC Hospital , Abu Dhabi
• 4th April 2009

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Hyperprolactinemia Infertility

• PRL is a 198 amino acid polypeptide chain
  produced in the lactotroph cells of the anterior
  pituitary gland.
• High PRL Amenorrhea
• Infertility
• Galactorrhea

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Hyperprolactinemia Infertility

• Frequency 1 of general population
• Patients presenting with galactorrhea and
  amenorrhea 75 have high PRL
• 30 have prolactin-secreting tumors.
• 60-80 can achieve pregnancy after treatment.

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Hypothalamic Control of Anterior Pituitary
Inhibitory Factors PIF Dopamine
Stimulating Factors Prolactin-releasing peptide
(PRRP) TRH , VIP ,Oxytocin
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Increase Pituitary Size in Pregnancy

• Physiological
• Increased weight (660-760 mg)
• Volume increase of 30 above the
  pregestational volume

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Increase Pituitary Size in Pregnancy

• Prolactin secreting lactotrophs, which
  normally constitute up to 20 of pituitary cells
  in men and in nulliparous women, increase to the
  extent that, by the end of pregnancy, they make
  up as many as 50 of pituitary cells.

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Prolactin level During Pregnancy

• Very high levels of estrogen increases the
  circulating levels of prolactin which begin to
  rise at 5-8 weeks
• End of the first trimester
• 20-40 ng/mL
• End of the second trimester
• 50-150 ng/mL
• End of the third trimester
• 100-400 ng/mL

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Serum Prolactin Concentrations During Pregnancy
Serum prolactin concentrations as a function of
time of gestation, showing the increase in
prolactin as pregnancy progresses. The zone lines
represent the range of values that can be seen.
Data from Tyson, JE, Ito, P, Guyda, H, et al, Am
J Obstet Gynecol 1972 11314.
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Fetal Prolactin

• Fetal prolactin levels parallel maternal
  levels because of a similar estrogenic effect.
• At birth 80-500 ng/mL
• Transient galactorrhea following birth
• (Witch milk)

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Decidual Prolactin

• The product of the uteroplacental unit.
• Identical to pituitary prolactin.
• Amniotic fluid PRL levels are very high
• End of the 2nd trimester 4000-6000 ng/mL At term
  200-800 ng/mL
•  Not inhibited by dopamine or dopaminergic
  agonist drugs

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Decidual Prolactin

• Not affected by dopamine or dopaminergic agonist
  drugs.
• Does not contributes to the elevation of maternal
  or fetal serum prolactin levels in normal
  pregnancy.

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Prolactin After Delivery

• Maternal PRL decline rapidly after delivery,
  reaching baseline within 1-3 weeks postpartum in
  non lactating women.
• In nursing women each suckling triggers PRL
  release which decreases as nursing becomes less
  frequent.

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Prolactin After Delivery

• A reduction of 50 occurs in basal and
  stimulated levels of serum prolactin following a
  pregnancy, regardless of maternal age at first
  pregnancy or breastfeeding in subsequent
  pregnancies. 

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EXPECTED PROBLEMS

• Control of hyperprolactinemia
• Increase tumor size
• Pituitary insufficiency
• Delivery
• Lactation

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EXPECTED PROBLEMS

• Control of hyperprolactinemia
• Increase tumor size
• Pituitary insufficiency
• Delivery
• Lactation

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EXPECTED PROBLEMS

• Control of hyperprolactinemia
• Increase tumor size
• Pituitary insufficiency
• Delivery
• Lactation

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EXPECTED PROBLEMS

• Control of hyperprolactinemia
• Increase tumor size
• Pituitary insufficiency
• Delivery
• Lactation

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EXPECTED PROBLEMS

• Control of hyperprolactinemia
• Increase tumor size
• Pituitary insufficiency
• Delivery
• Lactation

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Risks of Prolactinoma In Pregnancy

• Risks to the mother
• Increase in adenoma size sufficient to
• Cause neurologic symptoms
• Visual field defect
• Cause secondary pituitary defect
• Diabetes insipidus
• Hypopituitarism

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Risks of Prolactinoma In Pregnancy

• Risks to the mother
• Increase in adenoma size sufficient to
• Invade the surrounding
• Para pituitary structures
• (cavernous sinus)
• Cranial nerve palsies

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Risks of Prolactinoma In Pregnancy

• Risks to the mother
• Microadenomas
• The risk of a clinically important increase
• in the size of a microprolactinoma is small
• Neurologic symptoms 5.5
• Headaches 3.3 Diabetes insipidus 1
• Headaches and a visual field defects1 

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Risks of Prolactinoma In Pregnancy

• Risks to the mother
• Macroadenomas
• Tumor enlargement (no treatment) 23
• Symptomatic 36
• Neurologic symptoms 13
• Headaches 9 Diabetes insipidus 1
• Headaches and a visual field defects24 

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Risks of Prolactinoma In Pregnancy

• Risks to the fetus
• Determined principally by the type of
• treatment.

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Measurement of Serum Prolactin

• Fasting
• Complete rest for at least 10 minutes
• Through indwelling butter fly cannula
• Avoid tight clothes
• Drugs increasing PRL secretion

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Treatment of Prolactinoma

• Medical therapy with DA is effective to induce
• ovulation and shrink the tumor.
• Microprolactinoma
• Discontinue DA when pregnancy is documented
• Observe carefully for evidence of tumor growth 

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Treatment of Prolactinoma

• Symptoms suggestive of tumor growth
• Persistent recurrent headaches
• Visual field changes
• Diabetes insipidus

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Treatment of Prolactinoma

• Macroprolactinoma
• DA throughout pregnancy.
• Monthly visual-field examinations.
• Serum prolactin is not useful in detecting tumor
  growth or in indicating any lack of tumor growth.

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Treatment of Prolactinoma

• Macroprolactinoma
• MRI symptoms of tumor enlargement and/or
  visual-field defects. 
• Surgical decompression in cases resistance to DA
  or if there is evidence of rapid tumor growth not
  responding to DA.

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Treatment of Prolactinoma

• Cabergoline is a dopamine agonist that can be
  given once weekly.
• It is useful in women who are resistant to
  bromocriptine.
• Patients who cannot tolerate bromocriptine.

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Treatment of Prolactinoma

• Data available on 329 pregnancies in which
  cabergoline was administered to facilitate
  ovulation do not show increased risk of ectopic
  or multiple birth deliveries or malformations.

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Treatment of Prolactinoma

• Termination of the pregnancy is not
• necessary if a patient inadvertently becomes
  pregnant while taking cabergoline.
• More data are needed to establish its long
• term safety.

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Cabergoline Valve Disease

• Pooled data from 6 selected studies using
  cabergoline in patients with either tumor or
  non-tumor hyperprolactinemia showed that
  treatment with cabergoline was associated with
  increased risk of tricuspid valve regurgitation.

Bogazzi F et al J Endocrinol Invest Dec 2008
31(12) 1119-23
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Cabergoline Valve Disease

• No difference in prevalence of aortic or mitral
  valve regurgitation.
• Regurgitation was only an echo finding with no
  symptoms of valvular disease.
• Echo is recommended in all cases treated with
  cabergoline.
• Bogazzi F et al J Endocrinol Invest Dec
  2008 31(12) 1119-23

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Treatment of Prolactinoma

• Bromocriptine Safe in pregnancy
• In more than 6000 pregnancies , no increase in
  the incidence of
• Spontaneous abortions
• Trophoblastic disease
• Multiple pregnancies
• Congenital malformations

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Treatment of Prolactinoma

• Follow-up of children exposed to bromocriptine
  in early pregnancy
• No increase in adverse effects up
• to age 9 years.

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Treatment of Prolactinoma

• In 100 women who took bromocriptine during weeks
  20-41 of gestation, only 2 abnormalities were
  noted
• (1 talipes and 1 undescended testicle)

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• Case From the GDC Hospital

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History

• D. K. Female Syrian
• DOB 22/11/1980
• May 2007
• Secondary amenorrhea , weight gain
• chronic intermittent bitemporal headaches
• and spontaneous galactorrhea
• Clinically euthyroid

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History

• Diagnosed to have hyperprolactinemia
• Started on Cabergoline 0.5 mg twice weekly .
• Periods regular and normal
• Continued to have headaches

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Pituitary MRI , March 2008
Pituitary MRI (Al Noor Hospital) pituitary
microadenoma 8 mm in diameter
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History

• May 2008
• Married for 6 months
• Prolactin 87.86 ugm/mladvised to increase the
  dose of Cabergoline to 1.5 mg /week in 3 doses,
  warned about the risk of pregnancy

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Pregnancy

• 7th July,2008
• 6 weeeks pregnant
• Headaches increased
• No visual or DI symptoms
• Perimetry normal
• Prolactin 155 ug/ml

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Follow Up During Pregnancy

• 4th September 2008
• Severe headaches , frontal and bitemporal ,
  no visual changes , no nausea or vomiting, no DI
  symptoms
• Normal optic disc
• prolactin 68.9 ng/ml
• Add Mefanemic acid forte

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Follow Up Pituitary MRI

• 8th November 2008
• Rounded mass 15.6x15 mm replacing the
• whole anterior pituitary with very small
• rim of post. pituitary seen around.
• It has a mixed iso and hyperintense
• signal on T1 homogenously hyperintense
• on T2 T2 FLAIR sequence..

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Follow Up Pituitary MRI

• Pressure effect on the suprasellar cistern and
  pit. stalk which showed marked antero-superior
  displacement.
• MRI finding consistent with pit. macroadenoma
  with hemorrhage and infarction.

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Pituitary MRI, November 2008
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Follow Up During Pregnancy

• 2nd December 2008
• Less headaches
• Normal optic disc, No ophthalmoplegia
• Perimetry (Al Noor Hospital) Normal
• Prolactin 35.16
• FT3 3.55 pmol/L , FT4 12.56 pmol/L, TSH
  2.25 uIU/ml , Cortisol 1065 nmol/L

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Visual Field Perimetry , 8th Months Pregnancy
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Follow Up In Pregnancy

• 18th January 2009
• No headaches , generalized itching
• No visual symptoms, No DI Symptoms
• Normal optic disc ,Normal perimetry
• Prolactin 37.83 ng/ml
• FT33.31 pmol/L , FT413.42 pmol/L TSH2.1

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Follow Up In Pregnancy

• 28th January 2009
• Elective CS (Al Noor Hospital)
• Healthy male baby , Weight 3140 gm
• No maternal complications
•  

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Changes In Prolactin Level
Delivery
S. Prolactin ugm/ml
2008
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Postpartum Follow Up

• 9th February , 2009
• Not lactating
• Headaches very slight
• Vision normal , no diplopia
• Euthyroid , Normal optic disc
• Prolactin 30.66 ng/ml , ACTH 27.11 pg/ml
  Cortisol 757.7 nmol/L ,TSH 3.83 uIU/ml

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Pituitary MRI , 1 Month Postpartum
Pituitary MRI Macroprolactinoma with cystic
changes
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Autoinfarction (autocure) of Prolactinoma

• Prolonged treatment with DA
• Irradiation
• Rapid tumor growth exceeding its blood supply
  (?? mechanism similar to Sheehans syndrome)

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