**5. Hyperprolactinemia and infertility**

Prolactin is a pituitary-derived hormone that plays an important role in a variety of reproductive functions. It is an essential factor for normal production of breast milk following childbirth. Additionally, prolactin negatively modulates the secretion of pituitary hormones responsible for gonadal function, including luteinizing hormone and folliclestimulating hormone. Clnincally significant hyperprolactinemia may result in hypogonadism, infertility, and galactorrhea, or in some cases it may remain asymptomatic for a long period. (Klibanski 2010) The most commonly cited indications for treatment of microprolactinomas is infertility and hypogonadism. Hypogonadism and infertility associated closely with the treatment: DA agonists can restore normal PRL levels and consequently the normal gonadal function . According to the date of a meta-analyis, patients treated with bromocriptine had normalization of prolactin levels and it was successful in 53% of patients with infertility. Studies with cabergoline showed similar results: cabergoline was shown more effective than bromocriptine reducing PRL levels, or in symptoms of amenorrhea/oligomenorrhea, or in some of the patient-important outcomes. (Gillam 2006; Wang 2012)

Prolactin is under dual regulation by hypothalamic hormones delivered through the hypothalamic–pituitary portal circulation. The differential diagnosis and causes of pathological hyperprolactinemia are summarized in Figure 1.

The predominant signal is inhibitory, preventing prolactin release, and is mediated by the neurotransmitter dopamine. The stimulatory signal is mediated by the hypothalamic TRH. The balance between the two opposite signals determines the amount of prolactin released from the anterior pituitary gland (Verhelst; 2003).

**Figure 1.** Prolactin is under dual control from the hypothalamus.

#### **6. Hyperprolactinemia management**

156 Prolactin

(Sonino 2007)

1989).

(Reis, 1996).

subjects (Sonino, 2004).

Freeman, 2000; Fava, 1981.)

**5. Hyperprolactinemia and infertility** 

score provided by DCPR tests have been demonstrated to be a valuable tool for psychological assessment in endocrine disease from diagnostic to follow-up periods.

 In clinical environment the variability of PRL concentration in random estimations underline the need for special testing to rule out stress-related hyperprolactinemia and diagnostic pitfalls. It was recommended by the results, that two or three serial PRL determinations in resting conditions provide more reliable results (Muneyyirci-Delale,

 In experimental conditions, hyperprolactinemia and stress interact differentially according to the length of the stimuli and that is connected to the immune response modulated by PRL. Surgical or restraint stress induce marked (2x- 4x) increase of plasma PRL of control rats, but interestingly did not change the PRL levels of hyperprolactinemic rats. In both cases the plasma glucose levels reported elevated

 It is suggested as a result of a retrospective observational study, that life events such as changes in subject's social or personal environment indicated that these stressful conditions may provoke hyperprolactinemia. Even an exposure during childhood to a stressful environment maybe associated with hyperprolactinemia and/or galactorrhea later in life as a response to specific environmental changes (Sobrinho, 1984). Patients with hyperprolactinemia reported significantly more life events, these events rated as being of "moderate", marked or severe "negative" impact compared with control

 There is evidence that several external stress-factors may contribute to the occurrence of hyperprolactinemia. In theory, stress might have been involved in facilitation of a clonal proliferation of a single mutated cell and cause prolactinomas. Patients in functional hyperprolactinemic status, stress might trigger neuroendocrine changes involving DA and/or serotonin, which both can consequently affect PRL release. (Verhelst, 2003;

Prolactin is a pituitary-derived hormone that plays an important role in a variety of reproductive functions. It is an essential factor for normal production of breast milk following childbirth. Additionally, prolactin negatively modulates the secretion of pituitary hormones responsible for gonadal function, including luteinizing hormone and folliclestimulating hormone. Clnincally significant hyperprolactinemia may result in hypogonadism, infertility, and galactorrhea, or in some cases it may remain asymptomatic for a long period. (Klibanski 2010) The most commonly cited indications for treatment of microprolactinomas is infertility and hypogonadism. Hypogonadism and infertility associated closely with the treatment: DA agonists can restore normal PRL levels and consequently the normal gonadal function . According to the date of a meta-analyis, patients treated with bromocriptine had normalization of prolactin levels and it was successful in 53% of patients with infertility. Studies with cabergoline showed similar results: cabergoline

 The first steps in cases of signs of hyperprolactinemia should be a critical diagnosis, as discussed above, may involve dynamic testings, assessment for macroprolactinemia and further laboratory tests to eliminate false positive or negative results.

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

Prolactin and Infertility 159

**8. Recommendations for drug-induced hyperprolactinemia** 

follows (Melmed 2011):

hyperprolactinemia.

prolactin-lowering drug.

**9.1. Bromocriptine (Parlodel)** 

with the patient's physician.

**9. Treatment of hyperprolactinemia** 

treated with a group of medications known as dopamine agonists.

hyperprolactinemia when it is caused by other medications.

effects. Generally with time, the side effects stop anyway.

Specific recommendations for management of drug-induced hyperprolactinemia are as

 In a symptomatic patient with suspected medication-induced hyperprolactinemia, the drug should be discontinued for 3 days or an alternative drug substituted, and the serum prolactin measurement should then be repeated. However, the patient's physician should be consulted before an antipsychotic agent is discontinued or substituted. If the drug cannot be discontinued and the onset of the hyperprolactinemia does not coincide with starting therapy, magnetic resonance imaging (MRI) of the pituitary gland may distinguish medication-induced hyperprolactinemia from

symptomatic hyperprolactinemia caused by a pituitary or hypothalamic mass. Patients with asymptomatic medication-induced hyperprolactinemia should not be treated. Estrogen or testosterone can be used in patients with long-term hypogonadism (hypogonadal symptoms or low bone mass) caused by medication-induced

 If it is not possible to stop the drug causing medication-induced hyperprolactinemia, cautious administration of a dopamine agonist should be considered, in consultation

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

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

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

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

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


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

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