Hyperprolactinemia is not itself a cause of diabetes, although prolactin levels are raised in those with fasting hyperglycemia. There is however interest in the possibility that raised prolactin levels offer some protection against diabetic retinopathy. This article reviews the pathophysiology and treatment of hyperprolactinaemia.
Identification of prolactin (PRL) as a distinct hormone, capable of lactogenic activity, dates well back to the early 1970s. This 23kDa and 199 amino acid polypeptide is synthesized in the lactotroph cells of the anterior pituitary . Prolactin constitutes 1% of pituitary gland by weight compared to growth hormone, except during pregnancy and lactation, when this compartment expands.
Prolactinomas are the most common functioning tumor of the pituitary (35-40%). The female to male ratio is 10:1. Microadenoma is more common in females and macroprolactinomas are more prevalent in males. Fewer than 30% of microadenomas are thought to progress to macroadenoma.
Prolactinomas are the most common pituitary tumor found in MEN syndromes. Malignancy is rare accounting for less than a third of prolactinomas.
Diabetes and Elevated Prolactin (other causes ruled out)
A study conducted in 1985 looked at the possibility that there might be a relationship between duration of diabetes, A1C, plasma glucose and diabetic retinopathy. Only fasting plasma glucose was significantly associated with elevated PRL, and the authors suggested that the upper reference range for PRL should be raised in those with diabetes.
However a recent report in 2010 found elevated PRL levels in diabetes to be protective as far as diabetic retinopathy was concerned. Intraocular conversion of PRL to vasoinhibins prevents ischemic damage and reduces vascular permeability. This finding also opens up the area of new drug development whereby inducing an elevated PRL could be used to prevent or downstage the staging of retinopathy.
Prolactin: Mechanism of action
Immediately after childbirth, prolactin in the presence of cortisol initiates and maintains lactation. It also inhibits LH & FSH release from the anterior pituitary inducing physiological secondary amenorrhea. Prolactin is also important during puberty where it stimulates the growth of the alveolar component of breast tissue.
Structurally prolactin is similar to GH resulting in PRL surges during stress. However these surges are not as prominent as lactation where there is a 10-fold rise in its concentration. Dopamine exerts an inhibitory influence on PRL whereas TRH has the opposite effect. During lactation the sucking stimuli is the most powerful driving force to keep the cycle going.
These positive stimuli lead to PRL secretion from the anterior pituitary, stimulating milk release, and consumption of milk by the baby reinforces this stimulation.
Causes of hyperprolactinoma
Two important causes of hyperprolactinemia have to be ruled out before looking out for others. These are physiological stimuli (pregnancy, sexual intercourse, suckling & stress) and medications.
- Dopamine receptor antagonists (metoclopramide, domperidone),
- Neuroleptics (phenothiazines, risperidone, olanzapine),
- Antidepressants (tricyclic, MAO-inhibitors, SSRIs),
- Anti-hypertensives (verapamil, methyldopa, reserpine),
- Opiates & cocaine and
Other causes include:
- Pituitary tumors (prolactinomas, macroadenoma-related stalk compression & mixed GH/PRL tumors),
- Parasellar causes (hypothalamic- stalk compression; infiltration-sarcoidosis, Langerhan’s cell histiocytosis; Empty Sella syndrome),
- Metabolic (Primary hypothyroidism, chronic renal and liver disease) and
- Miscellaneous (chest wall lesions for example zoster, idiopathic & macroprolactin).
(A). Effects due to hyperprolactinemia (In both micro- & macroprolactinoma) :
(1) Specific to Females:
- Galactorrhea in approximately 90% of women
- Menstrual disturbances (amenorrhea, oligomenorrhea & infertility)
Premenopausal women presents with secondary amenorrhea and galactorrhea. If we exclude pregnancy, hyperprolactinemia is the cause for amenorrhea in 10%-20% cases. It is important to remember that even mild degree of PRL elevation can cause infertility in spite of normal menstrual cycle.
Postmenopausal women do not present with galactorrhea. Signs and symptoms due to mass effect is the common presentation.
(2). Specific to males:
- Loss of libido.
- Erectile dysfunction.
- Infertility. Elevated PRL inhibits testosterone secretion resulting in the above-mentioned clinical picture.
- Galactorrhea in <10% males.
- Gynaecomastia – Uncommon.
(3). Manifestations common to both sexes:
- Hypogonadotropic hypogonadism. It should be remembered that the loss of libido from hyperprolactinoma could be an independent effect irrespective of hypogonadism.
- Long term effect: Decrease in bone mineral density.
(B). Mass effect (Macroprolactinoma only):
- Visual Field defects.
- Cranial nerve palsies (cavernous sinus infiltration)
- CSF leak (rare).
(a). Normal level: <500mU/l (20mcg/l) in women (non-pregnant) & <300mU/l (12mcg/l) in males.
(b). During pregnancy the levels can go up to 800mU/l (320mcg/l) in the third trimester.
(c). Mild elevation of PRL should be rechecked and offending medications should be identified.
(d). Moderately elevated PRL defined arbitrarily as a range of 500-2000 mU/l (25-100 mcg/l) is seen with drugs, hypothyroidism, renal & hepatic insufficiency, stalk compression, Acromegaly and chest wall injury. Among medication-induced causes anti-emetics (domperidone & metoclorpramide alone or as a part of anti-migrane combination drugs) & tranquilizers (chlorpromazine) can elevate PRL to a greater extent (5000 mU/l) . Moderate elevations are seen with atypical antipsychotics and herbal medications. In such a scenario the offending drug should be discontinued for at least 3 days and a repeat estimation of PRL should be done .
(e). PRL level: >3000 mU/l (>150 mcg/l) is indicative of Microprolactinoma.
(f). PRL level: >6000 mU/l (>300 mcg/l) is indicative of Macroprolactinoma.
(g). PRL level <2000 mU/l with a pituitary macro lesion is indicative of “disconnection” hyperprolactinoma from a non-functioning pituitary macroadenoma.
(h). Due to history of co-secretion GH in 20-25% cases this entity has to be ruled out. In cases of macroprolactinoma it is better to perform a full pituitary function testing.
Certain important considerations while interpreting the PRL assay results:
Macroprolactin: Normal human prolactin molecule is structurally composed of a fusion of several molecular forms of differing molecular weight. These include monomeric PRL (23kDa), big PRL (50-60kDa) & big-big PRL (Macroprolactin: 150-170 kDa). In individuals with normal serum PRL macroprolactin constitutes ~1% of the sera which dramatically increases to 25% once PRL level crossed the upper limit of normal. This factor requires correction, as macroprolactin is not associated with macroprolactinoma. This correction can be achieved by polyethylene glycol (PEG) precipitation whereby the larger molecules are precipitated out of the equation.
The “Hook Effect”: This is a laboratory artifact where extremely high PRL levels most likely from a large prolactinoma saturates both the capture as well as detection antibodies giving rise to falsely low, normal or slightly elevated PRL values. Performing the test with a 1:100-1000 dilution can neutralize this effect.
Once a biochemical confirmation has been achieved ophthalmological examination (including visual field) & imaging (MRI with gadolinium contrast) has to be performed.
It has to be remembered a pituitary microadenoma with normal PRL may be detected while performing imaging for an unrelated cause. These are “incidentalomas”. Conversely even with an elevated PRL MRI may not pick up a microprolactinoma.
Management (drugs, hypothyroidism and other causes having been ruled out)
Aims of therapy
For microprolactinoma the aim is to improve libido, restore gonadal function and give relief from galactorrhea .
For macroprolactinoma the pressing issue is that of mass effect, decreasing the tumor size and then restoration of gonadal function & libido.
For most the above aim can be achieved with dopamine agonists [DA] (bromocriptine & cabergoline). Due to greater efficacy in reducing tumor size & PRL level as well as lesser dose frequency (2x per week) cabergoline is preferred over bromocriptine . The Endocrine Society Clinical Practice Guidelines 2011 recommends against using dopamine agonists (DA) in asymptomatic patients. Those with amenorrhea as their only symptom can be treated with DA or oral contraceptives.
Unresponsive patients while on maximal dose of bromocriptine should be switched over to cabergoline. Those resistant to usual doses of cabergoline should be up titrated to the maximal upper limit of dosage or tolerable limit. In rare cases in females where cabergoline is not tolerated while increasing the dosage it can be given transvaginally. In those with prolactinoma who wish to conceive, reduction in tumor size should be attempted prior to pregnancy. If DA is not tolerated surgery is an option. On the other hand those with macroprolactinoma who become pregnant can be continued with DA (bromocriptine favored). Appearance of symptoms suggestive of mass effect warrants a visual field testing & MRI.
Cabergoline and Valvulopathy
Cabergoline and not bromocriptine is a 5-hydroxytryptamine-2B-receptor agonist. Administering it at a high dose defined as ≥ 3mg/day for ≥ 6 months is associated with valvular heart disease (regurgitations), pulmonary fibrosis and retroperitoneal fibrosis. However usage of such high dosage is seen in Parkinsonism and not prolactinomas. In rare instances of resistant prolactinomas requiring higher doses these adverse events should be kept in mind. Follow up has to be done with a baseline echocardiography and then after 3-6 months and annually thereafter.
Surgery (second-line approach) is indicated in the presence of DA failure, intolerability, and those with severe vision threatening mass effects. Transphenoidal surgery is the preferred surgical procedure. The success of surgery depends on the surgeon’s expertise and it is not uncommon to come across recurrences.
Radiotherapy is reserved for those with recurrence (post surgery) and malignant prolactinomas although temozolomide is an alternative for the later scenario.
Those who maintain a normal PRL level for 2 years and no residual tumor on MRI can discontinue DA therapy. For the rest who do not fulfill this criteria should be maintained on the lowest possible dose of DA.
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