**4. Causes of high prolactin levels**

#### **4.1. Pituitary tumours**

150 Prolactin

before also.

if they squeeze their nipples.

cm in diameter as "macroadenoma".

**3. Measurement of prolactin** 

macroprolactinoma. (Melmed, 2011)

discharge is the result of persistant high PRL levels stimulating the mammary gland for milk production. Some women may see galactorrhea occur spontaneously. Others may see it only

As diagnostic practice, after signs and labtests have been evaluated the magnetic resonance imaging (MRI) of the pituitary gland should be performed in all patients. A pituitary adenoma with a diameter of less than 1 cm is defined as "microadenoma" and one above 1

Prolactin can be measured with a simple blood test drawn at the fertility doctor's office. In order to get accurate results, prolactin should be drawn first thing in the morning. Since PRL may serve as a hormone to affect reproductive functions, sexual contact, stimulation of nipples in human may cause a not just immediate but also next-day-long alterations of the PRL secretory pattern. (Kruger 2012) These fluctuations are measured on the next day to produce a PRL elevation around noon, additional of the regular circadian rhythm of PRL levels, as the peak on the morning. Accordingly it is important to note that the woman should have the instructions to eat nothing from the night before and to avoid any stimulation of the breast and nipples, included sexual intercourse as well, from the day

Since stimulation of the breast /nipples (stress such as physical exam) may cause immediate release of PRL one common mistake that doctors make is to draw a prolactin blood test immediately after a patient has had a breast exam in the office. These women will have high prolactin levels because of the exam and therefore they may show false (i.e. transient) increase of PRL levels. Prolactin should also be drawn early in the menstrual cycle - before

A prolactin level of 5-20 ng/mL is considered normal in both sexes, according to some laboratories and test references the male and female (a bit higher) normal range may differ. A level above 20 ng/mL in two successive measurements is defined as hyperprolactinemia (7). According to WHO standards: 1 μg/L = 21.2 mIU/L. PRL levels > 250 ng/mL usually indication for prolactinoma, when PRL > 500 ng/mL it is considered as diagnosis for

There are cases when false positive and elevated PRL levels are measured: two high molecular mass forms of prolactin (PRL) in serum have been identified: macroprolactin (bigbig PRL, > 100 kDa) and big PRL (40-60 kDa). Big PRL is a consistent "normal" component of total serum PRL but rarely cause of hyperprolactinemia. Macroprolactin is usually a complex of PRL and IgG in composition, it is formed in the circulation from monomeric PRL with a molecular mass of 150-170 kDa, but may have some additional variability in composition. In labor tests the PRL in the complex remains reactive to a variable extent in immunoassays. Individuals may show a different pattern of % of these variants, or even can be a predominant immunoreactive component of circulating PRL and the cause of apparent

ovulation. This is because prolactin levels are naturally higher after ovulation.

Pituitary adenomas are the most common tumour type in the pituitary gland. There is approximately 10% incidence was shown obtained by post-mortem autopsy, with similar ratio of male and female patients. The most frequently detected tumours (over 39%) are sparsely granulated PRL cell adenomas. The others types are GH cell or mixed PRL/GH adenoma, ACTH cell adenoma/Crooke's cell adenoma (~14%) ; Gonadotroph cell adenoma (6.6%); Null cell adenoma/oncocytoma (~32%) and other or unclassified types (Buurman, 2006).

Invasive tumours with multiple recurrences are only classified as aggressive tumours or "atypical adenomas". Tumours with systemic metastasis must be considered as carcinomas, and "only" make up 0.1% to 0.2% of all pituitary tumours, but with very poor prognostics of 66% mortality (Oh, 2012). However it was suggested that a full picture inlcuded clinical signs (gender, DA-resistant hyperprolactinemia, etc) , radiological status (invasive macro or giant tumour) and histological signs of angiogenesis, mitoses level, vascular invasion and molcular biology parameters (Ki-67 > 3 %, p53 positive, up-regulation of genes related to invasion and proliferation, and allelic loss of chromosome 11) should be taken into account considering the potential malignancy, prognosis of prolactin secreting tumours and identify the optimal therapy as early as possible. The key question is to identify factors associated with tumour aggressiveness. The approach combined genomic and transcriptomic analysis focus to the subtype of pituitary tumour able to identify molecular events associated with the aggressive and malignant phenotypes. Allelic loss in certain loci of chromosome 11 has been detected in tumours with signs of malignancy, potentially responsible for triggering the aggressive and malignant phenotypes. Within the recent years there are an increasing number of genes or molecular signs that has been associated with pituitary tumorigenesis to develop predictive and potential prognostic markers. (Zemmoura, 2012; Dworakowska, 2012; Wierinckx 2011)

About one-third of all pituitary tumours are not associated with hypersecretory syndromes but, rather, present with symptoms of an intracranial mass, such as headaches, nausea, vomiting or visual field disturbances. Only rare cases of pituitary tumours are considered as malignant prolactinoma. Tumours that produce growth hormone (GH) may also secrete prolactin in nearly 25% of cases. This is a common source of misdiagnosis, as the features of prolactin excess may capture attention while the more subtle features of GH excess go unnoticed.

#### *4.1.1. Characteristics of pituitary adenomas*

In some people, a small group of cells may form a cyst in the pituitary gland which produces elevated levels of prolactin. These cysts are called prolactinomas or pituitary adenomas. It is unclear exactly how these cysts get started. Recent investigations on pituitary tumours reported that approximately 12% of pituitary glands (obtained by autopsy of 3048 patients) are shown histologically diagnosed but clinically inapparent adenoma. Among the mean tumour size is approx 1.9mm. According to published data two-thirds of adenomas has a tumour size <3 mm, half of them were smaller than 1 mm in diameter and ~23% was between 3-10mm. In this study only few (3/76) tumours were identified as macroadenomas corresponding to a tumour size >10 mm. (Buurman, *2006)*

Prolactin and Infertility 153

 According to a recent clinical study in Japan, treatment with Cabergoline achieved a high pregnancy rate with uneventful outcomes in infertile women with prolactinoma, independent of tumour size and bromocriptine resistance or intolerance. Over 90% of patients in the study conceived pregnancies, and one-third of the macroprolactinomas disappeared. Cabergoline monotherapy could serve as an alternative of the conventional combination bromocriptine therapy with surgery or irradiation in macroprolactinomas.

The hyperprolactinemia of hypothyroidism is related to several mechanisms. In response to the hypothyroid state, a compensatory increase in the discharge of central hypothalamic thyrotropin releasing hormone (TRH) results in increased stimulation of prolactin secretion. Although TRH was originally named for its ability to trigger the release of thyroidstimulating hormone (TSH) in mammals, it became apparent that TRH exerts multiple hypophysiotropic activities also in human. Stimulation with TRH will provide a diagnostic test to demonstrate a TSH release curve typical of the subclinic hypothyroidism. PRL is under tonic inhibition by the hypothalamus by way of the PRL inhibitory factor, DA. PRLreleasing factors include TRH., Increased release of TRH may also cause a sustained stimulation of prolactin release from the pituitary gland. There are several clinical reports presented the correlation between subclinic hypothyroidism-hyperprolactinemia and sterility. Treatment with thyroid hormone supplements will result in correction of both the

Asymptomatic patients with intact gonadal and reproductive function and moderately elevated prolactin levels may have macroprolactinemia (Vallette-Kasic, 2002). Hypersecretion of PRL by lactotroph cells of the anterior pituitary cause hyperprolactinemia. Patients with hyperprolactinemia may have radiologically undetected microprolactinomas, but some of them may present other causes of hyperprolactinemia characterised as a symptom of macroprolactinemia, with a predominance of higher molecular mass prolactin forms (big-big prolactin, MW > 150 kDa). This term should not be confused with macroprolactinoma, which refers to a large pituitary tumour greater than 10

The prevalence of macroprolactinemia varies between 15-46% in hyperprolactinemic populations, and it may because confusing tests results that could not be differentiated from true hyperprolactinemic patients, on the basis of clinical features alone. The pathophysiology of macroprolactinemia is based on a mechanisms of the increased antigenicity of these molecules, leading to the appearance of autoantibodies against PRL, which can consequently reduce the bioactivity of PRL and provide extended half-life. Therefore macroprolactinemia is manifested with less frequent clinical symptoms in macroprolactinemic patients and the tests results mainly due to the delayed clearance of

(Ono, 2010)

**4.2. Hypothyroidism** 

thyroid feedback and the high prolactin levels.

**4.3. Macroprolactinemia** 

mm in diameter.

The prevalence of clinically apparent prolactinomas ranges from 6–50/ 100,000 in reported populations (Daly, 2006; Fernandez 2010). The prevalence of "ever-treated" hyperprolactinemia is approximately 20 /100,000 in male patients and approximately 90 /100,000 in female patients. (Kars, 2009)

The adenomas can be seen and measured using MRI and classified based on their size.

Small adenomas are known as microadenomas. They measure less than one centimetre in diameter. This is the most common type of adenoma found. Microadenomas can even be present in healthy people who do not have high prolactin levels. Microadenomas can be treated with medication. They do not grow large and do not need to be treated if hormone levels are normal. Microprolactinomas usually follow a benign course and rarely progress to macroprolactinomas. However, in rare cases microadenoma may transform to other tumours.


Adenomas larger than 1 centimetre are called macroadenomas. If untreated, macroadenomas can grow further and start to compress the nearby tissues and structures causing life-threatening events or even fatal outcome. The closest structures are the optic nerves, internal carotid arteries. If a macroadenoma causes compression of the optic nerves, partial blindness can result. For this reason, it is important to treat macroadenomas whether or not a woman is interested in getting pregnant. Medication can be used to treat them but if that fails, surgery may be necessary.

 According to a recent clinical study in Japan, treatment with Cabergoline achieved a high pregnancy rate with uneventful outcomes in infertile women with prolactinoma, independent of tumour size and bromocriptine resistance or intolerance. Over 90% of patients in the study conceived pregnancies, and one-third of the macroprolactinomas disappeared. Cabergoline monotherapy could serve as an alternative of the conventional combination bromocriptine therapy with surgery or irradiation in macroprolactinomas. (Ono, 2010)

### **4.2. Hypothyroidism**

152 Prolactin

tumours.

*4.1.1. Characteristics of pituitary adenomas* 

/100,000 in female patients. (Kars, 2009)

(Guastamacchia, 2007)

that fails, surgery may be necessary.

In some people, a small group of cells may form a cyst in the pituitary gland which produces elevated levels of prolactin. These cysts are called prolactinomas or pituitary adenomas. It is unclear exactly how these cysts get started. Recent investigations on pituitary tumours reported that approximately 12% of pituitary glands (obtained by autopsy of 3048 patients) are shown histologically diagnosed but clinically inapparent adenoma. Among the mean tumour size is approx 1.9mm. According to published data two-thirds of adenomas has a tumour size <3 mm, half of them were smaller than 1 mm in diameter and ~23% was between 3-10mm. In this study only few (3/76) tumours were identified as

The prevalence of clinically apparent prolactinomas ranges from 6–50/ 100,000 in reported populations (Daly, 2006; Fernandez 2010). The prevalence of "ever-treated" hyperprolactinemia is approximately 20 /100,000 in male patients and approximately 90

Small adenomas are known as microadenomas. They measure less than one centimetre in diameter. This is the most common type of adenoma found. Microadenomas can even be present in healthy people who do not have high prolactin levels. Microadenomas can be treated with medication. They do not grow large and do not need to be treated if hormone levels are normal. Microprolactinomas usually follow a benign course and rarely progress to macroprolactinomas. However, in rare cases microadenoma may transform to other

 A case history it was reported that a microadenoma transformed to macroprolactinoma within 10 month, probably due to estrogen therapy applied. The case report emphasizes the role of dopaminergic agonist in treatment of hyperprolactinemia. (Garcia, 1995) A case history of a 22 -year-old woman with the signs of galactorrhea and slight hyperprolactinemia , showed 7-mm intrapituitary lesion which responded to treatment with cabergoline. This PRL-secreting microadenoma has a sudden change within 4 years of diagnose. The case represents a rapid evolution from a microprolactinoma initially responding to dopamine agonists to a fatal pituitary carcinoma.

Adenomas larger than 1 centimetre are called macroadenomas. If untreated, macroadenomas can grow further and start to compress the nearby tissues and structures causing life-threatening events or even fatal outcome. The closest structures are the optic nerves, internal carotid arteries. If a macroadenoma causes compression of the optic nerves, partial blindness can result. For this reason, it is important to treat macroadenomas whether or not a woman is interested in getting pregnant. Medication can be used to treat them but if

The adenomas can be seen and measured using MRI and classified based on their size.

macroadenomas corresponding to a tumour size >10 mm. (Buurman, *2006)*

The hyperprolactinemia of hypothyroidism is related to several mechanisms. In response to the hypothyroid state, a compensatory increase in the discharge of central hypothalamic thyrotropin releasing hormone (TRH) results in increased stimulation of prolactin secretion.

Although TRH was originally named for its ability to trigger the release of thyroidstimulating hormone (TSH) in mammals, it became apparent that TRH exerts multiple hypophysiotropic activities also in human. Stimulation with TRH will provide a diagnostic test to demonstrate a TSH release curve typical of the subclinic hypothyroidism. PRL is under tonic inhibition by the hypothalamus by way of the PRL inhibitory factor, DA. PRLreleasing factors include TRH., Increased release of TRH may also cause a sustained stimulation of prolactin release from the pituitary gland. There are several clinical reports presented the correlation between subclinic hypothyroidism-hyperprolactinemia and sterility. Treatment with thyroid hormone supplements will result in correction of both the thyroid feedback and the high prolactin levels.

#### **4.3. Macroprolactinemia**

Asymptomatic patients with intact gonadal and reproductive function and moderately elevated prolactin levels may have macroprolactinemia (Vallette-Kasic, 2002). Hypersecretion of PRL by lactotroph cells of the anterior pituitary cause hyperprolactinemia. Patients with hyperprolactinemia may have radiologically undetected microprolactinomas, but some of them may present other causes of hyperprolactinemia characterised as a symptom of macroprolactinemia, with a predominance of higher molecular mass prolactin forms (big-big prolactin, MW > 150 kDa). This term should not be confused with macroprolactinoma, which refers to a large pituitary tumour greater than 10 mm in diameter.

The prevalence of macroprolactinemia varies between 15-46% in hyperprolactinemic populations, and it may because confusing tests results that could not be differentiated from true hyperprolactinemic patients, on the basis of clinical features alone. The pathophysiology of macroprolactinemia is based on a mechanisms of the increased antigenicity of these molecules, leading to the appearance of autoantibodies against PRL, which can consequently reduce the bioactivity of PRL and provide extended half-life. Therefore macroprolactinemia is manifested with less frequent clinical symptoms in macroprolactinemic patients and the tests results mainly due to the delayed clearance of

PRL. According to recent publications of Isik et al, evaluating over 300 hyperprolactinemic patients, over 26% of them resulted in elevated macroprolactin levels, with the less frequent signs of galactorrhea or abnormal MRI results compared those to patients with predominant monomer hyperprolactinemia. The other symptoms and frequency of amenorrhea, infertility, irregular menses, gynecomastia, and erectile dysfunction were similar in both groups. (Isik, 2012)

Prolactin and Infertility 155

act as dopaminergic neurotransmitters/ receptor blockers can also cause endocrine side effects, as hyperprolactinaemia and it is most common side effect of first-generation antipsychotics. The second- and thirdgeneration antipsychotics have a weaker affinity for D2 dopamine receptors, thus hyperprolactinemia is less common when such medication is used. (Uzun et al. 2005). The risk of side effects caused by antipsychotics is individual and it does not depend solely on the therapeutic dose and may have influence on some

Some types of anti-depressants, serotonin reuptake inhibitors, SRIs (fluvoxamine;

A high prolactin level can sometimes be related to physical stress. Even drawing blood can by itself cause someone to produce and immediate prolactin-release. PRL eleveation can also detected in response to strong or sudden external stimuli in general, such as stressful environmental conditions, or can be related to physchological reasons. This latter can be evaluated by stress profile or measured by experimental conditions, such as "Screamer Index", which is shown resulting in values to be parallel to levels of hyperprolactinemia in women. (Harrison, 1988; Cepisky, 1992). On the other hand, anxiety and irritability maybe a result of hyperprolactinemia. In rat models PRL increased the stimulatory effect of ACTH-

 Endocrine abnormalities are frequently associated with a wide range of psychological symptoms. These symptoms may reach the level of psychiatric illness (mainly mood and anxiety disorders) or just being identified by the subclinical forms of assessment provided by the Diagnostic Criteria for Psychosomatic Research (DCPR). In a population study reported by Sonino et al, (2007), the majority of patients suffered from at least one of the three DCPR syndromes considered: irritable mood (over 45%), demoralization, persistent somatization. Long-standing endocrine disorders may imply a degree of irreversibility of the pathological process. Endocrine treatment may cause even the worsening of psychological symptoms. The methodology and assessment

predisposing conditions. (Ružić 2011)

 Some types of sedatives Catecholamine depletor Dopamine synthesis inhibitor

Antacids (cimetidine)

**4.6. Stress** 

Opiates and opiate antagonists

 Neuropeptides Anticonvulsants

Other medications which may increase prolactin levels:

Estrogen Oral contraceptives (birth control pills)

induced corticosterone secretion (Jaroenporn, 2007).

A medication for nausea (Reglan, metoclopramide)

Some types of blood pressure medications (methyldopa, verapamil)

fluoxetine; paroxetine, duloxetine etc)

Macroprolactinemic patients have no clinical symptoms of hyperprolactinemia and may have no pituitary adenomas. It is still controversial whether macroprolactinemia is a benign condition that does not need further investigation and treatment. Patients can be screened for macroprolactinemia by PEG (polyethylene glycol) precipitation as a standard laboratory test with a results of recovery of ≤40% to normal monomeric PRL level is used as an indication of macroprolactinemia (Tamer, 2012). The clinical importance of this test is based on the lower prevalence of pituitary adenomas in this group, compared to "true hyperprolactinemic" patients.

#### **4.4. PCOS (polycystic ovary syndrome)**

PCOS is a common problem that can cause infertility by inhibiting ovulation, affecting 3.5- 10% of the reproductive age of women. For unknown reasons, some women with PCOS may have slightly high PRL levels. PCOS similar to hypoprolactinemic are both common causes of secondary amenorrhoea in women. The relationship between PCOS and hyperprolactinemia so far has been reported still with controversial results: it seems that PCOS is very prevalent with hyperprolactinemia, nevertheless there are different reasons of altered regulation of gondotropin secretion, and suggests that these conditions have independent origins. Recent investigators using serial serum sampling have excluded transient elevations of PRL and have shown a less frequent association of these two disorders. According to clinical guidelines PCOS patients with increased PRL levels must be investigated for other causes of hyperprolactinemia, because hyperprolactinemia may be due to a reason of concomitant disease, but not proved the cause-relationship to PCOS. Treatment of infertility associated with PCOS has changed in the last decade due to the introduction of new medications such as insulin-sensitizing drugs, aromatase inhibitors, gonadotropin treatment etc. (Bracero 2001, Urman, 2006, Escobar-Morreale, 2004)

 In a study conducted in Brazil, among the 82 PCOS women, 13 (16%) presented high PRL levels (over 100 microg/l). There were several reasons of hyperprolactinemia: pituitary adenoma; drug-induced hyperprolactinemia, or macroprolactinemia. The nonhyperprolactinemic PCOS patients (over 80%) represented normal PRL levels. The authors concluded that hyperprolactinemia is not a clinical manifestation of PCOS. (Filho, 2007)

#### **4.5. Medications**

Some medications can cause higher levels of prolactin to be produced. The most common medications that do this are known as anti-psychotic medications. The antipsychotics mostly act as dopaminergic neurotransmitters/ receptor blockers can also cause endocrine side effects, as hyperprolactinaemia and it is most common side effect of first-generation antipsychotics. The second- and thirdgeneration antipsychotics have a weaker affinity for D2 dopamine receptors, thus hyperprolactinemia is less common when such medication is used. (Uzun et al. 2005). The risk of side effects caused by antipsychotics is individual and it does not depend solely on the therapeutic dose and may have influence on some predisposing conditions. (Ružić 2011)

Other medications which may increase prolactin levels:


154 Prolactin

groups. (Isik, 2012)

hyperprolactinemic" patients.

(Filho, 2007)

**4.5. Medications** 

**4.4. PCOS (polycystic ovary syndrome)** 

PRL. According to recent publications of Isik et al, evaluating over 300 hyperprolactinemic patients, over 26% of them resulted in elevated macroprolactin levels, with the less frequent signs of galactorrhea or abnormal MRI results compared those to patients with predominant monomer hyperprolactinemia. The other symptoms and frequency of amenorrhea, infertility, irregular menses, gynecomastia, and erectile dysfunction were similar in both

Macroprolactinemic patients have no clinical symptoms of hyperprolactinemia and may have no pituitary adenomas. It is still controversial whether macroprolactinemia is a benign condition that does not need further investigation and treatment. Patients can be screened for macroprolactinemia by PEG (polyethylene glycol) precipitation as a standard laboratory test with a results of recovery of ≤40% to normal monomeric PRL level is used as an indication of macroprolactinemia (Tamer, 2012). The clinical importance of this test is based on the lower prevalence of pituitary adenomas in this group, compared to "true

PCOS is a common problem that can cause infertility by inhibiting ovulation, affecting 3.5- 10% of the reproductive age of women. For unknown reasons, some women with PCOS may have slightly high PRL levels. PCOS similar to hypoprolactinemic are both common causes of secondary amenorrhoea in women. The relationship between PCOS and hyperprolactinemia so far has been reported still with controversial results: it seems that PCOS is very prevalent with hyperprolactinemia, nevertheless there are different reasons of altered regulation of gondotropin secretion, and suggests that these conditions have independent origins. Recent investigators using serial serum sampling have excluded transient elevations of PRL and have shown a less frequent association of these two disorders. According to clinical guidelines PCOS patients with increased PRL levels must be investigated for other causes of hyperprolactinemia, because hyperprolactinemia may be due to a reason of concomitant disease, but not proved the cause-relationship to PCOS. Treatment of infertility associated with PCOS has changed in the last decade due to the introduction of new medications such as insulin-sensitizing drugs, aromatase inhibitors,

gonadotropin treatment etc. (Bracero 2001, Urman, 2006, Escobar-Morreale, 2004)

 In a study conducted in Brazil, among the 82 PCOS women, 13 (16%) presented high PRL levels (over 100 microg/l). There were several reasons of hyperprolactinemia: pituitary adenoma; drug-induced hyperprolactinemia, or macroprolactinemia. The nonhyperprolactinemic PCOS patients (over 80%) represented normal PRL levels. The authors concluded that hyperprolactinemia is not a clinical manifestation of PCOS.

Some medications can cause higher levels of prolactin to be produced. The most common medications that do this are known as anti-psychotic medications. The antipsychotics mostly


#### **4.6. Stress**

A high prolactin level can sometimes be related to physical stress. Even drawing blood can by itself cause someone to produce and immediate prolactin-release. PRL eleveation can also detected in response to strong or sudden external stimuli in general, such as stressful environmental conditions, or can be related to physchological reasons. This latter can be evaluated by stress profile or measured by experimental conditions, such as "Screamer Index", which is shown resulting in values to be parallel to levels of hyperprolactinemia in women. (Harrison, 1988; Cepisky, 1992). On the other hand, anxiety and irritability maybe a result of hyperprolactinemia. In rat models PRL increased the stimulatory effect of ACTHinduced corticosterone secretion (Jaroenporn, 2007).

 Endocrine abnormalities are frequently associated with a wide range of psychological symptoms. These symptoms may reach the level of psychiatric illness (mainly mood and anxiety disorders) or just being identified by the subclinical forms of assessment provided by the Diagnostic Criteria for Psychosomatic Research (DCPR). In a population study reported by Sonino et al, (2007), the majority of patients suffered from at least one of the three DCPR syndromes considered: irritable mood (over 45%), demoralization, persistent somatization. Long-standing endocrine disorders may imply a degree of irreversibility of the pathological process. Endocrine treatment may cause even the worsening of psychological symptoms. The methodology and assessment 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. (Sonino 2007)

Prolactin and Infertility 157

**Neurogenic** Chest-wall injury Breast stimulation Breast-feeding

Pregnancy Estrogen

+

\_

**Reduced PRL elimination**

Renal failure Hepatic insufficiency

+

+

**Physiologic causes**

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;

Prolactin is under dual regulation by hypothalamic hormones delivered through the hypothalamic–pituitary portal circulation. The differential diagnosis and causes of

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

> Neuroleptics: phenothiazines, haloperidol Antihypertensives: calcium-channel blockers, Psychotropic agents: tricyclic antidepressants

> > \_

Anti-ulcer agents: H2 antagonists

pathological hyperprolactinemia are summarized in Figure 1.

from the anterior pituitary gland (Verhelst; 2003).

**Hypothalamic PRL stimulation** Primary hypothyroidism Adrenal insufficiency

+

**Increased PRL production**

Pituitary tumours: Adenomas

Ovarian: polycystic ovarian syndrome

+

Hypothalamic stalk interruption Hypophysitis (inflammation)

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

 The first steps in cases of signs of hyperprolactinemia should be a critical diagnosis, as discussed above, may involve dynamic testings, assessment for macroprolactinemia

**Anterior pituitary lobe Prolactin production**

TRH Dopamine + \_

**Medications**

Opiates

and further laboratory tests to eliminate false positive or negative results.

**Macroprolactinemia**

+

**6. Hyperprolactinemia management** 

Wang 2012)

