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14 The patient with hyperprolactinemia
John Ayuk
Department of Endocrinology, University Hospitals Birmingham, UK
Case History: A 29‐year‐old woman with a 4‐year history of infertility was referred for IVF treatment. As she had become tearful and depressed, her primary care physician had prescribed an antidepressant. She had no other medical history of note. Menarche was at the age of 14, and her periods had been normal and regular up until 3 years ago, when she developed oligomenorrhea. Blood tests carried out at her first clinic visit showed serum prolactin of 200 μg/L (4000 mIU/L). Her follicle stimulating hormone (FSH), luteinizing hormone (LH) and tubal assessment were normal. A seminal fluid analysis was also normal.
Background
Human prolactin (PRL) is a polypeptide hormone comprising 199 amino acid residues. PRL is predominantly synthesized in and secreted from the lactotroph cells of the anterior pituitary gland under the control of dopamine. 80–90% of serum PRL circulates as the biologically active monomeric PRL, with dimeric and polymeric isoforms, termed macroprolactin, making up the remainder [1,2]. Macroprolactin has decreased biological activity and clearance. The most obvious function of PRL in humans is to support postpartum lactation [2]. During pregnancy, PRL concentration increases up to 10‐fold, and remains elevated during lactation under the stimulus of suckling [3]. PRL blocks the action of LH on the ovary or testis, producing hypogonadism [2]. Hyperprolactinemia inhibits ovulation, resulting in infertility. For this reason, measurement of serum PRL concentration is necessary when investigating ovulatory infertility [4]. Hyperprolactinemia may be asymptomatic, but in women of childbearing age it commonly presents with oligomenorrhea, loss of libido or galactorrhea [5].
Transient rises in PRL levels can occur during the late follicular phases of both natural and stimulated cycles [6]. There is evidence that high responders to ovarian stimulation are more likely to have higher incidence of transient hyperprolactinemia than intermediate or low responders [7]. Furthermore, serum PRL levels during an ART cycle are strongly correlated with peak estradiol levels [7]. However, there is no evidence that oocytes retrieved or fertilized, or the pregnancy rates are affected by transient hyperprolactinemia [6–9]. Such transient hyperprolactinemia during an ART cycle is therefore unlikely to be clinically significant.
Causes of hyperprolactinemia
The causes of hyperprolactinemia can be classified as physiological, pharmacological and pathological [10].
Physiological causes
Pregnancy and lactation are the commonest causes of hyperprolactinemia. Macroprolactin (larger molecular forms of PRL), which has no biological activity or clinical significance, can be detected in some assays [2]. Stress, excessive exercise and convulsions can also result in hyperprolactinemia, as can chest wall/nipple stimulation, even in nonlactating women.
Pharmacological causes
Many medications can cause hyperprolactinemia, predominantly via inhibition of dopamine synthesis or blockade of endogenous dopamine receptors [10,11]. The most common medications to cause hyperprolactinemia are antipsychotics, antidepressants and some antiemetics (Table 14.1).
Pathological causes
Pituitary tumors. Pituitary tumors can cause hyperprolactinemia via two mechanisms; prolactinomas secrete excess PRL, while large nonfunctioning pituitary adenomas can cause pituitary stalk compression, disrupting the communication between the dopaminergic neurons that control PRL secretion and lactotrophs. Pituitary stalk disruption can also occur following pituitary surgery or trauma. Hyperprolactinemia due to pituitary stalk disruption is usually modest, with levels rarely exceeding 150 μg/L (~3000 mIU/L), whereas prolactinomas can be associated with levels > 1000 μg/L (~20000 mIU/L) [12,13].
Renal failure. Hyperprolactinemia can occur in up to 30% of patients with chronic kidney disease, most likely due to decreased renal clearance of PRL or impairment of dopamine’s regulatory action by uremia [14].Table 14.1 Medications which cause hyperprolactinemia [10,11].AntipsychoticsPhenothiazines: chlorpromazine, trifluoperazine, fluphenazine, perphenazineThioxanthenes: thiothixeneButyrophenonesAtypical antipsychotics: risperidone, olanzapine, quetiapine AntidepressantsTricyclic antidepressants: imipramine, amitriptylineMAO inhibitors: tranylcypromineSSRIs: fluoxetine, paroxetine, citalopram, fluvoxamine Gastrointestinal medicationsMetoclopramideDomperidoneCimetidine Antihypertensivesα‐methyldopaReserpineVerapamil Estrogens Opioids
Primary hypothyroidism. Primary hypothyroidism can occasionally cause a mild increase in PRL, mediated primarily by increased secretion of TRH [5].
Polycystic ovary syndrome (PCOS). Early literature documented mild hyperprolactinemia in up to 30% of women with PCOS [15]. However more recent
