Invest Clin 62(4): 378 - 406, 2021 https://doi.org/10.22209/IC.v62n4a08

Corresponding author: José Núñez-Troconis. Departamento de Obstetricia y Ginecología, Facultad of Medicina,

Universidad del Zulia, Maracaibo, Venezuela. E-mail: jtnunezt@gmail.com.

Primary Dysmenorrhea: pathophysiology.

José Núñez-Troconis1, Daniel Carvallo2 and Elizabeth Martínez-Núñez2

1Departamento de Obstetricia y Ginecología, Facultad of Medicina, Universidad

del Zulia, Maracaibo, Venezuela.

2Escuela de Medicina “José María Vargas”, Facultad of Medicina, Universidad Central

de Venezuela, Caracas, Venezuela.

Key words: menstruation; menstrual cycle; dysmenorrhea; primary dysmenorrhea;

pathophysiology; inflammation.

Abstract. The present study was conducted to investigate and analyze the

recent and relevant studies about primary dysmenorrhea and its pathophysiol-

ogy. Literature searches were performed electronically in PubMed, Medline, ISI,

DOAJ, Springer, Embase. Web of Knowledge, DOAJ, Google Scholar and the

Cochrane Library for original articles written in English and in Scielo, Lanti-

dex, Imbiomed-L, Redalyc and Google Scholar for original articles written in

Spanish. The searches included the key words (Mesh): menstruation, menstrual

period, menstrual cycle, dysmenorrhea, primary dysmenorrhea, inflammatory

substance and inflammatory markers. Publications from January 1980 to Feb-

ruary 2021 were reviewed. Dysmenorrhea is the most common gynecologic con-

dition experienced by menstruating women. It is characterized by crampy lower

abdominal pain that can range widely in severity, and associated to others symp-

toms. Its overall impact often has significant medical and psychosocial implica-

tions. The hallmark of primary dysmenorrhea is painful menses in the absence

of any associated macroscopic pathologic process, and it occurs in up to 50%

of menstruating females and causes significant disruption in quality of life and

absenteeism. An excessive or imbalanced amount of prostanoids and possibly

eicosanoids released from the endometrium during menstruation have been

mentioned as the main cause of primary dysmenorrhea. The uterus is induced

to contract frequently and dysrhythmically, with increased basal tone and in-

creased active pressure. Uterine hypercontractility, reduced uterine blood flow

and increased peripheral nerve hypersensitivity induce pain. Diagnosis rests on

a good history with negative pelvic evaluation findings. This narrative review

investigated and analyzed the pathophysiology of primary dysmenorrhea and

the implications of other chemical substances.

Primary Dysmenorrhea: pathophysiology 379

Vol. 62(4): 378 - 406, 2021

Dismenorrea Primaria: fisiopatología.

Invest Clin 2021; 62 (4): 378-406

Palabras clave: menstruación; ciclo menstrual; dismenorrea; dismenorrea primaria;

patofisiología; inflamación.

Resumen. La presente revisión fue realizada con el objeto de investigar y

analizar los estudios más recientes y relevantes sobre la dismenorrea primaria y

su fisiopatología. La literatura revisada fue realizada electrónicamente en Pub-

Med, Medline, ISI, DOAJ, Springer, Embase. Web of Knowledge, DOAJ, Google

Scholar y la Librería Cochrane para los artículos escritos en inglés. Scielo, Lan-

tidex, Imbiomed-L, Redalyc y Google Scholar fueron revisados en búsqueda de

artículos escritos en español. La búsqueda incluyó las palabras claves (Mesh):

menstruación, periodo menstrual, ciclo menstrual, dismenorrea, dismenorrea

primaria, substancias inflamatorias y marcadores inflamatorios. Se revisaron

publicaciones desde enero 1980 a febrero 2021. La dismenorrea es la condi-

ción ginecológica más común presente en la mujer menstruante. Se caracte-

riza por dolor en el abdomen bajo tipo cólico, su severidad es variable y está

asociada con otros síntomas. Su impacto general tiene implicaciones médicas y

psicosociales significativas. La característica de la dismenorrea primaria son las

menstruaciones dolorosas en ausencia de un proceso patológico macroscópico,

ocurre hasta en un 50% de las mujeres menstruantes y causa alteración de la

calidad de vida y ausentismo. Un exceso o desbalance de la cantidad de prosta-

noides y posiblemente liberación de eicosanoides por el endometrio durante la

menstruación han sido mencionados como la principal causa de la dismenorrea

primaria. El útero es inducido a contraerse frecuente y disritmicamente con au-

mento del tono basal e incremento de presión activa. La hipercontractibilidad

del útero reduce el flujo sanguíneo e incrementa la hipersensibilidad periférica

lo cual induce dolor. Esta revisión narrativa investigó y analizó la patofisiología

de la dismenorrea primaria y las implicaciones de otras sustancias químicas.

Received: 26-03-2021 Accepted: 14-06-2021

INTRODUCTION

The uterus is a dynamic organ. It not

only responds and changes in a sensitive way

to action of the classic hormonal signals (the

endocrine events of the menstrual cycle), but

it is also composed of complex tissues, with

important autocrine and paracrine func-

tions. The most dynamic tissue of the uterus

is the endometrium. Every endometrial cycle

has, as its only goal, the support of an early

embryo (1). If the pregnancy does not oc-

cur, menstruation follows by the end of the

menstrual cycle. As we know, menstruation,

also known as menses, menstrual period or

period, is the regular discharge of blood and

mucosal tissue from the inner lining of the

uterus through the vagina. Approximately

50% of the menstrual detritus is expelled

in the first 24 hours of menstrual flow. The

menstrual fluid is composed of the autolyzed

endometrial tissue, inflammatory exudate,

380 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

red blood cells and proteolytic enzymes. The

autolyzed endometrial tissue is composed of

a variety of functional states including disar-

ray and breakage of glands, fragmentation of

vessels and stroma with persisting evidence

of necrosis. The high fibrinolytic activity al-

lows the emptying of the uterus by liquefac-

tion of tissue and fibrin (1,2).

It is becoming increasingly accepted

that many normal reproductive processes ex-

hibit signs of inflammation. Such processes,

include ovulation, menstruation, implanta-

tion and parturition (3). These events are

associated with up-regulation in the expres-

sion of a host of inflammatory mediators,

which include cytokines, growth factors and

lipid mediators that influence the growth

and function of the immune and vascular

compartments (3-5). In addition, the female

reproductive tract has the remarkable char-

acteristic, which is the capacity to resolve

these inflammatory events rapidly in order

to re-establish the normal reproductive func-

tions (5). The resolution of these inflamma-

tion events is the clearance of leukocytes

and tissue debris as well as restoration of

mucosal and vascular function in the affect-

ed tissue. Inflammation is an active process

that involves the release of inflammatory cy-

tokines, chemokines and peptide growth fac-

tors. This establishes a gradient for the re-

cruitment of neutrophils and macrophages

to the site of injury. Injury also promotes

the activation of the coagulation and fibri-

nolysis system, which operates in tandem to

control clotting and remodelling of the vas-

culature. This facilitates tissue regeneration

and extravasation of neutrophils at the site

of injury via dilatation and edema. Tissue

remodeling also involves production of local

inflammatory mediators such as kinins, his-

tamine and eicosanoids such as prostanoids

(prostaglandins, prostacyclins and throm-

boxanes) and leukotrienes (5).

The endometrium secretes many sub-

stances and regulating molecules. Besides,

to produce a supportive and nutritive envi-

ronment for the early embryo, the endome-

trium plays an important role in suppressing

the immune response within the pregnant

uterus. The endometrium secretes or pro-

duces different substances or regulating

molecules involved in inflammation and im-

mune responses such as prostaglandins, leu-

kotrienes, tromboxanes, different cytokines:

interleukin (IL)-1α, IL-1β, IL-6, Interferon-γ,

colony stimulating factor-1, tumor necrosis

factor-α, leukemia inhibiting factor (1).

There are three disorders related to the

menstruation or menstrual period: premen-

strual syndrome or premenstrual dysphoric

disorder, premenstrual migraine and dys-

menorrhea (6),

The objective of this narrative review ar-

ticle is to review and analyze the pathophysi-

ology and the role of the different inflamma-

tory markers have in the pathogenesis of the

primary dysmenorrhea (PD).

MATERIAL AND METHODS

Study design

The present study was conducted to

investigate and analyze recent and relevant

studies about PD and inflammatory mark-

ers. Studies published in English and Span-

ish were included in the review.

In accordance with the PRISMA guide-

lines, we identified published studies through a

systematic and electronical review of the litera-

ture searches of PubMed, Medline, ISI, DOAJ,

Springer, Embase. Web of Knowledge, DOAJ,

Google Scholar and the Cochrane Library for

original articles written in English and in Scie-

lo, Latindex, Imbiomed-L, Redalyc and Google

Scholar for original articles written in Spanish.

The searches included the key words (MESH):

menstruation, menstrual period, menstrual

cycle, dysmenorrhea, primary dysmenorrhea,

inflammatory substance, inflammatory mark-

ers, and the following search terms: Dysmen-

orrhea” AND “menstrual cycle OR menstrual

period OR inflammatory markers OR inflam-

matory substances OR pathophysiology”. In

addition, reference lists and citation histories

were checked during the search.

Primary Dysmenorrhea: pathophysiology 381

Vol. 62(4): 378 - 406, 2021

Inclusion Criteria

Selection criteria included randomized

clinical trials, observational trials, open-la-

bel non-randomized trials and case reports.

The Cochrane Library was searched for re-

views. Publications from January 1980 to

February 2021 were reviewed.

Information Extraction

The electronic search and eligibility of

the studies were evaluated by the author. The

author reviewed, analyzed and discussed the

PD and inflammatory markers (see Fig. 1).

Dysmenorrhea

Dysmenorrhea is one of the most com-

mon gynecologic problems in reproductive

age women and is the most common gy-

necological symptom reported by women,

irrespective of nationality and age (6-8).

Dysmenorrhea is the pain that occurs with

menstruation, usually cramping in nature

and centered in the lower abdomen (6).

The term dysmenorrhea is derived from the

Greek words dys (difficult, painful, or ab-

normal), meno (month), and rrhea (flow).

Dysmenorrhea has significant medical and

Fig. 1. Flow chart of study selection.

382 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

psychosocial implications. Dysmenorrhea

is potentially the most underdiagnosed

gynecologic condition because of common

societal beliefs regarding a lack of effec-

tive treatments and expectations about

the burden of menstruation (9). Accord-

ing to World Health Organization, the

prevalence of dysmenorrhea ranges be-

tween 1.7% to 97% (10). Ninety percent of

women experience some severity of men-

strual pain, which is variable by geographi-

cal location and population. One third to

one half of these women report moderate

or severe symptoms (6-8,11-20). Symp-

toms are frequently associated with time

lost from school, work or other activities

(21). In spite of the frequency and severity

of dysmenorrhea, most women do not seek

medical treatment for this condition (22).

Dysmenorrhea is classified as primary and

secondary (6). Table I shows the differences be-

tween primary and secondary dysmenorrhea.

The age is an important and determinant fac-

tor of menstrual pain, being more pronounced

in adolescents than in older women (22,23).

Associated factors for more severe episodes

of dysmenorrhea may include early menarche,

heavy and increased duration of menstrual flow

and family history (7,12, 24). There is some

evidence that parous women have less severe

dysmenorrhea (23-25). The studies have shown

that smoking and alcohol consumption wors-

ens primary menstrual pain (7,19, 23, 25, 26).

There is some suggestion that frequent life

changes, fewer social supports, and stressful

close relationships may be associated with in-

crease of dysmenorrhea (27). Different authors

(28,29) mentioned that mood disorders are

associated with primary dysmenorrhea (PD).

There may be an increased prevalence of dys-

menorrhea in lower socioeconomic groups

(11). Also, there is controversy about the as-

sociation of obesity (12,24), physical activity

(24,26) and alcohol (12,24-26) with PD.

Primary Dysmenorrhea

Primary dysmenorrhea usually begins

during adolescence, only after ovulatory cy-

cles are established; usually, the symptoms

start after the first 6-months and 24 months

after the onset of menarche (6,30-32); 20–

45% of teenage girls are ovulatory by 2 years

and 80% by 4–5 years after menarche (6).

The prevalence of primary dysmenor-

rhea is highly underestimated, and is dif-

ficult to establish, because few affected

women seek medical treatment, despite

the substantial distress experienced, as

many consider the pain to be a normal

part of the menstrual cycle rather than a

disorder (28). Many cases thus remain un-

documented (33). Due to the lack of stan-

dard methods for assessing the severity of

dysmenorrhea, the prevalence has been

estimateted between 45 and 95% of men-

struating women (34,35), with very severe

primary dysmenorrhea estimated to affect

10–25% of women of reproductive age and

this is not affected by height, weight, or

regularity of the menstrual cycle (12,36).

The overall prevalence of primary dysmen-

orrhea among adolescent girls is between

60 to 90% (6,7,20, 30, 37- 40), and an ap-

proximately 15% of adolescent girls seek

medical attention (6). Between 2 and 29%

will suffer from severe pain (6).

Risk factors

PD is positively associated with

stress, family history of dysmenorrhea, a

body mass index less than 20 or over 30

kg/m2, depression, early menarche (be-

fore age 11), longer intermenstrual inter-

vals (≥ 35 days) and duration of bleeding

(≥7 days), heavy bleeding, premenstrual

molimina, nulliparity, history of sexual

assault, frequent consumption alcohol,

smoking (Table II) (6, 7, 25, 32). About

50% of students reported a family history

of dysmenorrhea (30). PD decreases with:

age increases (prevalence of PD decreases

to 67% by age 24), parit (but not in those

who had a miscarriage or abortion), exer-

cises, stable relationships, and the use of

oral contraceptives (6, 30, 32, 41). Ado-

lescents ranging from 7.7% to 57.8% miss

Primary Dysmenorrhea: pathophysiology 383

Vol. 62(4): 378 - 406, 2021

school or work, 21.5% of them miss social

activities and 15% have to limit their daily

activities despite the use of medication

(6, 30). As it was mentioned before, the

prevalence of PD decreased to 67% by age

24, with 10% still reporting some limita-

tions.

PD is characterized or described as a

sharp ache or dull pain, intermittent spams

or cramps usually located in the midline

suprapubic area that begins between a few

hours before and a few hours after the on-

set of the menstrual bleeding (9, 22, 31,).

The pain can irradiate to the back or inner

of the legs or/and the lower back. Nausea,

vomiting, diarrhea, fever, fatigue, malaise,

and lightheadedness are systemic symptoms

very common. Symptoms or pain peak with

the maximum blood flow and may persist up

to 2 to 3 days (6, 9, 31).

TABLE I

DYSMENORRHEA DIFFERENCES.

Dysmenorrhea Primary Secondary

Onset Within 3 years after menarche More after 5 years after menarche

Age 12-25 years old Over 30 years old

Aging Gradually improve Become worse

Pathophysiology No underlaying gynecological

pathology Underlying pathology

Time Menstruation Menstruation and/or other time

Duration 4-72 hours > 1 day

Nature Spasmodic Variable-achy, spasmodic

Accompanying

symptoms

Heavy menses, nauseas, vomit,

headache, backache, syncope,

diarrhea

Dyspareunia, dyschezia, sinusorraghia,

infertility, heavy menses, vaginal

discharge, intermenstrual bleeding,

chronic pelvic pain, bowel and urinary

symptoms

Location Central Variable, often eccentric

Marriage Improve No change

Post-partum Improve No change

Finding Normal Different gynecological pathologies:

endometriosis, adenomyosis, PID, etc.

Clinical

investigation

Normal Fixed retroverted uterus, thickened

uterosacral ligaments, endometriotic

nodules, on vaginal exam myomas,

enlarged tender uterus, adnexal

masses

Special investigation Ultrasound: normal pelvic Ultrasound: myomas, adenomyosis,

endometriomas,

Relieving factors NSAIDs, OCs, heat, childbirth,

cervical dilation, others. NSAIDs, heat, menstrual suppression

Response to NSAID/

COC

Ye s Yes, but may require further

treatments

NSAIDs: non-steroidal anti-inflammatory drugs; OCs: oral contraceptives.

384 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

Etiology

Zhou et al. (30) mentioned four pos-

sible etiological aspects of PD:

1.- Brain abnormality: in recent years,

there have been several scientific reports on

brain abnormal structure changes and con-

nectivity in dysmenorrheic females using

fMRI. Tu et al. (42) in 2010 among women

with PD found that they had smaller gray

matter volume in brain regions in pain

transmission and higher levels sensory pro-

cessing, and larger gray matter volume in

regions in pain modulation and endocrine

function regulation compared with healthy

controls. In 2016, Liu et al. (43) reported

that PD women had significantly increased

cortical thickness in the orbitofrontal cortex

(OFC), insula (INS), primary/secondary sen-

sory area (SI/SII), superior temporal cortex

(STC), precuneus, and posterior cingulate

cortex (PCC) but PD women also have de-

creased subcortical volumes of the caudate,

thalamus, and amygdala. Dun et al. (44)

found lower gray matter density in the left

anterior insula (aINS) in PD patients. In ad-

dition, it has been observed changed in neu-

ro-connectivity in patients with PD. Different

reports have revealed abnormal white mat-

ter integrity involved in pain transmission

and modulation systems at periovulation in

these patients. Dun et al. (45) and Liu et al.

(46) have mentioned that these white matter

microstructure alterations could be closely

related with the intensity of menstrual pain.

In addition, an abnormal anterior cingulate

cortex (ACC) connectivity has been related

to the PD pain sensation and regulation

(47). PD patients have a dynamic regional

spontaneous activity which changes during

the whole period cycle and the altered brain

regions are involved in decreasing pain mod-

ulations, the default mode network (DMN),

and the sensory modulation (48). Wu et al.

(49) reported that in PD women had a re-

gional reduction in homogeneity in the ven-

tromedial prefrontal cortex part of the DMN,

during the periovulatory phase; hypocon-

nectivity of the DMNsalience network and

hyperconnectivity of DMNexecutive control

network across the menstrual cycle. Also,

young women with PD have increased theta

oscillations in different brain regions: in the

right side parahippocampal gyrus, right pos-

terior insula, and left anterior/middle cin-

gulate gyrus during the menstrual phase. In

the left side: the bilateral anterior insula and

the left middle/ inferior temporal gyrus dur-

ing the periovulatory phase.

2.- Gene variation: Zhou et al. (30) sug-

gest that there are several genotype and

allele frequencies in PD women compared

with the healthy controls, including TNF

α308, macrophage migration inhibitory fac-

tor gene 173, estrogen receptor-1 gene brain

derived neurotrophic factor gene Val66Met,

cytochrome P450 2D6 gene, glutathione S

transferase Mu gene, Familial Mediterranean

fever (MEFV) gene, and others. The geno-

type and allele frequencies of TNF α308 ge-

netic polymorphisms differ significantly be-

tween dysmenorrhea patients and controls.

Dogru et al. (51) proved that TNF α308 GG

genotype might be a useful tool to predict

the susceptibility to the dysmenorrhea. Mac-

TABLE II

RISK FACTORS.

Adolescence

Anxiety or stress

Body mass index<20 or >30 kg/m2

Depression

Disrupted social networks

Family history, especially in a first-degree

relative

Early Menarche (before 12 years old)

Longer intermenstrual periods

Heavy and longer bleeding

Nulliparity

Pre-menstrual molimina

History of sexual assault

Smoking

Alcohol

Primary Dysmenorrhea: pathophysiology 385

Vol. 62(4): 378 - 406, 2021

rophage migration inhibitory factor gene

173G>C polymorphism is also significantly

associated with age at menarche and a his-

tory of back pain among dysmenorrhea pa-

tients (51). Lee et al. (52) mentioned that

the brain derived neurotrophic factor gene

Met/Met homozygosity, may be associated

with an increased risk of PD and a possible

regulator of menstrual pain and pain related

emotions in PD. Erten et al. (53) reported

that patients with dysmenorrhea showed a

significant increase in the frequency of the

Familial Mediterranean fever (MEFV) gene

mutations compared with the control group.

Also, Liedman et al. (54) reported that the

gene expression for the oxytocin receptor

was significantly lower in women with dys-

menorrhea than in healthy women.

3.- Metabolism: some studies have

shown that serum nitric acid (NO) levels

are higher and serum homocysteine levels

are lower among PD patients, than in the

healthy controls. Lee et al. (52) hypoth-

esized that NO affects the homocysteine

metabolic pathway, and contribute to dys-

menorrheal symptoms. Yeh et al. (55) and

Turhan et al. (56) reported higher plasma

Malondialdehyde (MDA) levels, an oxida-

tive stress marker in patients with dysmen-

orrhea compared to those in the healthy

controls. MDA is generated during lipid

peroxidation, and serves as a marker of tis-

sue injury (57). Dikensoy et al. (58) fur-

ther revealed that the serum levels of MDA,

NO, and adrenomedullin were significantly

higher in PD patients compared to that of

the control group on the first and the 21st

day of the menstrual cycles, suggesting that

the possibility that lipid peroxidation and

oxidative stress might play a significant role

in the etiopathogenesis of PD. The plasmat-

ic concentration of oxytocin is significantly

higher during the menstrual period and va-

sopressin plasmatic concentrations are low-

er during the ovulation in PD patients com-

pared with healthy women (30). Liedman

et al. (54) found that the gene expression

for the oxytocin receptor was significantly

lower in women with dysmenorrhea than in

healthy women. AbdulRazzak et al. (59, 60)

reported a relationship among low levels of

Vitamin D, low calcium intake and dysmen-

orrhea in adolescents and young women.

The same authors mentioned that women,

who have dysmenorrhea, have a high prev-

alence of Vitamin D-deficient, secondary

hyperparathyroidism and low dietary cal-

cium intake. Different authors (61-63) have

shown that the Vitamin D supplementation

intake among PD patients had a significant

reduction of pain compared with the pla-

cebo group. Orimadegun et al. (64) found

the level of alpha tocopherol (vitamin E)

was considerably lower in women who expe-

rience PD than controls suggesting relative

deficiency of this antioxidant.

4.- Pain threshold difference: recent

studies indicated that women with PD are hy-

persensitive to experimental pain compared

with controls. Iacovides et al. (28) published

a detailed review about the hyperalgesia in

PD patients. They pointed out that two fea-

tures of this hyperalgesia in women with PD:

1) an increased sensitivity to experimental

pain during the menstruation as well as

during painfree follicular phase of the men-

strual cycle; 2) the hyperalgesia occurred in

muscles within and outside the area of men-

strual pain.

Endometrial Menstrual Cycle

The menstrual cycle and its physiology,

is characterized by the addition of a series of

anatomic, functional and hormonal changes

within the glandular component of the en-

dometrium, as well as its vascular and stro-

mal constituents, which are mediated by

feedback mechanisms that respond to endo-

crine, autocrine and paracrine factors. It is

defined as the interval from the first day of

menstruation to the beginning of the next

one (65,66). The changes can be divided

into five phases: 1) the preparation of the

menstrual endometrium, 2) the proliferative

phase, 3) secretory phase, 4) the endome-

trial preparation for the implantation, and

386 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

5) the endometrial breakdown phase. The

entire process is an integrated evolutionary

cycle of endometrial growth and regression,

which is repeated some 400 times during

the adult life of the human female (1).

The endometrium is divided into two

distinctive layers. Its upper 2/3 constitutes

the functionalis layer, which has the func-

tion of preparing the uterus for implanta-

tion of the blastocyst; thus, it has a pivotal

importance in the processes of proliferation,

secretion and, particularly, endometrial

degeneration during menstruation. Its re-

generation is provided by the basalis layer,

which is located on the lower 1/3 of the en-

dometrium (1).

The first episode of menstrual bleeding

is known as menarche, which occurs approxi-

mately two years after telarche, between the

ages of 8.5 to 13 years old, marking the be-

ginning of women’s reproductive life, which

ceases when they achieve menopause. Men-

arche is followed by approximately 5–7 years

of increasing regularity as cycles shorten to

reach the usual reproductive-age pattern. In

the 40s, cycles begin to lengthen again. The

usual duration of menstrual flow is 4–6 days,

but many women have flow for as little as 2

days and as much as 8 days. The normal vol-

ume of menstrual blood loss is 30 mL; great-

er than 80 mL is abnormal. Approximately

50% of the menstrual detritus is expelled

in the first 24 hours of menstrual flow. The

menstrual fluid is composed of the autolyzed

functionalis layer, inflammatory exudate, red

blood cells, and proteolytic enzymes, espe-

cially, plasmin which lyses fibrin clots as they

form. The high fibrinolytic activity advances

emptying of the uterus by liquefaction of tis-

sue and fibrin. If the rate of flow is great,

clotting can and does occur. Most women

(90%) have menstrual cycles with an interval

of 24–35 days (1,6).

The normal menstrual cycle, constitut-

ed by follicular and luteal phases, has a dura-

tion of 28 ± 7 days, lasting around 2-7 days.

Nonetheless, this length is completely vari-

able between women, changing from men-

arche to menopause, and constantly show-

ing high variability during each particular

phase of the cycle. The follicular phase lasts

around 10 to 23 days, a 14.6-days mean du-

ration; while the luteal phase has a duration

of 7 to 19 days (mean:13.6 days). Menstrua-

tion is the external sign of women’s cyclicity

and it takes place at the beginning of the

follicular phase and at the end of the luteal

phase (66,67). Thus, the follicular phase is

constituted by menstruation and the prolif-

erative phase, and the luteal phase includes

the secretory phase (1). The uterus blood is

supplied by the two uterine arteries, which

are branches of the internal iliac arteries; at

the lower part of the uterus, the uterine ar-

tery separates into the vaginal artery and an

ascending branch that divides into the arcu-

ate arteries. The arcuate arteries go parallel

to the uterine cavity and anastomose with

each other, forming a vascular ring around

the cavity. Small centrifugal branches (the

radial arteries) leave the arcuate vessels,

perpendicular to the endometrial cavity, to

supply the myometrium. Once these arteries

enter to the endometrium, small branches

(the basal arteries) extend laterally to supply

the basalis layer. These basal arteries do not

demonstrate a response to hormonal chang-

es. The radial arteries continue in the direc-

tion of the endometrial surface, now assum-

ing a corkscrew appearance and change the

name for spiral arteries so that they supply

blood to the functionalis layer of the endo-

metrium. This spiral artery segment is very

sensitive to hormonal changes. One reason

that the functionalis layer is more vulner-

able to vascular ischemia is that there are no

anastomoses among the spiral arteries. The

endometrial glands and the stromal tissue

are supplied by capillaries that emerge from

the spiral arteries, at all levels of the endo-

metrium. The capillaries drain into a venous

plexus and eventually, into the myometrial

arcuate veins and into the uterine veins. This

unique vascular architecture is important to

allow the repeated sequence of endometrial

growth and desquamation (1) (see Fig. 2).

Primary Dysmenorrhea: pathophysiology 387

Vol. 62(4): 378 - 406, 2021

The menstrual endometrium is a rela-

tively thin but dense tissue. As we mentioned

before, the endometrium is composed by a

stable, basalis component and a variable,

but small, amount of residual stratum spon-

giosum. During the menstruation, this latter

tissue displays a variety of functional states

including disarray and breakage of glands,

fragmentation of vessels and stroma with

persisting evidence of necrosis, white cell in-

filtration, and red cell interstitial diapedesis.

When the remnants of menstrual shedding

dominate the overall appearance of this tis-

sue, evidence of repair in all tissue compo-

nents can be detected. Endometrial regener-

ation begins and originates in epithelial and

stromal stem cells. Endometrial epithelial

stem cells have been found in glands within

the basalis layer and are thought to be re-

sponsible for the re-epithelialization of the

exposed surface of the endometrium and

subsequent glandular proliferation to regen-

erate the functionalis layer under the influ-

ence of increasing estrogen levels following

menses. Endometrial mesenchymal stem/

progenitor cells are found around blood ves-

sels in the basalis layer. These progenitor

cells are thought to contribute to regenera-

tion and growth of the endometrial functio-

nalis stroma (68).

Once menstruation starts, during the

follicular phase, estradiol (E2) level starts

progressively rising, as well, leading to the

endometrial proliferation by the mid-follic-

ular phase. The hypothalamus-pituitary-go-

nadal (HPG) axis is activated, inducing the

secretion of follicle-stimulating hormone

(FSH), via gonadotropin-releasing hormone

(GnRH), through a positive feedback of the

axis. During the follicular phase, the domi-

nant ovarian follicle secretes most of E2 and

growths at a rate 1-4 mm/day (65,67,69).

The follicle growth and increased E2 secre-

tion, as well as the increase in E2 receptors

Fig. 2. The Uterine Vasculature.

Adapted from Uterine blood flow during pregnancy. Apaza-Valencia J, Guerrero MH. Rev Peru Gine-

col Obstet. 61(2); abr./jun. 2015. Available from: http://www.scielo.org.pe/scielo.php?script=sci_ar

ttext&pid=S2304-51322015000200006. Reviewed on March 29, 2021.

388 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

throughout the endometrium, are charac-

teristics of the proliferative phase, with pro-

liferation of the endometrial glands, stromal

and endothelial cells, and the restoration

of the endometrium provided by the basa-

lis layer (1). Considering that ovarian hor-

mones constitute the main mediators of the

HPG axis in females (65), the high concen-

tration of E2 decreases FSH levels via a nega-

tive feedback of the HPG axis, but a release

of luteinizing hormone (LH) takes place,

marking the beginning of the luteal phase.

Thirty-six hours later, the oocyte is released

from the ovarian follicle, a process known as

ovulation, ceasing epithelial proliferation.

The high LH levels induce the transforma-

tion of the dominant follicle into the corpus

luteum, which secretes progesterone (P);

however, P production also takes place dur-

ing the follicular phase, although it is quan-

titatively lower (1,65,67). The expression of

P receptors throughout the endometrium

is induced by the high levels of E2, during

the follicular phase, via E2 receptor-α (ER-

α), which are then inhibited by P. Progester-

one prepares the endometrium for the em-

bryo implantation, during the days 21 or 22

of the cycle, and also, for decidualization,

which plays a pivotal role in menstruation,

implantation and placentation, defined as

endometrial hemostasis. If fertilization and

implantation do not take place, the corpus

luteum will regress and the secretion of P

ceases, with vasoconstriction of spiral ar-

terioles that produces an epithelial lesion,

induced by hypoxia, characterized by vaso-

motor reactions, apoptosis and tissue loss,

causing the consequent degeneration and

desquamation of the functionalis layer of the

endometrium and, thus, marking the begin-

ning of the next follicular phase (1,67).

Inflammatory responses during

menstruation

As it has been mentioned before, the

endometrium is constituted by a simple co-

lumnar epithelium lying over a multicellu-

lar stroma, comprised by connective tissue

components, fibroblast-like stromal cells,

tubular glands, spiral arteries and recruited

innate immune cells. Endometrial stromal

cells are originated form the differentiation

of endometrial progenitor stem cells, locat-

ed in its basal layer, and, through a process

known as decidualization, are transformed

into decidual cells, which induce a propi-

tious environment for the embryo implanta-

tion and consequent placental development.

This process begins with the intracellular

production of cAMP in the perivascular en-

dometrial stromal cells, which eventually

spread through the entire stroma, and in-

duces the expression of progesterone-depen-

dent proteins (70).

The female reproductive system pres-

ents molecular and cellular mediators as-

sociated to inflammation, which are ex-

pressed fundamentally during ovulation and

menstruation, particularly, during the early

follicular phase (71,72). P withdrawal pro-

duces endometrial tissue edema, increased

vascularization, and vessel permeability and

fragility (71). Changes in the endometrium

are examples of cyclic inflammatory activity,

not only characterized by cellular inflamma-

tion, but by an outer tissular destruction as

well, and whose repair mechanisms prepare

the endometrium for the onset of the next

menstrual cycle (71,72). Concerning ste-

roid hormones (estrogens, androgens and

glucocorticoids), the androgen receptor is

downregulated in the endometrial function-

al layer’s stromal cells during the secretory

phase and upregulated in the endometrial

epithelial cells during the last stages of the

proliferative phase. In addition, once locally

generated cortisol binds to the nuclear glu-

cocorticoid receptor in the endometrium,

it limits inflammation at other tissue sites,

mainly inhibiting angiogenesis. On the other

hand, the concentrations of the estrogen re-

ceptor, located in the nuclei of both, epithe-

lial and stromal cells of the endometrium,

decline in the luteal phase, while the proges-

Primary Dysmenorrhea: pathophysiology 389

Vol. 62(4): 378 - 406, 2021

terone receptor’s concentrations tend to de-

cline only in the glandular epithelium, aug-

menting during the proliferative phase (71).

The decidualized stroma, in response

to the reduction of steroid hormones, stim-

ulates the release of cytokines (interleu-

kin (IL)-6 and tumor necrosis factor-alpha

(TNF-α), chemokines and their ligands

(CCL11, CCL2, CXCL10 and CXCL8), ad-

hesion molecules, and granulocyte-macro-

phage colony-stimulating factor (GM-CSF),

followed by the release of leukocyte’s matrix

metalloproteinase causing the endometrial

glandular layer’s disruption, as a product of

P withdrawal, processes that are regulated

by cyclo-oxygenase 2 (COX-2) and NF-kappa

B (NF-kB) (70,72). The intercellular adhe-

sion molecule 1 (ICAM-1) and vascular cell

adhesion molecule 1 (VCAM-1), whose ex-

pression elevates during the early and mid-

follicular phases, including ovulation, are

also involved in the inflammatory process of

leukocyte trafficking (71). The tissue’s dis-

ruption is exacerbated by the entrance of en-

dometrial neutrophils that also contain high

levels of metalloproteinases (70,72).

Quantitatively, the endometrial leuko-

cyte population varies between 8.2% to 15%

of the endometrial stromal cell compart-

ment, during the proliferative phase of the

menstrual cycle, while immune cells vary

between 20-25% to 40-45% of the cell com-

partment, during the same phase. The reso-

lution of menstrual-related inflammation

also depends on the phagocytosis of apop-

totic cells by macrophages, which can either

proliferate in the endometrium or be derived

from monocytes that were recruited into the

endometrial tissue, under the action of IL-4

in Th2 inflammatory responses, as well as

other chemotactic stimuli, such as CCL2 or

monocyte chemoattractant protein-1 (MCP-

1), highly expressed in the endometrium

during the late secretory phase (71).

During the onset of menstruation,

prostaglandin F2α (PGF2α) and endothe-

lin-1 induce the vasoconstriction of the spi-

ral arteries of the uterus; while excessive

PGE2 production, at the expense of PGF2α,

allows their vasorelaxation, causing the pro-

liferation of the vascular smooth muscle

cells in endometrial blood vessels, allowing

an increase in blood flow, due to a regula-

tion of the vascular tone and contractility, by

smoothelin and calponin, and thus inducing

arteriogenesis (70,72). However, decreased

vasoconstriction during menstruation does

not only depend on the decreased produc-

tion of the former vasoactive substances,

but also on the aberrant maturation of the

spiral arterioles of the uterus, throughout

the preceding menstrual cycle. Vasocon-

striction may also induce hypoxia in the

menstrual endometrium, which studies have

shown that is necessary for the initiation of

menstruation. The cellular response to hy-

poxia is regulated by hypoxia inducible fac-

tor (HIF), which has been detected in the

endometrium, but only during the perimen-

strual phase, and has proven to have roles

in inflammation, metabolism, angiogenesis,

mitogenesis and apoptosis. HIF-1 also pro-

motes the increase of the vascular endothe-

lial growth factor (VEGF) in the endometrial

tissue during menstruation, characterized

by its angiogenic effects, contributing to an

efficient endometrial repair (70, 73).

The levels of C-reactive protein (CRP),

as a hepatic pro-inflammatory marker, reach

their peak during the early follicular phase,

considering that their increase is associat-

ed with endogenous progesterone’s levels.

Cathepsins B, L, and S are also endometrial

proteinases that allow its normal develop-

ment and functionality during the entire

menstrual cycle, in relation to proteolytic

processes. Regarding the peak for both se-

lectins, -P and E-selectins-, it tends to vary.

Chiareti et al. (71) observed a slight in-

crease of P-selectin during the luteal phase,

while E-selectin remained unaltered during

both phases of the cycle. IL-6 also elevates

during the follicular phase of the menstrual

cycle, inducing the synthesis of, both, CRP

and pentraxin-3 (PTX-3), which is upregu-

lated during ovulation; it also constitutes

390 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

an early marker for endothelial dysfunction,

and has proven to play a role in innate im-

munity, female fertility and pro-coagulation

activity, being largely responsible for the

inflammatory activity during the early fol-

licular phase (71).

Due to an increase in erythrocytes’

catabolism, reticulocyte counts, and nitric

oxide (NO) and progesterone expression

and activation of heme oxygenase 1 (HO-

1), particularly in the myometrial, vascular

endothelial and smooth muscle cells, the

production of endogenous carbon monoxide

(CO) is elevated during the luteal phase of

the menstrual cycle, providing protection

against the endothelial oxidative stress. NO

levels augment in the midcycle (74).

Pathophysiology of dysmenorrhea

It is becoming increasingly accepted

that many normal reproductive processes

display signs of inflammation. Such process-

es include ovulation, menstruation, implan-

tation and parturition (3, 5). All of these

events are associated with up-regulation in

the expression of a host of inflammatory me-

diators, which include cytokines, growth fac-

tors and lipid mediators that influence the

growth and function of the immune and vas-

cular compartments (3,75,76).

Another remarkable feature of the fe-

male reproductive tract is its capacity to re-

solve these inflammatory events rapidly to

re-establish normal reproductive function.

The resolution of inflammation involves the

clearance of leukocytes and tissue debris as

well as restoration of mucosal and vascular

function in the affected tissue. Until recent-

ly, resolution of inflammation was consid-

ered a passive process that came about as

a result of dissipation in the expression of

local inflammatory mediators. In response

to the tissue injury there are specific anti-

inflammatory and pro-resolution biochemi-

cal pathways that are activated, which fa-

cilitate the reestablishment of homeostasis

in the affected tissues (5,76). Furthermore,

it is well recognized that inflammation me-

diated alterations in immune cell and vas-

cular function are important components

of many pathologies which include cancer,

chronic inflammatory diseases, allergy,

asthma, atherosclerosis, autoimmunity,

transplant rejection and metabolic and de-

generative diseases. Moreover, alterations

or disruption in the onset of the pro-reso-

lution pathways may lead to uncontrolled

inflammation and the onset of disease and

there is evidence in animal models that the

administration of pro-resolution mediators

can help control and resolve inflammation

(76).

The female reproductive system pres-

ents molecular and cellular mediators as-

sociated to inflammation, which are ex-

pressed fundamentally during ovulation and

menstruation, particularly during the early

follicular phase (71,72). Progesterone with-

drawal produces endometrial tissue edema,

increased vascularization, and vessel per-

meability and fragility (70). Changes in the

endometrium are examples of cyclic inflam-

matory activity (71), not only characterized

by cellular inflammation, but by an outer

tissular destruction, as well, whose repair

mechanisms prepare the endometrium for

the onset of the next menstrual cycle (72).

Concerning steroid hormones (estrogens,

androgens and glucocorticoids), the andro-

gen receptor is downregulated in the endo-

metrial functional layer’s stromal cells dur-

ing the secretory phase and upregulated in

the endometrial epithelial cells during the

last stages of the proliferative phase. In ad-

dition, once locally generated cortisol binds

to the nuclear glucocorticoid receptor in

the endometrium, it limits inflammation at

other tissue sites, mainly inhibiting angio-

genesis. On the other hand, the concentra-

tions of the estrogen receptor, located in the

nuclei of both, epithelial and stromal cells

of the endometrium, decline in the luteal

phase, while the progesterone receptor’s

concentrations tend to decline only in the

glandular epithelium, augmenting during

the proliferative phase (70).

Primary Dysmenorrhea: pathophysiology 391

Vol. 62(4): 378 - 406, 2021

In spite of the huge amounts of stud-

ies, the mechanism of PD is not fully un-

derstood. Previous studies have shown that

dysmenorrhea is a complex process that may

depend on many factors (77-79). It is well

known that the menstrual cycle is depen-

dent on cyclic changes in ovarian hormone

concentrations secretions and therefore also

on cyclic changes in prostaglandin level and

uterine contractile activity (89-82). In 1965,

Pickles et al. (82) noted that one of the fac-

tors contributing to dysmenorrhea might

be an increase in prostaglandin concentra-

tions before menstruation. This suggestion

was confirmed years later by other authors

who showed that prostaglandins production

increases in dysmenorrhea (83). Although

the specific contributions of these various

mechanisms and substances are not yet per-

fectly understood, the pathophysiology of

dysmenorrhea has solidly moved beyond a

psychosomatic cause (9,30).

In normal eumenorrheic women, the uter-

us has well defined contraction patterns that

are influenced by sex steroids, prostaglandins,

and other uterotonic substances throughout

the menstrual cycle and menstrual period (84).

During the menstruation, the uterine basal tone

is minimal, less than 10 mm Hg, there are 3-4

contractions in 10 minutes period with active

pressures at the peak of a contraction reach-

ing up to 120 mm Hg and the contractions are

synchronous and rhythmical (84). Women with

primary dysmenorrhea, uterine contractions

during menses begin from an elevated level

of basal tone (>10 mm Hg), generate higher

intrauterine pressures that frequently reach

150–180 mm Hg and can exceed 400 mm Hg,

occur more frequently (>4–5/10 minutes),

and are not rhythmic or coordinated. When

intrauterine pressure exceeds arterial pressure

for a sustained period of time, ischemia results

in the production of anaerobic metabolites that

stimulate small type C pain neurons, which

contributes to the pain of PD. When more than

one abnormal contraction occurs, they syner-

gize with each other so that the pain threshold

is exceeded with smaller changes than if only

one abnormal contraction is present. Classical-

ly, as it has been mentioned before, PD begins

just before or coincident with the onset of is

exceeded with menses and declines gradually

over the subsequent 72 hours. The menstrual

cramps are intermittent, vary in intensity, and

usually are centered in the suprapubic region,

although some women also experience pain in

their thighs and lower back (6, 84).

During the menstrual period, when ex-

foliation of the endometrium occurs, metal-

loproteinases (MMPs) play an important role.

They are enzymes produced by endometrial

cells and leukocytes. The secretion of MMPs

is probably inhibited by the P, so when the

P decreases, increase the MMPs secretion

(80). Before menstruation, endometrium

tissue gets the characteristics of inflamma-

tion process, it becomes red and edematous.

Endometrial edema is consequence of the

local increased production of chemokines

including interleukin-8 (IL-8), proinflam-

matory cytokines such as IL-1, Il-6 and tu-

mor necrosis factor (TNF) and leukocytes

inflow: uterine NK cells, neutrophils, eosino-

phils, macrophages and activated mast cells

(5,79). After the ovulation both hormones: P

and E2 affect the endometrium. During the

secretory phase, P level increases and has

anti-inflammatory action, inhibiting the re-

lease and activation of MMPs. Three days be-

fore the onset of the menstrual period, P and

E2 levels decrease which initiate the endo-

metrial transformation or change: vasomo-

tor reactions, apoptosis, tissue atrophy and

bleeding or menstruation (85). After ovula-

tion, fatty acids are accumulated in phos-

pholipids in the cell membrane. Omega-6

fatty acid and arachidonic acid are released

only when the level of progesterone begins

to fall (86).

Prostaglandins and prostanoids

An excess or imbalance of prostaglan-

dins (PGs), vasopressin and other chemical

substances derived from phospholipids has

been proposed to cause dysmenorrhea and is

no longer heavily disputed (9). Evidence for

392 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

this theory includes measurements of the

prostaglandins PGF2α, PGE2, and vasopres-

sin in menstrual fluid that correlate with

adverse symptoms of dysmenorrhea. In ad-

dition, these chemicals are known to cause

symptoms of increased uterine contractility

and cramping, nausea, vomiting, and diar-

rhea in other clinical situations (9). PGs pro-

duce vasoconstriction of the blood vessels,

decreasing the blood supply to the uterus,

and produce abnormal contractile activity of

the uterus, which leads to ischemia, hypoxia

of the uterus and increased sensitivity of the

nerve endings (31, 79, 81). Evidences indi-

cate that PD is caused by myometrial isch-

emia due to frequent and prolonged uterine

contractions. Studies of uterine blood flow

using Doppler ultrasonography have revealed

that uterine and arcuate artery resistance

on the first day of menses is significantly

higher in women with PD than in women

without dysmenorrhea, suggesting that

constriction of uterine vessels is one of the

causes of pain, which induces abnormal and

intense uterine contractions. The uterine

contractions decrease or reduce the uterine

blood flow, leading to uterine hypoxia and

ischemia and more painful uterine contrac-

tions (6, 9, 84). The association of PD with

ovulation makes sense on a physiologic level

because of the normal sequence of cyclical

endometrial growth. The increase in serum

P following ovulation in the secretory endo-

metrium causes and increases substantial

stores or reserves of arachidonic acid, which

is a precursor to PGs: PGF2α and PGE2,

prostacyclin, and leukotrienes: thromboxane

A2 (Tx A2); all promote uterine contractions

and act as potent vasoconstrictors during

the menses (3, 9). Higher concentrations of

PGF2-α and PGE2 have been proved to be

present in the endometrium and menstrual

fluid of women who have primary dysmenor-

rhea (9). PGF2α always stimulates uterine

contractions and is the primary mediator of

PD. Endometrial concentrations of PGF2-α

and PGE2 correlate with the severity of dys-

menorrhea. Uterine smooth muscle contrac-

tions are the cause of the crampy, spasmodic

lower abdominal and low back pain typical of

PD (see Fig. 3).

The increased secretion of vasoactive

prostanoids is considered as one of the most

important cause responsible for the etiology

of PD and it is supported by: 1) the similarity

between the clinical symptoms of PD and the

uterine contractions and side and adverse ef-

fects that can be observed in prostaglandin

induced abortion or labor; 2) it has been

demonstrated an increase in prostanoids

concentrations during the menstrual period

in women with PD compared with eumen-

orrheic women; 3) numerous clinical trials

have demonstrated the efficacy of cyclooxy-

genase inhibitors in relieving the pain of PD

and in decreasing or suppressing the amount

prostanoids in the menstrual fluid (32, 84).

The role of other protanoids such as

Tx-A2, prostacyclin and leukotrienes in the

pathogenesis of PD is neither fully under-

stood, nor adequately studied. Prostacyclin,

a potent vasodilator and uterine relaxant,

appears to be reduced in primary dysmenor-

rhea (32). The increase of leukotriene pro-

duction, by the 5-lipoxygenase pathway, may

contribute to some forms of PD that are not

responsive to nonsteroidal anti-inflammatory

drugs (NSAID) (87). Human endometrium

and myometrium can synthesize leukotrienes

(87); this confirms that the functional activi-

ty of the 5-lipoxygenase pathway and leukotri-

enes are involved in myometrial contractions

(88). In women with PD there are significant-

ly higher concentrations of menstrual leu-

kotrienes (89, 90), especially leukotriene C4

and leukotriene D4, than in women without

dysmenorrhea (91). Because specific binding

sites for leukotriene C4 are demonstrable in

myometrial cells (92), it is likely that leukot-

rienes contribute to the uterine hypercon-

tractility seen in PD (see Fig. 4).

PGs and prostanoids are biosynthesized

from arachidonic acid through the COX path-

way after production of arachidonic acid from

hydrolysis of phospholipids by the lysosomal

enzyme phospholipase A2. The stability of

Primary Dysmenorrhea: pathophysiology 393

Vol. 62(4): 378 - 406, 2021

lysosomal activity is regulated by several fac-

tors such as P levels. High levels of P produce

the stability of lysosome activity (32, 36).

When pregnancy does not occur, P levels de-

cline during the late luteal phase. This sta-

bilizing effect on endometrial lysosomes dis-

appear and the phospholipase A2 is released

causing the lability of lysosomes and release

of their phospholipase enzyme, which then,

hydrolyzes the cell membrane phospholipids

to generate arachidonic acid as well as ico-

satetraenoic acid. These compounds serve as

the precursors for the COX and lipoxygenase

pathways (28). This is regulated by cyclic ade-

nosine phosphate (cAMP). Via cAMP, PGs pro-

duction can be stimulated by substances such

as adrenaline, peptide hormones and steroid

hormones, but also by mechanical stimuli

and tissue trauma (28, 93,94).

Others chemical substances, cytokines

and others pro-inflammatory factors

in primary dysmenorrhea

Vasopressin

It has also been shown that vasopres-

sin plays a role in the pathophysiology of

dysmenorrhea (95), although, the role of

vasopressin in the pathogenesis of PD is

controversial (32, 96, 97). Vasopressin is a

hormone secreted by the pituitary gland, its

secretion is stimulated by cyclic changes in

estradiol levels. This hormone may contrib-

ute to uterine contraction activity (86). Its

concentration is lower during the follicular

phase and increases during the ovulation.

Also, the increased levels of circulating va-

sopressin during the menstrual period that

have been reported in women with PD, can

Fig. 3. Possible mechanism of primary dysmenorrhea.

Adapted from Dawood MY: Hormones, prostaglandins and dysmenorrhea. In Dawood MY [ed]: Dys-

menorrhea. Baltimore, Williams & Wilkins, 1981).

Available from https://clinicalgate.com/pelvic-pain-2/. Reviewed on March 28, 2021.

394 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

produce dysrhythmic uterine contractions

that reduce uterine blood flow and cause

uterine hipoxia (98). Vasopressin exerts

its uterine effects mainly via the vasopres-

sin V1a receptor (99,100). The etiological

importance of vasopressin in dysmenorrhea

has been postulated by the therapeutic ef-

fect of the peptide analogue 1-deamino-

2-DTyr (Oet)-4-Thr-8-Orn-oxytocin, which

competitively blocks the vasopressin V1a

and oxytocin receptors of the uterus (101).

An orally active vasopressin V1a and the

oxytocin receptor blocking agent, SR

49059, was also shown to inhibit vasopres-

sin effects on uterine contractility and to

be therapeutically active in dysmenorrhea

when given prophylactically before the on-

set of symptoms (102,103). However, other

investigators could not confirm elevated

plasma vasopressin in women with PD and

have found that the vasopressin antagonist

atosiban had no effect on menstrual pain,

intrauterine pressure, or uterine artery pul-

satility index in PD women (97).

Fig. 4. Role of prostaglandins and prostanoids in primary dysmenorrhea.

Adapted and modified from Barcikowska Z, Rajkowska-Labon E, Grzybowska ME, Hansdorfer-Korzon

R, Zorena K. Inflammatory Markers in Dysmenorrhea and Therapeutic Options. Int J Environ Res

Public Health. 2020 Feb 13;17(4):1191. doi: 10.3390/ijerph17041191.

Primary Dysmenorrhea: pathophysiology 395

Vol. 62(4): 378 - 406, 2021

Tumor necrosis factors alpha

Activated macrophages produce proin-

flammatory cytokines: TNF-α, interleukin-1

(IL-1), IL-6, etc. responsible for upregulat-

ing inflammatory responses (104,105). It

has also been reported that these mediators

stimulate the synthesis or release of pros-

taglandins (105,106), producing excessive

contraction of the uterine muscle, which

leads to ischemic pain of primary dysmenor-

rhea. Plasma IL-6 and TNF-α levels has been

found higher in women with dysmenorrhea

compared to women without menstrual dis-

orders (104). Also, TNF-α is a cytokine that

is responsible for inhibiting endometrial

proliferation and induces apoptosis. Previ-

ous studies have shown that endometrial

cells produce increased concentration of

TNF-α during menstruation (105). More-

over, Dogru et al. (107) showed that the TN

-308G > A gene polymorphismis strongly

associated with susceptibility to dysmenor-

rhea in the Turkish female population. The

authors (107) demonstrated that the pres-

ence of the -308A TNF-α allele can protect

against dysmenorrhea and suggested that

the TNF-α-308, GG genotype may be a use-

ful tool for predicting susceptibility to dys-

menorrhea. Recent studies have shown that

intensive aerobic exercises not only cause a

reduction in the levels of the metabolite of

prostaglandins:13,14-dihydro-15-ketopros-

taglandin F2 αlfa (KDPGF2α), but also re-

duce the level of TNF-α, as well as reduce the

intensity of pain associated with dysmenor-

rhea (105).

Interleukin 6

IL-6 is a pleiotropic cytokine with

multi-directional effects on the cells of the

innate and acquired immunity system. The

main role of IL-6 is to initiate and regu-

late the acute inflammatory response and

to facilitate the development and targeting

of the acquired response. IL-6 exhibits pro

and anti-inflammatory properties and is now

considered an important target for clinical

intervention (108). In a study of women with

a normal menstrual cycle, significant vari-

ability in plasma cytokine levels, including

IL-1β, IL-6, IL-8, and IL-10 were observed

(109). Levels of several factors increased dur-

ing ovulation and then achieved their peak

during menstruation, which is considered

by some scientists to be a proinflammatory

event (85). Levels of IL-1β, IL-6, and IL-8

were inversely correlated with estradiol and

progesterone levels. However, Angstwurm et

al. (110) demonstrated an increase in IL6

concentration in the follicular phase when

the level of E2 increased. After ovulation, in

the luteal phase, when there was a 10-fold

increase in P, the level of IL-6 in plasma de-

creased 1.5–4.4 times. Others authors have

shown (104, 111, 112) an increased IL-6

concentration in women with dysmenorrhea

compared to women without dismenorrhea.

Konecna et al. (112) have demonstrated that

the level of IL6 was statistically significantly

higher during the luteal phase compared to

the follicular phase.

C-Reactive Protein

C-Reactive Protein (CRP) is a clinically

recognized as an acute phase protein. It is

assumed that normal CRP concentrations in

healthy people should not exceed 3 mg/L.

During the acute phase reaction, which is

a defense response to inflammation, infec-

tion or injury, the concentration of serum

CRP can increase up to 1000-fold, reaching

its maximum concentration after 24–48 h

(113,114). CRP is an important marker of

the ongoing inflammatory response, with

a relatively short half-life (~48 h), its con-

centration returns to its baseline in 7 to 12

days (114). CRP also supports the process

of phagocytosis, affecting monocytes, mac-

rophages, and neutrophils, as well as acting

in a chemotactic and opsonizing way (115).

In addition, it induces monocytes/macro-

phages to synthesize pro-inflammatory cy-

tokines and inhibits the synthesis of anti-

inflammatory cytokines. Studies conducted

in adult women have shown that increased

levels of CRP varied significantly across

396 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

the menstrual cycle. CRP was highest dur-

ing menses, decreased during the follicular

phase, was lowest on the expected day of

ovulation, and increased in the luteal phase

(116). Another study, showed that a ten-fold

increase in progesterone was associated with

a 23% increase in CRP (P = 0.01), a ten-fold

increase in estrogen was associated with a

29% decrease in CRP (P = 0.05) (1`17). In

a study, with the participation of healthy

women, CRP levels were positively correlat-

ed with the severity of menstrual symptoms,

the strongest being mood and pain symp-

toms (118).

Vascular Endothelial Growth Factor

Few studies indicate the involvement of

vascular endothelial growth factor (VEGF)

in the process of dysmenorrhea among

women with endometriosis (119, 120). It is

known that VEGF is the strongest factor in-

volved in the embryonic development, men-

strual cycle, and in ovarian endometriomas

(121). Although VEGF is produced by cells

and tissues of the reproductive tract, such

as the endometrium, ovary and placenta;

VEGF receptors are found only in the en-

dothelial cells. VEGF has been shown to

stimulate endothelial cell proliferation, mi-

gration and increase vascular permeability

(122). Recent reports have shown a rela-

tionship between the production of VEGF,

macrophage migration inhibitory factor

(MMIF), hypoxia-inducible factor-1α (HIF-

1α) and the stage of endometriosis, as well

as the severity of dysmenorrhea (119). The

expression of all three proteins in endome-

trial tissues and in serum increased signifi-

cantly with the severity of pain (P <0.05).

Thus, the authors conclude that MMIF,

HIF-1α and VEGF expression in serum can

be used to assess the stage of endometrio-

sis, as well as the severity of dysmenorrhea

(119).

Asymmetric dimethylarginine

Increase in the concentrations of

asymmetric dimethylarginine (ADMA) is ac-

cepted as a marker of endothelial dysfunc-

tion (123). By inhibiting nitric oxide (NO),

ADMA level increases, and has been shown

to be a risk factor for endothelial dysfunc-

tion and cardiovascular disease in end-stage

renal disease (124). It is responsible for in-

creased cardiovascular morbidity and mor-

tality in patients with renal disease (125),

cause worse outcome in idiopathic pulmo-

nary hypertension patients (126), and prob-

ably, play a role in the pathogenesis of cere-

brovascular disorders by increasing vascular

stiffness and decreasing cerebral perfusion

(127). ADMA is an endogenous inhibitor of

NO synthase, and its accumulation has been

associated with reducing NO bioavailabil-

ity and increasing superoxide generation

(128). NO is a potent inhibitor of platelet

aggregation and a powerful vasodilator; it

is responsible for uterine quiescence dur-

ing pregnancy and also appears to relax the

nonpregnant myometrium (129, 130). Inhi-

bition of NO synthesis cause vasoconstric-

tion and increase in oxidative stress, both

of which would be reflected in increased

ADMA concentrations, as it has been dem-

onstrated by Alkdemir et al. (131). Unfor-

tunately, the results of use of NO donors

to treat PD have been controversial. Some

authors (132, 133) have reported an effec-

tive relief of pain in 90% of the patients and

statistically superior results, compared to

placebo. However, Facchinetti et al. (134)

reported a reduced efficacy compared to di-

clofenac. Alkdemir et al. (131) mentioned

that it should be kept in mind in a patient

with PD, since she could have a endothe-

lial dysfunction because of elevated ADMA

levels. Knowing that dysmenorrhea affects

only a part of the female population, the

imbalance between vasodilatation and va-

soconstriction is present only in some

women. Alkdemir et al. (131) have showed

that ADMA concentrations are increased in

women with PD compared to healthy con-

trols. This might provide further insight

into the pathophysiology of this common

and devastating disorder.

Primary Dysmenorrhea: pathophysiology 397

Vol. 62(4): 378 - 406, 2021

Nitric oxide

NO is a vasodilatory substance produced

by endothelial or other cells that play a role

in the physiological control of blood pressure

(135). It is involved in many different physi-

ological processes, including blood pressure

regulation, platelet aggregation, and cyto-

toxicity (136). NO is an important source

of free radical production in tissue damage

and NO levels decrease in the case of endo-

thelial dysfunction (137). There are results

showing that serum NO levels are higher and

serum homocysteine levels are lower among

PD patients than in the healthy controls. It

is hypothesized that NO affects the homo-

cysteine metabolic pathway, and contribute

to dysmenorrheal symptom (138).

Malondialdehyde

Malondialdehyde (MDA) is generated

during lipid peroxidation, serving as a mark-

er or indicator of lipid peroxidation, an oxi-

dative stress marker, and tissue injury (64,

139). Turhan et al. (56), Orimadegun et al.

(64), and Yeh et al. (140), have reported

higher plasma MDA levels in patients with

dysmenorrhea compared to those in the

healthy controls. Also, Dikensoy et al. (141)

found that the serum levels of MDA, NO, and

adrenomedullin were significantly higher in

PD patients compared to that of the control

group on the first and the 21st day of the

menstrual cycles, suggesting that the pos-

sibility that lipid peroxidation and oxidative

stress might play a significant role in the

etiopathogenesis of PD.

Heme oxygenase 1

Heme oxygenase-1 (HO-1) is a ratelim-

iting enzyme which has an important role in

the oxidative catabolism of heme to generate

carbon monoxide, iron, and biliverdin. HO-1

has been reported to have cytoprotective ef-

fects in oxidative stress conditions (142).

Different authors (143-147) have shown

that HO-1 has extensive tissue protection via

anti-oxidative, anti-inflammatory, anti-apop-

totic and immunoregulatory activities. Akoy

et al. (143) found in fasting blood samples

taken from 28 nulliparous women with PD,

that they had higher HO-1, MDA, and NO

levels compared with controls. HO-1 levels

are increased by compensatory mechanisms

to protect the balance between oxidant and

antioxidant system in patients with dysmen-

orrhea (143).

Nitrotyrosine

3-Nitrotyrosine(3-NT) is a product of

tyrosine nitration mediated by reactive ni-

trogen species such as peroxynitrite anion

and nitrogen dioxide. Nitrotyrosine is identi-

fied as an indicator or marker of cell dam-

age, inflammation as well as NO production.

3-NT is formed in the presence of the active

metabolite NO. Generally, in many disease

states, oxidative stress increases the produc-

tion of superoxide (O2−) and NO forming

peroxynitrite (ONOO−) a destructive free

radical oxidant. The production of ONOO−

is capable of oxidizing several lipoproteins

and of nitrating tyrosine residues in many

proteins. It is difficult to determine the pro-

duction of ONOO−, usually nitrotyrosine in

proteins are the detectable marker for indi-

rectly detecting ONOO−. It is detected in

large number of pathological conditions and

is considered a marker of NO-dependent,

reactive nitrogen species-induced nitrative

stress. Orimadegun et al. (64) found higher

levels of 3-HT in patients with PD compared

to control patients, however, Turhan et al.

(56) and Yeo et al. (148) have reported no

significant difference in the plasma level

of 3-NT of women with dysmenorrhea and

healthy control.

CONCLUSIONS

Today, it is well accepted that repro-

ductive processes in women are regulated

by inflammatory events. The control of the

onset and resolution of these inflammatory

events ensures a normal reproductive func-

tion. Exacerbated or premature activation of

inflammation can contribute to disease. Un-

398 Núñez-Troconis et al.

Investigación Clínica 62(4): 2021

derstanding the molecular control of inflam-

mation and its resolution in the reproduc-

tive tract may give us insight into how these

may be corrected therapeutically in disease

PD is commonly a simple diagnosis that

can be made accurately with an attentive

history and, in young women who have clas-

sic symptoms and no specific indication, a

pelvic examination is often unnecessary in

the initial evaluation. The opportunity for

primary care practitioners to support wom-

en is the best approach to this chronic recur-

rent discomfort and to minimize an adverse

life impact is significant and valuable. Iden-

tification of patients who are incapacitated

by their symptoms, or have symptoms that

represent underlying pathology, is a criti-

cal component of a careful history. The wide

range of treatments available for PD ensures

that all females who have the symptoms can

find relief with relatively safe and inexpen-

sive treatments with limiting negative side

effects. The opportunity to counsel and sup-

port healthy lifestyle choices contribute

positively to the general health and provide

symptom relief of this condition. As so many

disorders encountered in primary care medi-

cine, dysmenorrhea give to clinicians the

opportunity to teach, counsel, and support

patients toward not only the relief of symp-

toms, but also, to get an optimal health.

As it has been mentioned before, the

pathophysiology of PD is primarily linked to

elevated levels of PGs. Low P levels in the

late luteal phase of the menstrual cycle is re-

ported to increase the synthesis of PGs, pro-

inflammatory cytokines (IL-6 and TNF-α)

and other, possible, pro-inflammatory fac-

tors are also implicated in the pathogenesis

of primary dysmenorrhea, but a better un-

derstanding of the pathophysiology of PD

may lead to better treatments.

ACKNOWLEDGMENTS

The author thanks the graphic designer

Melissa Núñez for her help in the adaptation

and modification of graphics.

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