Hyperprolactinaemia E22.1

Hyperprolactinaemia is a complex of symptoms called galactorrhoea, (oligo-)amenorrhoea with hypogonatropism and an increase in the blood prolactin level. Prolactin (PRL), a 23kD peptide hormone, is produced in the pituitary gland, but also extrahypophysically in the mammary glands, decidua, prostate, skin, peripheral blood cells and possibly in the brain (Cabrera-Reyes EA et al. 2017). The half-life of prolactin in plasma is 40-45 minutes.

In the circulation, prolactin also exists, for example, as dimer (50-kDa "big-prolactin") or as macro-prolactin (50 kDa "big-prolactin"; 150- to 170-kDa "big-big-prolactin") through complex formation with immunoglobulins (Chahal J et al. 2008).

Physiological hyperprolactinemia: This is usually mild to moderate.

• Postpartum lactation: Tactile stimulation of the female nipple during lactation. Sucking stimuli cause considerable PRL stimulation and cause short-term exaggerated increases in PRL levels.
• Gravidity: At the end of pregnancy, concentrations of 200-500ug/l are measured. Postpartum, PRL levels fall back to baseline within 4-6 weeks.
• Puberty and menopause: In females, there is an increase in PRL levels of about 50% during puberty. After menopause, the value drops again by the same factor. In men, there are no known PRL fluctuations in the individual phases of life.
• Stress (physical and/or psychological): physical exertion, hypoglycemia, myocardial infarction, surgery. During stress, the concentrations of PRL, growth hormone, ACTH, TSH increase. The PRL increase is probably not mediated by suppression of dopaminergic inhibition but by a PRL releasing factor, possibly vasoactive intestinal polypeptide (VIP).

Pathological hyperprolactinemia.

• PRL-producing benign tumors of the anterior pituitary (prolactinoma - macroprolactinoma, microprolactinoma): Prolactinomas account for 25-30% of all pituitary tumors. Rarer are other endocrine active pituitary adenomas that co-form prolactin cosecretorily (see also under Paraneoplastic Syndromes).
• Disruption of PIH (prolactin inhibitory hormone) transport to the adenohypophysis or disruption of PIH production: compression by an endocrine inactive or non-PRL-producing tumor;
• Suprasellar tumors (e.g., craniopharyngeoma, dermoid cysts, Hodgin's disease, lymphomas).
• Pituitary stalk transection
• Granulomatous diseases of the basal meninges (e.g. sarcoidosis)
• Primary hypothyroidism: about 40% of patients develop hyperprolactinemia due to hypothalamic stimulation (caused by endogenous TRH).
• Renal insufficiency: about 30% of renal insufficient patients develop hyperprolactinemia.
• Hemodialysis patients: about 80% of these patients develop hyperprolactinemia.
• Renal insufficiency: about 30% of renal insufficient patients develop hyperprolactinemia of FSH and LH, by which ovulation is triggered. Impaired gonadal function is causative of decreased fertility during lactation.
• Medications: These are dopamine receptor antagonists (the biogenic amine dopamine is identical to the hypothalamic PRL inhibiting factor-PIN), dopamine store depleting pharmaceuticals, and antidepressants and hormones. In detail: chlorpromazine, perphenazine, sulpiride, metoclopramis, domperidone, pimozide, tricyclic antidepressants, buturophenones, alpha-methyldopa, reserpine, cimetidine, estrogens, antiandrogens. Hyperprolactinemia stimulates the production of dopamine in the hypothalamus, which in turn causes inhibition of GnRH. The inhibition suppresses the stimulation

The etiology of hyperprolactinemia is heterogeneous. It can be physiological, pathological or pharmacological. Increased prolactin concentrations inhibit the synthesis of male and female sex hormones (testosterone and oestrogens, respectively) over several steps.

Reduction of libido in men and women. In women, hyperprolactinaemia leads to secondary amenorrhoea with anovulation, lidbido disorders, hirsutism, seborrhoea. Galactorrhea can occur as a further symptom.

In men the testosterone level is reduced. This leads to libido disorders, erectile dysfunction and a reduction in the volume of ejaculate. In addition, gynecomastia and, rarely, galactorrhoea can occur.

Signs of a pituitary tumour (visual field restrictions, paresis of the eye muscles, headaches, cerebral disorders up to coma (foramen monroi blockade)

Hyperprolactinemia can be diagnosed on the basis of two blood samples. Prolactin concentrations >200ug/l are almost always indicative of a prolactinoma. Exclusion of other endocrinological causes (TSH determinations, pregnancy test)

Laboratory with basal prolapse prophylaxis (blood samples taken on 3 different mornings).

The treatment of hyperprolactinemia depends on its cause.

• Triggering drugs should be reduced or replaced in their dosage.
• In the presence of a prolactinoma, treatment depends on the size of the tumour. Small prolactinomas are treated with medication. This inhibits the production of prolactin and normalises the blood value. The tumours shrink in about 70% of those affected. However, drug treatment has numerous side effects (nausea with nausea as well as tiredness and constipation) and often an improvement of the symptoms is achieved after a few days. The dose of the medication should be increased slowly to avoid possible side effects such as nausea, drop in blood pressure and dizziness. If necessary, the additional administration of sex hormones (estrogens, testosterone) can be useful.
• Nowadays, surgery is only considered in cases of proven therapy failure ("dopamine resistance") or if life-threatening complications occur (e.g. cerebral haemorrhages). The probability of a relapse is between 50 and 100%. Pituitary gland functions can also be impaired.
• Radiation therapy is only used after unsuccessful drug or surgical treatment, as serious side effects are to be expected. These include the loss of other pituitary gland functions (secretion of the hormones gonadotropin and growth hormone). Furthermore, a normalisation of the prolactin levels only occurs after several years.

When measured in the morning, an increased prolactin level may be explained by the circadian rhythm.

Due to the molecular heterogeneity of prolactin, especially in macroprolactinemia, there is a considerable variability of prolactin levels measured with different immunoassays. With newer immunoassays only a small part of the samples are disturbed by macroprolactin.

Synonyms from the time before prolactin measurements, which still occasionally occur, are:

• Ahumada-del-Castillo-Argonz syndrome: hyperprolactinaemia in nulliparae without evidence of prolactinoma
• Argonz-Ahumada-Castillo syndrome: combination of galactorrhea and amenorrhea
• Chiari drum syndrome: pronounced and persistent postpartum galactorrhea and amenorrhea
• Forbes-Albright Syndrome: Galactorrhea and amenorrhea in pituitary tumor

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