Review: The role of zinc in the endocrine system

Abstract

Zinc is essential in the regulation of a variety of physiological and biochemical events in the organism. It plays a critical role in maintaining the cell membrane integrity, protein-carbohydrate-lipid metabolism, immune system, wound injury and in the regulation of a number of other biological processes associated with normal growth and development. Physiological and biochemical levels of many hormones are affected by zinc metabolism. Therefore, growth impairment, hypogonadism, and some endocrine diseases are associated with the deficiency of zinc. These effects of zinc are considered versatile. Zinc increases the synthesis of the growth hormone and its number of receptors; thus, it is an important mediator in the binding of this hormone to its receptor. Found in a large quantity in the pancreas tissue, zinc has a part in the regulation of the effect of insulin. Zinc is involved to much more thyroid hormone metabolism such as hormone synthesis, receptor activity, conversion of T4 to T3, and production of carrier proteins. The low levels of zinc and high levels of leptin in obese individuals point to a critical relationship between zinc and leptin. Zinc is related to enzyme activity to melatonin synthesis. Melatonin has regulatory activity for zinc absorption from gastrointestinal system. Zinc particularly affects the conversion of testosterone to dihydrotestosterone, as 5α-reductase that is involved in this conversion is a zinc-dependent enzyme. In consideration of these relations, zinc is accepted to play critical roles in the endocrine system. The aim of the current review is to draw attention to the effects of zinc on the endocrine system.

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REVIEW
The role of zinc in the endocrine system
Abdulkerim Kasim Baltaci1, Rasim Mogulkoc1 and Saltuk Bugra Baltaci1
Selcuk University, Medical School, Department of Physiology, Konya, Turkey
Abstract: Zinc is essential in the regulation of a variety of physiological and biochemical events in the organism. It plays
a critical role in maintaining the cell membrane integrity, protein-carbohydrate-lipid metabolism, immune system, wound
injury and in the regulation of a number of other biological processes associated with normal growth and development.
Physiological and biochemical levels of many hormones are affected by zinc metabolism. Therefore, growth impairment,
hypogonadism, and some endocrine diseases are associated with the deficiency of zinc. These effects of zinc are
considered versatile. Zinc increases the synthesis of the growth hormone and its number of receptors; thus, it is an
important mediator in the binding of this hormone to its receptor. Found in a large quantity in the pancreas tissue, zinc
has a part in the regulation of the effect of insulin. Zinc is involved to much more thyroid hormone metabolism such as
hormone synthesis, receptor activity, conversion of T4 to T3, and production of carrier proteins. The low levels of zinc
and high levels of leptin in obese individuals point to a critical relationship between zinc and leptin. Zinc is related to
enzyme activity to melatonin synthesis. Melatonin has regulatory activity for zinc absorption from gastrointestinal
system. Zinc particularly affects the conversion of testosterone to dihydrotestosterone, as 5α-reductase that is involved in
this conversion is a zinc-dependent enzyme. In consideration of these relations, zinc is accepted to play critical roles in
the endocrine system. The aim of the current review is to draw attention to the effects of zinc on the endocrine system.
Keywords: Zinc, endocrine system, hormones
INTRODUCTION
Although zinc, among other metals, is the 23rd most
abundant element in the earth’s crust, it enjoys the
privilege of being the most commonly used element in
biology (Vallee and Auld 1989). Zinc was first described
in 1509 and zinc deficiency was first shown in mice in
1934 (Bannister 1988; Prasad 1969). Its biological
function was revealed in 1940 when carbonic anhydrase
was established to be dependent on zinc for its catalytic
activity (Bannister 1988; Prasad 1969). Dietary zinc
deficiency in humans was first reported by Dr. Prasad in
1963 (Prasad et al., 1963). When it was suggested that
zinc deficiency could be responsible for the growth
retardation and hypogonadism in the adolescent boys in
Egypt, these cases were supplemented with zinc (12-24
months). After the supplementation, secondary sexual
characteristics developed in all cases and both
hypogonadism and growth retardation were stamped out.
This clinical condition arising from zinc deficiency was
included into the body of literature as Prasad’s Syndrome
(Prasad et al., 1963). In early 1970s, the hereditary
disease called acrodermatitis enteropathica was
documented to be associated with the impaired intestinal
absorption of zinc and studies about this trace element
started to grow in number (Barnes and Moynahan 1973).
Zinc and growth
Zinc has a positive influence on growth and development.
One of the main reasons for this positive effect is the
involvement of zinc in the bone metabolism. The
concentration of zinc in the bones is higher in comparison
to other tissues. Zinc increases the production of certain
proteins in osteoblast that suppress the osteoclasts
production. And also zinc is vehicle D vitamin’s affects in
bone tissue (Salgueiro ve ark. 2002). Alkaline phosphates
is a enzyme that zinc dependent and increases to calcium
storage. Zinc is induce to alkaline phosphatase (Brandao-
Neto ve ark. 2006). The role of zinc on carbonhydrate,
lipid and protein metabolism is critical for increasing
bone mass and conservation of the mass (Brandao-Neto et
al., 2006). Zinc is related to synthesis and secretion of
growth hormone. Insuline like growth (IGF-I) factor is
mediated to affect of growth hormone and it a factor that
zinc dependent. (Brandao-Neto et al., 2006; MacDonald
2000). Although the amount of protein in the diet is
important, it has been suggested that zinc supplementation
is much more important to IGF-I synthesis in zinc
deficient animals (Brandao-Neto et al., 2006; MacDonald
2000). It was noted that when the animals with zinc
deficiency were administered growth hormone, IGF-1
concentration did not change (Oner et al., 1984; Dicks et
al., 1993), while zinc potentiated the action of IGF-1 in
cultured bone cells (Matsui and Yamaguchi 1995) and
increased IGF-1 synthesis (Yamaguchi and Hashizume
1994). In case of zinc deficiency, membrane signal
transmission and secondary messengers coordinating the
cell proliferation are negatively influenced. It was even
argued that zinc could act like IGF-1 and affect growth
*Corresponding author: e-mail: rasimmogulkoc@yahoo.com

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(Sandstead et al., 1998). Zinc is necessary for the
hormonal functions of hypophysis (Henkin 1976). Zinc
deficiency reduces the secretion of the growth hormone
from the hypophysis (Roat et al., 1979) and its circulating
concentration (Roth and Kirchgessner 1997). Likewise,
zinc deficiency results in the development of receptor
resistance for both the growth hormone and IGF-1 and the
resistance is broken down upon dietary supplementation
of zinc (Ripa and Ripa 1996). Thus, zinc plays a crucial
part at the receptor level as well (Ripa and Ripa 1996).
There is a binding site for zinc in the growth hormone,
which requires zinc for optimal functioning (Cunningham
et al., 1991). Zinc deficiency has been resulted in
decreases the combination of growth hormone receptor,
IGF-I synthesis and growth factor binding protein-3
(IGFBP-3) in rat (McNall et al., 1995). However, zinc
supplementation has corrected mentioned disturbances
(Imamoglu et al., 2005).
Zinc and thyroid
Among the endocrine functions associated with zinc are
the alterations in thyroid hormone metabolism and energy
consumption (Ganapathy and Volpe 1999). A number of
hypotheses have been proposed to explain how zinc
impacts thyroid hormone metabolism.
Zinc can directly affect the thyroid hormone synthesis.
Gupta and co-worker (1997) has reported that zinc
deficient diet caused to disturbance of thyroid hormone
synthesis and on thyroid gland structure such as atrophy
and degenerative alteration. Zinc is a important
antioxidant and zinc deficiency cause to oxidative stress
and this condition is lead to dysfunction of thyroid gland
eventough mechanism is not clear (Ganapathy and Volpe
1999).
Zinc is considered necessary for the receptor activity of
thyroid hormones (T3 in particular). It was claimed that T3
hormone receptor needed zinc to preserve its biologically
active condition (Freake et al., 2001).
Zinc can affect T4 hormone levels by increasing the
production of thyroxin-binding protein (Hartoma et al.,
1979).
Type I-5’ deiodinase is a dependent-zinc enzyme and is
required to conversion of T4 hormone to T3 (Wada and
King 1986). The activity of type I-5’deiodinase enzyme
and consequently conversion of T4 to T3 is curbed in zinc
deficiency (Wada and King 1986).
Both the hypothalamus and hypophysis are susceptible to
zinc deficiency (Pakary et al., 1991). Consequently, it was
suggested that zinc could be necessary for the enzymes
involved in TRH and TSH synthesis (Pakary et al., 1991).
However, this result is contentious. It was reported by
Brandao-Neto et al., (2006) that zinc did not alter TRH
and/or TSH synthesis in healthy males.
It can be said that the relationship between zinc and
thyroid hormones is not unidirectional, as impaired
thyroid functions affect body zinc levels (Maxwel and
Volpe 2007). That zinc concentrations were found lower
in hypothyroidism and higher in hypothyroidism, both of
which are thyroid gland diseases (Imamoglu et al., 2005),
substantiates the fact that the relation between zinc and
thyroid hormones is not a one-way relation.
Pawan et al., (2007) reported that both intestinal and renal
zinc uptake was significantly elevated in hyperthyroid rats
and therefore rats with hyperthyroidism had higher zinc
levels than their controls. It is accepted that the chief
reason of this condition is that Zip 10, a zinc-transporting
protein, is positively correlated with thyroid hormones in
the intestines and kidneys (Pawan et al., 2007).
However, it was revealed in a study of 34 hyperthyroid
patients that serum zinc content decreased considerably in
hyperthyroidism (Buchinger et al., 1988). It was reported
that the reduced serum zinc levels had two main reasons:
lower zinc absorption and increased urinary zinc
excretion (Kandhro et al., 2009).
Low serum zinc levels in thyroid cancer patients were
shown to be restored to normal after the operation (Al-
Sayer et al., 2004). It was stated that elevated serum zinc
levels after the operation in thyroid cancer patients was an
indicator of the success of the surgery and long-term
monitoring of zinc levels in patients with thyroid cancer
could be important (Al-Sayer et al., 2004).
Zinc and insulin
Zinc fulfills one of the major biochemical functions in the
organism through its effects on the carbohydrate
metabolism. Insulin is stored in the β cells of pancreas in
the form of crystals containing zinc (Scott 1934; Qadir et
al., 2015). Zinc is not only involved in the structure of
insulin, but also has critical effects on its activity (Jansen
et al., 2009).
That the glycemic control of diabetic individuals and
animals was maintained through zinc supplementation
attests to the insulin-like properties of zinc (Adachi et al.,
2004; Yoshikawa et al., 2001). Insulin-like effects of zinc
ions were first identified in isolated rat fat cells in 1982
(May and Contoreggi 1982). Basis of this affect which
zinc is lead to glucose entry to cells (May and Contoreggi
1982). Enhancer affect of zinc at the entry of glucose into
cell is a enzyme is present that called as insulin-
responsive aminopeptidase (IRAP). This molecule has
been expressed in muscle and adipose tissue (Keller et al.,
1995). This zinc-dependent molecule (IRAP) is required
for the maintenance of the glucose transporter 4 (GLUT
4) levels IRAP is important to regulation of GLUT 4
levels that a glucose transporter protein (Keller et al.,
1995). Ezaki (1989) has show that zinc provides

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settlement to GLUT 4 to cell membrane, consequently
accelerate to glucose entry to cell. The other molecule
glycogen syntesis kinase (GSK-3β) is affectted by zinc
and this molecule is affect insuline mechanism. The level
and the activity of this molecule is elevated particularly in
type II diabetes patients. Elevated levels of GSK-3β in
type II diabetes patients disrupt the glycogen level and
cause insulin resistance (Ilouz et al., 2002). Zinc inhibits
glycogen synthase kinase 3β and reduces blood glucose
by increasing glucose intake of the cell (Ilouz et al.,
2002). Consequently, zinc affects the insulin pathway in
several ways (Attia et al., 2015):
1. By stimulating the phosphorylation of insulin receptor
beta subunit
2. By causing the inhibition of GSK-3β, zinc produces
insulin-like effects. This makes zinc a treatment option in
diabetes mellitus or insulin resistance. Oral or
intraperitoneal administration of zinc as a GSK-3β
inhibitor in animal models rapidly lowered the blood
glucose level and restored both insulin responses and
insulin sensitivity (Henriksen et al., 2003; Plotkin et al.,
2003).
A high number of studies investigating the zinc
metabolism in diabetic humans and animals reveal that
urinary zinc excretion is higher in diabetic humans and
animals in comparison to the controls (Awadallah et al.,
1978; Canfield et al., 1984). Although the cause of the
increase in urinary zinc excretion in diabetic humans and
animals has not been conclusively explained, some
reports point to a correlation between urine volume and
increased urinary zinc (Awadallah et al., 1978; Canfield
et al., 1984). Increased blood glucose concentration,
higher glycose and protein excretion through the urine,
and elevated urinary zinc are further factors (McNair et
al., 1981; Quilliot et al., 2001). One of the reasons for the
increase in the urinary excretion of zinc in diabetes is
caused by high blood glucose osmotic diuresis. These
results are also supported by the observation of reduced
urinary zinc loss when blood glucose is reduced with
insulin therapy (Lau and Failla 1984; McNair et al.,
1981). Besides urinary zinc excretion, another possible
mechanism to explain zinc loss in diabetes is increased
intestinal zinc secretion. Calcium, magnesium, phytate,
phosphates and other chelating agents prevent intestinal
zinc absorption and then lead to increased intestinal zinc
secretion (Jansen et al., 2009). Increased urinary zinc loss
commonly found in diabetic patients suggests that if the
zinc they lose through the urine is not compensated, these
patients develop zinc deficiency.
Type II diabetes is usually associated with lower plasma
or serum zinc, whereas plasma or serum zinc in type I
diabetes is commonly higher, especially at the outset
(Aguilar et al., 2007; Pedrosa et al., 1999). At the onset of
type I diabetes, when the beta cells are destroyed, zinc
levels are found higher, but after hyperzincuria offsets
zinc secretion from the beta cells, zinc levels drop. This
hypothesis is supported by the duration of type I diabetes
and the negative correlation between plasma and serum
zinc (Jansen et al., 2009; Pedrosa et al., 1999).
Zinc and thymuline
A great many of the diseases that develop in humans
bring about changes in the zinc metabolism (Salguerio et
al., 1999; Salguerio et al., 2000). Zinc has a critical role
in regulation of cellular immune function (Tipu et al.,
2012). Thereafter, zinc deficiency has increases trend to
infections in human and animals (Prasad 2009; Salguerio
et al., 2000). One of the important roles of zinc is induce
DNA, RNA and protein synthesis for required
immunologic reactions. This effect of zinc is provided by
zinc include enzymes such as DNA-RNA polymerase and
thymidine kinase (Salguerio et al., 1999; Salguerio et al.,
2000). Therefore, the effects of zinc are sure to be seen in
immunological reactions (Prasad 2009; Salguerio et al.,
2000). Currently, it is a widely accepted view that the
deficiency of no other element can cause as much damage
as zinc deficiency, which is the most common cause of
immunodeficiency (El- Fekih et al., 2011; Prasad 2009;
Salguerio et al., 2000). Therefore, zinc deficiency in diet
lead to inhibition of T-cell activity, thus cell immunity
and its products sitokin secretion is affected by adversely
(Kahmann et al., 2006). Zinc is an essential element for
the thymus endocrine activity. Thymuline is known to be
important in cellular immune function and this molecule
is zinc-dependent hormone (Hadden 1988). When it is not
bound to zinc, thymuline is not only inactive, but also
exercises inhibiting effects on active thymuline (Hadden
1988; Mocchegiani et al.,1995). Zinc-thymuline complex
is formed by TEC (Thymic Epithelial Cells) (Hadden
1988). TEC uptakes zinc from the circulation (Hadden
1988). Thymuline is provides to zinc transport to T-
lymphocyte (Hadden 1988; Mocchegiani et al.,1995). The
secretion of zinc-thymuline complex by TEC is
stimulated by zinc and Interleukin-1 (IL-1) (Hadden
1988; Mocchegiani et al.,1995). Together with working
by coordination IL-1 and zinc-thymuline complex
increases sitokin production of T-lymphocyte and support
receptor activity. (Hadden 1988; Mocchegiani et
al.,1999). As a consequent, immune function of thymus is
controlled by sensitive neuroendocrine mechanism
(Hadden 1988). Apart from the Th1 cells and the
cytokines they secrete, zinc also affects the activation of
Natural Killer (NK) cells (Bao et al., 2003; Hadden
1988).
Zinc and neuropeptide-y (NPY)
Zinc plays a key role in the regulation of nutrition. It has
been shown that zinc supplementation prevents reduce
food intake and body weight is seen zinc deficiency (Jing
et al., 2008). The significant effects of zinc on appetite
include changes in the sense of taste (Jing et al., 2008).

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The mechanism that enjoys widest recognition is the one
by which the taste changes result from altered
neurotransmitter concentrations at the general or local
hypothalamic level due to changed zinc status
(Birmingham and Gritzner 2006). In anorexia caused by
due to zinc deficiency has been shown that significant
reductions in body weight in rats. However, zinc
supplementation to these animals has prevented anorexia
and weigth loss (Birmingham and Gritzner 2006, Jing et
al., 2008). Similar findings have been reported in patients
with anorexia nervousa (Safai-Kutti 1990). Therefore,
zinc deficiency was reported to contribute to AN
symptoms (Safai-Kutti 1990). In order to restore the
normal body weight in the process of recovery from AN,
the diet must certainly contain an adequate amount of
zinc. It was already shown that the hypothalamic zinc
levels dropped in AN, and zinc supplementation increased
the body weight (Safai-Kutti 1990).
In anorexia associated with zinc deficiency, there is a
significant relation between zinc, and NPY and galanin
regulation (Selvais et al., 1997). Selvais et al. (1997)
demonstrated that NPY mRNA was elevated in the
hypothalamus of rats fed on a zinc-deficient diet, but no
similar increase was established in NPY levels. Likewise,
Lee et al., (1998) found a 100% increase in NPY mRNA,
but a 50% increase in NPY levels in zinc deficiency.
Actually, there is not any study reporting a decrease in
NPY levels in zinc deficiency (Lee et al., 1998; Selvais et
al., 1997). Therefore, zinc may be responsible for NPT
resistance in anorexia nervousa (Lee et al., 1998; Selvais
et al., 1997). It is suggested that this resistance may be
caused by factors such as disruption of the conversion
process of pro-NNPY to active NPY, reduced NPY
secretion from the neurons, and a decrease in NPY signal
formation (Lee et al., 1998; Selvais et al., 1997). The
concentration of galanin, an appetite-stimulating peptide
like NPY, falls significantly in zinc deficiency (Lee et al.,
1998; Selvais et al., 1997). Galanin mRNA in the
hypothalamus was reported to be low in zinc deficiency,
while Kennedy et al., (1998) showed that the galanin
concentration in the paraventricular nucleus (PVN) of the
rats without zinc deficiency was 120 times higher than
that in the zinc-deficient rats. Galanin mitigates the effect
of NPY during anorexia (Kennedy et al., 1998). The
failure of the body to increase food intake despite
elevated NPY levels in zinc deficiency may be attributed
to the suppression of galanin concentration.
Zinc and leptin
Recent studies about the relation between zinc and leptin
indicate that zinc may have a critical effect on leptin
secretion (Baltaci et al., 2005; Chen et al., 2000). Chen
and co-worker (2000) have reported high leptin and lower
zinc levels in obese mice. Zinc supplementation to these
animals has increased leptin levels and treatment to
obesity. In the light of mentioned findings they postulated
that zinc deficiency may lead to leptin resistance (Chen et
al., 2000). Zinc may either directly affect the leptin gene
expression or indirectly cause leptin production by
increasing the glucose utilization of the fat tissue. It was
reported that zinc deficiency in mice which had
hyperglycemia induced by streptozotocin (STZ) inhibited
leptin secretion, whereas supplementation of zinc at a
physiological dose might cause an increase in both leptin
levels and glucose intake (Chen et al., 2001). Zinc
deficiency also inhibited the secretion of interleukin-6
(IL-6) from adipose tissue in the same rats (Chen et al.,
2001). This result is of particular interest as the structure
of leptin and leptin receptors is similar to that of IL-6
(Chen et al., 2001). Consequently, it was demonstrated in
the concerned study that metabolic defects that developed
in hyperglycemic mice induced by STZ could be
corrected by zinc supplementation at a physiological dose
(Chen et al., 2001). Perhaps the most remarkable study
about the relationship between zinc and leptin is the study
by Ott and Shay (2001). The researchers explored how
zinc deficiency influenced leptin gene expression and
leptin secretion in adipose tissue. They found a reduced
amount of Ob mRNA in the fatty tissue, as well as
significantly lower leptin secretion from the adipose
tissue in rats fed on a zinc-deficient diet (Ott and Shay
2001). Interestingly, they observed an important decrease
in the leptin secretion from each gram of fatty tissue of
zinc-deficient rats, in comparison to their controls (Ott
and Shay 2001). In relation to the significantly inhibited
insulin levels in zinc-deficient rats, the authors concluded
that reduced insulin levels and the weaker insulin
response might be responsible for the decrease in Ob gene
expression (Ott and Shay 2001). The major question that
needs to be answered is whether the decrease in leptin
gene expression is caused by a decrease in transcription,
as zinc is involved in the structure and function of RNA
polymerase (Mohommad et al., 2012). Zinc deficiency
principally alters the composition of the cell’s mRNA
synthesis (Mohommad et al., 2012). Proteins are found in
smaller amounts, or are not found at all, in zinc-deficient
systems, relative to zinc-sufficient ones (Mohommad et
al., 2012).
The relationship between zinc and leptin was investigated
in 9 healthy individuals in whom zinc-deficiency was
induced (Chen et al., 2001; Mohommad et al., 2012). It
was established that zinc deficiency critically inhibited
leptin secretion from the adipose tissue and IL-2 and
TNF-α levels displayed a significant fall parallel to the
inhibited leptin levels (Mantzoros et al., 1998). The
individuals in the study were seen to have a significant
increase in leptin secretion, as well as remarkable
elevations in IL-2 and TNF-α concentrations after zinc
supplementation (Mantzoros et al., 1998). It was
concluded in the study that there was a positive
correlation between zinc and leptin and that elevated IL-2
and TNF-α levels might be mediating this effect of zinc

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on leptin (Mantzoros et al., 1998). This claim suggesting
that zinc is a regulator of leptin concentration in humans
was supported by various results, including those obtained
by Chen et al. (2000).
In a study which examined the effects of zinc and
testosterone supplementation on plasma leptin levels of
castrated rats, zinc supplementation was found to increase
plasma leptin and LH levels of castrated rats, relative to
their controls (Baltaci et al., 2006). Zinc supplementation
was also established to prevent the suppression caused by
testosterone supplementation in leptin and LH levels
(Baltaci et al., 2006).
The study suggests that leptin secretion is related to LH at
the hypophyseal level and zinc has a critical part in this
relation (Baltaci et al., 2006).
In conclusion, there is a proven positive correlation
between zinc and leptin. These results may have major
clinical implications.
Zinc and testosterone
It has been accepted that zinc is present almost each
enzyme system and has a critical role in male
reproduction system (Stallard ve ark 1997, Vallee and
Falchuk 1993). It has been known zinc has provide sperm
membrane integrity, increases sperm motility, helezonic
movement of sperm tail (Omu ve ark 2015; Wong ve ark
2001). In varicole patients, zinc supplementation for 6
months has been resulted in seminal plasma activity
(Nematollahi-Mahani ve ark. 2014). Prostate is the organ
that has the highest zinc concentration in the body and
testis tissue also contains high concentrations of zinc
(Bedwal and Bahuguna 1994). Thus, zinc is closely
related to the male reproductive hormones. Severe and
moderate zinc deficiency in males causes hypogonadism
(Prasad et al., 1996). Zinc may have functional effects on
the male reproductive system in two ways:
1. Zinc affects the testis tissue (Ozturk et al., 2005).
2. Zinc influences the male reproductive system through
the gonadotropic hormones (Baltaci et al., 2006).
Zinc deficiency disrupts the activity of angiotensin
converting enzyme (ACE) which is involved in the
production of adrenal androgens (Kwok et al., 2010) and
this disruption results in reduced testosterone production
and the inhibition of spermatogenesis (Bedwall and
Bahuguna 1994). Zinc is required for the conversion of
testosterone to its active form, dihydrotestosterone (Om
and Chung 1996). The 5α-reductase enzyme that has a
part in this conversion is a zinc-dependent enzyme (Om
and Chung 1996).
Zinc influences the male reproductive system by way of
gonadotropic hormones as well (Mantzoros et al., 1998;
Ozturk et al., 2006). It was shown that zinc deficiency in
male rats considerably inhibited not only testosterone, but
also LH and FSH secretion (Ozturk et al., 2006), while
zinc supplementation brought about an increase in LH and
FSH levels (Baltaci et al., 2006).
It is acknowledged that zinc deficiency suppressed the
receptor activity of androgenic hormones and thus zinc
had a critical part in the regulation of male reproductive
functions (Om and Chung 1996).
Zinc and estrogen
Zinc plays a critical role in the reproductive physiology of
females (Akhtar et al., 2014; Stallard and Reeves 1997). It
was shown in a study that LH and FSH levels were
significantly inhibited in female rats fed on a zinc-
deficient diet (Vallee and Falchuk 1993). Besides, it was
reported that disrupting the production and secretion of
LH and FSH in females, zinc deficiency gave rise to an
abnormal ovarium, reduced estrogen secretion, and thus
disturbed the estrus cycle (Stallard and Reeves 1997).
Maybe the fundamental mechanism underlying the effects
of zinc on the female and male reproductive systems is
based on the relationship between zinc and hormone
receptors (Om and Chung 1996; Vallee and Falchuk
1993). Sex hormones secreted by the female and male
reproductive system are bound to their specific receptors
(Dylewski et al., 1986; Vallee and Falchuk 1993). The
hormone-receptor complex is bound to RNA polymerase,
a zinc metalloenzyme, and a specific DNA segment in the
nucleus (Dylewski et al., 1986). Zinc deficiency prevents
the binding of the hormone-receptor complex to DNA.
Thus, the activation of the genes regulated by these
receptors is blocked (Dylewski et al., 1986). This event
provides at least a partial explanation for the
endocrinological abnormalities associated with zinc
deficiency (Dylewski et al., 1986; Vallee and Falchuk
1993). Furthermore, zinc has a direct effect on the activity
of RNA polymerase (Dylewski et al., 1986). This can be
considered a mechanism explaining the unresponsiveness
of zinc-deficient animals to estrogens (Dylewski et al.,
1986; Vallee and Falchuk 1993).
Zinc and melatonin
Pineal gland is the brain region which is richest in zinc
(Fabris et al., 1991). Plasma melatonin levels drop by
aging (Reiter et al., 1981). Similarly, it was shown that
gastrointestinal zinc absorption was reduced and plasma
zinc levels decreased with aging in both humans
(Turnlund et al., 1986) and animals (Sugarman and
Munro 1980). In a study by Mocchegiani et al., (1996),
one-month melatonin administration (100µg/mouse) to
pinealectomized mice converted the body zinc content
values from negative to positive. Interruption of the
melatonin administration for one month brought the
negative body zinc content values back in the same mice.
Another round of one-month melatonin administration to

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these mice corrected the negative zinc pool. Similar
results were put forward in aged mice (Mocchegiani et
al., (1994). The aforementioned studies suggest that zinc
absorption in the digestive system may be related to
melatonin. The presence of melatonin receptors in the
digestive system strengthens this idea (Lee 1992, Lee ve
Pang 1993). The relation between zinc and melatonin is
not one-way. Zinc is involved in the synthesis of
melatonin synthesis in pineal gland (Johnson 2001).
Serotonin synthesis is a important step in melatonin
synthesis and the role of zinc is critical in this process.
Especially in serotonin formation, in reaction catalyzed by
L-amino acid decarboxylase zinc has play as a cofactor
(Johnson 2001). Already, it has been reported that zinc
deficiency caused to decrease in melatonin levels, but
zinc supplementation led to significantly increases in
melatonin production (Bediz ve ark. 2003).
CONCLUSION
Zinc, which plays a key role in growth, development, and
the reproductive system, is the only metal found in almost
all enzyme classes. Physiological and biochemical levels
of many hormones are affected by the zinc metabolism. In
consideration of these relations, zinc is accepted to play
critical roles in the endocrine system.
When the considered relationship between zinc and
endocrine system it can be postulated that
1. Zinc is effective on growth via growth hormone,
IGF-1, insuline and thyroid hormones.
2. Pubertal period, zinc plays a critical role in the
development of gonadal function.
3. IGF-like affects of zinc show that it is important for
prevents of diabetes and importance of the
carbohydrate metabolism.
4. Zinc affect thymic function, thereafter it has
regulatory function in cellular immunity.
5. Relationship among the zinc, leptin and NPY show
that zinc has a role in regulation of body weigth and
feeding.
6. Because of the relationship between zinc and pineal
gland-melatonin synthesis, zinc may be a potantial
significant for saving brain function and delays of
aging.
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