Dysmenorrhoea in Their Third and Fourth Decade of Life in Association with an Existing Condition

REVIEW

time after menarche but is most commonly observed in women Dysmenorrhoea in their third and fourth decade of life in association with an existing condition. Akshatha Kulkarni Shilpa Deb Risk factors Risk factors for primary dysmenorrhea include earlier age at menarche, heavy menstrual flow, nulliparity, family history of Abstract dysmenorrhoea, and stress. Dysmenorrhoea is a medical condition characterised by severe uterine According to NICE Clinical Knowledge Summary on Dysme- pain during menstruation manifesting as cyclical lower abdominal norrhoea (November 2018). pain. It is commonly classified into primary dysmenorrhoea in the Primary dysmenorrhoea improves with increased age, absence of co-existent pathology and secondary dysmenorrhoea parity, and use of oral contraceptives. when there is an identifiable pathological condition. About 40e70% There is inconsistent and conflicting evidence on the of women of reproductive age suffer with dysmenorrhoea along with association between primary dysmenorrhoea and modifi- its associated psychological, physical, behavioural and social distress. able factors, such as cigarette smoking, diet, obesity, The exact pathophysiological processes are not fully understood but it depression, and abuse. probably reflects increased myometrial activity induced by an excessive production of prostaglandin causing ischaemia (uterine ‘angina’). Pathophysiology History is critical in establishing the diagnosis of dysmenorrhoea and also in differentiating between primary and secondary dysmenorrhoea. The most important physiological event reported with dysme- Mainstay treatment is generally supportive providing symptomatic re- norrhoea is increased myometrial activity with accompanying lief and more directive surgical treatment is reserved for specific sec- uterine ischemia (uterine ‘angina’), which stimulates the type C ondary causes of dysmenorrhoea or for refractory cases. Therefore, afferent pain neurones. patients with primary dysmenorrhoea may simply need reassurance In a normal menstrual cycle, at the end of the luteal phase as and simple analgesics, while those with secondary dysmenorrhoea the corpus luteum regresses after non-fertilisation of an ovum, require investigation and treatment of the underlying organic problem. there is a decline in progesterone levels. It is this withdrawal of We present an overview of managing this condition. progesterone that leads to the shedding of endometrium and, during its destruction, an increase in inflammatory cyto- Keywords dysmenorrhoea; menstrual disorders; primary; secondary kines, vascular endothelial growth factors and matrix metal- loproteinases (MMPs). This leads to a degradation and loss of integrity of blood vessels and destruction of endometrial inter- Background stitial matrix and hence the bleeding of menstruation. Uterine Dysmenorrhoea is a very common gynaecological condition contraction and vasoconstriction is caused by the disintegrating affecting anywhere from 45 to 95% of women with one in five endometrial cells releasing PGF2a which is a myometrial stimu- cases being severe. Dysmenorrhoea is a medical condition lant and vasoconstrictor. The uterine contractions and ischaemia characterised by severe uterine pain during menstruation mani- that results from decreased blood flow results in uterine pain. festing as cyclical lower abdominal or pelvic pain, which may also radiate to the back and thighs. The term dysmenorrhoea is Primary dysmenorrhoea derived from the Greek words ‘dys’ meaning difficult, painful or In women with primary dysmenorrhoea there are increased abnormal, ‘meno’ meaning month and ‘rrhea’ meaning flow. levels of inflammatory markers such as vasopressin, prosta- It is commonly divided into primary dysmenorrhoea, where glandins PGE2 and PGF2a and leukotrienes in endometrial fluid. there is no co-existent pathology, and secondary dysmenorrhoea PGF2a is a potent myometrial stimulant and vasoconstrictor. where there is an identifiable pathological condition known to Leukotrienes increase myometrial stimulation and vasoconstric- contribute to painful menstruation. Symptoms of primary dys- tion as well as increasing the sensitivity of pain fibres. Vaso- menorrhoea begin a few hours before the start of menstruation pressin stimulates uterine activity, decreased uterine blood flow and are often relieved during the first few days of bleeding. and, in vitro, constricts uterine arteries. The primary stimulus for The initial onset of primary dysmenorrhoea is usually shortly these increased levels is unknown but it is thought that this after menarche (6e12 months), when ovulatory cycles are myometrial activity is modulated and augmented by prosta- established. Secondary dysmenorrhoea can also occur at any glandin synthesis. In addition to stimulating uterine contractions, PGF2 and PGE2 can cause contraction of bronchial, bowel, and vascular smooth muscle resulting in bronchoconstriction, nausea, vomiting, diarrhoea and hypertension. Diarrhoea and Akshatha Kulkarni MBBS MS DNB MRCOG is a Senior Registrar in nausea are commonly associated with primary dysmenorrhoea. Obstetrics and Gynaecology at Queen’s Medical Centre, Nottingham, Compared with controls, women with primary dysmenor- UK. Conflicts of interest: none declared. rhoea have increased uterine pressures from increased uterine muscle activity and frequency of contractions (frequently more Shilpa Deb MBBS DGO PhD MRCOG is a Consultant in Obstetrics and Gynaecology at Nottingham University Hospitals NHS Trust, Queen’s than 150 mmHg). Doppler flow studies have supported this by Medical Centre Campus, Nottingham, UK. Conflicts of interest: none showing higher uterine and arcuate artery resistance on the first declared. day of menses in women with primary dysmenorrhoea than in

controls. Pain fibres are also stimulated from ischaemia caused - Drug history, including prior treatment and effect. by vasoconstriction and anaerobic metabolites produced by an o Examination: ischaemic endometrium which stimulate type C pain neurons. - Perform an abdominal examination in all women d to Added to this is the possible effect of psychological and assess for large fibroids and other masses. behavioural factors which can act centrally and contribute to - Perform a pelvic examination (including a speculum pain perception. There is an increased prevalence of dysmenor- examination of the cervix), except in young women who are rhoea in women with a history of sexual abuse but there is little not sexually active if the symptoms are suggestive of pri- research into this compared to other chronic pelvic pain mary dysmenorrhoea. syndromes. o Consider the following investigations: - An ultrasound scan d to rule out fibroids, adnexal Secondary dysmenorrhoea pathology, and endometriosis. Secondary dysmenorrhoea is caused by an underlying pelvic - High vaginal and endocervical swabs d if the woman is at pathology. Endometriosis is the most common cause. However, risk of a sexually transmitted infection, especially if pain is there is no correlation between the severity of the disease associated with vaginal discharge and abnormal vaginal and extent of pain. Pelvic Inflammatory Disease causes both bleeding. increased inflammatory mediators and scar tissue. Adenomyosis - Pregnancy test d to exclude an ectopic pregnancy. causes tonic contractions through endometrial gland infiltration Primary dysmenorrhoea is the most likely diagnosis and polyps, submucous fibroids and IUDs cause increased uter- when: ine contractions in order to expel them. All of the less common o Menstrual pain starts 6e12 months after the causes of dysmenorrhoea are due to abnormal uterine contrac- menarche, once cycles are regular. tions. See Table 1 for a comparison of primary and secondary o Pain, usually cramping in nature, occurs in the lower dysmenorrhoea. abdomen but may radiate to the back and inner thigh. o Pain starts shortly before the onset of menstruation and Evaluation of dysmenorrhoea lasts for up to 72 h, improving as the menses progresses. Secondary dysmenorrhoea must be excluded before considering o Non-gynaecological symptoms, such as nausea, vom- a diagnosis of primary dysmenorrhoea. iting, diarrhoea, fatigue, irritability, dizziness, bloat- o History and clinical assessment: ing, headache, lower back pain, and emotional - Relation of pain to menarche. symptoms, are present. - Characteristics of the pain, including type of pain, timing o Other gynaecological symptoms are not present. and duration, severity, and exacerbating and alleviating o Pelvic examination is normal. factors. Secondary dysmenorrhoea is the most likely diagnosis - Any associated symptoms, including other gynaecological when: symptoms and non-gynaecological symptoms. o Pain starts after several years of painless periods. - Menstrual history, including length of menstrual cycle, o Pain is not consistently related to menstruation alone regularity, and duration, and the volume of menstrual flow. and may persist after menstruation finishes or may be - Risk factors for primary dysmenorrhoea, such as family present throughout the menstrual cycle but is exacer- history of dysmenorrhoea. bated by menstruation. - Medical history. Several conditions (for example, irritable o Other symptoms are present, including: bowel syndrome and lactose intolerance) can mimic pain - Other gynaecological symptoms, such as dyspareunia, similar to dysmenorrhoea. vaginal discharge, menorrhagia, intermenstrual - Obstetric history, including plans for pregnancy. bleeding, and postcoital bleeding.

Differential characteristics of primary and secondary dysmenorrhoea

Primary Secondary

Age (years) 16e25 30e45 Onset of pain Just prior to menstruation (spasmodic). Pain often progresses through late luteal (congestive). Pathophysiology Excess prostaglandins and leukotrienes. Underlying disorder. Symptoms Usually self-limiting, lasts for ﬁrst 1e3 days Associated with other features related to menstruation. underlying disease. Responds to COCP and NSAIDs, Periods Resistant to COCP and NSAIDs. normal or light. Periods often heavy. Signs Unremarkable Dependent on cause but may include a tender, enlarged, ﬁxed, retroverted uterus with adnexal tenderness and a mass

Table 1

For primary dysmenorrhoea, history and examination should Major causes of secondary dysmenorrhoea suffice and further investigation is rarely necessary. If there are Gynaecologic disorders: atypical symptoms or a trial of non-steroidal anti-inflammatory C Endometriosis medication or combined oral contraceptive is unsuccessful then C Adenomyosis pelvic ultrasound scan should be considered. For secondary C Pelvic inflammatory disease dysmenorrhoea pelvic USS should be considered. Hysteroscopy C Fibroids and laparoscopy have a role in confirming a suspected diagnosis C Endometrial polyps and treating the underlying pathology (See Tables 2 and 3). C Ovarian cysts C Intrauterine contraceptive device Management C Intrauterine adhesions (Asherman’s syndrome) For primary dysmenorrhoea, treatment is based on tackling the C Congenital obstructive mullerian malformations aetiology with cyclo-oxygenase inhibitors and inhibiting ovula- C Pelvic congestion syndrome tion. Treatment of secondary dysmenorrhoea targets the cause. C Cervical stenosis One must treat women individually taking account of their age, Non-gynaecologic disorders: desire for fertility and concurrent symptoms. C Inflammatory bowel disease Many studies have employed patient self-reporting using a C Irritable bowel syndrome visual analogue or other pain scale, quality of life scales, or other C Urogenital disease similar measures such as the Menstrual Distress or Menstrual C Psychogenic disorders Symptom Questionnaires. Additional measures include analysis of the proportion of women requiring analgesics in addition to Table 2 their assigned treatment and recording the percentage of women - Non-gynaecological symptoms, such as rectal pain reporting restriction of social activities or absence from work or and bleeding (which may be associated with school. Whichever system is used, grading dysmenorrhoea ac- endometriosis). cording to severity of pain and limitation of daily activity will o Pelvic examination is abnormal, although the absence help guide the treatment strategy and catalogue the response to of abnormal findings does not exclude secondary treatment. dysmenorrhoea

Clinical features and evaluation of some common causes of secondary dysmenorrhoea

Condition Clinical features Evaluation

Endometriosis (most common cause of Cyclical or chronic pelvic pain frequently Transvaginal pelvic ultrasound is highly secondary dysmenorrhoea) occurring prior to menstruation and accurate for ovarian endometrioma. accompanied by heavy menstrual bleeding MRI may be indicated for deep infiltrating and deep dyspareunia. endometriomas. Laparoscopy allows confirmation of diagnosis and treatment Adenomyosis Usually associated with menorrhagia and Transvaginal ultrasound or MRI. intermenstrual bleeding. Enlarged, tender, boggy uterus on examination. Fibroids Lower abdominal pain, frequently Transvaginal/transabdominal ultrasound accompanied by menorrhagia; a pelvic mass may be identified on examination PID Lower abdominal pain and tenderness that Cervical infection with Chlamydia trachomatis may be accompanied by dyspareunia, or Neisseria gonorrhoeae is confirmatory. abnormal vaginal bleeding, and abnormal May have elevated C-reactive protein. vaginal discharge. In acute infection, fever Transvaginal ultrasound useful in detecting may be present. tubo-ovarian masses. Endometrial polyps Menorrhagia, congestive and spasmodic Transvaginal USG, saline infusion sonography, dysmenorrhoea and intermenstrual bleeding hysteroscopy. Pelvic congestion syndrome Chronic pelvic pain that increases Radiological imaging is frequently used to premenstrually; with prolonged standing, confirm the clinical suspicion of this condition. postural changes, walking, or activities that Gold standard is selective venography. increase intra-abdominal pressure; and after intercourse (postcoital ache).

Table 3

According to NICE Clinical Knowledge Summary for Managing few small trials. There was no evidence that COX-2-specific Dysmenorrhoea (Nov 2018): inhibitors were more effective or tolerable for the treatment of 1. First-line treatment for women with primary dysmenor- dysmenorrhoea than standard NSAIDs, although data was very rhoea should be a non-steroidal anti-inflammatory drug scanty. (NSAID), unless contraindicated. (Figures 1 and 2) Women with dysmenorrhoea have high levels of prostaglan- Licensed indications dins (hormones known to cause cramping abdominal pain). o Ibuprofen, naproxen, and flurbiprofen are licensed for the NSAIDs act by blocking prostaglandin production by inhibiting treatment of dysmenorrhoea. the action of cyclo-oxygenase (COX, an enzyme responsible for o Mefenamic acid is also licensed for the treatment of dys- the formation of prostaglandins). menorrhoea; however, there are concerns that it is more The COX enzyme exists in two forms: COX-1 and COX-2. likely to cause seizures in overdose than other NSAIDs. It Standard NSAIDs (such as ibuprofen, naproxen, and mefenamic has a narrow therapeutic window, which increases the risk acid) are considered ’non-selective’ because they inhibit both of accidental overdose. The National Poisons Information COX-1 and COX-2 enzymes. Coxibs (such as celecoxib and Service considers an ingestion of 40 mg/kg or more to be etoricoxib) are highly selective for COX-2 but can interact with potentially toxic. This means that a woman who weighs 50 COX-1 in certain circumstances. kg would only need to ingest one extra dose of 500 mg of A Cochrane systematic review compared 20 different NSAIDs mefenamic acid in 24 hours (total of 2000 mg) to be (18 non-selective and two COX-2-specific) with placebo, para- considered to be at risk of toxicity. cetamol, or each other in 5820 women with dysmenorrhoea and 2. Offer paracetamol if NSAIDs are contraindicated or not found that: tolerated, or in addition to an NSAID if the response is - NSAIDs were more effective for pain relief than placebo but insufficient. were associated with more adverse effects. Evidence from the Cochrane systematic review showed that - NSAIDs appeared to be more effective for pain relief than NSAIDs appeared to be more effective than paracetamol in the paracetamol. There was no evidence of a difference with treatment of primary dysmenorrhoea. However, paracetamol is a regard to adverse effects, although data was very scanty. well-tolerated analgesic and is a widely used alternative to NSAIDs for musculoskeletal pain. Choice of NSAIDs Options include ibuprofen, naproxen, mefenamic acid, flurbi- If the woman does not wish to conceive, consider prescribing a profen, or tiaprofenic acid. 3e6 month trial of a hormonal contraceptive as an alternative The Cochrane systematic review found little evidence of the first-line treatment. superiority of any individual NSAID for either pain relief or Combined hormonal contraceptives, including combined oral safety, but the available evidence had little power to detect such contraceptives, the contraceptive ring, and the transdermal differences as most individual comparisons were based on very patch, all work to decrease the endometrial lining, which

Action of NSAIDS

Cell membrane phospholipids

Phospholipase A2

Arachidonic acid

COX1 and 2 – NSAIDs

Prostaglandin G2

Peroxidase

Prostaglandin H2

PG12 TXA2

PGF2alpha PGE2

Figure 1

Treatment of dysmenorrhoea

Dysmenorrhoea

History, examination and investigations

Primary Secondary dysmenorrhoea dysmenorrhoea

Contraception Contraception Treat the cause not needed needed

Consider laparoscopy NSAIDs COC if not done previously to exclude NSAIDs COC secondary + paracetamol + NSAIDs causes of dysmenorrhoea

Figure 2

produces prostaglandins and leukotrienes that contribute to the (Mirena) contraceptives may also be considered after a full menstrual pain. In addition, their role in inhibiting ovulation and discussion of the advantages and disadvantages. subsequent progesterone production also decreases the forma- Oral progestogen-only contraceptives tion of prostaglandins and leukotrienes. Thus, these products iv. An observational study assessed the effects of desogestrel have been prescribed for primary dysmenorrhea, as well as some 75 mg (Cerazette) in women with dysmenorrhoea and causes of secondary dysmenorrhea, particularly endometriosis. found that dysmenorrhoea resolved or considerably a. Monophasic combined oral contraceptive (COC) prepara- improved in 93% of the study population. tions containing 30e35 mg of ethinylestradiol and nor- Parenteral progestogens ethisterone, norgestimate, or levonorgestrel are usually first v. A review of open-label, non-comparative and comparative choice. studies assessed the effects of etonogestrel subdermal i. A Cochrane systematic review found limited evidence implant (Implanon, which is bioequivalent to Nexplanon) that COCs are effective for relieving pain associated with on menstrual bleeding patterns and found that it reduced primary dysmenorrhoea. However, the overall quality of both the incidence and severity of dysmenorrhoea. Most the trials was poor, some trials were over 25 years old, women (77%) who had baseline dysmenorrhoea experi- and some used COCs with higher doses of oestrogen enced complete resolution of symptoms. than is present in currently available products. vi. Some experts recommend that parenteral progestogens ii. Despite the limited trial evidence, COCs are widely rec- (such as depot medroxyprogesterone acetate) may be ommended by experts for this indication, and the added considered in the treatment of dysmenorrhoea. Depot contraceptive advantages make them a suitable first-line medroxyprogesterone acetate works primarily by sup- option for some women. pressing ovulation; it can also induce endometrial atrophy. iii. COCs containing 20 mg of ethinylestradiol are less One of its benefits is amenorrhea with a resultant reduction preferred because they are more likely to cause un- in the incidence of dysmenorrhea. scheduled bleeding. b. Intrauterine contraception b. Oral (desogestrel 75 mg), parenteral (Depo-Provera or Sayana i. A longitudinal population study assessed the prevalence Press, and Nexplanon), and intrauterine progestogen-only and severity of dysmenorrhea in women using an

intrauterine contraception and found that the after childbirth. The prognosis of secondary dysmenorrhoea is levonorgestrel-releasing intrauterine system (LNG-IUS, not known as its severity, progression and eventual outcome Mirena) was associated with reduced dysmenorrhea depend on the underlying pathology. severity compared with other methods of contraception (barrier methods, natural family planning, coitus inter- Conclusions ruptus, and sterilization) or no method of contraception. Dysmenorrhoea has a significant physical, behavioural, psycho- The copper intrauterine device (Cu-IUD) did not reduce logical and social impact, affecting a large proportion of women the severity of dysmenorrhea when compared with other of reproductive age. The exact pathophysiological processes are methods of contraception. not fully understood but it probably reflects increased myo- ii. The RCOG guideline states that non endometriosis-related metrial activity induced by an excessive production of prosta- cyclical pain also appears to be well controlled by the glandin causing ischaemia. Mainstay of treatment is generally LNG-IUS. It is also an option for those who do not require supportive providing symptomatic relief with NSAIDs or COCP contraception, particularly older women who have had and more directive surgical treatment should be reserved for children and women with heavy menstrual bleeding. specific secondary causes of dysmenorrhoea or for refractory 3. If the response to individual treatments is insufficient, a cases. A combination of an NSAID (or paracetamol) and hormonal contraception may be considered. 4. Consider recommending the following non-drug measures (in addition to drug treatments) to help reduce pain: Practice points c. Local application of heat (e.g. a hot water bottle or heat patch). C Around 45e95% of menstruating women suffer with d. Transcutaneous electrical nerve stimulation (TENS) d dysmenorrhoea set to a high frequency. C Increased myometrial activity induced by an excessive production Heat therapy and transcutaneous electrical nerve stimula- of prostaglandin causing uterine ischaemia is the most accepted tion (TENS) pathophysiological mechanism A systematic review assessed the effectiveness of heat therapy C Primary dysmenorrhoea is seen in young women with ovulatory and TENS interventions for pain relief and quality of life cycles and is characterised by spasmodic menstrual pain starting improvement in women with primary dysmenorrhea. just before menstruation lasting for 24e48 h. There is no coex- i. Evidence from trials on heat therapy showed individual isting pathology improvement in pain levels. C Secondary dysmenorrhoea is always associated with an underly- ii. Evidence from trials on TENS showed relatively positive ing pathology and is characterised by congestive menstrual pain, effects in pain reduction. Overall, the evidence suggested which increases progressively through the late luteal phase, that conventional TENS is better option in dysmenorrhoeal peaking with onset of menstruation pain relief than other forms of TENS (such as acupuncture- C History is critical in establishing the diagnosis of dysmenorrhoea like TENS, and OVA TENS) and that high-frequency TENS C Treatment is aimed at symptomatic relief with analgesics e is more effective for pain relief, although there was insuf- especially NSAIDs e and at treating the underlying pathology. ficient to determine the effectiveness of low frequency TENS in reducing dysmenorrhea. 5. Other non-drug measures e. There is a lack of good-quality evidence to support the use of FURTHER READING herbal remedies, dietary supplements, acupuncture, Best Practice BMJ. Assessment of dysmenorrhoea. BMJ, 2018. acupressure, spinal manipulation, behavioural therapy, and COG. The initial management of chronic pelvic pain. Royal College of exercise to treat dysmenorrhoea. In addition, herbal rem- Obstetricians and Gynaecologists, 2012. edies have the potential to cause adverse effects and may Lacovides S, Avidon I, Baker FC. What we know about primary interact with other medicines. dysmenorrhea today: a critical review. Hum Reprod Update 2015; Prognosis 21: 762e78. There are very few longitudinal studies examining the progres- Proctor M, Farquhar C. Diagnosis and management of dysmenor- e sion and eventual outcome of primary or secondary dysmenorrhoea. Br Med J 2006; 332: 1134 8. rhoea. Primary dysmenorrhoea often improves in the third Wallace S, Keightley A, Gie C. Dysmenorrhoea. The Obstetrician & e decade of a woman’s reproductive life and appears to be reduced Gynaecologist 2010; 12: 149 54.