Effect of pregnancy hormones on pain perception in the peripartum period: A narrative review

Abstract

Pregnancy is a period marked by significant hormonal fluctuations, which can influence pain perception. There are only a limited number of analgesic options that are considered safe for newborns and mothers. Understanding the impact of pregnancy hormones on pain sensitivity can be crucial for effective pain management during childbirth and the postpartum period. The literature shows encouraging evidence of the role of pregnancy hormones on pain modulation, with some studies suggesting a potential reduction in pain sensitivity. Studies have shown progesterone to be associated with reduced post-cesarean pain scores and anesthesia requirements, while oxytocin levels inversely correlated with post-cesarean pain severity in some studies. However, the overall evidence remains inconclusive, indicating a need for further research to elucidate the complex mechanisms underlying hormonal modulation of pain perception during pregnancy and postpartum accurately. This narrative review summarizes the available literature to provide insights into the mechanisms and role of pregnancy hormones including progesterone, estrogen, and oxytocin in pain modulation during pregnancy, delivery, and the peripartum period. Future research should focus on clarifying the mechanisms through which pregnancy hormones influence pain perception and identifying individual factors that may contribute to variability in pain sensitivity among pregnant individuals. Well-designed randomized controlled trials should be planned to evaluate the effect of hormonal therapy on pain modulation in the peripartum period. This knowledge would help to generate evidence and design pain management protocols for obstetric patients.

Introduction

Pregnancy is widely recognized as one of the most hormonally dynamic physiological states experienced by humans. Throughout pregnancy and childbirth, ovarian hormone levels undergo significant fluctuations, encouraging researchers to explore how these hormones impact pain sensitivity because women tend to experience pain differently than men.[1] Estrogen, for instance, can affect the primary afferents of trigeminal and pudendal nerves. Ovarian hormones also modulate neuromodulators and neurotransmitters like substance P, dopamine, serotonin, acetylcholine, γ-aminobutyric acid (GABA), glutamate, β-endorphin, and norepinephrine [Figure 1]. These hormones also influence other biological and cognitive functions, potentially increasing female sensitivity to environmental stimuli.[2] It has been reported that during pregnancy, there may be an increase in the pain perception threshold in preparation for labor. Preclinical studies have shown that an increase in the ovarian hormones 17-beta-estradiol, progesterone, or oxytocin promotes analgesia in the peripartum period.[3,4,5] The possible actions of pregnancy-related hormones (estrogen, progesterone, oxytocin, and relaxin) on pain modulation in the peripartum period at the level of receptors, signaling pathways, and effector organs have been listed in Table 1.

Figure 1.

Pathways of the effect of pregnancy-related hormones on neuromodulation of pain transmission. Source: The figure has been created with BioRender.com. GABA = gamma-aminobutyric acid, GABA_AR = γ-aminobutyric acid type A receptor

Table 1.

Actions of pregnancy hormones on pain modulation during peripartum period

	Estrogen	Progesterone	Oxytocin	Relaxin
Produced by	Ovary (corpus luteum), placenta	Ovary (follicle), placenta	Hypothalamus (neurons of SON and PVN)	Placenta, corpus luteum
Receptors	• mERα/β	• mPR	• OTR or V1aR	• RXFP1
	• GPER1	• PGMR C-1/2 • GABAAR		• RXFP2
Signaling pathways	• MAPK/ERK	• cAMP/PKA	• MAPK	• ERK1/2
	• PI3K/AKT	• Ca2+/PKC	• RhoA/ROK	• PKB/AKT
	• PKC	• C-SRC/MAPK	• cPLA2	• PKC
	• PKA	• PI3K/AKT	• Ca2+/MLC kinase	• cAMP/PKA
	• ERα/β
Uterus	• Endometrial thickening • Thins cervical mucus and more alkaline	• Enhances vascularization of the endometrium in the luteal phase • Makes cervical mucus more viscous	• Contraction of the uterus and myoepithelial cells in mammary gland during birth and lactation	• Inhibits uterine contraction and relaxes ligaments of the pelvis • Promotes cervical ripening
Brain	• 🠉 5-HT • 🠉 Noradrenaline • 🠉Hippocampal responsiveness • 🠉🠋Anxiety/stress	• Positively modulates GABAAR • Promotes myelination • Sedative • Analgesic	• Modulates microglia • Promotes GABA switch • Stimulates maternal care • Neuroprotection	• Modulates emotional behavioral function • Stimulates NO generation by cAMP levels • Neuronal plasticity
Spinal cord	• Modulation of pain sensitivity	• Neuroprotective • Mediates hypersensitivity after nerve root damage	• Activates inhibitory GABA-ergic interneurons • 🠉intracellular Ca2+ current • Reduces pain	Neuroprotective
Peripheral nerve	• 🠉Uterine nerve sensitivity • 🠉Glutamatergic nociceptor activity	• Release of NO • Neuroprotective	• Activates V1aR that reduces the activity of ASIC, P2X receptors, and Ca2+channels • Analgesia	• 🠉cAMP • Memory formation in the hippocampus and amygdala

5-HT=5-hydroxytryptamine, ASCI=acid-sensing ion channel, Ca2+/MLC kinase=calcium ion/myosin light chain kinase, Ca2+/PKC=calcium ion/protein kinase C, cAMP=cyclic adenosine monophosphate, cAMP/PKA=adenosine 3′,5′-cyclic monophosphate/dependent protein kinase A, cPLA2=cytosolic phospholipase A2, C-SRC/MAPK=cellular sarcoma kinase/mitogen-activated protein kinase, ERα/β = estrogen receptor subtypes alpha (Erα) and beta (Erβ), ERK1/2=extracellular signal-regulated kinase 1/2, GABAAR = γ-aminobutyric acid type A receptors, GPER1=G protein-coupled estrogen receptor 1, MAPK/ERK=mitogen-activated protein kinase/extracellular signal-regulated kinase, mERα/β = membrane estrogen receptors subtypes alpha (Erα) and beta (Erβ), mPR=membrane progesterone receptor, NO=nitric oxide, OTR or V1aR=oxytocin receptor or vasopressin receptor 1A, RhoA/ROK=Ras homolog family member A/Rho-associated protein kinase, RXFP1=relaxin family peptide receptor 1, RXFP2=relaxin family peptide receptor 2, PGMR C-1/2=progesterone receptor membrane component 1/2, PI3K/AKT=phosphoinositide 3-kinase/AKT, PKA=protein kinase A, PKB/AKT=protein kinase B/AKT, PKC=protein kinase C, PVN=paraventricular nucleus, SON=supraorbital nerve, V1aR=vasopressin receptor 1A

Researchers have observed contradictory findings regarding pain perception during pregnancy. While some studies have shown an increased heat pain tolerance (HPTo) during labor, others have shown no changes in pain threshold with forehead pressure, heat, and responses to mechanical or electrical stimuli. Oxytocin, whose endogenous production increases during pregnancy, has demonstrated antihyperalgesic effects in preclinical and clinical studies.[6,7,8,9,10]

Effective analgesia following cesarean section (CS) is a significant worry for patients and obstetricians, as good analgesia ensures early ambulation that helps prevent thromboembolism, promotes gut motility, shortens recovery, and enhances infant care. Pregnancy can alter the minimum alveolar concentration of volatile anesthetics,[11] and progesterone has been reported to possess anesthetic properties.[12,13] Even the structure of the GABA-A receptor, which plays a vital role in nociception, has revealed 19 different subunits with allopregnanolone binding sites, thereby hinting at a possible mechanism of action of progesterone through its metabolite. The possible molecular mechanism of action of progesterone and its metabolites to reduce pain perception is illustrated in Figure 2. The incidence of persistent post-cesarean pain is lower than persistent postsurgical pain in non-obstetric populations, suggesting a possible beneficial effect of pregnancy.[14] Increased endogenous production of oxytocin during pregnancy has shown antihyperalgesic effects in preclinical and clinical studies.[10]

Figure 2.

(a) Mechanism of action of progesterone and its metabolites. (b) GABA A receptor structure has 19 different subunits with allopregnanolone binding site. Source: The figure has been created with BioRender.com. 3α-HSD=3α-hydroxysteroid dehydrogenase type 1, 5α-DHP=5α-dihydroprogesterone, 5α-reductase=5-alpha reductase, AC=adenylate cyclase, cAMP=cyclic adenosine monophosphate, ERK/MAPK=extracellular signal-regulated kinase/mitogen-activated protein kinase, GABA=gamma-aminobutyric acid, GABA_AR=γ-aminobutyric acid type A receptor, mPR=membrane progesterone receptors, PGMRC1=progesterone membrane receptor component 1, PKA=protein kinase A, PR=progesterone, PXR=pregnane X receptor

Understanding the mechanisms and effects of pregnancy-induced hormonal fluctuations on pain sensitivity and analgesia is crucial for effective pain management during childbirth and postpartum recovery. Therefore, we planned this review to analyze the mechanisms and role of pregnancy hormones on pain modulation during pregnancy, delivery, and the peripartum period. To the best of our knowledge, there is no such narrative review in the Indian scenario focusing on the impact of pregnancy-related hormones on peripartum analgesic pathways.

Material and Methods

Search strategy

A literature search was performed by using a comprehensive search strategy based on the following terms and phrases on electronic databases: “effect of pregnancy hormones on pain perception,” “effect of progesterone on pain perception during peripartum,” “effect of oxytocin on pain perception during peripartum,” and “effect of estrogen on pain perception during peripartum.” We searched the Web of Science, PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for publications till April 1, 2024. Published review articles and editorials were also included. All references for selected articles were searched to check if any relevant article was missing.

Study selection

The titles and abstracts of all citations were screened by two authors (AM and AG) to identify all relevant studies. After that, the full text of all selected studies was read to assess whether the studies applied to the topic. We included in this narrative review only studies on the analgesic effect of pregnancy hormones on pain perception during delivery and the peripartum period as the primary outcome. We excluded the studies that (i) did not report heat or pain threshold measures in pregnant women; (ii) did not report the levels of pregnancy hormones; (iii) gave inaccurate information on the results of interest; and (iv) did not have full text. Studies in a language other than English, without full text, or not fully published (conference abstract) were excluded. Animal studies were also excluded. Any disagreements between the review authors were sorted out after discussion with the other authors.

Data extraction

A comprehensive text review was conducted to ascertain the fulfillment of inclusion criteria. Data was extracted using a standardized approach to ensure consistency and precision. Data collected from different studies were based on (i) the type of hormones studied, (ii) the study population, (iii) the intervention arm, (iv) the mode of intervention, (v) the perioperative pain score, and (vi) the levels of preoperative pregnancy hormones.

Observations

The various studies investigating the effect of pregnancy hormones on pain perception during the peripartum period, meeting the inclusion criteria, have been summarized in Table 2. Palagiano et al.[15] conducted a survey with a prospective, randomized, double-blind design in which 50 patients aged between 21 and 40 years and diagnosed with threatened abortion were included and randomized to receive either one dose of vaginal progesterone 8% per day (equivalent to 90 mg of progesterone) or a placebo. Pain intensity was evaluated using a 5-point scale. The findings demonstrated a notable decrease in pain among patients in the intervention group. The study, therefore, conclusively showed that vaginal progesterone effectively alleviates pain in cases of threatened abortion.

Table 2.

Studies investigating the effect of pregnancy hormones on pain perception

Author, year, country	Hormones studied	Type of study	Study population	Case cohort/intervention arm	Control cohort/control arm	Outcome measures	Results	Association between studied hormone and analgesia
Frolic[16]	Serum progesterone, estrogen, oxytocin levels	Prospective cohort	n=32 At term posted for elective CS		Nil	Heat pain threshold and tolerance, estrogen, progesterone, and oxytocin levels Measured at 1) term and 2) 4–8 weeks postpartum	Hormone levels reduced significantly, but pain threshold did not	Nil
Palagiano[17]	Vaginally administered progesterone (Crinone 8%)	RCT	n=50 <12 weeks pregnancy, with diagnosis of threatened abortion	Progesterone gel (applied for 5 days after diagnosis)	Placebo gel	Pain scores and uterine contractions	Progesterone was effective in reducing the pain and frequency of the uterine contractions, that decreased after 5 days of vaginal progesterone administration (P<0.005)	+
Kashanian[18]	Serum progesterone	Prospective cohort	n=166 At term posted for elective CS	High progesterone group- patients with progesterone level ≥ median (119.45)	Low progesterone group- patients with progesterone level < median (119.45)	1) Pain scores- measured before surgery, and at 4, 8, 12, 24 h after surgery 2) Progesterone levels- median serum progesterone level was 119.45 ng/ml	The mean pain scores at 4, 8, 12, and 24 h were significantly lower in high progesterone groupPutting three variables of age, gestational age, and BMI in a multiple regression model, progesterone level showed significant negative correlation with the pain score in hour 4 (P=0 001, r=-0.305), hour 8 (P=0 001, r=-0.461), hour 12 (P=0 001, r=-0.328), hour 24 (P=0 001, r=-0.409)	+
Lee[19]	Serum progesterone	Prospective observational study	n=100 At term posted for elective CS under GA	Higher than median progesterone group Mean prog levels was 128.2±83 ng/ml	Lower than median progesterone group	1) Preoperative Sr progesterone- mean serum progesterone=128.2±83.0 ng/ml 2) Sevoflurane consumption titrated by BIS 3) Postoperative VAS pain scores and cumulative analgesic consumption at 2, 24, and 48 h	Significant negative correlation was found between progesterone concentration and - 1) sevoflurane consumption (r=-0.26 [-0.44 to -0.05], P=0.01) 2) cumulative analgesic consumption at hour 2 (r=-0.20 [-0.39 to -0.01] P=0.05) hour 24 (r=-0.25 [-0.44 to -0.05], P=0.02) hour 48 (r=-0.28 [-0.46 to−0.08], P=0.01) Significantly low sevoflurane consumption and 48-h cumulative analgesic consumption in women with higher than median prog. concentration	+
Ende[20]	Plasma oxytocin	Prospective observational study	n=18 At term posted for elective CS under spinal anesthesia			1) Plasma oxytocin levels – 1 h before surgery, and 1 and 24 h after surgery 2) Incisional pain at 24 h	Incisional pain at 24 h was inversely correlated with oxytocin levels, with higher plasma oxytocin associated with lower pain (r, -0.52 and -0.66; P<0.05)	+

BIS=bispectral index, BMI=body mass index, CS=cesarean section, RCT=randomized controlled trials, VAS=visual analog scale

Frölich et al.[21] conducted a prospective cohort study involving 32 non-laboring women scheduled for elective cesarean delivery to assess potential correlations between changes in pregnancy hormone concentrations and alterations in temperature ratings by quantitative tests. These women were adults (19 and 40 years) with American Society of Anesthesiologists (ASA) physical status I or II and were with more than 37 weeks gestation. Heat pain threshold (HPTh), HPTo, progesterone, estrogen, and oxytocin levels were measured at term and repeated at 4–8 weeks postpartum. The study found that 52% of participants showed a reduction in HPTo and 55% showed a reduction in HPTh. However, all hormone levels decreased significantly after pregnancy during the postpartum visit (P < 0.029). Despite these hormonal changes, no significant changes were observed in heat pain measurements at the two time points. Furthermore, no association was found between oxytocin levels and heat pain measurements. These findings suggest that in human beings, fluctuations in hormones like progesterone, estradiol, or oxytocin do not predict the change in pain perception among women during the peripartum period.

To investigate the association between serum progesterone levels and post-cesarean pain perception, Kashanian et al.[22] included 166 pregnant women scheduled for elective cesarean delivery in a prospective cohort study. The patients comprised women with gestational age >37 weeks, a maximum of two previous CS, maternal age between 20 and 40 years, and absence of pregnancy and delivery complications. Before surgery, serum progesterone levels were measured. Pain scores were assessed using the visual analog scale (VAS) at 4, 8, 12, and 24 h postsurgery, and correlations between progesterone levels and pain were examined. Participants were stratified based on a mean progesterone level of 119.45 ng/ml into high progesterone (≥119.45 ng/ml) and low progesterone (<119.45 ng/ml) groups. Pain scores at different time intervals (4, 8, 12, and 24 h) were compared between these groups. The mean pain scores at each time point were significantly lower in the high progesterone group. Moreover, the high progesterone group had a significantly higher proportion of women with low pain scores (<5) at 12 and 24 h postsurgery. Furthermore, women with higher body mass index (BMI) exhibited lower progesterone levels. They reported higher pain scores at various time points, whereas those with lower BMI demonstrated lower pain scores during the same time intervals. A negative significant correlation was evident between progesterone levels and BMI and between progesterone levels and pain scores at 4, 8, 12, and 24 h postsurgery. In conclusion, serum progesterone levels exhibited a negative correlation with post-cesarean pain scores, indicating a potential role of progesterone in modulating pain perception following cesarean delivery.

In another investigation by Lee et al.,[11] the aim was to uncover potential associations between anesthetic or analgesic needs and maternal serum progesterone concentrations. A total of 100 pregnant women with ASA physical status I or II, aged between 20 and 45 years, scheduled for planned cesarean delivery under standard general anesthesia (GA) were included in the study. Anesthesia was induced using thiopental and rocuronium and maintained with sevoflurane 0.5%–2.0% and nitrous oxide 50% in oxygen, adjusted based on five hemodynamic parameters and bispectral (BIS) value. Vital signs, BIS, and end-tidal sevoflurane with consumption per hour were noted. Pain scores on VAS and cumulative analgesic consumption were noted postoperatively. A significant negative correlation was observed between hourly sevoflurane consumption and serum progesterone levels. Cumulative analgesic consumption at postoperative hours 2, 24, and 48 exhibited an inverse correlation with serum progesterone concentration. The current study revealed that maternal serum progesterone concentration is inversely related to the requirement of sevoflurane and postoperative analgesia in patients undergoing cesarean delivery under GA. Consequently, the sevoflurane and postoperative analgesic requirements for parturients undergoing cesarean delivery may be influenced by serum progesterone levels to some extent. Further investigations are needed to elucidate the impact of these hormones and endogenous opioids on anesthetic requirements in pregnant females and the potential interactions between female hormones and endogenous opioids.

Ende et al.[23] investigated the connection between plasma oxytocin levels and incisional pain following cesarean delivery in their pilot study. The study included 18 patients aged 18–50 years undergoing elective cesarean delivery. Plasma samples were collected 1 h preoperatively and 1 and 24 h postoperatively and analyzed using enzyme-linked immunosorbent assay for oxytocin levels. Pain assessments were conducted 1 day, 8 weeks, 3 months, and 6 months postoperatively. This study revealed an inverse correlation between postoperative pain severity and plasma oxytocin levels. Specifically, individuals with high oxytocin levels at 1 and 24 h in the postpartum period experienced lower post-cesarean acute pain scores. However, no significant correlation was observed between oxytocin levels at 1 and 24 h and the reported pain scores or opioid utilization at later time points.

Discussion

The role of hormones, particularly progesterone, estradiol, and oxytocin, in modulating pain perception during pregnancy and postpartum has been a subject of considerable interest and investigation. Research on the role of these hormones in modulating pain perception during pregnancy and postpartum has revealed several key findings.

Firstly, progesterone, essential for maintaining pregnancy, has been associated with various biological effects, including immunosuppression, which is essential for preventing miscarriage, particularly in the first trimester. Progesterone is known for its crucial role in establishing and maintaining pregnancy. Studies have shown that vaginal progesterone effectively reduces pain in patients with threa tened abortion, underscoring its role in regulating myometrial activity.[15]

Moreover, research suggests a potential correlation between maternal progesterone levels and anesthetic requirements during cesarean delivery, indicating a possible analgesic effect of progesterone.[11] Similarly, preclinical studies have suggested that progesterone could alleviate neuropathic pain, further highlighting its potential role in pain modulation.[16,17,18]

However, the relationship between hormonal fluctuations during pregnancy and postpartum and pain perception is complex and not fully understood. While some studies suggest a potential analgesic effect of progesterone, others have found inconsistent results. For instance, Palagiano et al.[15] observed reduced pain and uterine contractions in women treated with vaginal progesterone gel, while Rhudy and Bartley[19] did not find evidence of menstrual cycle phases affecting pain modulation. Similarly, Ren et al.[20] demonstrated that high plasma levels of progesterone in rats reduce the pain induced by inflammatory reactions. Frölich et al.[21] found no correlation between hormonal fluctuations and HPTo in non-laboring pregnant women.

Furthermore, oxytocin, another hormone implicated in pain modulation, has shown promise in alleviating visceral pain in animals.[24] However, its effects on experimental pain in humans are inconsistent, and physiological oxytocin levels during late pregnancy do not seem to impact HPTo significantly.[25] While Ende et al.[23] identified an inverse relationship between post-cesarean pain severity and plasma oxytocin levels, indicating a potential analgesic effect of oxytocin, the overall evidence regarding its role in pain perception remains inconclusive.

In summary, while progesterone and oxytocin show promise in modulating pain perception during pregnancy and postpartum, further research is needed to better understand their mechanisms of action and their implications for pain management strategies in pregnant and postpartum individuals.

Considering these results, it is evident that the relationship between pregnancy hormones and pain perception is multifaceted and likely influenced by various factors, including the type of pain, individual differences, and methodological considerations. While some studies suggest a potential analgesic effect of progesterone and oxytocin, others have failed to find significant correlations. Therefore, further research is required to elucidate the mechanisms underlying hormonal modulation of pain perception during pregnancy and postpartum accurately. Such insights could potentially inform the development of more effective pain management strategies for pregnant and postpartum individuals.

However, the interpretation of these findings is constrained by several limitations and variations in research quality. Methodological differences, such as variations in sample sizes, study designs, and pain assessment tools, contribute to inconsistent results across studies. Furthermore, the translation of preclinical findings to human experiences may be limited, necessitating cautious interpretation. The lack of standardized protocols for hormone measurement and pain assessment poses challenges in comparing findings across studies. Moreover, the focus on individual hormones may overlook potential interactions or synergistic effects among different hormones.

Future studies are necessary to properly understand how hormones affect pain perception throughout pregnancy and after giving birth, especially considering these constraints. Longitudinal studies with bigger sample size and standard methodologies are required to generate robust evidence. Investigating interactions between different hormones and their collective impact on pain perception may provide insightful information. Moreover, studies examining the effects of hormonal interventions on pain management strategies in pregnant and postpartum individuals are necessary. Ultimately, establishing specialized and successful pain management strategies depends on expanding our knowledge of the intricate interactions between hormones and pain perception throughout the peripartum period.

Conclusion

This narrative review tried to explore the mechanisms and role of pregnancy-induced hormonal changes on pain perception and analgesia during the peripartum period, which is crucial for effective pain management during childbirth and postpartum recovery. The role of pregnancy hormones is recently being explored in prospective studies, and the findings now suggest a promising role of progesterone and oxytocin in modulating pain perception during the peripartum period. Further research is needed to better understand their mechanisms of action and their implications for pain management strategies in pregnant and postpartum individuals. Further research on the quantitative correlation between hormonal levels and pain is warranted to help clarify the exact implications of the findings on pain management strategies.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.