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Physiol. Res. 71: 193-198, 2022 https://doi.org/10.33549/physiolres.934824

REVIEW

Progesterone Inhibitory Role on Gastrointestinal Motility

Mohammad ALQUDAH

1,2

, Othman AL-SHBOUL

, Ahmed AL-DWAIRI

Doa´a Ghazi AL-U´DATT

, Abdelrahim ALQUDAH

Department of Physiology and Biochemistry, School of Medicine, Jordan University of Science

and Technology, Irbid, Jordan,

Department of Physiology, School of Medicine and biomedical

Sciences, Arabian Gulf University, Manama, Bahrain,

Department of Clinical Pharmacy and

Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan.

Received October 17, 2021

Accepted March 15, 2022

Epub Ahead of Print March 28, 2022

Summary

Progesterone is a steroidal hormone that is produced from the

corpus luteum of the ovaries and from the placenta. The main

function of progesterone is to promote the secretory

differentiation in the endometrium of the uterus and to maintain

pregnancy by inhibiting uterine contractions throughout

pregnancy. Progesterone performs its actions by activating the

classical progesterone nuclear receptors that affect gene

transcription and by the non-classical activation of cell surface

membrane receptors that accounts for the rapid actions of

progesterone. Besides the reproductive roles of progesterone, it

exerts functions in many tissues and systems such as the

nervous system, the bone, the vascular system, and the

gastrointestinal (GI) tract. This review will summarize the recent

literature that investigated the role of progesterone in GI tract

motility. Most literature indicates that progesterone exerts

an inhibitory role on gut smooth muscle cells in part by elevating

nitric oxide synthesis, which induces relaxation in smooth muscle.

Moreover, progesterone inhibits the signaling pathways that lead

to contraction such as Rho kinase inhibition. These data serve as

a quick resource for the future directions of progesterone

research that could lead to better understanding and more

effective treatment of gender-related GI tract motility disorders.

Key words

Progesterone  Smooth muscle  GI tract

Corresponding author

Department of Physiology, School of Medicine and medical

services, Arabian Gulf University, Manama, Bahrain, 26671.

Email: Mohammada@agu.edu.bh

Introduction

Progesterone is the natural progestin that is

mainly produced in the corpus luteum of the ovaries and

by the placenta. It is synthesized from the cholesterol

derivative, pregnenolone by the actions of the cholesterol

side-chain cleavage enzyme and 3-beta-hydroxysteroid

dehydrogenase [1,2]. Although the focus of progesterone

and its applications have been associated with female

physiology, it is present in male gonads and regulates

several male physiological and pathological functions

such as spermiogenesis and androgen synthesis [2,3].

Moreover, progesterone is produced in the male and

female central nervous systems (CNS) and all the

required enzymes and precursors for progesterone

synthesis are present in CNS where it acts directly on

neuronal tissues [4]. Furthermore, Progesterone exerts

several important functions in tissues other than the

reproductive tissue such as the cardiovascular, renal,

adipose, bone, and gastrointestinal tissues [3,5]. The aim

of this review is to summarize the role of progesterone in

gastrointestinal (GI) tract motility function and to

highlight the potential therapeutic benefits and risks of

progestin preparations in the GI tract.

Mechanism of progesterone actions

Progesterone produces its physiological

functions by activating classical and non-classical

signaling pathways [6]. In the predominant classical

194 Alqudah et al. Vol. 71

pathway, progesterone binds to its receptor; a member of

the nuclear receptor superfamily of transcription factors

[6]. There are two main isoforms of progesterone

receptors (PRs), PR-A and PR-B. Binding of

progesterone to PR induces its translocation to the

nucleus where the complex binds to progesterone

response elements and initiates or prevents the

transcription of a wide array of proteins [7]. However, the

non-classical pathway produces rapid actions by

activating cell surface receptors that resemble G protein-

coupled receptors [8]. Progestin binding to these

receptors rapidly activates various intracellular signaling

molecules such as elevation of intracellular calcium,

extracellular signal-regulated kinases 1 / 2 (ERK1/2),

mitogen-activated protein kinase (MAP) kinase

and Protein kinase B/phosphatidylinositol 3-kinases

(Akt/PI3K) (Fig. 1) [9].

Fig. 1. Progesterone mechanism of

action. The classical pathway

involves the nuclear progesterone

receptor (nPR) dimerization and

translocation to the nucleus to

induce genomic effects

via

activating or inhibiting gene

transcription. The non-classical

pathway is rapid action that

involves membrane progesterone

receptor (mPR) and the subse-

quent activation of several second

messengers such as elevation of

intracellular calcium (Ca

), extra-

cellular signal-regulated kinases

(ERK) and Protein kinase B (AKT)

Functions of progesterone

The main reproductive function of progesterone

is to promote the secretory differentiation in the

endometrium of the uterus during the second half of the

female sexual cycle [10]. These changes aim to prepare

the uterus for implantation of the fertilized ovum [10]. In

addition to this effect on the endometrium, progesterone

decreases uterine contraction force and frequency to

prevent the explosion of the newly implanted ovum and

maintains a quiescent environment for fetal development

[11]. Additionally, it influences the activity of the

intrauterine immune system through the regulation of

inflammatory mediators’ production from T cells. This

action of progesterone helps to maintain pregnancy as

well by increasing the immunological protection against

any potential microbial threats [12]. Moreover,

progesterone prepares the breasts for lactation through its

action to promote proliferation and enlargement of

alveolar cells of the breast [13].

In addition to the unquestionable role of

progesterone in reproduction, it has numerous functions

in various organs in the body. In the central nervous

system, progesterone is produced at high concentrations

from glial and neuronal cells [14]. Progestins produced in

the CNS are called neurosteroids. They modulate many

neuronal functions either by upregulating or

downregulating neurotransmissions and are involved in

cognition, memory, neuroprotection, and myelination

processes [14]. Moreover, progesterone is involved in

sexual and maternal behaviors [15,16]. Like in the

reproductive system, neurosteroids act through classical

and non-classical pathways in the CNS [17].

Progesterone plays an essential role in bone

physiology; it stimulates bone formation and slows down

resorption. However, its effect is influenced by estrogen,

age, and the predominant signaling pathways [18].

Progesterone has been studied in association

with diabetes and gestational diabetes. It inhibits glucose

uptake and increases liver gluconeogenesis [19].

Progesterone mediates this effect by acting on

progesterone receptor membrane component 1 in the liver

2022 Progesterone and Gut Smooth Muscle 195

that could exacerbate hyperglycemia in diabetes [19].

Conversely, progesterone improves neuronal glucose

metabolism through the augmentation of different

glucose transporters in neuronal cells [20]. The latter

effect may be responsible for the neuroprotective role of

progesterone.

The primary effects of progesterone on

myometrial smooth muscle cells’ contractility suggest

that it may exert similar actions on smooth muscle cells

of other tissues. PRs are present in vascular smooth

muscle cells and progesterone administration in humans

lowers blood pressure and inhibits angiotensin II-induced

contraction in vascular muscle cells [21,22]. The

relaxation effect of progesterone on vascular smooth

muscle is independent of vascular endothelium and

triggered directly via activation of PRs present in smooth

muscle cells [23]. The effects of progesterone on vascular

smooth muscle cells' tone involve several actions on

different signaling pathways that lead to smooth muscle

relaxation. One prevalent mechanism is the activation of

non-classical progesterone cell surface receptors that in

turn activate an inhibitory G protein and subsequently

activation of several intracellular pathways

that upregulate nitric oxide intracellular levels which

leads to inhibition of vascular smooth muscle contraction

[24]. Another pathway that is responsible for the

inhibitory effect of progesterone on vascular smooth

muscle cells contraction is the activation of the cyclic

adenosine monophosphate (cAMP) pathway which

inhibits contraction by reducing myosin light chain-20

(MLC 20) phosphorylation by activating progesterone

cell surface receptors directly and involving the MAP

kinase/ERK-, Akt/PI3K signaling activation [23].

Moreover, progesterone induces vascular smooth muscle

relaxation by reducing intracellular calcium levels

through activation of membrane progesterone receptor

alpha (mPRα)-dependent signaling pathways,

specifically, MAP and Akt signaling [25].

Similarly, progesterone targets the smooth

muscle of the gastrointestinal tract and affects the

contractile apparatus there. The remainder of this review

will summarize the recent advances in the role of

progesterone in gastrointestinal tract contraction

relaxation pathways.

Progesterone in Gastrointestinal tract

motility

Gastrointestinal tract motility is altered during

pregnancy as a result of plasma hormonal changes such

as progesterone levels. Progesterone affects

gastrointestinal motility where it enhances gastric

emptying at high doses as those seen toward the end of

pregnancy [26]. Smooth muscle cells from the colon of

women with intractable constipation and slow transit time

were studied by Zuo-Liang Xiao et al. to elucidate the

role of progesterone in constipation. They found that

smooth muscle cells from women with constipation

exhibited lower contraction compared to control samples.

Moreover, PRs were overexpressed in smooth muscle

cells from constipation women and there was

downregulation of Gαq/11 and up-regulation of Gαs,

responsible for contraction and relaxation respectively

[27]. Moreover, progesterone could increase gastric

sensitivity to inhibitory gut neurotransmitters such

as calcitonin gene-related peptide (CGRP) by enhancing

CGRP receptors in gastric tissue. This effect is correlated

with the levels of CGRP during pregnancy and could

account in addition to the reported disturbed gut motility

to the increased gut irritability as CGRP is one of the

main sensory neurotransmitters in the gut [28]. In vitro,

progesterone inhibited the resting tension of

the fundus and body longitudinal muscle strips, and it

inhibited the mean contractile amplitude of body and

antrum longitudinal and circular muscles [29]. The effect

of progesterone was mostly a direct effect on gastric

smooth muscle as inhibitors of other mediated pathways

did not influence the effect of progesterone on gastric

motility [29].

From another point of view, progesterone

decreased gastrointestinal tract inflammatory cytokines

such as IL-1β and tumor necrosis factor-alpha. Which

helps to protect the gut structure and prevents apoptosis

after gut inflammation [30]. This observation suggests the

potential use of synthetic progesterone in such situations,

especially if they are accompanied by diarrhea as these

inflammatory cytokines are known to enhance gut

motility [31, 32]. Moreover, progesterone provides

neuroprotective and anti-inflammatory effects on the

enteric nervous system in Parkinson's disease (PD) mice

model and thus could ameliorate the associated gut

motility disturbances in PD. This observation could

explain the beneficial effect of female hormones in PD

susceptibility [33]. However, these effects of

progesterone on gut motility are indirect effects through

the enteric nervous system.

Recently, the role of progesterone in gastric

smooth muscle motility was investigated in more detail

by Al-Shboul and co-authors [34-36]. Single smooth

muscle cells from rat gastric tissue were used to investigate

196 Alqudah et al. Vol. 71

the role of progesterone in gastric motility. Both isoforms

of progesterone receptors (PR), PR-A and PR-B are

present in gastric smooth muscle cells suggesting a direct

site of action of progesterone [35]. Preincubation of the

dispersed smooth muscle cells 10 minutes before the

administration of acetylcholine (Ach), inhibited the

induced contraction by acetylcholine. Moreover,

progesterone preincubation inhibited Ach-induced

Rho kinase II activity without affecting its expression level

suggesting that progesterone acts rapidly and directly of

gastric smooth muscle cells to inhibit the contractile

activity [34]. The same group showed that the effect of

progesterone on Ach-induced contraction was achieved by

the production of nitric oxide (NO] by progesterone from

smooth muscle cells. Nitric oxide in turn induces the

formation of cyclic guanosine monophosphate (cGMP)

that activates protein kinase A (PKG) that plays a key role

in smooth muscle relaxation [35].

Fig. 2. Effect of progesterone on

gut smooth muscle contraction:

Progesterone activates its cell

surface receptors (mPR), PR that

leads to NO production.

NO production leads to the

generation of cGMP from GTP

and in turn activation of PKG.

PKG acts to inhibit signaling path-

ways that provoke contraction

such as RhoK and activates the

signaling that leads to muscle

relaxation such as MLCP. mPR:

progeste-rone receptor, NO:

Nitric oxide, cGMP: cyclic guáno-

sine monophosphate, GTP: gua-

nosine triphosphate, PKG: protein

kinase G, RhoK: Rho kinase,

MLCP: myosin light chain

phosphatase

Similarly, Colon smooth muscle contractility

was increased in the inflammatory bowel syndrome

model induced by water immersion and animal restraint

in mice and this change was NO-dependent. Progesterone

administrations reversed the increased contractility by

elevating NO levels [37].

Future directions

Despite the obvious role of progesterone in

gastrointestinal tract function, little investigations

explored the topic in a mechanistic manner. This

necessitates future studies to target the detailed

mechanism of action of the inhibitory effect of

progesterone on gut motility. Additionally, progesterone

function in the GI tract should be studied in

a pathological context, such as inflammatory bowel

diseases, stress, and during pregnancy and lactation.

Conclusion

Progesterone inhibits gastrointestinal tract

motility by acting directly on gut smooth muscle cell

surface PRs. This leads to rapid changes in the

intracellular second messengers that affect contraction

relaxation pathways without the involvement of gene

transcription. One of the main downstream second

messengers to PRs is NO that acts

on Guanylate cyclase to generate cGMP and activation of

the subsequent PKG. In turn PKG acts on many

molecules in the contraction relaxation pathways to

decrease phosphorylation of MLC-20 and eventually

inhibition of contraction Fig. 2.

Conflict of Interest

There is no conflict of interest.

Acknowledgement

The authors would like to thank Dr. Hanan Ali Shatnawi

for her help to produce the figures of this work.

This work was supported by a grant from Jordan

University of Science and Technology, grant number

2017355

2022    Progesterone and Gut Smooth Muscle   197 
 
 
References 
 
1.  Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and 
its disorders. Endocr Rev. 2011;32(1):81-151. https://doi.org/10.1210/er.2010-0013 
2.  Cable  JK,  Grider  MH.  Physiology,  Progesterone.  StatPearls  [Internet].  Treasure  Island  (FL):  StatPearls 
Publishing; 2022 Jan. 
3.  Oettel  M,  Mukhopadhyay  AK.  Progesterone:  the  forgotten  hormone  in  men?  Aging  Male.  Sep 
2004;7(3):236-57. https://doi.org/10.1080/13685530400004199 
4.  Henderson  VW.  Progesterone  and  human  cognition.  Climacteric.  2018;21(4):333-340. 
https://doi.org/10.1080/13697137.2018.1476484 
5.  Taraborrelli  S.  Physiology,  production  and  action  of  progesterone.  Acta  obstetricia  et  gynecologica 
Scandinavica. 2015;94:8-16. https://doi.org/10.1111/aogs.12771 
6.  Garg D, Ng SSM, Baig KM, Driggers P, Segars J. Progesterone-Mediated Non-Classical Signaling. Trends 
in Endocrinology & Metabolism. 2017/09/01/ 2017;28(9):656-668. https://doi.org/10.1016/j.tem.2017.05.006 
7.  Wetendorf M, DeMayo FJ. Progesterone receptor signaling in the initiation of pregnancy and preservation of 
a healthy uterus. Int J Dev Biol. 2014;58(2-4):95-106. https://doi.org/10.1387/ijdb.140069mw 
8.  Valadez-Cosmes P, Vázquez-Martínez ER, Cerbon M, Camacho-Arroyo I. Membrane progesterone receptors 
in  reproduction  and  cancer.  Molecular  and  cellular  endocrinology.  2016;434:166-175. 
https://doi.org/10.1016/j.mce.2016.06.027 
9.  Simoncini  T,  Genazzani  AR.  Non-genomic  actions  of  sex  steroid  hormones.  European  journal  of 
endocrinology. 2003;148(3):281-292. https://doi.org/10.1530/eje.0.1480281 
10.  Bergeron  C.  Morphological  changes  and  protein  secretion  induced  by  progesterone  in  the  endometrium 
during  the  luteal  phase  in  preparation  for  nidation.  Human  reproduction.  2000;15(suppl_1):119-128. 
https://doi.org/10.1093/humrep/15.suppl_1.119 
11.  Putnam CD,  Brann DW, Kolbeck RC, Mahesh VB. Inhibition  of uterine contractility by progesterone and 
progesterone  metabolites:  mediation  by  progesterone  and  gamma  amino  butyric  acidA  receptor  systems. 
Biology of reproduction. 1991;45(2):266-272. https://doi.org/10.1095/biolreprod45.2.266 
12.  Arab  H,  Alharbi  AJ,  Oraif  A,  et  al.  The  Role  Of  Progestogens  In  Threatened  And  Idiopathic  Recurrent 
Miscarriage. Int J Womens Health. 2019;11:589-596. https://doi.org/10.2147/IJWH.S224159 
13.  Savouret  J,  Misrahi  M,  Milgrom  E.  Molecular  action  of  progesterone.  Oxford  reviews  of  reproductive 
biology. 1988;10:293-347. 
14.  Tsutsui K, Sakamoto H, Ukena K. Biosynthesis and action of neurosteroids in the cerebellar Purkinje neuron. 
The  Journal  of  Steroid  Biochemistry  and  Molecular  Biology.  2003/06/01/  2003;85(2):311-321. 
https://doi.org/10.1016/S0960-0760(03)00229-2 
15.  Frick KM,  Kim J. Mechanisms underlying the rapid effects of estradiol and progesterone on hippocampal 
memory  consolidation  in  female  rodents.  Hormones  and  behavior.  2018;104:100-110. 
https://doi.org/10.1016/j.yhbeh.2018.04.013 
16.  Kavaliers  M,  Bishnoi  IR,  Ossenkopp  K-P,  Choleris  E.  Differential  effects  of  progesterone  on  social 
recognition  and  the  avoidance  of  pathogen  threat  by  female  mice.  Hormones  and  Behavior. 
2021;127:104873. https://doi.org/10.1016/j.yhbeh.2020.104873 
17.  Patel  S. The  Effects  of Ovarian  Hormones  on  Memory Bias  and  Progesterone  Receptors  in  Female  Rats. 
Concordia University; 2020. https://spectrum.library.concordia.ca/id/eprint/987245/  
18.  Yao W, Dai W, Shahnazari M, Pham A, Chen Z, Chen H, Guan M, Lane NE. Inhibition of the progesterone 
nuclear receptor during the bone linear growth phase increases peak bone mass in female mice. PloS one. 
2010;5(7):e11410. https://doi.org/10.1371/journal.pone.0011410 
19.  Lee SR, Choi W-Y, Heo JH, Huh J, Kim G, Lee KP, Kwun HJ, Shin HJ, Baek IJ, Hong EJ.  Progesterone 
increases blood glucose via hepatic progesterone receptor membrane component 1 under limited or impaired 
action of insulin. Sci Rep. 2020;10(1):16316-16316. https://doi.org/10.1038/s41598-020-73330-7 

198   Alqudah et al.    Vol. 71 
 
 
20.  Wu H, Wu ZG, Shi WJ, Gao H, Wu HH, Bian F, Jia PP, Hou YN. Effects of progesterone on glucose uptake 
in  neurons  of  Alzheimer's  disease  animals  and  cell  models.  Life  Sciences.  2019/12/01/  2019;238:116979. 
https://doi.org/10.1016/j.lfs.2019.116979 
21.  Horwitz  KB,  Horwitz  L.  Canine  vascular  tissues  are  targets  for  androgens,  estrogens,  progestins,  and 
glucocorticoids. J Clin Invest 1982;69(4):750-758. https://doi.org/10.1172/JCI110513 
22.  Barbagallo  M,  Dominguez  LJ,  Licata  G,  Shan  J,  Bing  L,  Karpinski  E,  Pang  PK,  Resnick  LM.  Vascular 
effects  of  progesterone:  role  of  cellular  calcium  regulation.  Hypertension.  2001;37(1):142-147. 
https://doi.org/10.1161/01.HYP.37.1.142 
23.  Pang Y, Thomas P. Progesterone induces relaxation of human umbilical cord vascular smooth muscle cells 
through  mPRα  (PAQR7).  Molecular  and  Cellular  Endocrinology.  2018/10/15/  2018;474:20-34.  
https://doi.org/10.1016/j.mce.2018.02.003 
24.  Pang Y, Dong J, Thomas P. Progesterone increases nitric oxide synthesis in human vascular endothelial cells 
through  activation  of  membrane  progesterone  receptor-α.  American  Journal  of  Physiology-Endocrinology 
and Metabolism. 2015;308(10):E899-E911. https://doi.org/10.1152/ajpendo.00527.2014 
25.  Pang  Y,  Thomas  P.  Role  of  mPRα  (PAQR7)  in  progesterone-induced  Ca
2+
  decrease  in  human  vascular 
smooth  muscle  cells.  Journal  of  Molecular  Endocrinology.  01  Oct.  2019  2019;63(3):199-213. 
https://doi.org/10.1530/JME-19-0019 
26.  Liu C-Y, Chen L-B, Liu P-Y, Xie D-P, Wang PS. Effects of progesterone on gastric emptying and intestinal 
transit in male rats. World J Gastroenterol. 2002;8(2):338-341. https://doi.org/10.3748/wjg.v8.i2.338 
27.  Xiao Z-L, Pricolo V, Biancani P, Behar J. Role of progesterone signaling in the regulation of G-protein levels 
in  female  chronic  constipation.  Gastroenterology.  2005/03/01/  2005;128(3):667-675. 
https://doi.org/10.1053/j.gastro.2004.12.001 
28.  Yang X, Liu R, Dong Y. Regulative effects of ovarian steroids on rat gastric motility and sensitivity.  Acta 
Physiologica Sinica (Chinese Edition). 2006;58(3):275. 
29.  Wang  F,  Zheng  T-Z,  Li  W,  Qu  S-Y,  He  D-Y.  Action  of  progesterone  on  contractile  activity  of  isolated 
gastric strips in rats. World J Gastroenterol. 2003;9(4):775-778. https://doi.org/10.3748/wjg.v9.i4.775 
30.  Chen  G,  Shi  J-X,  Qi  M,  Wang  H-X,  Hang  C-H.  Effects  of  Progesterone  on  Intestinal  Inflammatory 
Response,  Mucosa  Structure  Alterations,  and  Apoptosis  Following  Traumatic  Brain  Injury  in  Male  Rats. 
Journal of Surgical Research. 2008/06/01/ 2008;147(1):92-98. https://doi.org/10.1016/j.jss.2007.05.029 
31.  Nalli  AD,  Kumar  DP,  Mahavadi  S,  Al-Shboul  O,  Alkahtani  R,  Kuemmerle  JF,  Grider  JR,  Murthy 
KS.   Hypercontractility  of  intestinal  longitudinal  smooth  muscle  induced  by  cytokines  is  mediated  by the 
nuclear  factor-κB/AMP-activated  kinase/myosin  light  chain  kinase  pathway.  J  Pharmacol  Exp  Therap 
2014;350(1):89-98. https://doi.org/10.1124/jpet.113.212522 
32.  Grider J. Interleukin‐1β selectively increases substance P release and augments the ascending phase of the 
peristaltic  reflex.  Neurogastroenterol  Motility.  2003;15(6):607-615.  https://doi.org/10.1046/j.1350-
1925.2003.00445.x 
33.  Jarras  H.  Effects  of  progesterone  at  the  enteric  level  in  a  mouse  model  of  Parkinson's  disease.  2019; 
Université Laval Biblioteque. https://corpus.ulaval.ca/jspui/handle/20.500.11794/37714  
34.  Al-Shboul O, Mustafa A, Al-hashimi F. Non-genomic effects of progesterone on Rho kinase II in rat gastric 
smooth muscle cells. Journal of Smooth Muscle Research. 2013;49:55-62. https://doi.org/10.1540/jsmr.49.55 
35.  Al‑Shboul  OA,  Mustafa  AG,  Omar  AA,  et  al.  Effect  of  progesterone  on  nitric  oxide/cyclic  guanosine 
monophosphate  signaling  and  contraction  in  gastric  smooth  muscle  cells  Corrigendum  in/10.3892/br. 
2019.1251. Biomed Rep 2018;9(6):511-516. https://doi.org/10.3892/br.2019.1251 
36.  Al-Shboul  OA,  Al-Rshoud  HJ,  Al-Dwairi  AN,  et  al.  Changes  in  gastric  smooth  muscle  cell  contraction 
during  pregnancy:  effect  of  estrogen.  Journal  of  pregnancy.  2019;2019. 
https://doi.org/10.1155/2019/4302309 
37.  Liu H-X, Pan H, Shi Z, Wang H. Estradiol and progesterone regulate the activities of colonic smooth muscle 
in water-immersion and restraint stress mice by modulating NO. Progress in Modern Biomed. 2013:05. 
 
 