Current and Emerging Therapies for Prolactinoma

IMELDA LAGULA-BILOCURA, M.D., FPCP, FPCEDM

Chong Hua Hospital

�Disclosure:

No conflict of interest

• To discuss current therapies for prolactinoma
• To discuss other treatment options for resistant prolactinoma

OBJECTIVE:

• Pathogenesis of prolactinomas
• Prolactin regulation
• Diagnosis- clinical, prolactin assay, neuroimaging
• Therapy – current and emerging
• Summary

OUTLINE:

PROLACTINOMA

• Is a pituitary adenoma that secretes prolactin
• The most common pituitary tumors
• 50% of all pituitary adenomas
• Histologically benign
• Arise from monoclonal expansion of pituitary lactotrophs
• Implicated genes:
• Pituitary tumor transforming gene
• Fibroblast growth factor 4

​

Pathogenesis: sporadic - mainly

familial – MEN1, Carney complex, MEN 4

Hypothalamus�(arcuate nucleus)

Anterior Pituitary�Gland Lactotrophs

Feedback Loop: Prolactin (PRL)

Prolactin Regulation

Authors: Nicola Adderley

Reviewers:

Andrea Kuczynski, Bernard Corenblum*�*MD at time of publication

William’s Textbook in Endocrinology

DA

PRL

Limbic System

Immune System Organs

Alveolar Cells of Breast Ducts

Hypothalamus

↓ GnRH secretion

↓ libido

↓ estradiol in females,

↓ testosterone in males

↓ FSH/LH

Promotes proliferation and maturation of immune cells

Milk production and release

Lactation

Sucking stimulus

(via spinal afferents)

Uterus, immune cells, breast tissue, prostate

TRH

−

+

+

+

Oxytocin

Williams Textbook of Endocrinology and Metabolism 14^th edition

• Chronic loss of neuro-hormonal

dopamine inhibition

​

• Protracted stimulation of adeno-

hypophysial cells by hormones

or growth factor

​

• in females:

Strong nuclear immuno-reactivity

for estrogen receptors and

pit-1 transcription factor

Pathogenesis of Prolactinoma

Williams Textbook of Endocrinology and Metabolism 14^th edition

Hyperplasia

​

​

Neoplasia of lactotrophs

Pathogenesis of Prolactinoma

Hypothalamus�(arcuate nucleus)

Anterior Pituitary�Gland Lactotrophs

Prolactin Regulation

Authors:�Nicola Adderley

Reviewers:

Andrea Kuczynski

Bernard Corenblum*�*MD at time of publication

DA

PRL

Limbic System

Immune System Organs

Alveolar Cells of Breast Ducts

Hypothalamus

↓ GnRH secretion

↓ libido

↓ estradiol in females,

↓ testosterone in males

↓ FSH/LH

Promotes proliferation and maturation of immune cells

Milk production and release

Lactation

Sucking stimulus

(via spinal afferents)

Uterus, immune cells, breast tissue, prostate

TRH

−

+

+

+

Oxytocin

Estrogen

Galactorrhea

Infertility

Superior extension: bitemporal hemianopsia

blindness

scotoma

loss of red color perception

​

Lateral extension compresses:

• Oculomotor nerve (III)
• Trochelar nerve (IV)
• Abducens nerve (VI)
• Ophthalmic branch of Trigeminal nerve (V1)
• Maxillary branch of Trigeminal nerve (V2)

Oculomotor nerve (III)

Trochear nerve (IV)

ptosis

diplopia

Abducent nerve (VI)

ophthalmoplegia

lateral rectus muscle palsy

Trigeminal nerve (V)

facial numbness

V1

V2

Inferior extension

• CSF rhinorrhea

SIGNS AND SYMPTOMS OF PROLACTINOMA

A detailed medical and pharmacological history be taken

​

Physiological , secondary, and iatrogenic causes of hyperprolactinemia should be ruled out

​

​

DIAGNOSIS

DIAGNOSIS

1. Single measurement of serum prolactin above the upper limit of normal

​

without excessive venipuncture stress in a symptomatic

patient (Level (1/ꚚꚚꚚꚚ)

​

​

​

​

J Clin Endocrinol Metab 96: 273–288, 2011

Italian Association of Clinical Endocrinologists

International chapter of Clinical endocrinology

Neuroendocrinology Grouip of SEEN

For large pituitary adenomas (i.e. >3 cm) associated with normal or mildly elevated PRL levels, PRL levels should be measured after serial sample dilution to rule out hook effect

- high serum prolactin saturates the assay antibodies

DIAGNOSIS

METHOD: Prolactin assay

Serial serum 1:100 dilution

Screen for macroprolactin in:

1. asymptomatic patients

​

• patients with atypical clinical picture

​

(3) patients with conflicting PRL results in distinct assays

​

(4) patients with lack of decline of serum PRL levels with DA

DIAGNOSIS

METHOD: Serum prolactin reassayed

Polyethylene Glycol Precipitation of Prolactin antibodies

Italian Association of Clinical Endocrinologists (AME) and International Chapter of Clinical Endocrinology (ICCE).

Position statement for clinical practice: prolactin-secreting tumors

• Normal Prolactin
• >20 ng/mL ( 400mIU/L) in men
• >25ng/mL (500mIu/L) in women

( 1ng/mL = 21.2 mIU/L)

​

• PRL levels higher than 200 ng/ml (4000 mIU/L)
• is strongly indicative of prolactinoma

​

• PRL levels higher than 500 ng/ml (10,000 mIU/L)
• is exclusively observed in prolactinoma

HYPERPROLACTINEMIA:

DIAGNOSIS

II. Imaging Studies

​

MRI with Gadolinium contrast of the Pituitary – imaging of choice (1/ꚚꚚꚚꚚ)

​

High Resolution Computed Tomography (Level (1/ꚚꚚꚚ)

​

A. Microprolactinomas : <10 mm in diameter

B. Macroprolactinomas : >10 mm in diameter

C. Giant Prolactinomas : >40 mm in diameter

CLASSIFICATION OF PROLACTINOMAS BASED

ON TUMOR SIZE

DIAGNOSIS

III. Supplemental Test

1. Screening for Adenohypophysial Function at diagnosis

1. All patients with macroprolactinoma
2. In microprolactinoma only if there is clinical suspicion

Adenohypophysial Evaluation:

1. Thyrotropic : TSH / Free T4
2. Gonadotropic : FSH/LH
3. Corticotropic : Cortisol
4. Somatotropic : IGF1

Neuro-ophthalmological Evaluation:

1. visual acuity
2. Computed campimetry
3. Extrinsic eye movement
4. Pupil and fundus examination

DIAGNOSIS

III. Supplemental Test

2. Evaluate insulin-like growth factor I (IGF-I ) levels in all PRL-secreting

tumors at diagnosis

​

3. Bone mineral densitometry – to screen osteoporosis for those with long

history of hypogonadism

DIAGNOSIS

III. Supplemental Test

4. Genetic testing for prolactinoma should be done based on

1. Family history
2. Early onset of the adenoma (i.e. before 20 years)
3. Aggressive behavior (i.e. uncontrolled tumor growth despite appropriate treatment)
4. Concomitant other endocrine diseases

MEN 1 : MEN 1 gene

Carney’s Complex : PRKAR1A gene

MEN 4 : CDKN1B gene

​

Goals of treatment:

​

1. Decrease PRL levels and reverse clinical signs

​

• Decrease tumor size

​

• Restore gonadal function and other pituitary hormone deficiencies

​

• Prevent tumor recurrence and progression

TREATMENT

​

INDICATIONS:

1. Avoid effects of hyperprolactinemia
1. Hypogonadism
2. Bothering galactorrhea
3. Infertility
4. Osteoporosis

​

• Compressive tumor effect

​

TREATMENT

CURRENT MANAGEMENT OF PROLACTINOMA

1. Medical

​

• Surgery

​

• Radiotherapy

​

1. Dopamine Agonists
• First line treatment for all symptomatic prolactinoma

PHARMACOTHERAPY / MEDICAL MANAGEMENT

Dopamine Agonists

• Cabergoline

​

• Bromocriptine

​

• Quinagolide

​

• Lisuride

​

• Pergolide

MEDICAL TREATMENT

Characteristics of Dopamine agonists

BRC: bromocriptine; MacroPRL: macroprolactinoma; MicroPRL: microprolactinoma

Clinical guidelines for diagnosis and treatment of prolactinoma and hyperprolactinemia

Endocrinol Nutr. 2013;60:308---19.

These mainly occur at the start of treatment

Initial doses should therefore be very low, and be gradually increased:

​

• Gastrointestinal (most common): nausea, vomiting, constipation, reflux, and dyspepsia.

​

• Neurological: headache, dizziness, dyskinesia, and confusion.

​

• Cardiovascular: postural hypertension, syncope, and finger vasospasm.

​

• Cerebrospinal fluid fistula: potential complication of treatment of big adenomas

​

• Other: dry mouth, muscle cramps, psychosis, and mania

​

• Impulse control disorder: pathologic gambling, hypersexuality

compulsive shopping / eating

SIDE EFFECTS

ECHOCARDIOGRAPHY

To rule out valvular disease -- Tricuspid regurgitation

​

• If with audible murmur

​

• More than 5 years of Cabergoline use with the dose of >3mg/week

​

• Those who maintain Cabergoline treatment after age 50

TREATMENT RESPONSE

1. Normalization of Prolactin levels

​

• Tumor size reduction

​

TREATMENT MONITORING

CRITERIA FOR DISCONTINUATION OF

DOPAMINE AGONIST TREATMENT

1. Treatment duration more than or equal to 2 years

​

• Normal prolactin level

​

• No radiographic image of adenoma

​

• Tumor size decrease: >50% compared to baseline

: macroadenoma decrease to <10 mm

5. Post-menopausal state

​

6. Pregnancy ***

​

7. Possibility of adequate medical monitoring

Clinical guidelines for diagnosis and treatment of prolactinoma and hyperprolactinemia

Irene Halperin Rabinovicha, Rosa Cámara Gómez , Marta García Mourizc , Dolores Ollero García-Agullóc , on behalf of the Neuroendocrinology Group of the SEEN

Remission

• Persistent normal prolactin level after 7-57 months (several months)

after DA withdrawal

​

• Monitoring after DA withdrawal
• Prolactin determination after 3 months, and thereafter
• MRI based on the severity of prolactin level

Indications of Continuous Dopamine Agonists Use

• Tumor size increase

​

• Persistent tumor size >10 mm

​

• Tumor margin very close to optic chiasm

​

• Cavernous sinus invasion

​

• Persistent high prolactin

​

• Microprolactinoma in males

​

• Impossibility of adequate medical monitoring

Clinical guidelines for diagnosis and treatment of prolactinoma and hyperprolactinemia

Irene Halperin Rabinovicha, Rosa Cámara Gómez , Marta García Mourizc , Dolores Ollero García-Agullóc , on behalf of the Neuroendocrinology Group of the SEEN

​

1. Dopamine Agonists
• First line treatment for all symptomatic prolactinoma

​

B. Estrogen

• Women with microprolactinoma not desirous of pregnancy
• Post- menopausal women

​

PHARMACOTHERAPY / MEDICAL MANAGEMENT

CURRENT MANAGEMENT OF PROLACTINOMA

1. Medical

​

• Surgery

​

• Radiotherapy

TRANSPHENOIDAL APPROACH

• most commonly used technique
• it is effective, minimally invasive, leaves no visible scar, and allows for faster recovery.

TRANSFRONTAL CRANIOTOMY

• Transphenoidal surgery is the recommended approach
• Craniotomy is required in some tumors depending on the location

Surgery

Surgery as Primary Treatment for Prolactinomas

• Large tumors with rapidly progressing and significant visual loss

​

• Patient refusal to undergo DA therapy

​

• Profound hypopituitarism at clinical presentation

Clinical guidelines for diagnosis and treatment of prolactinoma and hyperprolactinemia

Irene Halperin Rabinovicha, Rosa Cámara Gómez , Marta García Mourizc , Dolores Ollero García-Agullóc , on behalf of the Neuroendocrinology Group of the SEEN

Surgery as Secondary Treatment for Prolactinomas

• Tumor size increase despite optimum medical treatment
• Dopamine agonist intolerance/ Dopamine agonist resistance
• Macroadenoma refractory to treatment with dopamine agonists
• Microadenoma refractory to treatment with dopamine agonists in

a woman who wants to conceive

• Chiasm compression persisting after medical treatment
• Cystic prolactinoma not responding to medical treatment
• Cerebrospinal fluid fistula after the administration of dopamine agonists
• Macroadenoma in psychiatric patients in whom dopamine agonists are

contraindicated

Clinical guidelines for diagnosis and treatment of prolactinoma and hyperprolactinemia

Irene Halperin Rabinovicha, Rosa Cámara Gómez , Marta García Mourizc , Dolores Ollero García-Agullóc , on behalf of the Neuroendocrinology Group of the SEEN

Surgery

Success rate:

1. Experience and skill of neurosurgeon

​

• Tumor size and degree of invasion

​

• Initial serum prolactin level
• Pre-operative PRL <200 ng/mL – higher remission rate
• >500 ng/mL – unlikely to resolve to surgical cure
• >1000 ng/mL – unlikely to result to biochemical control

Surgery

​

Surgical cure rate:

• Microprolactinoma : 75-90%
• Macroprolactinoma : 18-80%

​

Best Predictor for Cure:

Prolactin level <5 mcg/L on the first post-op day

​

Remission:

Prolactin level <20mcg/L the day after surgery for those who did not receive Dopamine Agonist 4 weeks before surgery

Surgery

Complications of Transphenoidal surgery:

• Surgery related mortality 0%
• Persistent enuresis 2%
• Meningitis 1%
• CSF leak 2%
• Hypopituitarism 2%
• Hypoadrenocorticism 1-2%
• Hypogonadism 3-6%
• Hypothyroidism 1-6 %

Surgery

Recurrence:

• Microprolactinoma : uncommon
• Macroprolactinoma : more than 80% within 3 years

​

Treatment monitoring:

• Prolactin levels every 3 months for the first year and then annually for 5 years

Should surgery be used as first line treatment?

International Journal of Endocrinology Volume 2021,

Article ID 9930059, 11 pages https://doi.org/10.1155/2021/9930059

2276 studies identified

255 full-text articles retrieved

for detailed assessment

18 studies included in meta-analysis

2021 studies excluded on the

basis of title and abstract

No additional study identified through

manual search

237 studies excluded:

• Mixed-patients population

• Non-proplactinoma patients
• Lack of outcomes of interest
• Inappropriate study design
• Case report System review

Flowchart of the literature search yield and selected studies

International Journal of Endocrinology Volume 2021,

Article ID 9930059, 11 pages https://doi.org/10.1155/2021/9930059

Meta-analysis of remission rates as compared between surgery and medical treatment

International Journal of Endocrinology Volume 2021,

Article ID 9930059, 11 pages https://doi.org/10.1155/2021/9930059

J Clin Endocrinol Metab, March 2020, 150(3):e33–e42

Records identified through database searching (n=1926)

• PubMed (n=811)
• Embase (n=502)
• Academic Search Premier (n=262)
• Web of Science (n=191)
• Cochrane (n=62)
• CENTRAL (n=51)
• PsycINFO (n=29)
• Emcare (n=18)

Unique records screened

Full-text articles assessed for eligibility

(n=194)

Included articles

(n=80)

Medical therapy n=55; Surgery n=25)

Identification

Screening

Eligibility

Included

Analysis

Exclusion: duplicate articles n=619

Exclusion: based on title/abstract screening

n= 1113

Articles included per main analysis

• Biochemical control during medical therapy (n=40)
• Biochemical remission after medication withdrawal (n=17)
• Biochemical remission after surgery (n=25)
• Side effects during medical therapy (n=26)
• Complications of surgery (n=13)
• Health-related quality of life (n=6)
• Costs (n=3)

Exclusion: n= 114

• N<10 (n=3)
• No relevant outcome (n=2)
• No MRI for diagnosis (n=54)
• Craniotomy (n=21)
• Overlapping cohorts (n=27)
• Review 9n=1)
• Non-tumor hyperprolactinemia (n=1)
• No incidence rates for side effects (n=5)

​

J Clin Endocrinol Metab, March 2020, 150(3):e33–e42

J Clin Endocrinol Metab, March 2020, 150(3):e33–e42

J Clin Endocrinol Metab, March 2020, 150(3):e33–e42

J Clin Endocrinol Metab, March 2020, 150(3):e33–e42

Pooled event rates of side effects of dopamine agonists and complications of transsphenoidal surgery

J Clin Endocrinol Metab, March 2020, 150(3):e33–e42

J Clin Endocrinol Metab, March 2020, 150(3):e33–e42

Pooled event rates of side effects of dopamine agonists and complications of transsphenoidal surgery

CURRENT MANAGEMENT OF PROLACTINOMA

1. Medical

​

• Surgery

​

• Radiotherapy

RADIOTHERAPY

Goals of therapy

1. Inhibit tumor growth
2. Suppress hormone secretion
3. Suppress further progression of tumor remnants

• Second-line of treatment or adjuvant treatment

RADIOTHERAPY

Kinds of Radiotherapy

• Fractionated external beam radiotherapy (EBRT)
• also known as conventional radiotherapy
• normalization of prolactin 34.1%

​

• Stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT)
• tumor control rate 86-100%
• endocrine remission rate 6-81%

​

Fractionated external beam radiotherapy (EBRT)

Radiation therapy can be delivered in smaller doses over the course of several weeks (fractionated radiotherapy). Fractionated treatment is usually performed 5 days per week over the course of 5–6 weeks.

SRS -delivers a large dose of radiation on a single day

- generally less risky than traditional surgery

- ideal for cavernous sinus involvement

Stereotactic radiosurgery

Stereotactic radiosurgery

RADIOTHERAPY

​

Indications for Radiotherapy:

• Big tumors not candidate for surgery
• Non responders to dopamine agonist
• Aggressive prolactinomas or carcinomas

​

Side Effects:

• Hypopituitarism
• Occurrence of secondary intracranial neoplasm
• Cerebral injury
• Optic nerve damage

Special Population

Reproductive age

1. Planning pregnancy
1. Achieve normalization of prolactin level and tumor size <10 mm
2. Cabergoline should be shifted to Bromocriptine
3. Transphenoidal surgery

​

B. Pregnancy

Tumor growth

microprolactinoma: 2-4%

macroprolactinoma: 21%

macroprolactinoma with previous surgery or RT: 4-7%

​

Clinical evaluation: headache and visual field defect

microadenoma: per trimester

macroadenoma with prvious surgery or RT: per trimester

macroadenoma: clinical evaluation + campimetric study

​

Special Population

C. Postpartum and Lactation

• Breastfeeding is allowed for :

1. microadenoma

2. macroadenoma with no tumor size increase during pregnancy

​

Not recommended with macroadenoma esp. near the optic chiasm

​

​

D. Management

Bromocriptine – first line

Surgery

​

Special Population

Children and adolescent

• Mandatory treatment
• Dopamine agonist – first line of treatment
• Surgery if with compressive symptoms
• Radiotherapy limited for aggressive tumors

Menopause

• Microadenoma – treatment not necessary
• Macroadenoma – treat with usual treatment

Resistant Prolactinoma

Failure to achieve normal prolactin levels with the maximum tolerated

​

dose of dopamine agonist and the lack of 50% reduction in tumor size

​

• Bromocriptine 15 mg
• Cabergoline 1.5-3.0 mg

​

• Invasive macroprolactinoma

​

• Male patients

​

• Very young age

​

• Cystic prolactinoma

​

• Hemorrhagic or necrotic components

Resistant Prolactinomas frequently seen:

Management of Resistant Prolactinoma

• Reaching to maximum tolerated dose of Dopamine agonist/ escalating dose

​

• Switching to Cabergoline from Bromocriptine or vice versa

or as a second option using some DA

​

• Transphenoidal surgery

​

• If surgery fails, Radiotherapy

Emerging Management of Resistant Prolactinoma

Anastrazole

• DA sensitizing agents
• an aromatase inhibitor
• dose of 1 mg daily
• Treatment duration: 15–56 months
• volumetric tumor reduction of between 24.5–68.7%

Emerging Management of Resistant Prolactinoma

Somatostatin analogues

• Octreotide LAR
• Pasireotide

​

Pasireotide

• is a somatostatin analogue that binds to the type 2 and type 5

somatostatin receptors (SSTR2 and SSTR5)

• case reports of impressive responses both in terms of prolactin level

and tumor shrinkage

Aggressive / malignant prolactinomas

One that exhibit metastatic spread within or outside the CNS

​

Incidence: very low

​

Management:

DA + Surgery + Radiotherapy

Treatment of Aggressive / malignant prolactinomas

Temozolamide

​

• Recommended chemotherapy

​

• Salvage or metastases: established indication

​

• Demonstrated aggressiveness: recommended indication

​

• Anticipated aggressiveness: possible indication

​

​

​

Treatment of Aggressive / malignant prolactinomas

Temozolamide

​

• lipophilic oral alkylating agent that covalently attach to a methyl group to guanine bases within the DNA of a tumor causing mispairing and mismatch repair system (apoptosis and tumor regression)

​

• Dose of 150–200 mg/m2 for 5 consecutive days every 4 week

​

• Duration: 6–12 month course
• longer courses of 2 years or more are now recommended

​

Treatment of Aggressive / malignant prolactinomas

Temozolamide

• Side Effects: fatigue, nausea, cytopenia including leukopenia, thrombocytopenia or combination
• uncertain for fertility
• Rarely: aplastic anemia, acute liver injury ,SJS

​

• Efficacy: Reduction in tumor size is observed in >50% of cases

​

• (+) evidence of prolonged survival in responders
• Median survival: 44 months versus 16 months for nonresponder

​

Aggressive / Malignant Prolactinomas

Other emerging treatment

Immunotherapy

• Nivolumab and Ipilimumab
• been tried on limited occasions
• A phase 2 trial is now underway in the USA

​

Everolimus

an mTOR inhibitor

been reported to induce partial response in aggressive prolactinomas

Aggressive / malignant prolactinomas

Other emerging treatment

Peptide receptor radionuclide therapy (PPRT)

• ¹¹¹Ind-DTPA-octreotide and ¹⁷⁷Lu-DOTATOC
• used in a small number of patients with aggressive prolactin secreting tumors

​

Lapatinib

• tyrosine kinase inhibitor (TKI)
• targeting the epidermal growth factor receptors ErbB1 and ErbB2
• trialed in 4 patients at a dose of 1250 mg daily for 6 months
• may control tumor growth and reduce prolactin in selected patients

SUMMARY

• Prolactinomas – most common pituitary tumor

​

• Biologically diverse ranging from
• small indolent to large
• Invasive
• occasionally aggressive metastatic tumor

​

• Presents with clinical signs and symptoms of
• hyperprolactinemia and/or compressive symptoms

​

• Diagnosis :
• single determination of prolactin assay
• pituitary mass on imaging

SUMMARY

• Medical therapy with Dopamine agonist- first line of treatment
• Cabergoline > Bromocripitne

​

• Surgery: second line treatment
• DA resistance
• DA intolerance
• Pituitary apoplexy
• CSF leak

​

• Surgery as first line therapy
• Microprolactinoma
• Well capsulated macroprolactinoma

​

• Radiotherapy as adjuvant

SUMMARY

• Resistant prolactinoma
• Dose escalation
• DA switching
• Surgical debulking
• Radiotherapy
• Or combination of the above/

​

• Aggressive pituitary carcinoma
• Multi-modality treatment with chemotherapy
• Temozolamide - DOC
• Multidisciplinary team

​

THANK YOU FOR YOUR ATTENTION!