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Home , Carbetocin, Oxytocin

OHSUOxytocin Research Overview: past, present & future discovery

November 14, 2019 - Elise Erickson PhD, CNM Disclosures OHSU• No conflicts

2 Overview

• Briefly review from the literature on function broadly

• Oxytocin system in the process and pharmacologic implications for postpartum OHSUuterine function • Oxytocin discovery on the horizon

3 Physiology and Pharmacology OHSU

4 Hypothalamic Neuroendocrine

Paraventricular nuclei Anterior (6 cell types) Posterior ( terminals) Infundibulum Supraoptic Hypophyseal Portal Circulation OHSUnuclei

Anterior Pituitary

Oxytocin/

5

This Photo by Unknown Author is licensed under CC BY-SA Endogenous/Exogenous Oxytocin

Present Use Sir Henry Dale • 1953: Synthesized • ~25% induced • 1906: pituitary peptide sequence, • 30-57% (?) augmented extracts structure • AMTSL OHSUnd • 2 trimester termination/ • 1911: clinical use • 1955: miscarriage management • First peptide ever synthesized

1906 1911 1955 2019 Oxytocin (OXTR) Function OHSU

Bell, Erickson, Carter (2014) Journal of Midwifery and Women’s Health Where are oxytocin receptors found ?

• • Bone • Myometrium • • • • /Adrenal • Prostate • Blood vessels • Smooth muscle intestine OHSU• • Cancer cells • Platelets • Adipose cells

Yang, H.-P., Wang, L., Han, L., & Wang, S. C. (2013). Nonsocial Functions of Hypothalamic Oxytocin. ISRN Neuroscience. Japundzic-Zigon, N. (2013). Vasopressin and Oxytocin in Control of the Cardiovascular System. Current Neuropharmacology.

8 Peripheral oxytocin action

• Uterine • Myoepithelium of breast—milk ejection • production (decidua-maternal side placenta) • Decreased heart rate, blood pressure, temperature • Decreased OHSU• Suppression pro-inflammatory • Increased glucose uptake & • Cell growth (anti-proliferative) • Inhibits growth of adipose cells

Yang, H.-P., Wang, L., Han, L., & Wang, S. C. (2013). Nonsocial 9 Functions of Hypothalamic Oxytocin. ISRN Neuroscience. Central oxytocin action • HPA axis (CRH->Cortisol) • Dopaminergic pathways • OHSU• Vagus nerve: parasympathetic

Neumann, I. D. (2007). Stimuli and consequences of dendritic release of oxytocin 10 within the . Biochemical Society Transactions, 35(Pt 5), 1252–1257. OXT is a hypothalamic that functions like a and a OHSUthroughout the body. Regulation and Variation OHSU

12 How does endogenous oxytocin function vary between individuals? And does it make a difference OHSUduring the perinatal period? Knockout Mice Is oxytocin necessary for labor?

No OXTR OHSUWildtypeOXTR

Takayanagi, Y., Yoshida, M., Bielsky, I. F., Ross, H. E., Kawamata, M., Onaka, T., et al. (2005). Pervasive social deficits, but normal parturition, in -deficient mice. Proceedings of the National Academy of Sciences, 102(44), 16096–16101. Prostaglandin & Oxytocin Knockouts

Delivered Living Pups Days of gestation

OHSUNo OXTR No OXT

Yoshida, M., Takayanagi, Y., Ichino-yamashita, A., Sato, K., Sugimoto, Y., Kimura, T.. (2019). Functional hierarchy of required for successful parturition in mice. Endocrinology. 4 cases OHSU4 spontaneous labors at term 2 needed oxytocin augmentation in active phase 2 Cesareans, 1 instrument assisted birth 4 PPH (one delayed PPH) 4 no milk production Labor & Genotype OXTR

Single Nucleotide Polymorphism (SNP): a single variation in a genetic sequence that does not necessarily change the sequence of a , OHSUbut may influence the overall efficiency of intracellular signaling.

Oxytocin max Duration of Total Dose Cesarean birth infusion rate induced labor

Grotegut, C. A., Ngan, E., Garrett, M. E., Miranda, M. L., Ashley-Koch, A. E., & Swamy, G. K. 17 (2017). American Journal of and Gynecology 106 S. Vannuccini et al. / Annales d’Endocrinologie 77 (2016) 105–113 in the myometrial gap junction formation, and up-regulation of 2. Phases of human parturition myometrial oxytocin receptors. Indeed, endocrine or paracrine- autocrine factors from the feto-placental unit bring about a may be considered as consisting of four parturi- switch in the pattern of myometrial activity [3]. In fact, human tional phases (Fig. 1). During the first parturitional phase (phase parturition is an inflammatory and endocrine event, where the 0 – quiescent phase) the uterus is kept in a quiescent state through two systems interact modulating labor onset and progression the action of and other minor factors such as pros- [4]. tacyclin (PGI2), , -related peptide In the past, the placenta was believed to be a largely (PTHrP), -related peptide, vasoactive intestinal passive organ mainly responsible for delivering nutrients to peptide and (NO). All these agents act mediate the fetus. With progress in obstetric research, this concept an increased intracellular concentrations of cyclic has gradually shifted to one that recognizes the placenta monophospate (cAMP) or cyclic guanosine monophospate as a transient endocrine organ and a central regulator of (cGMP) which inhibit the release of intracellular calcium for maternal–placental–fetal physiology. Thus, the placenta ensures myometrial contractility. appropriate physiologic milieus for normal growth and devel- The second phase (phase 1 – activation phase) of parturition is opment of fetal, placental, and maternal tissues necessary for associated with activation of uterine function. A rise in a successful pregnancy. Indeed, the placenta represents a very and CRH together, possibly, with mechanical stretch may lead metabolically active organ during parturition. It is a source of a to up-regulation of a panel of required for contractions. large number of “information” molecules that, when released, These CAPs include connexin 43, prostaglandin and oxytocin can exert their biologic effects on the placenta itself but can also receptors (OTRs). enter the maternal and fetal circulation, thus acting as autocrine, In the third phase of parturition (phase 2 – paracrine, and endocrine factors [5,6]. phase), the uterus can be stimulated by uterotonics including Placenta produces a large variety of molecules including , oxytocin and CRH. The biochemical events steroid , hypothalamic-pituitary hormones, neuro- within the uterus resemble an inflammatory reaction, with , growth factors and cytokines, involved in parturition increased synthesis of cytokines. [7]. Steroid hormones include the common female gonadal The fourth phase of parturition (phase 3 – phase) steroid hormones, progesterone and . It is notewor- includes the uterine involution that follows the delivery of the thy that the placenta produces also hormones that are known fetus and the placenta. It has been primarily attributed to the to be produced by neuroendocrine organs, such as oxytocin, effects of oxytocin [9]. gonadotrophin-releasing hormone (GnRH), and CRH. However, the fetus itself plays a role in initiation of labor, 3. Hormones involved in parturition through the secretion of and other stimulators of prostaglandin synthesis [8]. 3.1. Estrogens Thus, inflammation, mechanical distension of the uterus at term and hormonal paracrine and autocrine signalling between Estrogens are essential for uterine development and function, the feto-placental unit and the mother seem to promote the playing a key role in uterine contractility. Human pregnancy is initiation of human parturition through coordinated activation characterized by a typical hyperestrogenic state. The placenta of stimulatory pathways and loss of uterine quiescence, which is the primary source of estrogens, and concentrations of enables contractions to occur. Oxytocin inestrogens parturition: increase in the maternal circulation with increasing OXT levels : Fetal blood > Maternal blood OHSU

OXT pulses in Fig. 1. Phases of human parturition.advanced labor 13x/hour (q 4-5 min) Vannuccini, S., Bocchi, C., Severi, F. M., Challis, J. R., & Petraglia, F. (2016). OHSU “…the need to ensure successful pregnancy likely produced a redundancy of pathways to ensure reliable uterine emptying and expulsion of the fetus.” OXT / OXTR might not be a primary driver of the innate physiology of labor onset but is likely important OHSUduring pushing and postpartum of OXT

Peptide • Half life • *Degradation

• Onset of action within 3 to 5 minutes

• Half-life studies: 3-6 minutes vs. 10 to 15 minutes OHSU(in blood, longer in CSF/brain) • Steady state 30 to 60 minutes

• Degraded/inactivated by “” • Zinc-dependent aminopeptidase • PLAP (placental aminopeptidase) 21 Oxytocin & Obesity

• Lower levels of oxytocin in circulation • Lower levels post-menopause + obesity  Estrogen promotes upregulation of OXTR • Less likely to start labor spontaneously OHSU• Require higher doses during labor augmentation • BMI >30, more likely to need to go over 20mu/min

Maestrini (2018) European Journal of Obesity Carlson (2015) Reproductive Biology & Endocrinology Adams et al (2019) Am. J Perinatology

22 Receptor Pharmacology OHSU Receptor  Upregulation (gestational age, hormone)  Desensitization (binding)  Degradation (via internalization) 23  Down-regulation (mRNA) Duration oxytocin No Downregulation Desensitization labor OXTR mRNA level OXT binding Spontaneous labor

60x less

HOURS IN LABOR Duration of oxt OHSUInduced labor 300x less

Phaneuf, S., et al (2000). and Fertility Maintenance dose mu/min

24 Pretreatment 2 hours Physiologic salt solution 10−9 to 10−12 M Concentrations CONTROL found in laboring Increasing test dose concentration women w/ augmentation. Low dose ------10-8M equivalent to a high dose protocols with induced labor. OHSUMedium dose 10-8M High dose Balki M et al. (2013) Anesthesiology. OXT and OXTR function varies by gestational age, body habitus, and OHSUin the presence of an agonist. • 4 previously published randomized controlled trials (published in the 1990s)

• n = 957 oxytocin vs. n = 1021 control group

• Effectiveness of prophylactic oxytocin for reducing PPH risk •OHSUWomen without synthetic oxytocin during labor • Meta-analytic statistical test Prophylactic oxytocin was not associated with lower rates of 1000mL blood loss, blood transfusion or need for more uterotonics meds. • OHSU Nurse-Midwifery Faculty Practice Repository • n= 2,322 vaginal (2012-2017) • Process Variables • OHSURole of Active Management of Third Stage Labor PHENOTYPES

Dysfunctional/ prolonged Physiologic/ not prolonged n = 819 (66% AMTSL, 33% did not) n = 1,028 (44% had AMTSL, 56% did not) More PPH Less PPH Less PPH w/ AMTSL (500mL) More PPH w/ AMTSL More retained Co-author: Dr. Nicole Carlson, PhD, CNM Current Study: Emory University

Oxytocin duration in labor and postpartum hemorrhage

Consortium for Safe Labor Dataset National dataset, mid 2000s

Term Vaginal Births without major PPH risks

Excluded: - Previa, Accreta, Abruption - Thrombophilia/embolic disorders - Major lacerations - Prolonged 3rd stage-- >95%tile (>15 minutes) OHSU- use in labor - Chorioamnionitis - Congenital anomalies 26,622 total sample size Postpartum Hemorrhage: 1,007 (3.78%) - EBL of 501mL or higher *manuscript in preparation - ICD9 Diagnosis Code PPH Frequency Following Vaginal Birth by Duration of Oxytocin Used in Labor. Consortium for Safe Labor Data 8 7.4

7 6.1 6 5.8 n = 14,347 p<0.001 5 n = 12,275 4.6 4.7 p<0.001 3.8 4 3.5 3.6 3.7 2.9 3 2.5 2.2 Frequency of Frequency Hemorrhage Postpartum (%) OHSU2 1

0 Spontaneous of Labor Duration of Oxytocin Used in Labor (hours) No oxytocin Up to 2 2.1-4 4.1-7 7.1 - 12 Over 12 *manuscript in preparation Risk for Postpartum Hemorrhage by Duration of Oxytocin Use Augmented and Induced Labors (n = 2

Augmentation All Oxytocin Use Induction Only Only

OR (95% CI) aOR (95% CI) aOR (95% CI) aOR (95% CI) Oxytocin Duration <=2 hours Reference Reference Reference Reference >2 hours to 4 hours 1.13 (0.89-1.42) 1.12 (0.87-1.43) 1.10 (0.73-1.63) 1.04 (0.76-1.45) >4 hours to 7 hours 1.47 (1.18-1.82)* 1.42 (1.13-1.79)* 2.08 (1.45-2.98)* 1.05 (0.75-1.42) >7 hours to 12 hours 1.84 (1.47-2.30)* 1.72 (1.35-2.20)* 2.29 (1.48-3.55)* 1.37 (1.01-1.86)* >12 hours 2.74 (2.15-3.48))* 2.42 (1.81-3.22)* 2.49 (1.34-4.63)* 2.05 (1.46-2.89)*

OHSUadjusted for parity, age, gestational age, level of weight gain, on admission

*manuscript in preparation Postpartum Hemorrhage Associated with Term Vaginal Birth by Duration of Oxytocin (n = 26,662) 10.0 9.0 9.1 8.0 p=0.03 7.0 p < 0.001 6.0 6.6 5.0 p = 0.006 4.8 4.0 4.4 4.3 p = 0.001 4.2 PPH Frequency PPH Frequency % 3.8 3.0 3.3 3.2 2.0 2.7 2.6 2.5 OHSU1.0 0.0 30 minutes or Less 31-59 minutes 60 to 179 minutes 180+ minutes Duration of Full Dilation No Oxytocin Oxytocin 4 hours or Less Oxytocin > 4 hours

*manuscript in preparation Other researchers:

In vitro studies • Oxytocin pretreatment on myometrium for 2 hours results in diminished response even after removing oxytocin for up to 90 minutes (Balki, 2016)

• Oxytocin receptor internalization occurred after 15 minutes of exposure and recovery to cell membrane took up to 4 hours after exposure to be similar to baseline (Conti, 2009)

In vivo studies • 490 women. Time from discontinuation of oxytocin during labor and Cesarean Delivery for dystocia was calculated (average of 99 minutes). OHSUEvery 10 minute increase in recovery = 10 mL less blood loss. • However amount of oxytocin and duration of exposure was most related to need for PPH interventions. (Tran, 2017).

• Women undergoing Cesarean required higher oxytocin dose infusions if oxytocin was previously administered (Lavoie, 2015). Use of OXT during labor contributes to increased risk for postpartum hemorrhage, need for prophylaxis and further PPH treatment due to OHSUfewer available receptors Future of Oxytocin Research OHSU

35 Future Oxytocin Therapeutics

• : longer-lasting agonist (40 min half life)

– Postpartum Hemorrhage?

• : oxytocin

– Preterm labor?

• Intranasal Oxytocin: (central vs. peripheral debate) OHSU– Obesity/ blood glucose regulation – Cardiovascular protection during ischemia

– Social behaviors/ mood symptoms

36 Oxytocin Receptor Expression In Pregnancy: When Does It Turn On?  Dr. Jessica Reid- Family Planning Fellow • samples myometrium throughout late 2nd trimester to term • determine at what gestational age OXTR expression increases • inform clinical management of post- hemorrhage

Higher DNAm = Lower OXTR OHSU less uterine tone • Postpartum Hemorrhage • More exogenous oxytocin

Secondary outcomes • Postpartum Mood • Suboptimal Summary

• OXT is a hypothalamic neuropeptide that functions like a neurotransmitter and a hormone.

• OXT / OXTR might not be a primary driver of the normal physiology of labor onset but is important during pushing and postpartum

• OXT and OXTR function varies by gestational age, body habitus, and in the presence of an agonist (endogenous/exogenous).

• Use of OXT during labor contributes to increased risk for postpartum OHSUhemorrhage, need for prophylaxis and further PPH treatment due to fewer available receptors

• Balancing goals of induced or speedy labor with need for functional oxytocin receptors after birth is something birth attendants should consider thoughtfully

38 References • Ottenhausen, M., Bodhinayake, I., Banu, M. A., Stieg, P. E., & Schwartz, T. H. (2015). Vincent du Vigneaud: following the sulfur trail to the discovery of the hormones of the posterior at Cornell Medical College. Journal of Neurosurgery, 1–5. • Martin, J. A., Hamilton, B. E., Osterman, M. J. K., Driscoll, A. K., & Drake, P. (2018). Births: Final for 2017. National Vital Statistics Reports, 67(8), 1–49. Gimpl, G., & Fahrenholz, F. (2001). The oxytocin receptor system: structure, function, and regulation. Physiol Rev, 81(2), 629–683. • Bell, A. F., Erickson, E. N., & Carter, C. S. (2014). Beyond labor: The role of natural and synthetic oxytocin in the transition to motherhood. Journal of Midwifery and Women’s Health, 59(1), 35–42. • Lee, H. J., Macbeth, A. H., Pagani, J. H., & Scott Young, W. (2009). Oxytocin: The great facilitator of life. Progress in Neurobiology, Vol. 88, pp. 127–151. • Yang, H.-P., Wang, L., Han, L., & Wang, S. C. (2013). Nonsocial Functions of Hypothalamic Oxytocin. ISRN Neuroscience. • Feldman, R., Monakhov, M., Pratt, M., & Ebstein, R. P. (2016). Oxytocin Pathway Genes: Evolutionary Ancient System Impacting on Human Affiliation, Sociality, and Psychopathology. Biological Psychiatry. • Bell AF, Carter CS, Steer CD, et al. Interaction between oxytocin receptor DNA methylation and genotype is associated with risk of postpartum in women without depression in pregnancy. Front Genet. 2015;6(38):1161–10.. • Kimmel M, Clive M, Gispen F, et al. Oxytocin receptor DNA methylation in . Psychoneuroendocrinology. • Reiner I, Van Ijzendoorn MH, Bakermans-Kranenburg MJ, Bleich S, Beutel M, Frieling H. Methylation of the oxytocin receptor gene in clinically depressed patients compared to controls: The role of OXTR rs53576 genotype. J Psychiatr Res. 2015;65:9-15.. • Behnia F, Parets SE, Kechichian T, et al. Fetal DNA methylation of spectrum disorders candidate genes: association with spontaneous preterm birth. Am J Obstet Gynecol. 2015;212(4):533.e1-.e9.. • Rijlaarsdam J, van Ijzendoorn MH, Verhulst FC, et al. Prenatal stress exposure, oxytocin receptor gene (OXTR) methylation, and child autistic traits: The moderating role of OXTR rs53576 genotype. Autism Res. 2017;10(3):430-438.. • Elagoz Yuksel M, Yuceturk B, Karatas OF, Ozen M, Dogangun B. The altered promoter methylation of oxytocin receptor gene in autism. J Neurogenet. 2016;30(3-4):280-284.. • Jack A, Connelly JJ, Morris JP. DNA methylation of the oxytocin receptor gene predicts neural response to ambiguous social stimuli. Frontiers in Human Neuroscience. 2012;6.. • KimOHSU J, Pitlick MM, Christine PJ, et al. Genome-wide analysis of DNA methylation in human amnion. ScientificWorldJournal. 2013;2013(4):678156–11.. • Mitsuya K, Singh N, Sooranna SR, Johnson MR, Myatt L. Epigenetics of Human Myometrium: DNA Methylation of Genes Encoding Contraction- Associated in Term and Preterm Labor1. Biol Reprod. 2014;90(5):590-598. • van Vliet, E. O. G., Nijman, T. A. J., Schuit, E., Heida, K. Y., Opmeer, B. C., Kok, M., … Oudijk, M. A. (2016). versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial. The Lancet, 387(10033), 2117–2124. • Jin, B., Du, Y., Zhang, F., Zhang, K., Wang, L., & Cui, L. (2016). Carbetocin for the prevention of postpartum hemorrhage: a systematic review and meta-analysis of randomized controlled trials. The Journal of Maternal-Fetal & Neonatal Medicine, 29(3), 400–407. • Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., … Hardan, A. Y. (2017). Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences of the United States of America, 114(30), 8119–8124. OHSUThank You

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