Hyperprolactinemia (HPL) is defined as serum prolactin (PRL) level above the upper normal limit. The normal ranges are represented by:
- Adult non-pregnant woman: 2.8 – 29.2 ng/ml
- Adult pregnant woman: 9.7 – 208.5 ng/ml
- Post-menopausal woman: 1.8 – 20.3 ng/ml
- Men: 2.1 – 17.7 ng/ml
The prevalence of HPL in the literature varies from 0.4% in an unselected normal population up to 5-17% in women with reproductive disorders (Diagnosis and Treatment of Hyperprolactinemia, 2011).
There are numerous conditions that may cause elevated PRL levels, which can be divided into three main categories: physiological, pathological and pharmacological. When HPL is identified in a patient, it is important to identify physiological etiologies, such as pregnancy, lactation and stress. It is also important to identify medications that alter dopamine tonus. When physiological and pharmacological causes to persistent HPL can be ruled out, a PRL-producing pituitary adenoma will be one likely explanation.
Elevated PRL levels without any visible pituitary adenoma and with other known causes of HPL excluded are considered as idiopathic HPL (Anterior Pituitary in Textbook of Endocrinology, 2007).
|Tuberculosis||Antihistamines H 2|
|Empty sella syndrome||Metoclopramide|
|Pituitary stalk section||Neuroleptics|
|Chronic renal failure||Perphenazine|
|Chest wall lesions||Estrogens|
|Polycystic ovarian disease||Opioids|
The classic clinical presentations in women with HPL are menstrual disturbances, infertility and galactorrhea (Menstrual pattern and ovarian function in women with hyperprolactinemia, 1985). In men, elevated PRL levels typically lead to hypogonadism, with a loss or decrease in libido, erectile dysfunction, impotence and oligospermia or azoospermia (PRL secreting adenomas in male patients, 2005). In HPL patients, elevated PRL levels cause hypogonadism by reducing luteinizing hormone (LH) pulsatility, possibly via inhibition of the hypothalamic gonadotropinreleasing hormone (GnRH). Furthermore, high PRL levels are considered to inhibit ovarian and potentially testicular function directly (Inhibition of gonadotropin hormone-releasing hormone release by prolactin from GT1 neuronal cell lines through prolactin receptors, 1994).
Both women and men with HPL and hypogonadism have an increased risk of reduced bone mineral density, most notably in trabecular bone (A longitudinal analysis of premenopausal bone loss in healthy women and women with hyperprolactinemia, 1992). Note that some symptoms may be due to mass effects of the pituitary tumour (e.g., headache, visual field defects or pituitary insufficiency).
A careful history, including medications, physical examination, screening blood chemistries, thyroid-function tests and pregnancy test will exclude almost all causes of HPL other than hypothalamic-pituitary disease. Consequently, the next step in the investigation is a radiological examination of the hypothalamic-pituitary region, preferably a magnetic resonance imaging (MRI) with gadolinium enhancement (Diagnosis and Treatment of Hyperprolactinemia, 2011).
The primary goal of treatment in HPL patients is to normalise PRL levels and thereby restore symptoms such as hypogonadism, infertility and galactorrhea, as well as to reduce tumour size, in patients with pituitary tumours.
Today, dopamine (DA) agonists are widely accepted as the first line treatment in patients with HPL (Diagnosis and Treatment of Hyperprolactinemia, 2011). There are three DA agonists available for treatment of HPL disorders: bromocriptine (Brc), cabergoline (Cab) and quinagolide.
* Brc is an ergot-derived DA agonist, with D2 receptor agonistic and D1 receptor antagonistic properties. It is also known to act on serotonin (5-HT) receptors.
* Cab is an ergot-derived DA agonist with high affinity for D2 receptors and low affinity for D1 receptors. Cab also has agonistic effects on 5-HT2A and 5-HT2B receptors.
* Quinagolide is a non-ergot oral DA agonist with specific D2 receptor affinity with little or no effect on D1 receptors.
(Receptor-binding and pharmacokinetic properties of dopaminergic agonists, 2008)
The most common side effects of all DA agonists are nausea, vomiting, headache and dizziness. These side effects can be minimised by starting the treatment with a low dose at bedtime and thereafter gradually increasing the dose. Other side effects might include constipation, dry mouth, dyspepsia, orthostatic hypotension, nasal congestion, psychiatric symptoms, digital vasospasm and, in some rare cases, pulmonary or retroperitoneal fibrosis. During the past years, concerns have been raised about the long term safety of Cab in the context of potential cardiac valve effects (Medical treatment of prolactinomas, 1999).
Because of the efficacy of medical treatment, among the patients suffering from hyperprolactinemia, only a minority of patients with prolactinomas require surgery. Indications for transsphenoidal surgery include intolerance or resistance to DA agonists, persistent visual field defects despite medical therapy and pituitary apoplexy with neurological signs in macroadenomas (Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas, 2006).
Another treatment option for prolactinoma patients not responding to medical treatment, surgery, or both is radiation therapy (Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas, 2006).
Role of Zinc in Hyperprolactinemia
An important aspect that has been seldom considered, is the role of Zinc (Zn2+) in prolactin synthesis, secretion and plasma concentration.
Some of the first studies go back to the 1980s, when it was evaluated the role that physiologically relevant Zinc concentrations might have on the pituitary synthesis and secretion of PRL. It was shown that Zinc in concentrations between 1 and 10 µM reduced PRL secretion in vitro and, to a lesser extent, also its synthesis. (Zinc may have a physiological role in regulating pituitary prolactin secretion, 1983)
Furthermore, the addition of Zn2+ to cell media was shown to suppress prolactin release in both bovine and rat pituitary gland cultures. (Pituitary hormone releasing or inhibiting activity of metal ions present in hypothalamic extracts, 1973)
Studies in humans have shown an inverse relation between Zn2+ intake and plasma prolactin concentration.
In 1999, McCrory et al. showed that plasma prolactin concentration is higher in lactating women who are dieting, and therefore have a lower Zinc intake.
(Randomized trial of the short term effects of dieting compared with dieting plus aerobic exercise on lactation performance, 1999)
Furthermore, Lunn et al showed that plasma prolactin concentration is higher in lactating women with poor nutrition and reduced Zn2+ intake, and decreases when they consume dietary supplements to increase their energy intake.
(The effect of improved nutrition on plasma prolactin concentrations and postpartum infertility in Gambian women, 1984)
Zn2+ deficiency has been associated with hyperprolactinemia in men. It has also been shown that Zn2+ treatment increased plasma Zn2+ level and reduced serum prolactin concentration.
(Effect of zinc supplementation on hyperprolactinemia in uraemic men, 1985).
Similarly, a study conducted in 2004 on lactating female rats has observed higher plasma prolactin concentration in female rats fed a Zn2+-deficient diet.
(Maternal Zinc deficiency raises plasma prolactin levels in lactating rats, 2004).
1. Zn2+ inhibits release of PRL granules by inhibiting thiol-disulfide interchange enzymes
Mechanisms responsible for the effect of low Zn2+ intake on plasma prolactin concentration may be attributed to prolactin production or secretion from the pituitary gland, as some of the aforementioned studies might suggest.
Biochemical details of this mechanism were described in a study that indicated that Zn2+ inhibits in vitro release of PRL from bovine adenohypophysias secretory granules in a dose-related fashion. With Zinc present, only ATP could restore the PRL release and no other known stimulators of release (reduced glutathione or bicarbonate) could restore the release. It was observed that thiol-disulfide interchange reactions may be critical for the release process. Zn2+ may inhibit these directly or it may inhibit enzymes involved in the interchange process. For example, a pituitary oxidoreductase is known which is capable of catalyzing disulfide interchange between glutathione and secretory granule protein disulfides. This is inhibited by metals, such as Zn2+.
(Divalent Cation inhibition of Hormone Release from Isolated Adenohypophysial Secretory Granules, 1983)
In addition, human prolactin was shown to bind Zn2+ in secretory granules, leading to aggregation and stabilization of the hormone.
(Prolactin (PRL) is a zinc-binding protein, 1996)
2. Zn2+ inhibits release of vescicles via activation of K ATP
Another potential mechanism has not been described in lactotroph cells yet, but has been described in pancreatic β-cells in the control of insulin release. The membranes of these cells are rich in ATP-dependent potassium channels (K ATP ). When the ATD/ADP ratio rises in the cytoplasm, K ATP channels close and the cell depolarizes. It has been recently described that Zn2+ activates K ATP , hyperpolarizing the cell, hence inhibiting further insulin release. This mechanism has also been described as the underlying mechanism for the inhibition of glutamate release in hippocampal neurons. There are evidence that this mechanism could also be present in lactotroph cells.
("Zinc inhibits glutamate release via activation of pre-synaptic K ~ ATP ~ channels and reduces ischaemic damage in rat hippocampus, 2004": http://www.ncbi.nlm.nih.gov/pubmed/15312179)
3. Zn2+ decreases PRL Affinity for its receptor
Finally, another possible mechanism involves the PRL pathway at the level of the binding between PRL and its receptor.
The binding reaction that takes place between PRL and its receptor results in the formation of a heterotrimeric complex with a 2:1 ratio of receptor to hormone. The formation of this ternary complex is believed to proceed in an ordered manner. Once the complex is formed, the intracellular domains of the receptor allow a receptor-associated JAK 2-mediated trans-phosphorylation of intracellular receptor tyrosines that permit the initiation of intracellular hormone action. It has been shown that the affinity of PRL for its receptors at site 1 was decreased 35-fold in the presence of 15uM of Zn2+.
(Obligate Ordered Binding of Human Lactogenic cytokines, 2010)
This was further investigated and it was shown that Zn2+ induces conformational changes in PRL, also keeping into consideration that the Zn2+ binding site is shared between the hormone and the receptor.
(Zinc binding to human lactogenic hormones and the human prolactin receptor, 2011)
Although not fully investigated, Zn2+ might become a potential therapeutic measure for idiopathic hyperprolactinemia. Evidence suggests that Zn2+ could decrease the secretion of PRL, hence decreasing the plasma levels. At the same time, decreasing the affinity for PRL to its receptor, Zn2+ could decrease the amplitude of the various effects that PRL has on its target cells.
Zinc, Prolactin and other systems
Zinc (Zn) is an essential micronutrient required for over 300 different cellular processes, including DNA and protein synthesis, enzyme activity, and intracellular signaling. Beside the prolactin pathway, Zinc is involved in many other systems, including in the production and secretion of insulin.
Zn is involved in a multitude of processes within the pancreas, including glucagon secretion, digestive enzyme activity, and insulin packaging, secretion, and signaling (Figure 1). As a result of this extensive physiological contribution, dysregulation of Zn metabolism within the pancreas impairs a multitude of key processes, including glycemic control, and is associated with pancreatic cancer and chronic pancreatitis (Zinc in Specialized Secretory Tissues: Roles in the Pancreas, Prostate, and Mammary Gland, 2011).
Figure 1. Zn transport in various pancreatic cell types.
(A) Localization of Zip1, Zip10, and Zip14 to pancreatic α-cells suggests that these transporters are responsible for importing Zn into the cell. Zn binds to and opens ATP dependent K(+) channels, allowing the efflux of Zn from the α-cell and inactivation of voltage dependent calcium channels, resulting in decreased glucagon secretion.
(B) Zn is transported into pancreatic β-cell cells via Zip4. ZnT8 is responsible for the transport of Zn into insulin granules. Autoantibodies to ZnT8 and polymorphisms of ZnT8 are associated with the onset of DM.
© Zip5 is responsible for the transport of Zn into pancreatic acinar cells. Zn is transported into zymogen granules by ZnT2 where it binds to and activates digestive enzymes that are subsequently secreted.
Ninety percent of those with diabetes have type-2 diabetes, characterized by insulin resistance, hyper insulinaemia, beta-cell dysfunction and subsequent cell failure. Insulin, is stored as a hexamer containing two Zinc ions in beta-cells of the pancreas and released into the portal venous system at the time of beta-cells de-granulation. The Zn(II) ions which are co-secreted with insulin suppress inherent amyloidogenic properties of monomeric insulin. It was shown that high concentrations of glucose decrease the islet cell labile Zinc and video fluorescence analysis showed Zinc concentrated in the islet cells was related to the synthesis, storage and secretion of insulin. In vitro data suggests that insulin binds to isolated liver membranes to a greater extent and that there is less degradation when co-administered with Zinc.
Furthermore, oxidative stress plays an important role in the pathogenesis of diabetes and its complications. Zinc is a structural part of key anti-oxidant enzymes such as superoxide dismutase, and Zinc deficiency impairs their synthesis, leading to increased oxidative stress. Studies have shown that diabetes is accompanied by hypozincemia and hyperzincuria.
Lastly, animal studies have shown that Zinc supplementation improves fasting insulin level and fasting glucose in mice. Human studies have also shown the beneficial effects of Zinc supplementation in both type-1 and type-2 diabetes.
(Effects of zinc supplementation on diabetes mellitus: a systematic review and meta-analysis, 2012).
As zinc deficiency has been linked to both hyperprolactinemia and diabetes, hyperprolactinemia by itself has been associated with impaired metabolism, including insulin resistance, glucose intolerance and hyperinsulinemia in several animal species. In women with microprolactinomas, the sensitivity to insulin is lower in hyperprolactinemia than in normoprolactinemia. (Insulin sensitivity and lipid profile in prolactinoma patients before and after normalization of prolactin by dopamine agonist therapy, 2011).
In a recent study, it was differing levels of circulating PRL have different activities on the glucose metabolism in rats. Both high and low dosages of PRL promoted β-cell mass but in a different manner: Low-PRL decreased β-cell apoptosis, whereas High-PRL increased its proliferation. However, only Low-PRL enhanced first-phase insulin secretion and improved insulin sensitivity at a hyperglycemic state in comparison to the control. Low-PRL also increased glucose infusion rates and decreased hepatic glucose output in hyperinsulinemic states, signifying an improvement in hepatic insulin sensitivity. However, High-PRL exacerbated hepatic insulin resistance compared with the control diabetic rats. (Central prolactin modulates insulin sensitivity and insulin secretion in diabetic rats, 2012).
One potential mechanism of the role of prolactin on insulin secretion is represented by the activation of the PRL receptor on beta-cells of the pancreas and its subsequent increase in insulin secretion. This is thought to be a mechanism developed to overcome the increase need of insulin during pregnancy (note that prolactin levels during pregnancy are higher).
Figure 2. Insulin-producing beta cells expand during pregnancy through pathways involving lactogenic and serotonergic signaling.
Prolactin and lactogenic hormones activate the prolactin receptor (PRLR). Activated PRLR increases the expression of serotonergic genes (Tph1 and Htr2b) and Foxm1 and decreases Men1 levels. Increased expression of Tph1 increases the conversion of tryptophan to serotonin (5-HT), which is secreted from the beta cell along with insulin. Once released, serotonin then activates the Gαq-coupled Htr2B receptor on the surface of beta cells to feed back to the islet microenvironment in an autocrine/paracrine manner. c-Src is phosphorylated in response to activation of Htr2B, which signals for increased expression of G1 cyclin proteins to stimulate cell cycle progression. Increased expression of G1 cyclins, coupled with reduced expression of cyclin-dependent kinase inhibitors, which results from the repression of Men1 expression, leads to cell cycle progression and increased beta cell replication. The increase in beta cell replication and beta cell mass in the pancreas is the physiological response to pregnancy-induced insulin resistance. Disruption of any of these pathways can contribute to the development of gestational diabetes.
As the above studies show a tight interconnection between prolactin, insulin and zinc, interestingly the dopamine agonist bromocriptine has been approved for the treatment of type 2 diabetes in the United States (Bromocriptine mesylate: FDA-approved novel treatment for type-2 diabetes, 2009).