HYPERPROLACTINEMIA

Introduction

Hyperprolactinemia is the most common endocrine disorder of the hypothalamic-pituitary axis. It refers to the consistent presence of abnormally high levels of prolactin in the blood after ruling out the physiological causes of prolactin hypersecretion. Normal levels are less than 580 mIU/L for women, and less than 450 mIU/L for men.¹

Prolactin is a 198-amino acid protein (23-kD) produced in the lactotroph cells of the anterior pituitary gland. It is mainly concerned with breast development during pregnancy and induction of lactation. It is secreted in a pulsatile manner, and increases with sleep, stress, pregnancy and chest wall stimulation or trauma.²

Prolactin secretion

Prolactin secretion is regulated by the predominantly tonic inhibitory effect of the hypothalamus. The hypothalamus secretes a prolactin-release-inhibiting factor (PIF) and a prolactin-releasing factor (PRF). The main PIF is dopamine, although non-catecholamine PIFs may also be involved. Additionally, gamma-aminobutyric acid (GABA) as well as other unidentified PIFs may play an inhibiting role. Thyrotropin-releasing hormone (TRH) can act as a PRF. Other PRFs include suckling, stress, vasoactive intestinal peptide (VIP), oxytocin, galanin and PHM-27.³

The principal action of prolactin is to induce and maintain milk production. This is done by stimulation of breast epithelial cell proliferation. Estrogen stimulates the proliferation of pituitary lactotroph cells, resulting in an increased quantity of these cells in premenopausal women, especially during pregnancy. However, lactation is inhibited by the high levels of estrogen and progesterone during pregnancy. But in the postpartum period, estrogen and progesterone levels fall rapidly, resulting in lactation.²

In response to suckling (or breast stimulation), tonic inhibition of prolactin secretion is overridden by neurogenetic signals from the breast through a multisynaptic pathway that stimulates PRF and inhibits dopamine.⁴

Pathophysiology of hyperprolactinemia

The prolactin inhibitory factors reach the pituitary via the hypothalamic-pituitary portal vessels.⁵   Dopamine acts on surface membrane dopamine D²   receptors on lactotroph cells. Disruption of the pituitary stalk and therefore the transport of dopamine to the lactotrophs, or blockade of endogenous dopamine receptors by certain drugs, leads to a moderate increase in prolactin secretion.

Hyperprolactinemia 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.¹

Causes of hyperprolactinemia

Hyperprolactinemia can be a part of normal body changes during pregnancy and breast feeding (physiological hyperprolactinemia). It can also be pathological, being caused by diseases affecting the hypothalamus and pituitary gland, or other organs such as the liver, kidneys, ovaries and thyroid. Pharmacological hyperprolactinemia occurs when the normal regulation of prolactin levels is disrupted by drugs, medicinal herbs and heavy metals.⁶

Table 1 enumerates the causes of hyperprolactinemia.⁷

Clinical presentation

In women, hyperprolactinemia may manifest as oligomenorrhea, amenorrhea, infertility, decreased libido and habitual abortion. Premenopausal women may also present with galactorrhea, which requires the presence of both estrogen and prolactin. Osteopenia may occur due to prolonged hypoestrogenism induced by hyperprolactinemia.⁸   This is borne out by the finding that 49% of hyperprolactinemic women with amenorrhea had a spinal bone density more than 1 SD below the normal mean, whereas women with hyperprolactinemia and normomenorrhea had normal bone mineral density.^9,10     Hyperprolactinemic women may also have signs of chronic hyperandrogenism, such as hirsutism and acne, possibly due to increased dehydroepiandrosterone sulfate secretion from the adrenals.¹¹

Men with hyperprolactinemia may present with infertility associated with decreased sperm production, galactorrhea, gynecomastia and decreased libido or potency. They may also have reduced muscle mass and, like women, are at increased risk of osteopenia.¹²

Macroprolactinomas can cause neurological symptoms in both sexes due to mass effects of the pituitary tumor. Symptoms include headaches and visual loss and also relate to cranial neuropathies, hypopituitarism, seizures and cerebrospinal fluid rhinorrhea.¹¹

Treatment

Before starting treatment, due consideration must be given to several aspects, such as the patient’s clinical presentation, the differences between microadenomas and macroadenomas concerning their natural history, the desire for pregnancy, and the patient’s treatment preference, if applicable. Hyperprolactinemia can be treated by medications, radiotherapy or surgery.

Medical treatment

The current gold standard medical treatment of hyperprolactinemia is with dopamine agonist drugs, such as bromocriptine, cabergoline and quinagolide. Cabergoline has a long half-life, allowing once or twice weekly dosing, and a better tolerability profile. However, data on its safety in pregnancy is limited compared to that of bromocriptine, on which a number of trials have been conducted and which is widely accepted by clinicians. Therefore, bromocriptine remains the treatment of choice in women requiring treatment for subfertility.

The effect of bromocriptine on pregnancy rate in infertile women with galactorrhea with or without high prolactin level was evaluated in a prospective study.¹³   Galactorrhea is one of the causes of infertility due to luteal phase defect and anovulatory cycles.

In this study, 205 infertile women (aged 18-39 years) with galactorrhea were treated with 2.5 mg bromocriptine twice a day for up to 6 months. This treatment led to positive signs of pregnancy in 76.1% of patients. The pregnancy rate was 81.7% in patients with high prolactin level (>20 ng/dl) and 74.3% in those with normal prolactin level (Fig. 2). Thus, bromocriptine can safely be recommended for the treatment of infertile women with galactorrhea, regardless of serum prolactin level.

In patients requiring surgical resection of prolactinomas, preoperative treatment with dopamine agonists can favorably alter the outcome of surgical intervention. This was the finding of a study¹⁴   which evaluated 253 patients with prolactinomas treated surgically. Both short- and long-term outcomes of patients treated with dopamine agonists prior to surgery were compared with those undergoing surgery as their initial treatment modality. The results showed that patients treated with dopamine agonists prior to surgery experienced greater reductions in prolactin levels, had lower prolactin levels, were more likely to have normal prolactin levels at long term follow-up, and were less likely to require additional therapy to control their prolactin levels.

These results provide strong evidence that, regardless of initial prolactin level, pretreatment with dopamine agonist drugs may induce tumor regression, enabling resection of a greater percentage of the tumor and leading to better control of the prolactin level.

Estrogen therapy may be used to replace dopamine agonists in women with idiopathic hyperprolactinemia (IH) or microprolactinoma who do not want to become pregnant and those suffering from estrogen deficiency, particularly if they are resistant to or intolerant of dopamine agonists.^15-17

Surgical treatment

Pituitary surgery, usually by the transsphenoidal approach, is generally reserved for prolactinomas resistant to dopamine agonist drugs.

Transsphenoidal surgery offers the possibility of achieving complete cure in selected patients, although at the expense of significant risk in terms of morbidity, especially hypopituitarism, and a very low mortality rate. Microadenomas are more amenable to surgery, with normal levels of serum prolactin being achieved in about 80% cases; but the recurrence rate is also high at ~25% at 5 years. Surgical results in macroprolactinomas are much poorer, mainly in big and/or invasive tumors.³

Radiotherapy

Fractionated radiotherapy is now rarely used in primary therapy of prolactinomas because of relatively poor results and also because it is fraught with the risk of postradiotherapy pituitary insufficiency. Gamma knife radiosurgery (GKS), in which radiation to the pituitary area is more focused, offers potential advantages over conventional forms of radiotherapy, as it can diminish the radiation dose to normal tissues.¹⁸

Conclusion

Hyperprolactinemia refers to the consistent presence of abnormally high levels of prolactin in the blood after ruling out the physiological causes of prolactin hypersecretion. The commonest causes of chronic hyperprolactinemia are a prolactinoma after pregnancy, primary hypothyroidism, and drugs that elevate serum prolactin levels. Treatment should aim to normalize prolactin levels, restore gonadal function, and reduce the effects of chronic hyperprolactinemia. Clinical signs and symptoms of hyperprolactinemia are usually resolved when prolactin levels are lowered to within the normal range. Dopamine agonists are the treatment of choice for the majority of patients. Transsphenoidal surgery is usually reserved for patients who are intolerant of or resistant to dopamine agonists or when hyperprolactinemia is caused by non-prolactin-secreting tumors compressing the pituitary stalk. Bromocriptine is a time-tested dopamine agonist, with ample evidence of its safety during pregnancy and hence remains the treatment of choice in hyperprolactinemic women wishing to conceive.

References

1. Hyperprolactinaemia. Available at http://en.wikipedia.org/wiki/Hyperprolactinaemia. Accessed on May 24, 2011.
2. Shenenberger D. Hyperprolactinemia. Available at: http://emedicine.medscape.com/article/121784-overview. Accessed on May 24, 2011.
3. Thorner MO, Bronstein MD. Hyperprolactinemia. Available at http://www.endotext.org/neuroendo/neuroendo6/neuroendo6.html. Accessed on May 24, 2011.
4. Lechan R. Pituitary Neoplasia. Available at: http://ocw.tufts.edu/Content/14/lecturenotes/265915. Accessed on May 24, 2011.
5. Molitch ME. Disorders of prolactin secretion. Endocrinol Metab Clin North Am 2001;30:585-610
6. Mancini T, Casanueva FF, Giustina A. Hyperprolactinemia and Prolactinomas. Endocrinology and Metabolism Clinics of North America 2008; 37 (1): 67.
7. Mah PM, Webster J. Hyperprolactinemia: Etiology, Diagnosis, and Management. Semin Reprod Med. 2002;20(4).
8. Klibanski A, Neer RM, Beitins IZ, Ridgway EC, Zervas NT, McArthur JW. Decreased bone density in hyperprolactinemic women. N Engl J Med 1980;303:1511-1514.
9. Biller BM, Baum HB, Rosenthal DI, Saxe VC, Charpie PM, Klibanski A. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992;75:692-697.
10. Klibanski A, Biller BM, Rosenthal DI, Schoenfeld DA, Saxe V. Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 1988;67:124-130.
11. Biller BM. Hyperprolactinemia. Int J Fertil Womens Med 1999;44:74-77.
12. Luciano AA. Clinical presentation of hyperprolactinemia. J Reprod Med 1999;44(suppl 12):1085-1090.
13. Eftekhari N, Mohammadalizadeh S. Pregnancy rate following bromocriptine treatment in infertile women with galactorrhea. Gynecol Endocrinol. 2009 Feb;25(2):122-4.
14. Sughrue ME, Chang EF, Tyrell JB, Kunwar S, Wilson CB, Blevins LS Jr. Pre-operative dopamine agonist therapy improves post-operative tumor control following prolactinoma resection. Pituitary. 2009;12(3):158-64.
15. Molitch ME. Disorders of prolactin secretion. Endocrinol Metab Clin North Am 2001;30:585-610.
16. Webster J. Clinical management of prolactinomas. Baillieres Best Pract Res Clin Endocrinol Metab 1999;13:395-408.
17. Rebar RW. Following patients under treatment for hyperprolactinemia. J Reprod Med 1999;44(suppl 12):1100-1104.
18. Landolt AM, Lomax N. Gamma knife radiosurgery for prolactinomas. J Neurosurg 2000;93(suppl 3):14-18.