Hyperprolactinaemia

Hyperprolactinaemia
Classification and external resources
Prolactin
ICD-10	E22.1
ICD-9	253.1
DiseasesDB	6314
eMedicine	med/1098
MeSH	D006966

Hyperprolactinaemia or hyperprolactinemia (HP) is the presence of abnormally-high levels of prolactin in the blood. Normal levels are less than 500 mIU/L for women, and less than 450 mIU/L for men.

Prolactin is a peptide hormone produced by the anterior pituitary gland primarily associated with lactation and plays a vital role in breast development during pregnancy. Hyperprolactinaemia may cause production and spontaneous flow of breast milk and disruptions in the normal menstrual period in women and hypogonadism, infertility and erectile dysfunction in men.

Hyperprolactinaemia can be a part of normal body changes during pregnancy and breastfeeding. It can also be caused by diseases affecting the hypothalamus and pituitary gland. It can also be caused by disruption of the normal regulation of prolactin levels by drugs, medicinal herbs and heavy metals. Hyperprolactinaemia may also be the result of disease of other organs such as the liver, kidneys, ovaries and thyroid.^[1]

Causes

Hyperprolactinaemia may be caused by either disinhibition (e.g., compression of the pituitary stalk or reduced dopamine levels) or excess production from a prolactinoma (a pituitary gland adenoma tumour). A blood serum prolactin level of 1000–5000 mIU/L could be from either mechanism, but >5000 mIU/L is likely due to the activity of an adenoma with macroadenomas (large tumours over 10 mm diameter) whose levels of prolactin are up to 100,000 mIU/L. Hyperprolactinaemia inhibits gonadotropin-releasing hormone (GnRH) by increasing the release of dopamine from the arcuate nucleus of the hypothalamus (dopamine inhibits GnRH secretion), thus inhibiting gonadal steroidogenesis, which is the cause of many of the symptoms described below.

There is a suspicion that Minoxidil, a potassium channel agonist, may be related to the development of this disease. A two-year test with Minoxidil, under normal dosing parameters, was carried out on rats, which caused phaeochromocytomas in both males and females, and preputial gland adenomas in males.^[2]

Physiological causes

Physiological causes (i.e., as result of normal body functioning): pregnancy, breastfeeding, mental stress, sleep, hypothyroidism.

Prescription drugs

Use of prescription drugs is the most common cause of hyperprolactinaemia. Prolactin secretion in the pituitary is normally suppressed by the brain chemical dopamine. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete prolactin. These drugs include the major tranquillizers (phenothiazines), trifluoperazine (Stelazine), and haloperidol (Haldol); antipsychotic medications in general; metoclopramide (Reglan), domperidone, cisapride used to treat gastro-oesophageal reflux and medication induced nausea(such as cancer drugs); and, less often, alpha-methyldopa and reserpine, used to control hypertension; and oestrogens and TRH. The sleep drug ramelteon (Rozerem) also increases the risk of hyperprolactinaemia. In particular, the dopamine antagonists metoclopramide and domperidone are both powerful prolactin stimulators and have been used to stimulate breastmilk secretion for decades. However since prolactin is antagonized by dopamine and the body depends on the two being in balance, the risk of prolactin stimulation is generally present with all drugs that deplete dopamine, either directly or as a rebound effect. Risperidone can also cause hyperprolactinaemia

Diseases

Prolactinoma or other tumours arising in or near the pituitary — such as those that cause acromegaly or Cushing's disease — may block the flow of dopamine from the brain to the prolactin-secreting cells, likewise, division of the pituitary stalk or hypothalamic disease. Other causes include chronic renal failure, hypothyroidism, bronchogenic carcinoma and sarcoidosis. Some women with polycystic ovary syndrome may have mildly-elevated prolactin levels.

Apart from diagnosing hyperprolactinaemia and hypopituitarism, prolactin levels are often determined by physicians in patients that have suffered a seizure, when there is doubt as to whether this was an epileptic seizure or a non-epileptic seizure. Shortly after epileptic seizures, prolactin levels often rise, whereas they are normal in non-epileptic seizures.

Idiopathic

In many patients, elevated levels remain unexplained and may represent a form of hypothalamic-pituitary dysregulation.

Symptoms

In women, a high blood level of prolactin often causes hypo-oestrogenism with anovulatory infertility and a decrease in menstruation. In some women, menstruation may disappear altogether (amenorrhoea). In others, menstruation may become irregular or menstrual flow may change. Women who are not pregnant or nursing may begin producing breast milk. Some women may experience a loss of libido (interest in sex) and breast pain, especially when prolactin levels begin to rise for the first time, as the hormone promotes tissue changes in the breast. Intercourse may become painful because of vaginal dryness.

In men, the most common symptoms of hyperprolactinaemia are decreased libido, erectile dysfunction, infertility and gynaecomastia. Because men have no reliable indicator such as menstruation to signal a problem, many men with hyperprolactinaemia being caused by an adenoma may delay going to the doctor until they have headaches or eye problems caused by the enlarged pituitary pressing against nearby optic nerves. They may not recognize a gradual loss of sexual function or libido. Only after treatment do some men realize they had a problem with sexual function.

Because of hypoestrogenism and hypogonadism (low testosterone), hyperprolactinaemia can lead to osteoporosis.

Diagnosis

A doctor will test for prolactin blood levels in women with unexplained milk secretion (galactorrhoea) or irregular menses or infertility, and in men with impaired sexual function and milk secretion. If prolactin is high, a doctor will test thyroid function and ask first about other conditions and medications known to raise prolactin secretion. While a plain X-ray of the bones surrounding the pituitary may reveal the presence of a large macro-adenoma, the small micro-adenoma will not be apparent. Magnetic resonance imaging (MRI) is the most sensitive test for detecting pituitary tumours and determining their size. MRI scans may be repeated periodically to assess tumour progression and the effects of therapy. Computed Tomography (CT scan) also gives an image of the pituitary, but it is less sensitive than the MRI.

In addition to assessing the size of the pituitary tumour, doctors also look for damage to surrounding tissues, and perform tests to assess whether production of other pituitary hormones is normal. Depending on the size of the tumour, the doctor may request an eye exam with measurement of visual fields.

The hormone prolactin is downregulated by dopamine and is upregulated by oestrogen. A falsely-high measurement may occur due to the presence of the biologically-inactive macroprolactin in the serum. This can show up as high prolactin in some types of tests, but is asymptomatic.

Treatment

Treatment is usually medication with dopamine agonists such as cabergoline,^[3] bromocriptine (often preferred when pregnancy is possible),^[4][5] and less frequently lisuride. A new drug in use is norprolac^[6] with the active ingredient quinagolide.

Vitex agnus-castus extract can be tried in cases of mild hyperprolactinaemia.^[7]

Historical eponyms

The following eponyms were established before prolactin levels could be measured reliably in the clinical setting. On occasion, they are still encountered:

1. Ahumada-DelCastillo Syndrome, which refers to the association of galactorrhoea and amenorrhoea.^[8]
2. Chiari-Frommel Syndrome, which refers to extended postpartum galactorrhoea and amenorrhoea.^[9]
3. Forbes-Albright Syndrome, which refers to galactorrhoea-amenorrhoea associated with a pituitary tumour.^[10]

References

1. ^ Mancini, T.; Casanueva, FF; Giustina, A (2008). "Hyperprolactinemia and Prolactinomas". Endocrinology & Metabolism Clinics of North America 37 (1): 67. doi:10.1016/j.ecl.2007.10.013. PMID 18226731 
2. ^ Minoxidil Official FDA information, side effects and uses
3. ^ Verhelst J, Abs R, Maiter D, et al. (July 1999). "Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients". J. Clin. Endocrinol. Metab. 84 (7): 2518–22. doi:10.1210/jc.84.7.2518. PMID 10404830. http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=10404830. 
4. ^ Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Scanlon MF (October 1994). "A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group". N. Engl. J. Med. 331 (14): 904–9. doi:10.1056/NEJM199410063311403. PMID 7915824. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=7915824&promo=ONFLNS19. 
5. ^ Colao A, Di Sarno A, Guerra E, De Leo M, Mentone A, Lombardi G (April 2006). "Drug insight: Cabergoline and bromocriptine in the treatment of hyperprolactinemia in men and women". Nat Clin Pract Endocrinol Metab 2 (4): 200–10. doi:10.1038/ncpendmet0160. PMID 16932285. 
6. ^ Sarno A, Landi M, Marzullo, et al. (November 2000). "The effect of quinagolide and cabergoline, two selective dopamine receptor type 2 agonists, in the treatment of prolactinomas". Clin. Endocrinol. 53 (5): 549–550. PMID 10931080. 
7. ^ Kilicdag, E.; Tarim, E.; Bagis, T.; Erkanli, S.; Aslan, E.; Ozsahin, K.; Kuscu, E. (2004). "Fructus agni casti and bromocriptine for treatment of hyperprolactinemia and mastalgia". International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 85 (3): 292–293. doi:10.1016/j.ijgo.2004.01.001. PMID 15145274.  edit
8. ^ Ahumada-del Castillo syndrome at Who Named It?
9. ^ Chiari-Frommel syndrome at Who Named It?
10. ^ Forbes-Albright syndrome at Who Named It?