**9. Treatment of hyperprolactinemia**

158 Prolactin

tumours, etc.

 Consider other underlying causes, such as suspected drug-induced hyperprolactinemia, hypothyroidism, elimination/renal failure, other persistent pituitary and parasellar

Identify the size of pituitary tumour and other anatomical circumstances.

The major steps of diagnosis of hyperprolactinemia is summarized in Figure 2.

Increased Prolactin levels

Pathological hyperprolactinemia

MRI of

Macroprolactinemi Repeat Rule out secondary causes

Correct underlying cause: replace thyroid hormone, remove/substitute potentially

offending medication

Normal pituitary Micro lesion (<10 mm) Macro lesion (≥10 mm)

Treatment

Apply pharmacotherapy treatment specified to patient

**Figure 2.** Approach to diagnosis of hyperprolactinemia.

Follow-up prolactin measurement once yearly

Asymptomatic Symptomati

diagnose hyperprolactinemia.

leading to a falsely low prolactin value.

hyperprolactinemia.

(Melmed 2011):

**7. Recommendations for the diagnosis of hyperprolactinemia** 

Specific recommendations for diagnosis of hyperprolactinemia include the following

 A single measurement of serum prolactin level can confirm the diagnosis if the level is above the upper limit of normal and the serum sample was obtained without excessive venipuncture stress. Dynamic testing of prolactin secretion is not recommended to

Macroprolactin evaluation is recommended in patients with asymptomatic

 When there is a discrepancy between a very large pituitary tumour and a mildly elevated prolactin level, serial dilution of serum samples is recommended to eliminate the "hook effect," or an artifact that can occur with some immunoradiometric assays As noted above, prolactin levels can often be corrected by stopping suspected medication or switching to a different medication type. Correction of hypothyroidism is also effective and specific to reduce PRL levels. If prolactin levels are persistently high, they can be effectively treated with a group of medications known as dopamine agonists.

According to our clinical practice patients with macroadenoma suggested to undergo transsphenoidal pituitary surgery. Medical treatment is given to the subjects with microadenoma, persistent postoperative hyperprolactinemia, and to those cases of hyperprolactinemia when it is caused by other medications.

From the available mediactions Bromocriptine 2.5 mg (Parlodel®, Novartis) once or twice a day or cabergoline 0.5 mg (Dostinex®, Pharmacia) once or twice a week is given as prolactin-lowering drug.

#### **9.1. Bromocriptine (Parlodel)**

Parlodel is an effective and inexpensive medication for high prolactin levels. Parlodel is usually taken at bedtime with a snack. This is because Parlodel will occasionally cause dizziness or stomach upset, so taking it before sleep and with food will reduce those side effects. Generally with time, the side effects stop anyway.

The prolactin levels can be rechecked in about three weeks. If the levels are still elevated the dose can be increased or a different medication can be tried. The administration of Parlodel can be stopped upon diagnosis of pregnancy. However, if a woman has a macroadenoma, Parlodel should be continued through pregnancy and delivery.

Prolactin and Infertility 161

 Symptomatic patients with prolactinomas who cannot tolerate high doses of cabergoline or who are unresponsive to dopamine agonist therapy should be offered trans-sphenoidal surgery. Patients intolerant of oral bromocriptine may respond to intravaginal administration. Radiation therapy is recommended for patients in whom

surgical treatment fails or for those with aggressive or malignant prolactinomas. Temozolomide therapy is recommended for patients with malignant prolactinomas.

Specific recommendations for management of prolactinoma during pregnancy are as

 Women with prolactinomas should discontinue dopamine agonist therapy as soon as pregnancy is recognized, except for selected patients with invasive macroadenomas or

 Unless there is clinical evidence for tumour growth, such as visual field impairment, routine use of pituitary MRI during pregnancy is not recommended in patients with

 Women with macroprolactinomas that do not shrink during dopamine agonist therapy or women who cannot tolerate bromocriptine or cabergoline should be counselled regarding the potential benefits of surgical resection before attempting pregnancy. Pregnant women with prolactinomas who experience severe headaches and/or visual field changes should have formal visual field assessment followed by MRI without

Bromocriptine therapy is recommended in patients who experience symptomatic

Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. A recently published study demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. This study indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists (Sonigo,

To sum up, the systematic reviews and meta-analyses affirm the use of dopamine agonists in treating hyperprolactinemia and reducing associated morbidity. Cabergoline was found to be more effective than bromocriptine in achieving normoprolactinemia and resolving amenorrhea/oligomenorrhea and galactorrhea. Radiotherapy and surgery are efficacious in

patients with resistance or intolerance to dopamine agonists (Wang, 2012).

**12. Recommendations for pregnant women with prolactinoma** 

Serum prolactin measurements should not be performed during pregnancy.

follows (Melmed 2011):

gadolinium.

2012).

adenomas abutting the optic chiasm.

microadenomas or intrasellar macroadenomas.

growth of a prolactinoma during pregnancy.

Due to the side effects, some women can not tolerate Parlodel. For these women, they may try alternatives, e.g. vaginal bioadhesive suppositories or inserted the pills vaginally instead of taking them orally.

#### **9.2. Cabergoline (Dostinex)**

Because it is more expensive, cabergoline is not usually the first choice for treatment of high prolactin levels. It is usually used when Parlodel is ineffective or a woman cannot tolerate the side effects. Cabergoline is a longer acting medication. It is usually given twice a week instead of every day.

The Endocrine Society has released a new clinical practice guideline for the diagnosis and treatment of patients with hyperprolactinemia (Melmed, 2011). The new recommendations for management of elevated levels of the PRL, which is associated with infertility, low sex drive, and bone loss, are listed.
