Chpt 59 Prolactin disorders

How would one evaluate for a hook effect when prolactin levels are not as high as expected?

(1) Repeat the test with a 1:1000 serum sample dilution. OR (2) Washout can be performed to eliminate excess unbound prolactin after binding to the first antibody.

What are the neurologic causes of hyperprolactinemia?

- Chest wall lesions (chest trauma, herpes zoster; neural mechanism similar to suckling) - Spinal cord lesions - Breast stimulation - Epileptic seizures

What are the hypothalamic causes of hyperprolactinemia?

- Craniopharyngioma, Meningioma, metastasis of other tumors - Vascular - Pituitary stalk section - Suprasellar surgery or mass extension - Radiation

What are prolactin inhibitory factors?

- Dopamine - Gonadotropin-releasing hormone (GnRH)-associated protein GABA

What are the medications that can cause hyperprolactinemia?

- Phenothiazines - Tricyclic antidepressants, SSRIs - Narcotics - Centrally acting anti-hypertensives (Methyl-dopa, reserpine) - Verapamil - OCPs - Antiemetics

What is the association between hyperprolactinemia and galactorrhea?

- Premenopausal women: Most patients with hyperprolactinemia do not have galactorrhea; most patients who have galactorrhea have normal prolactin levels. - Postmenopausal women: As they are markedly hypoestrogenemia the galactorrhea is rare. In this group of patients, hyperprolactinemia is recognized only when adenoma becomes so large that causes headache or visual disturbances.

What are other causes of hyperprolactinemia?

1) Hypothalamic 2) Granulomas, infiltrations 3) Neurologic 4) Medications 5) Idiopathic hyperprolactinemia 6) Decreased clearance of prolactin (ESRD) 7) Other - Pregnancy - Hypothyroidism - Cirrhosis - Adrenal insufficiency

Name five prolactin releasing "factors."

1) Serotonin 2) Thyrotropin-releasing hormone (TRH) 3) Vasoactive intestinal peptide (VIP) 4) Opioid peptides 5) Prolactin-releasing peptide (PRLrP) 6) Estrogens and the hormonal milieu of pregnancy 7) Growth hormone-releasing hormone (GHRH) 8) GnRH

What percentage of patients are resistant to bromocriptine and to cabergoline?

25% and 10%.

What percentage of women with high prolactin levels have galactorrhea?

33%.

What percentage has cessation of galactorrhea after bromocriptine therapy?

50% to 60% have cessation; 75% have reduction in galactorrhea. Thus, cessation of galactorrhea is slower and may not occur as frequently as resumption of ovulation/menses.

What percentage of hyperprolactinemic women achieve pregnancy with dopamine agonist therapy?

80%.

What percentage of circulating prolactin is monomeric?

85%. There are "big prolactin" (dimer) and "big big prolactin" (polymeric).

Dopamine agonists restore ovulation in what percentage of cases?

90%.

What is a malignant prolactinoma?

A prolactinoma that has metastases outside of the CNS (very rare).

What is the empty sella syndrome?

A syndrome associated with the incomplete development of the sellar diaphragm that allows the subarachnoid space into the fossa of the pituitary.

What are the physiologic prolactin concentrations after delivery and in response to suckling?

Basal rate is high comparing with nonpregnant state and may further increase in response to suckling (up to few hundreds ng/mL). Over 4 to 12 weeks, the prolactin level decreases to normal and there is no longer a rapid release of prolactin with each suckling episode.

What is the classic visual field impairment seen in patients with macroadenomas?

Bitemporal hemianopsia.

Which dopamine agonists are available for treatment of hyperprolactinemia?

Cabergoline—used once or twice weekly, probably more effective and less nauseating than bromocriptine, effective in patients resistant to bromocriptine as well. Bromocriptine—often used twice a day. It has been on the market for more then 20 years, which makes it a safe choice for pregnant patients Pergolide—no longer recommended as it has been shown to cause valvular heart disease Quinoglide, bromocriptine depo—are still being studied

What clinical risk is present in patients with long-term use of high-dose cabergoline?

Cardiac valvular regurgitation. But, most studies have shown no evidence of clinically significant heart valvular disease in patients receiving the usual doses of cabergoline.

What area is typically being invaded in patients with prolactin levels >2000?

Cavernous sinuses.

What are two treatment options for patients with amenorrhea caused by a microadenoma who do not desire pregnancy?

Dopamine agonist Oral contraceptive pill

How does dopamine suppress prolactin? Can prolonged suckling stimulate release of pro

Dopamine binds lactotroph cells and blocks prolactin secretion.

How is hypothyroidism associated with galactorrhea?

Excess TRH is released and acts as prolactin releasing factor, stimulating prolactin release from the pituitary.

What is the rationale for treatment of hyperprolactinemia?

Existing or impending neurologic symptoms due to the size of lactotroph adenoma. Endocrine effects of hypogonadism: In women infertility, oligomenorrhea or amenorrhea, hypoestrogenemia (which may lead to osteoporosis); in men decreased libido and energy, impotence, loss of sexual hair, osteoporosis, possibly loss of muscle mass. Galactorrhea may not be sufficiently bothersome to require treatment.

True or False. Women are more common than men to be dopamine agonist resistant.

False.

True or False: Are dynamic tests of prolactin secretion using TRH, L-dopa, nomifensine, or domperidone superior to a single prolactin measurement?

False.

What is the treatment of hyperprolactinemia?

First-line treatment is dopamine agonists as they decrease hyperprolactinemia due to any cause and decrease the size and secretion of most lactotroph adenomas.

What is the most common symptom patients report with intrasellar expansion?

Headache.

When may treatment with dopamine agonists for hyperprolactinemia be stopped?

If the prolactin levels have been normal for 2 years and there is no evidence of adenoma on MRI, then cessation of therapy can be considered. Prolactin level should be checked periodically as there is a significant rate of recurrence (26% to 69% recurrence rate depending on the cause and study during 4-5 years of follow-up).

Are lactotroph tumors benign in nature?

In most cases yes, but rare tumors can be malignant and metastasize.

What is the "hook effect" (when interpreting prolactin levels)?

In the presence of a macroadenoma, markedly elevated prolactin levels (5,000 ng/mL) can appear as mildly elevated levels (20-200 ng/mL) that is from the hook effect. This occurs because both the capture and signal antibodies in the sandwich immunoassays are saturated giving an artificially low result.

What is the role of radiation therapy in patients with lactotroph adenomas?

It decreases the size and secretion of adenoma, but it occurs slowly and prolactin may be elevated many years after treatment. Radiation is limited to patients after the debulking surgery of very large macroadenomas. With this treatment, there is 50% chance of loss of anterior pituitary hormone secretion during subsequent 10 years.

What occurs to the prolactin concentration in pregnant women?

It increases from the normal range 10-25 ng/mL to 200-400 ng/mL, as estrogen suppresses the hypothalamic dopamine.

When can one expect decrease in size of adenoma after initiation of dopamine agonist therapy?

It is always preceded by fall in prolactin levels. One may see tumor shrinking after 6 weeks, though usually it is observed within 6 months.

May patients with prolactin adenomas breastfeed? Does this depend on the size of tumor?

It is safe to breastfeed with a microadenoma or if there is an asymptomatic macroadenoma. Symptomatic patients with macroadenomas should be treated. If patients are receiving dopamine agonists, nursing should be stopped.

In asymptomatic patients with hyperprolactinemia, what laboratory test should be assessed to see if the elevated prolactin level consists of less bioactive forms?

Macroprolactin

What is the definition of a microadenoma and a macroadenoma?

Microadenoma is <10 mm in diameter. Macroadenoma is 10 mm in diameter or greater.

What are the side effects of therapy with dopamine agonists?

Most common is nausea. Others include postural hypotension, headache, dizziness, constipation, and fatigue. Less common are vomiting, nasal congestion, depression, and Raynaud phenomenon. Rare cardiovascular events.

Within what time period would one expect a recurrence in hyperprolactinemia for patients who have stopped their dopamine agonists after having normal levels for 2 years?

Most common to have recurrence within 1 year.

Do patients with microadenomas or macroadenomas have increased incidence of spontaneous miscarriage or other complications of pregnancy?

No.

Does the empty sella syndrome progress eventually resulting in pituitary failure?

No.

Is the decidual secretion of prolactin affected by dopamine agonist treatment?

No.

Should patients with asymptomatic medication-induced hyperprolactinemia be treated?

No.

Should serum prolactin measurements be performed in pregnant women with prolactinomas?

No.

When treating macroadenomas, is it necessary to check frequent (every 3 months) MRIs?

No. Serum prolactin can be followed alone. MRI should be obtained 6 months after treatment.

Does breast examination or nipple stimulation increase prolactin secretion in nonlactating women?

No. The magnitude of the increase in prolactin level is directly proportional to the degree of preexisting lactotroph hyperplasia due to estrogen.

For asymptomatic pregnant patients with prolactinomas, what clinical testing is indicated?

None. If severe headaches or visual field changes occur, then MRI and visual field testing are recommended.

According to the 2011 Endocrine Society Clinical Guidelines, how many prolactin levels should be obtained to diagnose hyperprolactinemia?

One. A single measurement of prolactin at a level above the upper limit of normal confirms the diagnosis as long as the serum sample was obtained without excessive venipuncture stress.

What is Sheehan syndrome?

Panhypopituitarism following infarction and necrosis of the pituitary secondary to postpartum hemorrhage.

When can one expect improvement in visual symptoms after initiation of dopamine agonist therapy?

Patient should be reassessed within 1 month, although improvement may occur within a 24 to 72 hours.

Is the management of patients with macroadenomas any different from those with lactotroph microadenomas before and during pregnancy?

Patients with a macroadenoma and those with evidence of compression of optic chiasm should be treated with transsphenoidal surgery with possible post-op radiation before pregnancy. If complications arise during pregnancy, the treatment of choice is bromocriptine. If the adenoma does not respond to medical therapy and vision is severely impaired, patients undergo surgery in the second trimester or after delivery if it is diagnosed in the third trimester. Pregnancy should be discouraged in patients not responsive to medical therapy. Follow-up depends on size of adenoma and complications.

What group of patients with prolactin adenomas should undergo surgery?

Patients with symptoms of hyperprolactinemia that did not respond to medical therapy, and patients with adenomas that do not shrink during therapy or patients with giant lactotroph adenomas (>3 cm) wishing to become pregnant.

What are the pituitary causes of hyperprolactinemia?

Pituitary disease (most common 50%). • Prolactinomas • Lymphocytic hypophysitis • Empty sella syndrome • Cushing disease • Growth hormone-secreting tumors • Plurihormonal

How does elevated prolactin cause amenorrhea?

Prolactin inhibits the pulsatile secretion of GnRH

What is the recommended follow-up for patients for whom dopamine agonists have been tapered or discontinued?

Prolactin level every 3 months for 1 year and then yearly prolactin level.

What is the most common pituitary tumor?

Prolactin-secreting adenoma.

What are the most common tumors associated with delay in pubertal development?

Prolactinomas and craniopharyngiomas.

What other causes of a mildly elevated prolactin level must be considered?

Recent meal, breast stimulation, coitus, exercise, or if the patient has just awakened.

What improvements in symptoms are expected in the majority of patients treated with dopamine agonists?

Resolution of visual field defects. Resolution of amenorrhea. Resolution of infertility. Improvement in sexual function.

"What specific medications can cause prolactin levels to be >200 ng/mL?

Risperidone and metoclopramide.

What is the best single predictor of persistent cure of prolactin adenoma with surgery?

Serum prolactin concentration of 5 ng/mL or less on the first postoperative day.

What is the regimen for cabergoline therapy?

Start 0.25 mg orally twice weekly, increase by 0.25 mg twice weekly at 4-week intervals; maximum 1 mg twice weekly.

What is the regimen for bromocriptine therapy?

Start at 1.25 mg after dinner or at bedtime for 1 week, then increase to 1.25 mg twice a day. After 1 month, evaluate for side effects and prolactin levels. May increase the dose up to 5 mg bid. The dose that results in normal serum prolactin level should be continued.

How can side effects of dopamine agonists be minimized?

Start with half dose, take it with food, give medication at bedtime, and then add second dose in the morning after the patient is tolerating the night dose. In women, nausea can be avoided by vaginal administration.

What is the natural history of microadenomas?

Studies with 4 to 6 years of follow-up show that 95% of microadenomas do not enlarge.

How does suckling affect prolactin secretion?

Suckling inhibits the production of prolactin inhibiting factor.

What medication is recommended to treat malignant prolactinomas?

Temozolomide therapy.

How does the hypothalamus maintain suppression of the pituitary prolactin secretion?

The hypothalamus delivers a prolactin-inhibiting factor through the portal circulation.

What are the risks of complications of microadenomas versus macroadenomas during pregnancy?

The risk is small for microadenomas at about 5% to 6% level, whereas for macroadenomas it might be as high as 36%. Complications are increase in adenoma size, headache, visual impairment, and diabetes insipidus.

During pregnancy, what areas contribute to prolactin secretion?

The uterus, maternal and fetal pituitaries.

What conclusions can be made based on prolactin serum levels?

• Normal values are generally <25 ng/mL (μg/L). • Slightly increased values (21-40 ng/mL) may be rechecked as they may reflect response to physiologic stimuli rather than true hyperprolactinemia. • 20 to 200 ng/mL can be found in any patient with hyperprolactinemia. • >250 ng/mL usually indicates the presence of a prolactinoma. • >500 ng/mL is diagnostic of a macroprolactinoma (>1 cm in diameter). • >1000 ng/mL is suggestive of macroadenomas >2 cm in diameter

Is there a place for estrogen therapy in patients with hyperprolactinemia?

There is a narrow group of patients that may benefit from estrogen therapy: patients with lactotroph microadenomas causing hyperprolactinemia and hypogonadism, not responding or not tolerating dopamine agonist treatment; patients with hyperprolactinemia and amenorrhea due to antipsychotic agents. In such patients, prolactin levels should be monitored regularly as there is a small risk of increasing the size of adenoma.

What is the treatment of hyperprolactinemia secondary to hypothyroidism?

Thyroid hormones, only.

What therapeutic options should be considered in patients desiring pregnancy but not responding to dopamine agonists?

Transsphenoidal surgery or ovulation induction.

What is the treatment of lactotroph microadenomas before and during pregnancy?

Treatment is with dopamine agonists; bromocriptine is the preferred medications as there is longer history of its safe usage during pregnancy. The goal is to decrease prolactin level to normal before conception (patient should attempt pregnancy after a few months of normal menses and prolactin levels) and stop the medication once pregnancy is confirmed. Medication may be restarted (and is effective) if complications arise.

True or False: Progression from microadenoma to macroadenoma is rare?

True.

True or False: Do symptoms of hyperprolactinemia correlate with its severity?

True. • Severe hyperprolactinemia (>100 ng/mL): Typically associated with overt hypogonadism, subnormal estradiol levels and its consequences: Amenorrhea, hot flashes, and vaginal dryness. • Moderate hyperprolactinemia (50-100 ng/mL) usually causes amenorrhea or oligomenorrhea. • Mild hyperprolactinemia (20-50 ng/mL) may cause only insufficient progesterone secretion and thus short luteal phase. Even without menstrual abnormalities these levels of prolactin are associated with infertility.

True or False: Does cabergoline have a higher frequency of pituitary tumor shrinkage compared with other dopamine agonists?

True. It is hypothesized that cabergoline has a higher affinity for the dopamine receptor binding sites.

When can one expect prolactin level to fall after initiation of dopamine agonist therapy?

Usually it happens within 2 to 3 weeks.

Can primary hypothyroidism appear similar to a pituitary tumor in imaging studies?

Yes, due to the hypertrophy of the thyrotrophs.

Can breast implants lead to galactorrhea in women with normal levels of prolactin?

Yes, due to the stimulation of the sensory afferent nerves.

Can mild hirsutism occur with ovulatory dysfunction caused by hyperprolactinemia?

Yes.

Can prolonged suckling stimulate release of prolactin and subsequent galactorrhea from a nonpregnant patient?

Yes.

Do normal ovulatory menstrual periods occur in women with hyperprolactinemia if they are given exogenous GnRH?

Yes.

Is galactorrhea more suspicious for malignancy if produced from a single alveolar duct?

Yes.

Can prolactin adenomas secrete other hormones?

Yes. Approximately 10% secrete growth hormone as well.

Can excessive estrogen lead to galactorrhea?

Yes. Estrogen can suppress the hypothalamus reducing the production of prolactin inhibiting factor.

Are lactotroph adenomas more frequent with multiple endocrine neoplasia type 1?"

Yes. Prolactinomas occur in 20%. " Excerpt From: Stephen Somkuti. "Obstetrics and Gynecology Board Review Pearls of Wisdom." iBooks. https://itunes.apple.com/WebObjects/MZStore.woa/wa/viewBook?id=6D8564903635DBD2A92CD7CC7850E9FC

Does the decidual endometrium have any endocrine function?

Yes. The secretion of prolactin.

Can other pituitary hormone levels be affected by a mass lesion in the area of sella turcica?

Yes. Thus, levels of all pituitary hormones should be checked in such situation.

If medication is the cause of galactorrhea, will discontinuation of the medication resolve the galactorrhea?

Yes. Usually within 3 to 6 months.