Hala Mosli PGY-5 November 4, 2009 MILK Hala Mosli PGY-5 November 4, 2009

Objectives: What is prolactin? Where does it come from? How is it regulated? Disorders of prolactin production.

Prolactin 198-Amino acid polypeptide hormone. Contains three intra-molecular disulfide bonds. Gene located on chromosome 6. Circulates in the blood in different sizes: Monomeric PRL (little PRL; 23 kd) Dimeric PRL (big PRL; 48-56 kd) Polymeric PRL (Big big PRL; >100 kd)

Shares a common tertiary structure with a family of polypeptide hormones, eg GH and HPL and are structurally related to members of the cytokine-hematopoietin family (EPO, GM-CSF, IL-2-IL-7). Biological effects produced by interacting with and dimerizing specific single transmembrane-domain receptors. The receptors belong to a superfamily of cytokine receptors.

Synthesized and secreted from the lactotrophs of the anterior pituitary gland. A precursor molecule (MW 40,000-50,000) is also secreted and may constitute 8-20% of prolactin immunoreactivity.

Regulation Hypothalamic control of PRL secretion is mainly inhibitory. Dopamine is the most important inhibitory factor.

Many factors influence PRL secretion: Physiologic Pharmacologic Pathologic

Lactotroph cells Make up 15-25% of functioning anterior pituitary cells. Absolute number does not change with age. Hyperplasia occurs during pregnancy and lactation.

Most PRL-expressing cells appear to arise from GH-producing cells. Two cell forms express PRL gene: Large polyhedral cells throughout the gland contain large secretory granules. Smaller, angulated or elongated cells clustered mainly in the lateral wings and median wedge sparse smaller granules. Occasional mammosomatotrophs cosecrete both GH and PRL, often stored within the same granules.

Functions Mammary gland development and lactation: Puberty: PRL is not essential for pubertal mammary gland development. Pregnancy: PRL increases to a mean of 207 μg/L. Amniotic fluid PRL is 100 times that level. Plays a role in mammary gland maturation in the third trimester of gestation.

Lactation: active lactation is due in part to a fall in estrogen and progesterone and an elevation of PRL after delivery. Suckling is essential to maintain lactation. Without suckling, prolactin levels fall to normal within 7 days post-partum. As nursing continues, PRL concentrations fall.

Each suckling episode causes an episodic rise in PRL. Milk yield does not closely correlate with serum PRL level. Suckling also stimulates oxytocin release from the posterior pituitary. Oxytocin induces milk ejection by stimulating the contraction of myoepithelial cells, as well having important effects on alveolar proliferation.

Immune function: PRL is a lymphocyte growth factor. It also stimulates immune responsiveness. PRL levels change in patients with Lupus and other immune disease. Exact role in immunomodulation is not clear.

Reproductive/ gonadal function: PRL has no physiologic role in the regulation of gonadal function. Hyperprolactinemia leads to hypogonadism. Exact mechanisms unknown but likely due to alteration of the hypothalamic-pituitary control of gonadotrophin secretion.

In women: In men: Shortened luteal phase. Normal basal LH and FSH normal but pulsatile secretion is decreased. This interferes with the midcycle LH surge. Anovulation, oligomenorrhea, amenorrhea Infertility In men: Decreased testosterone synthesis and decreased spermatogenesis. Decreased libido and impotence. Infertility.

PROLACTINOMA Definition: Prolactinomas are pituitary adenomas that express and secrete prolactin to variable degrees They are almost invariably benign. Occasionally, these adenomas can be aggressive or locally invasive and cause compression of vital structures. Malignant prolactinomas that are resistant to treatment and disseminate inside and outside the central nervous system are very rare

Epidemiology Prolactinomas are the most frequent pituitary tumors, with an estimated prevalence in the adult population of 100 per million population. Beckers et al. found a much higher prevalence at 55 per 71,000 (775 per million) inhabitants in Belgium.

Their frequency varies with age and sex, occurring most frequently in females between 20 and 50 yr old, when the ratio between the sexes is estimated to be 10:1. After the fifth decade of life, the frequency of prolactinomas is similar in both sexes. In the pediatric/adolescent age, prolactinomas are rare, but represent about half of all pituitary adenomas, which, overall, account for less than 2% of intracranial tumors

Classification Classified according to size into: Microadenomas: less than 10 mm in diameter Macroadenomas: more than 10 mm in diameter Over 90% of prolactinomas are small, intrasellar tumours that rarely increase in size.

Pathogenesis Multi-step process that involves dysregulation of cell growth or proliferation, differentiation, and hormone production. It may be initiated as a result of activation of oncogene function or after inactivation of a tumor suppressor gene, or both. Studies have demonstrated that pituitary tumors are monoclonal in origin thus tumors arise from a single cell mutation followed by clonal expansion.

Manifestations Related to excess hormone production: hyperprolactinemia. Mechanical symptoms. Symptoms of impaired pituitary function.

Excess hormone production: Galactorrhea-amenorrhea Infertility Decreased libido/ impotence.

Galactorrhea-amenorrhea syndromes: Three distinct clinical syndromes described: 1) the Chiari-Frommel Syndrome—amenorrhea, galactorrhea, and low urinary gonadotropins occurring postpartum 2) Ahumada-Argonz-del Castillo syndrome—nonpuerperal amenorrhea, galactorrhea, and low urinary gonadotropins with no evidence of a pituitary tumor on standard skull x-rays 3) Forbes-Henneman-Griswold-Albright syndrome—nonpuerperal amenorrhea, galactorrhea, and low urinary gonadotropins in association with a chromophobe adenoma

Other symptoms: Weight gain, fluid retention. Hirsutism Irritibality, anxiety and depression,

Mechanical symptoms: Headaches: A study was conducted by Strebel et al, to determine whether headaches in women with non-puerperal hyperprolactinemia were associated with hyperprolactinemia or the presence of a prolactinoma. Headaches were found to be four times more common in the presence of a prolactinoma than in its absence.

Visual field defects: Disorders of the visual fields have been documented in the literature in association with pituitary gland tumors since the early 1900’s. Types of bitemporal defects are stages in a progressive restriction of the visual fields. The field defect usually begins in the upper temporal quadrant and progresses into a bitemporal hemianopia. This may advance to involve the nasal aspects of the visual fields as well.

Cranial Nerve Palsies: Not a frequent manifestation. Pituitary adenomata tend to displace or encircle the cranial nerves rather than invade them. Seen in more aggressive, invasive tumors that extend into the cavernous sinus.

Cavernous Sinus Invasion by Pituitary Adenomas, Ahmadi et al AJR 146:257-262, February 1986

Impairment of Pituitary Function: Due to compression of normal pituitary tissue. Manifests as partial or panhypopituitarism. Almost always seen in macroadenomas.

Lab Evaluation Normal prolactin levels in women and men are below 25 μg/l and 20 μg/l, respectively, with the more commonly used assays (1μg/l is equivalent to 21.2 mIU/l) PRL values between the upper limits of normal and 100 μg/l (∼2000 mIU/l) may be due to psychoactive drugs, estrogen, or functional (idiopathic) causes, but can also be caused by microprolactinomas.

Most patients with PRL levels over 150 μg/l (∼3000 mIU/l) (five times higher than the normal values) will have a prolactinoma. Macroadenomas are typically associated with levels of over 250μg/l (∼5000 mIU/l),and in some cases over 1000μg/l (∼20000 mIU/l) Such values are not absolute; prolactinomas can present with variable elevations in PRL, and there may be dissociation between tumour mass and hormonal secretion.

There are two potential pitfalls in the diagnosis of a prolactinoma: Macroprolactin Hook effect

Macroprolactin is a complex of PRL and an IgG antibody. Serum PRL concentrations are elevated secondary to a reduced rate of clearance of this complex. Macroprolactin has reduced bioactivity and is present in significant amounts in up to 20% of hyperprolactinemic sera, resulting in pseudo-hyperprolactinaemia and potential misdiagnosis. Macroprolactin is detected by most but not all PRL assays; therefore each centre must know the specific characteristics of the prolactin immunoassay they use.

The ‘hook effect’ may be observed when the serum PRL concentration is extremely high, as in some cases of giant prolactinomas. The high amount of circulating PRL causes antibody saturation in the immunoradiometric assay, leading to artifactually low results. To overcome the hook effect, an immunoradiometric PRL assay should be performed at a serum dilution at 1 : 100, or alternatively should include a washout between the binding to the first antigen and the second step in order to eliminate excess unbound PRL. It has been recommended that the hook effect be excluded in all new patients with large pituitary macroadenomas who have normal or mildly elevated PRL levels.

Dynamic tests of prolactin secretion: Several dynamic tests of PRL secretion have been proposed as diagnostic tools in the evaluation of hyperprolactinaemia, These include the administration of TRH,L-dopa, nomifensine, domperidone, and insulin-induced hypoglycaemia. Despite the fact that some of these methods are useful in particular hands it is now widely accepted that the diagnosis of a prolactinoma should be confirmed by analysing basal PRL values, imaging the pituitary, and excluding other causes.

IMAGING: Gadolinium-enhanced MRI is the study of choice. Computed tomography (CT) with intravenous contrast enhancement is less effective than MRI in diagnosing small adenomas and in defining the extension of large tumours, but may be used if MRI is unavailable or contraindicated. However, microadenomas are present in about 10% of the normal population. Normal MRI examination does not necessarily exclude a microadenoma.

Patients with macroadenomas that abut the optic chiasm should undergo formal visual-field examination. Hyperprolactinaemia in the presence of an MRI-detected pituitary adenoma is consistent with but not unequivocally diagnostic of a prolactinoma, because any pituitary mass that compresses the pituitary stalk may cause hyperprolactinaemia. Unequivocal diagnosis requires pathological analysis, but prolactinomas are rarely surgically removed.

Therapy Medical Surgical Radiation

Medical Management Mainstay of management are dopamine agonists. Dopamine inhibition of PRL secretion is mediated by the D2 dopamine receptors expressed by normal and tumorous lactotrophs The inhibition of cAMP levels is a key step in the inhibition of PRL release by dopamine and it is likely that all dopaminergic ergot derivative share similar mechanisms of action.

Dopamine agonists reduce the size of prolactinomas by inducing a reduction in cell volume This is via an early inhibition of secretory mechanism, and a late inhibition of gene transcription and PRL synthesis They also cause perivascular fibrosis and partial cell necrosis. There may also be a true antimitotic effect of these drugs. Histologically, there is a reduction in secretory activity and cell size, an increase in immunoreactive PRL cellular content and inhibition of exocytosis

Bromocriptine, pergolide, and cabergoline are all ergot derivatives. The only nonergot derivative that is used in clinical practice is quinagolide.

1. Bromocriptine. The first medical treatment for prolactinomas; available for over 25 yrs. Bromocriptine-mesylate is a semisynthetic ergot derivative that has D2 receptor agonist and D1 antagonist properties. It has a relatively short elimination half-life; usually taken two or three times daily. Therapeutic doses are in the range of 2.5–15 mg/d, and most patients are successfully treated with 7.5 mg or less. However, doses as high as 20–30 mg/d can be used in “resistant” patients.

For microprolactinomas bromocriptine is successful in 80 to 90% of patients in normalizing serum PRL levels, restoring gonadal function, and shrinking tumor mass. For macroprolactinomas, normalization of serum PRL levels and tumor mass shrinkage occur in about 70% of patients treated with bromocriptine even at low doses; visual field defects improve in the majority of patients. Although prolactinomas usually remain sensitive to bromocriptine, it usually does not “cure” these pituitary adenomas, and the withdrawal of therapy often results in recurrence; tumor regrowth may occur later, with the consequent risk for compromised vision

Prolonged bromocriptine treatment has been associated with increased fibrosis of prolactinomas and with increasing tumor consistency. In most patients, headache and visual field defects improve dramatically within days after the first administration of bromocriptine, with gonadal and sexual function improving even before complete normalization of serum PRL levels. PRL normalization with bromocriptine is also associated with an increase in bone density both in women and in men and with improvement of semen quality in men.

Other formulations of bromocriptine, long-acting and the long-acting repeatable forms for IM injections, an intranasal powder, and an intravaginal tablet, were developed to overcome side effects such as nausea, vomiting, postural hypotension, and headache. Despite promising data none of these formulations were ever introduced in the pharmaceutical market for hyperprolactinemia. Bromocriptine has been largely superseded by more potent compounds with longer lasting effects and improved side effect profiles. Nevertheless, it is still widely used to treat prolactinomas, primarily in young women desiring pregnancy

2. Cabergoline. D2 selective agonist widely used to treat prolactinomas. Strongly suppresses PRL secretion both in vivo and in vitro First line therapy for prolactinomas. Fewer side effects than other dopamine agonists therefore better patient compliance.

3. Pergolide. A synthetic ergoline derivative with long-acting D2 and D1 agonist properties. Approximately 100 times more potent than bromocriptine Suppresses PRL secretion for up to 24 h after a single dose, allowing effective control of hyperprolactinemia with once daily dosing. Approved in the United States only for the therapy of Parkinson’s disease, where it has been used at doses more than 10 times those used for PRL-secreting tumors.

Pergolide has advantages over bromocriptine in that it only requires once a- day dosing and is approximately one fifth of the cost. In short-term studies, pergolide has been shown to effectively lower PRL levels. In an open-label, randomized, controlled, multicenter study, Lamberts and Quik reported that bromocriptine and pergolide were equally effective in lowering serum PRL levels and in inducing tumor shrinkage; a high incidence of adverse events, such as nausea, dizziness, vomiting, asthenia, headache, and decrease in blood pressure, was reported with both drugs. Data concerning the reduction of macroprolactinoma size by pergolide are limited

4. Quinagolide: An octahydrobenzyl(g)-quinoline nonergot oral dopamine agonist with specific D2 receptor activity. Several studies demonstrated that once-daily quinagolide treatment in women with hyperprolactinemia reduced PRL levels and tumor size and relieved gonadal dysfunction, thereby restoring fertility

Other dopamine agonist compounds Lisuride hydrogen maleate is another synthetic ergot derivative, with PRL inhibitory activity in experimental models of hyperprolactinemia Terguride, an analog of lisuride, binds to D2 receptors. Neither lisuride nor terguride is currently used in the treatment of prolactinomas.

Serotonin receptor antagonists Metergoline is a nonselective antagonist for 5-hydroxytryptamine-1B and 5-hydroxytryptamine-1D receptors that has been used to treat hyperprolactinemia in the past. Found to be effective in normalizing gonadal function and in restoring fertility in women, no data are available in patients with macroprolactinomas or in men with hyperprolactinemia. Metergoline is seldom, if ever, used today in the treatment of prolactinomas.

Oral contraceptives for hypogonadism Hypogondal women with microprolactinomas may be treated for their hypogonadism with oral contraceptives, provided that their PRL levels do not increase substantially and there is no evidence of tumor enlargement. Series of patients with prolactinomas who are treated with oral contraceptives for hypogonadism have not shown substantial risk for tumor enlargement. It is advisable to monitor patients who use oral contraceptives carefully with periodic measurement of PRL and imaging.

What to expect with medical management? Tumour shrinkage can often be observed within a week or two after starting therapy, but may not start for several months. Continued tumour shrinkage may occur for many months or even years. Repeat the MRI 2–3 months after starting therapy then at longer intervals.

Several studies have demonstrated recovery of impaired anterior pituitary function in association with tumour shrinkage and ovulatory menses return in over 90% of premenopausal women. Dopamine agonists usually restore visual function to an extent similar to that produced by surgical decompression of the chiasm in macroprolactinoma patients. Patients with macroprolactinomas who have visual field defects are no longer considered to be neurosurgical emergencies.

When/how to stop medication When the PRL level has been normal for at least 2 years AND the size of the tumour decreased by more than 50%, the dose of the dopamine agonist can be gradually decreased, because at this stage low doses are likely to maintain stable PRL levels and tumour size. In patients with macroadenomas suspension of therapy may lead to tumour expansion and recurrence of hyperprolactinaemia. Close follow-up is necessary when the drug is tapered or withdrawn in patients with macroprolactinomas.

Special situations Malignant prolactinomas: Initially present as resistant prolactinomas or with dissociation between serum PRL levels and tumour mass. there is no typical clinical presentation of these tumours except as a failure of dopamine agonist therapy or recurrence after surgery. Usually, pathological information is unremarkable,

Surgery and radiotherapy are the only treatments available but are only palliative. Chemotherapy provides little or no benefit. Experience managing malignant prolactinomas is very limited. These cancers are uniformly fatal, but fortunately are very rare.

Pregnancy and prolactinoma Women with prolactinomas who are pregnant or who wish to become pregnant should be guided through the process by an endocrinologist for a number of reasons. During pregnancy, there can be a substantial increase in the volume of the prolactinoma that may in turn compromise visual fields. Serum PRL levels do not reliably reflect an increase in the size of prolactinomas. Dopaminergic drugs cross the placental barrier; their effects on the fetus should be carefully considered.

There are four main issues with respect to pregnancy and prolactinomas: hyperprolactinaemia and fertility, safety of dopamine agonists, tumour growth lactation.

Long-term follow-up The minimal length of dopamine agonist therapy should be 1 year. Long-term remission can occur after a period of several years of dopamine agonist treatment. There are no signs to predict whether drug discontinuation will be successful

A recent report indicates that dopamine agonists can be safely withdrawn in patients with long-term normalization of prolactin levels and no evidence of tumour on MRI. If a patient has normal PRL levels after therapy with dopamine agonists for at least 3 years and the tumour volume is markedly reduced, a trial of tapering and discontinuation of these drugs may be initiated. Such patients need to be carefully followed to detect recurrence of hyperprolactinaemia and tumour enlargement so that treatment can be resumed.

Other therapies Trans-sphenoidal surgery Does not reliably lead to a long-term cure, Recurrence of hyperprolactinaemia is frequent. Up to 10% of patients may require surgery if they do not respond to dopamine agonists or if visual field deficits do not improve.

Other indications for surgery include apoplexy with neurological signs in macroadenomas; cystic macroprolactinomas (which generally do not shrink in response to dopamine agonist treatment) causing neurological symptoms intolerance to dopaminergic agonists. The possibility of cure by surgery versus long-term dopamine agonist therapy should be discussed with the patient Patient preference is also an indication for surgery.

Radiotherapy External radiation is rarely required to treat prolactinomas and is associated with a significant incidence of major side-effects: Hypopituitarism, Damage to the optic nerve Neurological dysfunction Increased risks of stroke Secondary brain tumours. Radiotherapy is not an acceptable primary therapy for prolactinomas Reserved for patients who do not respond to dopamine agonists, those who are not cured by surgery, or for those very rare cases of malignant prolactinoma.

THANK YOU

References Williams textbook of Endocrinology 11th Edition. Journal of Mammary Gland Biology and Neoplasia, Vol. 7, No. 3, July 2002 ( C° 2002)Growth Hormone and Prolactin—Molecular and Functional Evolution. Isabel A. Forsyth and Michael Wallis. Greenspan’s Basic and Clinical Endocrinology. Medication-Induced Hyperprolactinemia, Mayo Clin Proc. • August 2005;80(8):1050-1057, Mark Molitch. PROLACTIN AND ITS DISORDERS,Laurence Katznelson,Anne Klibanski Pediatric Endocrinology: Mechanisms, Manifestations, and Management (1st Edition) Clinical Endocrinology (2006) 65, 265–273 doi: 10.1111/j.1365-2265.2006.02562.x, Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

Strebel et al, Headache, Hyperprolactinemia and Prolactinomas, Obstetrics and Gynecology, August 1986 A STUDY OF THE: VISUAL FIELDS \VITH WHITE AND COLOURED OBJECTS IN CASES OF PITUITARY TUMOUR WITH ESPECIAL REFERENCE TO EARLY DIAGNOSIS By Paul Enoksson Cavernous Sinus Invasion by Pituitary Adenomas, Ahmadi et al AJR 146:257-262, February 1986 Gillam et al. Treatment of Prolactinomas Endocrine Reviews, August 2006, 27(5):485–534 525 Endocrine-Related Cancer (2001) 8 287–305 Pituitary tumors: pathophysiology, clinical manifestations and management B M Arafah and M P Nasrallah Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas Felipe F. Casanueva*, Mark E. Molitch†, Janet A. Schlechte, Clinical Endocrinology (2006) 65, 265–273