Download Hyperprolactinaemia: metabolic consequences

Archives of Perinatal Medicine 20(2), 93-95, 2014
ORIGINAL PAPER
Hyperprolactinaemia: metabolic consequences
ANNA KOSTRZAK, BŁAŻEJ MĘCZEKALSKI
Abstract
Prolactin (PRL) is an anterior pituitary hormone first identified in 1933. PRL is secreted in a pulsatile fashion
and is under chronic inhibition by dopamine. Hyperprolactinaemia is the most common disorder of the hypothalamic-pituitary axis. Chronic excess of prolactin disrupts the normal pulsatile secretion of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) and follicle-stimulating hormone (FSH). It resulted in
estrogen deficiency. The primary function of PRL is the initation and maintenance of lactation and breast
development. For some years multifunctional role of PRL has been demonstrated. Hyperprolactinaemia has been
reported to be associated with abnormalities of lipid metabolism- hypertriglicerydemia and hypercholesterolemia.
Excess of prolactin links to insulin resistance and reduced glucose tolerance. Hyperprolactinaemia related to
hypoestrogenism is involved in decrease of bone mineral density leading to osteopenia and osteoporosis.
Key words: prolactin, hyperprolactinaemia, lipid profile, obesity, reduced glucose tolerance
Introduction
Prolactin (PRL) is an anterior pituitary hormone
first identified in 1933 [1]. PRL is secreted in a pulsatile
fashion and is under chronic inhibition by dopamine [2].
Hyperprolactinaemia is the most common disorder of
the hypothalamic-pituitary axis [3]. Chronic excess of
prolactin disrupts the normal pulsatile secretion of
gonadotropin releasing hormone (GnRH) and luteinizing
hormone (LH) and follicle-stimulating hormone (FSH).
It resulted in estrogen deficiency [4]. The primary function of PRL is the initation and maintenance of lactation
and breast development [5]. During the pregnancy prolactin initate and maintain milk production. PRL acts to
increase arginase activity, stimulate the ornithine decarboxylase activity and enhance the rate of transport of
polyamines into the mammary glands. It results in increasment of spermine and spermidine synthesis which
is important for the milk production [5].
For some years multifunctional role of PRL has been
demonstrated. Hyperprolactinaemia has been reported
to be associated with abnormalities of lipid metabolismhypertriglicerydemia and hypercholesterolemia [6]. Excess of prolactin links to insulin resistance and reduced
glucose tolerance [7]. Hyperprolactinaemia related to
hypoestrogenism is involved in decrease of bone mineral
density leading to osteopenia and osteoporosis [8].
Prolactin secretion and forms
PRL is a 23 kDa polypeptide hormone (198 amino
acid) syntetised in the anterior lobe of pituitary gland [1].
PRL is secreted in pulsatile way [3]. Day time pulses are
modified by meals, stress, exercise and intercourse [3].
Syntesis of PRL is under control of releasing ang
inhibiting factors. The main mechanism is control by
inhibitory effect of dopamine [9]. Thyroid-releasing hormone (TRH), vasoactive intestinal peptide (VIP), oxytocin and galanin stimulate prolactin secretion [10].
PRL circulates in a multiple forms in the serum
blood: the predominant form is monomeric PRL (molecular weight 23 kDa), big prolactin (molecular weight 50
kDa) and big-big prolactin (molecular weight more than
150 kDa) [11].
Macroprolactinaemia is a condition in which the large amount of PRL is composed of big-big prolactin. The
big-big form of prolactin (macroprolactinaemia) is biologically inactive [12].
Because of variety of PRL molecule patients with
high prolactin serum concentration should be screened
for the presence of macroprolactin by using polyethylene
glycol precipitation test [12].
Pathology of hyperprolactinaemia
Hypeprolactinaemia is one of the most common
endocrine disorder of the hypothalamic-pituitary axis [3].
The prevalence of hyperprolactinaemia is 9-17% in
women with reproductive disturbances [13]. Its prevalence has been also reported among 20% of women with
polycystic ovarian syndrome [14].
Hyperprolactinaemia is regardes as a condition of
elevated PRL serum concentration. Excess of PRL inhi-
Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
94
A. Kostrzak, B. Męczekalski
bits hypothalamic secretion of gonadotropin-releasing
hormone (GnRH) which decreases secretion of luteinizing hormone (LH) and follicle-stimulating hormone
(FSH). The main consequence is estrogen deficiency
(hypoestrogenism) [15].
Hypeprolactinaemia can be related to the physiological processes such as: pregnancy, lactation, breast stimulation, activity and sleep [16].
Pathological hyperprolactinaemia is associated with
some endocrine diseases: PCOS, Addison’s disease,
acromegaly and hypothyroidism [17].
Excess of PRL can be related to the pharmacological
agents: antipsychotics (neuroleptics, opiates, antidepressant), antihypertensive drugs (verapamil, methyldopa,
reserpine), gastrointestinal medications (metoclopramid) [18].
Hyperprolactinaemia can also a result of disrupting
dopamine transport in portal vessel and it’s reported in
prolactinoma, meningoma and severe head trauma [19].
Common signs and symptoms of hyperprolactinaemia can be presented in women and men. It is more easy
to diagnose hyperprolactinaemia in women than in men.
Patients with high prolactin serum concentration
present menstrual disturbances and galactorrhoea [20].
High prolactin serum concentration is regarded as the
important cause of infertility in women and men [21].
Hyperprolactinaemia due to increased dehydroepiandrosterone sulfate secretion can lead to hirsutism and
acne problems [22]. In men symptoms of hyperprolactinaemia are mainly connected to gynecomastia, erectile
dysfunction and decreased libido [23].
Metabolic consequences of hyperprolactinaemia
PRL exerts a wide variety of effects on metabolic
processes.
For many years high prolactin serum concentration
has been reported as a important factor which induces
hyperphagia and promotes the weight gain [24]. Several
studies reported higher body weight gain in patients
with macroprolactinomas [24].The mechanisms are not
so clear but studies consider a few factors: reduction in
dopaminergic tone, decreased adiponectin and hypogonadism [24].
Hyperprolactinaemia impaires lipid metabolism. The
possible mechanism is related to the inhibition of the release of adipokines [25]. Hypeprolactinaemia has been
linked to hypertriglicerydemia and hypercholesterolemia
in patients with prolactinoma [25]. Excess of prolactin in
women with secondary amenorrhoea and estrogen deficiency may lead to elevation in total cholesterol (TCH),
low density lipoprotein (LDL) and decreased in high
density lipoprotein (HDL) [25]. Some studies reported
that the presence of prolactinoma has been associated
with metabolic abnormalities such as hyperlipidemia, low
plasma LDL levels activity and insulin resistance [26].
High prolactin serum concentration is a potent costimulator of platelet aggregation so can be involved in hypercoagulable state observed in pregnancy and the puerperium [26].
Some researches speculated that hyperprolactineamia reduces glucose tolerance [27]. The prodiabetic
effect of PRL was demonstrated in few studies. Excess
of PRL seems to play a key role in glucose abnormalities
and hyperinsulinemia. Increased insulin resistance using
homeostasis model assessment (HOMA) index has been
described in hyperprolactinaemic patients [28]. Adiponectin is correlated with obesity and development of
the diabetes mellitus type 2. Hypeprolactineamia inhibits
adiponectin secretion in vivo in humans. Probably the
same mechanism is leading to hypoadiponectinemia and
causes impaired glucose tolerance in hyperprolactinaemic patients [28].
Hyperprolactinaeamia is related to the decrease of
body mass density and leads to osteopenia or osteoporosis [29]. The possible mechanism of the reduced bone
mineral density is probably associated with hypoestrogenism. A lot of studies demonstrated the influence of
high prolactin serum concentrations on the bone metabolism. High prevalence of the vertebral fractures in
women with prolactin-secreting pituitary adenoma has
been reported [29]. The fractures occurred more frequently in patients with untreated hyperprolactinaemia
versus patients treated with cabergoline therapy [30].
The main conclusion regarded that hyperprolactinaemia
is associated with high prevalence of radiological vertebral fractures in women with prolactin – secreting adenoma [30].
Conclusions
Hyperprolactinaemia is mainly related to menstrual
disorders and infertility. However it also seems to be
associated with some metabolic abnormalities such as:
hypercholesterolemia, insulin resistance, reduced glucose tolerance, weight gain and decreased bone mineral
density.
References
[1] Riddle O., Bates W.R., Dykshorn W.S. (1932) A new hormone of the anterior pituitary. Proc. Soc. Exptl. Biol.
Med. 29: 1211-1212.
Hyperprolactinaemia: metabolic consequences
[2] Debeljuk L., Lasaga M. (2006) Tachykinins and the control of prolactin secretion. Peptides. 27(11): 3007-19.
[3] Chachal J., Schlechte J. (2008) Hyperprolactinemia. Pituitary 11(2): 141-6.
[4] Mah P.M., Webster J. (2002) Hyperprolactinemia: etiology, diagnosis, and management. Semin. Reprod. Med.
20(4): 365-74.
[5] Nelson W. (2002) Endocrine control of mammary gland.
Physiol. Rev. 1936, 16: 488-526.
[6] Ben-Jonathan N., Hugo E.R., Brandebourg T.D., LaPensee C.R. (2006) Focus on prolactin as a metabolic
hormone. Trends. Endocrinol. Metab. 17(3): 110-6. Epub
2006 Mar 6. Review.
[7] Bahceci M., Tuzcu A., Bahceci M., Tuzcu S. (2003) Is
hyperprolactinemia associated with insulin resistance in
non-obese patients with polycystic ovary syndrome? J. En-
docrinol. Invest. 26(7): 655-9.
[8] Gordon C.M., Nelson L.M. (2003) Amenorrhea and bone
health in adolescents and young women. Curr. Opin. Obstet. Gynecol. 15(5): 377-84.
[9] De Zegher F., Van Den Berghe G., Devlieger H., Eggermont E., Veldhuis J.D. (1993) Dopamine inhibits
growth hormone and prolactin secretion in the human
newborn. Pediatr. Res. 34(5): 642-645.
[10] Bachelot A., Binart N. (2007) Reproductive role of prolactin. Reproduction 133(2): 361-9.
[11] Lawson D.M., Stevens R.W. (1980) Size heterogeneity of
pituitary and plasma prolactin: effect of chronic estrogen
treatment. Life Sci. 20, 27(16): 1489-94.
[12] Fahie-Wilson M.R., John R., Ellis A.R. (2005) Macroprolactin; high molecular mass forms of circulating prolactin.
Ann. Clin. Biochem. 42(Pt 3): 175-92.
[13] Davis J.R. (2004) Prolactin and reproductive medicine.
Curr. Opin. Obstet. Gynecol. 16(4): 331-7.
[14] Verhelst J., Abs R. (2003) Hyperprolactinemia: pathophysiology and management. Treat Endocrinol. 2(1): 23-32.
[15] Mah P.M., Webster J. (2002) Hyperprolactinemia: etiology, diagnosis, and management. Semin. Reprod. Med.
20(4): 365-74.
[16] Noel G.L., Suh H.K., Frantz A.G. (1974) Prolactin release
during nursing and breast stimulation in postpartum and
nonpartum subjects. J. Clin. Endocrinol. Metab. 38: 413-
[19] Mancini T., Casanueva F.F., Giustina A. (2008) Hyperprolactinaemia and prolactinomas. Endocrinol. Metab. Clin.
North. Am. 37(1): 67-99.
[20] Whittaker P.G., Wilcom T., Lind T. (1981) Maintained
fertility in a patient with hyperprolactinemia due to big,
big prolactin. J. Clin. Endocrinol. Metab. 53: 863-866.
[21] Panidis D., Rousso D., Skiadopulos S, Panidou E. (1997)
Mamopoulos M. Evaluation of semen parameters in man
with hyperprolactinemia induced by metoclopramide.
Arch. Androl. 39(3): 237-42.
[22] Lobo R.A., Kletzy O.A., Kaptein E.M., Goebelsman U.
(1980) Prolactin modulation of dehydroepiandrosterone
sulfate secretion. Am. J. Obstet. Gynecol. 138: 632-636.
[23] Venetikou M.S., Lambou T., Gizani D. (2008) Hyperpro-
lactinaemia due to hypothalamic-pituitary disease or druginduced in patients with erectile dysfunction. Andrologia
40(4): 240-4.
[24] Schmid C., Brandle M. (2006) The influences of hyperpro-
lactinaemia and obesity on cardiovascular risk markers:
effects of cabergoline therapy. Clin. Endocrinol. (Oxf)
65(6): 827-8.
[25] Fahy U., Hopton M.I., Hartog M., Bolton C.H., Hull
M.G.R. (1999) The lipoprotein profile of women with hyperprolactinaemic amenorrhoea. Human Reproduction
14(2): 285-287.
[26] Pelkonen R., Nikkilä E.A., Grahne B. (1982) Serum lipids,
postheparin plasma lipase activities and glucose tolerance
in patients with prolactinoma. Clin. Endocrinol. (Oxf)
16(4): 383-90.
[27] Erem C., Kocak M., Nuhoglu I., Yimaz M., Ucuncu O.
(2010) Blood coagulation, fibrinolysis and lipid profile in
patients with prolactinoma. Clin. Endocrinol. (Oxf) 73(4):
502-7. doi: 10.1111/j.1365-2265.2009.03752.x.
[28] Shibli-Rahhal A., Schlechte J. (2008) The effects of hyperprolactinaemia on bone and fat. Pituitary 13.
[29] Naidoo U., Goff D.C., Klibanski A. (2003) Hyperprolac-
tinemia and bone mineral density: the potential impact of
antipsychotic agents. Psychoneuroendocrinology 28 Sup-
pl. 2: 97-108.
[30] Abraham G., Paing W.W., Kaminski J. et al. (2003) Effects
of elevated serum prolactin on bone mineral density and
bone metabolism in female patients with schizophrenia:
a prospective study. Am. J. Psychiatry 160(9): 1618-20.
21.
[17] Berinder K., Stackenas I., Akre O. et al. (2005) Hyper-
prolactinemia in 271 women: up to three decades of
clinical follow-up. Clin. Endocrinol. (Oxf) 63(4): 450-455.
[18] David S.R., Taylor C.C., Kinon B.J. (2000) The effects of
olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin. Ther.
22: 1085-1096.
95
J
Anna Kostrzak
Department of Gynecological Endocrinology
Poznan University of Medical Sciences
60-535 Poznań, Polna 33, Poland