The Long-term Effects of Metoclopramide-induced Hyperprolactinemia

Metoclopramide, brand name Reglan, is a prokinetic agent that works by speeding the
flow of the upper digestive tract (American Society of Health-System Pharmacists, 2010). This
drug is used to relieve the symptoms of Gastroesophageal Reflex Disease, slow the emptying of
the stomach in diabetics (American Society of Health-System Pharmacists, 2010), and to prevent
vomiting, nausea and aspiration after anesthesia (Arvela et al., 1983). Metoclopramide is the
preferred drug in pregnant women undergoing Caesarean sections and/or severe morning
sickness in the first trimester. The issue ran into with metoclopramide is that it is a dopamine
antagonist (Arvela et al., 1983), meaning that it will block neurotransmitters. In the case of a
pregnancy we are concerned with the increased concentrations of prolactin, hyperprolactinemia,
in the mother and fetus because of blocked prolactin inhibiting factors. Hyperprolactinemia
occurs in 20-30 percent of women and causes failure to ovulate, to become pregnant, causes
irregular menses, or infertility as a result of the blocked hormones, such as estrogen (American
Society for Reproductive Medicine, 2014). The Department of Epidemiology Research, Statens
Serum Institute, Copenhagen, Denmark (Fox, 2015) found no evidence of congenital birth
defects due to the use of metoclopramide. The question arises with the lack of long-terms studies
of the mother returning to regular cyclicity after parturition and weaning and the maturation of
her off-spring who had metoclopramide-induced hyperprolactinemia. To fully understand the
long-term effects of hyperprolactinemia on the off-spring, we must also evaluate prolactins six,
broad functions of water and electrolyte balance, growth and development, endocrinology and
metabolism, brain and behavior, reproduction, and immune regulation and protection (Grattan,
2015).

Understanding the effects of hyperprolactinemia on prolactin receptors in the uterus

(PRLR-S3) and in the pituitary gland (PRLR-S2) is a step forward in therapeutic strategies for
hyperprolactinemia-infertile women (Amaral et al., 2013). Amaral et.al., studied receptor
expression of metoclopramide induced hyperprolactinemia on 64 ovarioectomized mice. The
mice were treated with progesterone and estrogen to test the receptor expression. A total of 7
different control groups were:
In two groups both of ovarioectomized mice, one treated with metoclopramide,
estrogen, and progesterone and the other group metoclopramide, estrogen, and progesterone PRLR-S2 showed the largest receptivity to ovarioectomized groups treated with steroidal
hormones in isolation and metoclopramide. PRLR-S1 had the largest uterine expression with
ovarioectomized females with no treatment. Uterine PRLR-S2 was more expressive for
metoclopramide treated intact females than non-treated intact females. Ovarioectomized females
treated with metoclopramide, estrogen, and progesterone had the highest receptivity to uterine
PRLR-S3. In intact females treated with metoclopramide, the PRL gene expression increased
only in the pituitary gland. This could be a result of hormones other than progesterone and
estrogen. The high levels of prolactin in ovarioectomized females treated with metoclopramide
and progesterone indicates the role of progesterone in increasing mRNA in the expression of
prolactin (Johren et al. 1997). This provides evidence that metoclopramide and progesterone
share the same signal pathways. In the uterus, receptor expression was similar among the
different groups due to prolactin circulation during estrous (Binart et al., 2010).
The Department of Histology, Medical Institute of Chuvash State University preformed
research to find proliferative and morphogenetic uterine responses to estrogen of mice induced to
hyperprolactinemia (Gunin et al., 2002). Four different treatments were done: no treatment,

treatment of estrogen only, treatment of estrogen and bromocriptine, treatment of estrogen and
metoclopramide, and treatment of estrogen and prolactin
In Estrogen receptor- is known to limit the uterine response to estrogen and is associate
with the shifts in uterine weight, proliferation, and morphogenesis. Receptor- was increased in
mice treated with estrogen and bromocriptine and was decreased in mice treated with estrogen
and prolactin or metoclopramide. -Catenin is a part of Wnt pathway and is important director in
endometrial carcinogenesis. In the animals treated with bromocriptine and estrogen, -catenin
uterine levels were lower than the groups treated with estrogen and prolactin and
metoclopramide. Although -catenin was increased in animals treated with estrogen and
prolactin or metoclopramide, because of the decrease in uterine morphogenesis there was a
reduction in expression of the -catenin.
Geoffrey Harris, 1948 proposed that prolactin secretion is controlled by the brain and that
the hypothalamo-prolactin axis is very different from other pituitary functions. Lactotroph cells
were found in the anterior pituitary gland and worked as a dopamine (prolactin-inhibitory
hormone) (Mansour et al., 1990). The denervation of mammary stimuli provided evidence that
dopamine responses are not cued solely by tactile stimuli such as suckling (Grattan, 2015). There
is the possibility that prolactin promotes and inhibits its self through the same neural pathway.
Other factors that stimulate or inhibit prolactin are ovarian steroids which act on lactotrophs to
prolactin gene expression (Fink, 1988). While the causes of prolactin are not fully understood, its
functions in metabolism and fertility are important. Metabolically, prolactin acts upon
adipocytes leptin production and the pancreas insulin expression. These contributions of
prolactin may have adverse effect such as increased food intake and diabetes (Grattan, 2015).

Understanding prolactin receptors will open doors for understanding metoclopramide and
other dopamine antagonist induced hyperprolactinemia. Strong evidence shows that treatment of
steroidal hormones, estrogen, increases the gene expression for prolactin. Hyperprolactinemia
causes a reduction in the amplitude and frequency in LH (Bohnet et al., 1976), thus failure to
ovulate in women and failure to produce testosterone in men. In hyperprolactinemia patients,
resistance to leptin increases appetites (Naef & Woodside, 2007) adding to weight gain and
adipose tissue. In addition, prolactin increases the expression of glucose transporter 2 promoting
the entry of glucose into -cells (Petryk et al., 2000). This increased expression of the cell
transporter eventually causes insulin resistance and in a pregnant female gestational diabetes
(Ramos-Roman, 2011).
Metoclopramides use can be very beneficial in eliminating side effects of pregnancy,
anesthesia, and radiation. Increased understanding of prolactins receptors will help with
understanding the side effect of dopamine antagonist drugs. Although metoclopramide does not
have any immediate congenital effects on the fetus, a question for consideration is how will the
maturing off-spring that was exposed to hyperprolactinemia be able to synthesize prolactin? This
question includes the off-springs ability to produce normal levels of prolactin throughout its life,
the off-springs metabolism and digestive-neuroendocrine system and what treatments can be
used to help the affected off-spring.

Experimental design
High prolactin levels (hyperprolactinemia) is known to cause infertility and a disturbance
in metabolism. Metabolic and reproductive functions off-spring of females who were exposed to
a dopamine antagonist (metoclopramide) during pregnancy change as the off-spring mature.
Uterine prolactin receptors are different in expression than pituitary prolactin receptors.
Therefore, it is expected no congenital defects, but fetal exposure to hyperprolactinemia will
affect the off-springs neuroendocrine systems of the metabolism and reproductive system
(especially in off-spring of gestational diabetic mothers).
Together, 40 sows will be fed the same diets and will have a synchronized estrus,
therefore, will be bred approximately about the same time. This will eliminate any outlaying
variables. Of the 40 sows, 20 will be taken to a different barn and will be injected with
metoclopramide intramuscularly once daily throughout the first trimester. The treated sows will
be placed in a separate barn from non-treated sows (control group) to reduce the chances of
pheromones impacting hormones between the different groups. Using metoclopramide in the
first trimester will match human usage when morning sickness is generally worse. At the end
of each trimester, maternal and fetal prolactin, insulin and leptin blood levels will be evaluated.
At parturition and weaning, blood levels of the mother and off-spring will be taken again to see
the differences in prolactin, leptin, and insulin levels as the off-spring become less dependent.
Around 3 months of age and again at 7 months, blood levels prolactin, insulin, and leptin will be
taken of only the off-spring. This will give us a pre-/postpubertal indicator of how the off-spring
are maturing in relationship to fetal exposure to hyperprolactinemia. In all this experiment will
take roughly 11 months in order to synchronize the sows, breed them, and allow for enough time
for the off-spring to reach puberty.

References:
ASHP. 2010. MedlinePlus: Metoclopromide. Available at:
https://www.nlm.nih.gov/medlineplus/druginfo/meds/a684035.html. Accessed October 6, 2015.
ASRM. 2014. American Society for Reproductive Medicine: hyperprolactinemia. Available at:
https://www.asrm.org/FACTSHEET_Hyperprolactinemia_Prolactin_Excess/. Accessed October
6, 2015.
Arvela, P., Jouppila, R., Kauppila, A., Pakarinen, A., Pelkonon, O., and Tuimala, R. 1983.
European Journal of Clinical Pharmacy. Eur J Clin Pharmacol 24:345 - 348.
Amaral, V.C., Maciel, G.A.R., Carvalho, K.C., Marcondes, R.R., Soares, J.M., and Baracat, E.C.,
2013. General and Comparative Endocrinology (Vol. 139) Elsevier Inc.
Binart N., Bachelot A., and Bouilly J., 2010. Impat of prolactin receptor isoforms on
reproduction. Trends in Endocrinology and Metabolism 21: 362 - 368
Bohnet H.G., Dahlen H.G., Wuttke W., and Schneider H.P., 1976. Hyperprolactinemia
anovulatory syndrome. Journal of Clinical Endocrinology and Metabolism 42: 132 143.
Fink G., 1988. Oestrogen and progesterone interactions in the control of gonadotropin and
prolactin secretion. Journal of Steroid Biochemistry 30: 169 178.
Fox, S. 2016. Metoclopramide: No link seen with birth defects, stillbirth. Medscape Medical
News 310: 1601 - 1611.
Gunin, A.G., Emelianov, V., Tolmachev, A.S., and Tolmacheva A. 2002. Effect of prolactin and
dopaminergic drugs on uterine response to chronic estrogen exposure. Journal of Endocrinology
172: 61 69.
Grattan, D.R. 2015. 60 Years of Neuroendocrinology: The Hypothalamo-prolactin axis. Journal
of Endocrinology 226: T101 T122.
Harris G.W., 1949. Neural control of the pituitary gland. Physiological Reviews 28: 139 179
Johren O., Sanvitto G.L., Egidy G., and Saavedra J.M. 1997. Angiotensin II AT1A receptor
mRNA expression is induced by estrogen-progesterone in dopaminergic neurons of the femal rat
arcuate nucleus. Journal of Neurosciences 17: 8283 8292.
Mansour A., Meador-Woodruff J.H., Bunzow J.R, Civelli O., Akil H., and Watson S.J., 1990.
Localizationof dopamine D2 receptor of mRNA and D1 and D2 receptor binding in the rat brain
and pituitary: an in situ hybridization-receptor autoradiographic analysis. Journal of
Neuroscience 10: 2587 2600

Naef I. and Woodside B., 2007. Prolactin/leptin interactions in the control of food intake in rats.
Endocrinology 148: 5977 5983.
Petryk A., Fleenor D., Driscoll P, and Freemark M., 2000. Prolactin induction of insulin gene
expression: the roles of glucose and glucose transporter-2. Journal of Endocrinology 164: 277
286.
Ramos-Roman M.A., 2011. Prolactin and lactation as modifiers of diabetes risks in gestational
diabetes. Hormone and Metabolic Research 43: 593 600.