Menstruation itself occurs as a result of cyclic hormonal variations (Fig. 45.1). During the first half or follicular phase of the menstrual cycle, the endometrium thickens under the influence of increasing levels of oestrogen (most notably estradiol, which at the peak of its preovulatory surge reaches around 2000 pmol/L) secreted from the developing ovarian follicles. Once the serum oestrogen level has surpassed a critical point it triggers, by positive feedback, the anterior pituitary to release, about 24 h later, a surge of luteinising hormone (LH; up to 50 iu/L) and after 30–36 h, ovulation follows.

Fig. 45.1 The hormonal events that occur during the menstrual cycle in women.

After ovulation, which occurs around day 14 of a 28-day menstrual cycle, and as the luteal phase progresses, the endometrium begins to respond to increasing levels of progesterone. Both progesterone and oestrogen are secreted from the corpus luteum which is formed from the remains of the ovarian follicle after ovulation. The lifespan of the corpus luteum is remarkably constant and lasts between 12 and 14 days; hence, the length of the second half or the luteal phase of the menstrual cycle is between 12 and 14 days. Between days 18 and 22 of a 28-day cycle, both sex steroids peak, with levels of progesterone reaching around 30 nmol/L. As progesterone has a thermogenic effect upon the hypothalamus, basal body temperature increases by about 1 °C in the second half of an ovulatory cycle (Fig. 45.2). Most ovulatory cycles range from 21 to 34 days.

Fig. 45.2 Typical temperature chart from a 28-day ovulatory menstrual cycle.

These synchronised changes mean that about a week after ovulation, the endometrium is prepared for implantation, providing fertilisation has taken place. If conception does not occur, then luteolysis begins and steroid levels fall. This means that the endometrium cannot be maintained, there is a loss of stromal fluid, leucocyte infiltration begins and there is intraglandular extravasation of blood. Finally, endometrial blood flow is reduced and this leads to necrosis and sloughing, that is menstruation. Initially, the blood vessels that remain intact after sloughing are sealed by fibrin and platelet plugs; subsequent haemostasis is probably achieved as a result of vasoconstriction of the remaining basal arteries. Nitric oxide may be involved in the initiation and maintenance of menstrual bleeding by promoting vasodilation and inhibiting platelet aggregation. The myometrium is the muscular layers of the uterus that contract spontaneously throughout the menstrual cycle, the frequency of these contractions being influenced by the hormonal milieu. The myometrium is also more active during menstruation. The average blood loss per period is between 30 and 40 mL.

There is evidence which suggests a physiological and pathological role for the local hormones, known as prostaglandins, in the process of menstruation. Prostaglandins are 20-carbon oxygenated, polyunsaturated bioactive lipids, which are cyclo-oxygenase-derived products of arachidonic acid. Indeed, both the myometrium and the endometrium are capable of synthesising and responding to prostaglandins. A potential role for another family of autocoids, the leukotrienes, in the regulation of uterine function remains uncertain, although it is known that leukotrienes can also be synthesised from arachidonic acid by lipoxygenase enzymes (Fig. 45.3).

Fig. 45.3 Eicosanoid biosynthesis and inhibition.

Disorders associated with menstruation are a major medical and social problem for women which also impact upon their families.

Premenstrual syndrome (PMS)

PMS encompasses both mood changes and physical symptoms. Symptoms may start up to 14 days before menstruation, although more usually they begin just a few days before and disappear at the onset of, or shortly after, menstruation. However, for some women, the beginning of menstruation may not signal the complete resolution of symptoms. Numerous studies have demonstrated that this condition can cause substantial impairment of normal daily activity, including reduced occupational activity and significant levels of work absenteeism. Severity varies from cycle to cycle and may be influenced by other life factors such as stress and tiredness. The most severe form of PMS may be referred to as premenstrual dysphoric disorder (PMDD) as defined by the Modified Diagnostic and Statistical Manual of Mental Disorders appendix IV, or DSM-IV (American Psychiatric Association, 2000) and for which the criteria are set out in Box 45.1. Other bodies (American College of Obstetricians and Gynecologists, 2000) have published diagnostic criteria for PMS (Box 45.2). There is considerable overlap between PMS and PMDD.

Box 45.1 Summary of DSM-IV diagnostic criteria for premenstrual dysphoric disorder (PMDD)

One-year duration of symptoms which are present for the majority of cycles (occur luteal/remit follicular)

Five of the following symptoms (with at least one of these*) must occur during the week before menses and remit within days of menses.

• Irritability*

• Depressed mood or hopelessness*

• Affective lability* (sudden mood swings)

• Tension or anxiety*

• Decreased interest in activities

• Change in sleep patterns

• Difficulty concentrating

• Feeling out of control or overwhelmed

• Lack of energy

• Other physical symptoms, for example, breast tenderness, bloating

• Change in appetite, for example, food cravings

Seriously interferes with work, social activities, relationships

Not an exacerbation of another disorder

Confirmed by prospective daily ratings during at least two consecutive symptomatic cycles

Box 45.2 Diagnostic criteria for premenstrual syndrome (PMS)

Patient reports ≥1 of the following affective and somatic symptoms during the 5 days before menses in each of three prior menstrual cycles:

Affective	Somatic
Depression	Breast tenderness
Angry outbursts	Abdominal bloating
Irritability	Headache
Anxiety	Swelling of extremities
Confusion
Social withdrawal

Symptoms relieved within 4 days of menses onset without recurrence until at least cycle day 13

Symptoms present in absence of any pharmacological therapy, hormone ingestion, or drug or alcohol abuse

Symptoms occur reproducibly during two cycles of prospective recording

Patient suffers from identifiable dysfunction in social or economic performance

Epidemiology

Up to 95% of menstruating women experience some changes premenstrually. Clinically relevant PMS occurs in about 15–20% of these women and PMDD has an estimated incidence of 3–8%. It has been estimated that PMS may account for over 17 million disability-adjusted life years (DALYS) in the European Union. PMS affects young and older women alike and does not appear to be influenced by parity. Severe PMS is more common in the 30–40 year age range, and married women with young children commonly seek help. Certain events may be linked with the onset of PMS, including childbirth, cessation of oral contraceptive use (incidence of reported PMS is lower in pill users), sterilisation, hysterectomy or even increasing age. PMS may be exacerbated by other stresses, typically those associated with family life. Women with a body mass index over 30 are more likely to suffer from PMS. There is also some evidence that crimes, accidents, examination failure, absenteeism and marital disturbances may be more common premenstrually.

Aetiology

PMS is not seen before puberty, during pregnancy or in postmenopausal women, and therefore, the ovarian hormones have been implicated. The mineralocorticoids, prolactin, androgens, prostaglandins, endorphins, nutritional factors (e.g. pyridoxine, calcium and essential fatty acids) and hypoglycaemia may be involved. In addition, changes in CNS function have been implicated as cerebral blood flow in the temporal lobes is decreased premenstrually in PMS sufferers, and noradrenergic cyclicity is disrupted. As symptoms vary so much from cycle to cycle, and from individual to individual, it is likely that different aetiological factors apply to different women, all of which may be affected by extenuating emotional circumstances. There is some evidence that predisposition to PMDD may be familial.

Symptoms

Symptoms occur 1–14 days before menstruation begins and disappear at the onset or shortly after menstruation begins. For the rest of the cycle, the woman feels well. Symptoms are cyclical, although they may not be experienced every cycle, and can be either physical and/or psychological (see Boxes 45.1. and 45.2 for symptomatology). The lives of the 5% or so of women who are severely affected may be completely disrupted in the second half of the menstrual cycle. The symptoms of PMS tend to decrease as a woman gets closer to the menopause as her ovulatory cycles become less frequent.

Management

The first step in the management of PMS is recognition of the problem and realisation that many other women also suffer. Keeping a menstrual diary is useful and will establish any link between symptoms and menstruation, and this will provide a cornerstone for diagnosis. After a few months, it will allow the patient to make predictions and help her deal with changes when they arrive. The effectiveness of medical intervention depends upon which symptoms are being experienced, underlining the importance of a menstrual diary and experimentation. In terms of treatment, self-help and perseverance will be required in the management of PMS. The wide variety of symptoms may require exploring a number of treatment options before optimal relief can be achieved.

Non-pharmacological strategies

Maintenance of good general health is important, especially with respect to diet and possible deficiencies. Dietary modifications that may be helpful include restricting caffeine and alcohol intake. Smoking can also exacerbate symptoms. Exercise may help, as may learning simple relaxation techniques. If fluid retention is a problem, then reducing fluid and salt intake may be of value. Increasing the intake of natural diuretics such as prunes, figs, celery, cucumber, parsley and foods high in potassium such as bananas, oranges, dried fruits, nuts, soya beans and tomatoes may all be useful. Hypoglycaemia may also be involved in premenstrual tiredness, so eating small protein-rich meals more frequently may help.

Results from clinical trials involving pyridoxine (vitamin B₆) have shown conflicting results. However, some women do respond to pyridoxine and show improvement, particularly with respect to mood change, breast discomfort and headache. A typical dosage regimen would be 50 mg twice daily after meals or 100 mg after breakfast. The dose should not exceed 100 mg a day. Gastric upset and headaches have been reported at doses greater than 200 mg. High doses over long periods have also been associated with peripheral neuropathies. Pyridoxine should be commenced 3 days before symptom onset and continued for 2 days after menstruation has started.

Calcium supplementation has shown some activity in reducing emotional, behavioural and physical symptoms. Likewise, there is limited evidence that supplementation with γ-linolenic acid, found in evening primrose oil, gives relief from physical symptoms, especially breast tenderness.

Pharmacological management

Progestogens

Synthetic progestogens, in preparations such as Cyclogest® and Duphaston®, have been used in the past. However, because of the lack of convincing trial evidence and the risk of side effects, the use of progestogens is no longer recommended. Possible side effects include weight gain, nausea, breast discomfort, breakthrough bleeding and changes in cycle length. Problems arise because some synthetic progestogens, especially 19-nor compounds such as norethisterone and levonorgestrel, also display some affinity for glucocorticoid, mineralocorticoid and androgen receptors. The specificity of these synthetic agents is influenced by the substituents present on the steroid nucleus, particularly at C13. For example, the third-generation progestogens that have an ethyl group at C13 (gestodene, desogestrel and norgestimate) have the least androgenic activity of all the 19-nor compounds but are still orally active.

Combined oral contraceptives (COC)

Some women are helped by the COC pill because it prevents ovulation from taking place. However, the use of exogenous oestrogen may be contraindicated because it can increase the risk of venous thromboembolism. This occurs because oestrogen decreases blood levels of the potent natural anticoagulant antithrombin III and at the same time increases serum levels of some clotting factors. Women with other risk factors for thromboembolic disease should also avoid this form of therapy. The incidence of venous thromboembolism in healthy, non-pregnant women who are not taking an oral contraceptive is about five to ten cases per 100,000 women per year. For those using COCs containing second-generation progestogens, for example, levonorgestrel, this incidence is about 15 per 100,000 women per year of use. Some studies have reported a greater risk of venous thromboembolism in women using preparations containing the third-generation progestogens desogestrel and gestodene. The incidence in these women is about 25 per 100,000 women per year of use. However, it should be noted that the absolute risk of venous thromboembolism in women using COCs containing these third-generation progestogens remains very small and well below the venous thromboembolism risk associated with pregnancy.

It is thought that use of third-generation progestogens is associated with increased resistance to the anticoagulant action of activated protein C. Oral contraceptive treatment diminishes the efficacy with which activated protein C down regulates in vitro thrombin formation. This is known as activated protein C resistance and is more pronounced in women using the COC pills containing desogestrel than in women using those containing levonorgestrel. However, it has also been recognised that women who do react to third-generation progestogens with venous thromboembolism may be revealing a latent thrombophilia. There are several conditions, congenital or acquired, that can cause thrombophilic alterations. A genetic factor known as factor V Leiden mutation is the most common inherited cause of thrombophilia, and this mutation results in resistance to the effects of activated protein C. Carriers of this mutation have more than a 30-fold increase in risk of thrombotic complications during oral contraceptive use, although this has been disputed (Farmer et al., 2000) because no increase in risk of venous thromboembolism was found with the third-generation progestogens. In conclusion, if there is a history of thromboembolic disease at a young age in the immediate family, then disturbances of the coagulation system must be ruled out.

The combination of ethinylestradiol with drospirenone is also available as an oral contraceptive and appears to be useful in the management of PMS. Drospirenone is a derivative of spironolactone, with affinity for progesterone receptors, but it also acts as a mineralocorticoid antagonist. This progestogen, therefore, alleviates some of the salt-retaining effects of the ethinylestradiol.

Bromocriptine

Bromocriptine stimulates central dopamine receptors and thus inhibits the release of prolactin. It may be useful for breast tenderness and occasionally has beneficial effects upon fluid retention and mood changes. It should be used in small doses, for example, 1–1.25 mg at bedtime with food, to avoid the side effects of nausea and faintness due to hypotension. The dose can be slowly increased to 2.5 mg twice a day if required. It is advised that ergot-derived dopamine receptor agonists, such as bromocriptine, have been associated with pulmonary, retroperitoneal and pericardial fibrotic reactions (Anon, 2002). Excessive daytime sleepiness and sudden onset of sleep can also occur with dopaminergic drugs.

Danazol

Danazol is a synthetic steroid derived from ethisterone. It is weakly androgenic and has been described as an attenuated androgen. Danazol interacts with androgen receptors, but it also has some affinity for the progesterone receptor. It inhibits the pulsatile release of gonadotrophins from the anterior pituitary and so abolishes cyclical ovarian activity, leading to amenorrhoea in the majority of women and a subsequent fall in serum oestrogen levels. However, because of the high incidence of side effects, it tends to be used as a last resort for relief of severe mastalgia and mood changes. These side effects relate to the androgenicity of the compound and include nausea, giddiness, muscular pain, weight gain, acne and virilisation. These can be minimised by using low doses of 200 mg a day.

Gonadotrophin-releasing hormone analogues

GnRH analogues, sometimes referred to as gonadorelin analogues, are useful for managing the physical symptoms, but are less effective with respect to emotional symptoms. These agents inhibit the hypothalamic–pituitary–gonadal axis. However, they can only be used for short periods of time, no more than 6 months, because they induce a hypo-oestrogenic state, and therefore bone loss becomes significant after 6 months’ treatment. Should a patient respond well to GnRH analogues for PMS following hysterectomy, because of underlying pelvic pathology, bilateral oophorectomy may also be of benefit.

Prostaglandin synthesis inhibitors

Improvements in tension, irritability, depression, headache and general aches and pains can be seen in some women who take prostaglandin synthesis inhibitors. Most of the information available centres upon the use of mefenamic acid at doses of 250 mg three times a day 12 days before a period is due, increasing to 500 mg three times a day 9 days before the period and continuing until the third day of menstruation. Other inhibitors of prostaglandin synthesis are likely to be just as effective and may be associated with fewer side effects. Some experimental evidence, however, suggests that, in addition to being a cyclo-oxygenase inhibitor, mefenamic acid also has activity as an antagonist at prostaglandin E receptors, and therefore this may be useful if heavy menstrual bleeding is also a problem. For optimum effectiveness, this form of therapy should be started 24 h before the onset of symptoms. However, this starting point may be difficult to predict for women with irregular cycles.

Antidepressants

The selective serotonin reuptake inhibitors (SSRIs) are becoming more popular in the treatment of PMS-related depression because they are effective and well tolerated (Brown et al., 2009). Several randomised controlled trials using fluoxetine, sertraline, citalopram, fluvoxamine or paroxetine concluded that SSRIs are an effective first-line therapy for severe PMS and the side effects at low doses are generally acceptable. Two studies also found that not only do SSRIs improve behavioural symptoms, but some improvement in physical symptoms was also noted. Common side effects experienced include headache, nervousness, drowsiness and fatigue, sexual dysfunction and gastro-intestinal disturbances. Other agents such as tricyclic antidepressants and anxiolytics such as buspirone have been used. However, they appear to improve fewer PMS symptoms than the SSRIs.

St John’s Wort has been used to reduce the severity of PMS, but the available evidence is limited.

Dysmenorrhoea

Dysmenorrhoea is usually subdivided into primary and secondary dysmenorrhoea. The former may also be referred to as spasmodic dysmenorrhoea, which is a uterine problem and is predominantly a complaint of young women. Secondary dysmenorrhoea is so called because it occurs secondary to some underlying pelvic pathology such as endometriosis or pelvic inflammatory disease (PID).

Epidemiology

The estimates vary but epidemiological studies suggest that between 50% and 80% of women will suffer from dysmenorrhoea at some time during their reproductive life, and up to 15% of these women will be seriously debilitated by the condition, with social and economic consequences. In the USA, it has been estimated that dysmenorrhoea accounts for the loss of 600 million working hours which equates to >2 billion dollars. Women in Western countries now have fewer pregnancies and this may be a contributory factor in the increasing prevalence of dysmenorrhoea.

Primary dysmenorrhoea

Aetiology and symptoms

The incidence of primary dysmenorrhoea peaks in women in their late teens and early 20s, the pain coinciding with establishment of ovulatory cycles. A typical sufferer will usually complain of lower abdominal pain (cramping), which may radiate down into the thighs, and backache. Some women also suffer gastro-intestinal symptoms (nausea, vomiting, diarrhoea), headaches and faintness. Symptoms are intense on the first day of menses but rarely continue beyond day 1 or 2 of the cycle. Factors that appear to increase the severity include young age at menarche, extended duration of menstrual flow (pain can be most severe when the flow is lighter), smoking and parity (the prevalence and severity of dysmenorrhoea is decreased in parous women). Other factors such as weight, length of menstrual cycle or frequency of physical exercise do not influence the condition.

In terms of aetiology, studies carried out in the 1950s and 1960s first drew attention to the possible role of the prostaglandins. This was followed by many in vivo studies which showed that women suffering from primary dysmenorrhoea do have greater concentrations of prostaglandins, predominantly PGF_2α, and to some extent PGE₂, in their menstrual fluid compared with matched control subjects. Such a prostaglandin imbalance would favour increased myometrial contractility. The effects of the prostaglandins on human myometrium are now well documented, and increased biosynthesis of prostaglandins may also account for the gastro-intestinal problems encountered by some sufferers. A role for the prostaglandins is substantiated by the fact that women whose diet contains more omega-3 fatty acids tend to suffer less. When eicosapentaenoic acid (EPA) is the substrate for prostaglandin biosynthesis, prostaglandins of the three series are produced (e.g. PGE₃ and TXA₃). Such local hormones are less potent stimulators of the myometrium and less effective vasoconstrictors. Other potential mediators are the endothelins, vasoactive peptides produced in the endometrium that may play a role in the local regulation of prostaglandin synthesis, and vasopressin, a posterior pituitary hormone that stimulates uterine activity and decreases uterine blood flow. The smaller branches of the uterine arteries are very sensitive to the vasoconstrictor actions of these mediators, and it is these resistance vessels that are important in the control of uterine blood flow. The interrelationship between blood flow and myometrial activity is summarised in Fig. 45.4.

Fig. 45.4 The interactive role of myometrial stimulants and vasoconstrictive agents in the pathway leading to pain in dysmenorrhoea.

Measurements of intrauterine pressure and myometrial activity have been made for research purposes, but there are no simple objective measurements for dysmenorrhoea.

Secondary dysmenorrhoea

Aetiology and symptoms

Secondary dysmenorrhoea tends to afflict women in their 30s and 40s, and usually occurs as a consequence of some other pelvic pathology such as endometriosis or pelvic inflammation. In terms of symptoms, it differs from primary dysmenorrhoea in that the pain may actually start before menstruation begins, continue for the duration of menses and be associated with abdominal bloating, backache and a general feeling of ‘heaviness’ in the pelvic area. The intrauterine contraceptive device may also exacerbate menstrual pain, since it causes localised inflammation that triggers the release of prostaglandins. The prostaglandins may also be implicated in the chain of events that lead to pain associated with secondary dysmenorrhoea. For example, if the cause is endometriosis, in which endometrial tissue is found outside the uterine cavity, then this extrauterine tissue can also synthesise prostaglandins, which may in turn disrupt normal uterine function.

Treatment

In terms of analgesia, the most rational choice would be a non-steroidal anti-inflammatory drug (NSAID) (Zahradnik et al., 2010), as these compounds decrease prostaglandin biosynthesis by inhibiting cyclo-oxygenase. Differences in anti-inflammatory activity between different NSAIDs are small. However, there is considerable variation in individual patient tolerance and response, and a lack of response to one particular agent does not mean that a patient would not respond to a different NSAID.

Mefenamic acid is frequently used to manage pain due to dysmenorrhoea. As previously stated, this compound not only inhibits prostaglandin production but also appears to possess some prostaglandin E receptor blocking activity which may serve to augment its effect. However, these preparations are not suitable for all women and some, about 30% of women, will not respond. There is substantive evidence (Marjoribanks et al., 2010) that NSAIDs are effective in the treatment of dysmenorrhoea and are more effective than paracetamol. However, there is insufficient evidence regarding the comparative efficacy of individual agents in terms of superiority of analgesia or side-effect profile.

The lack of an effect with an NSAID may be explained by pathway diversion, since the arachidonic acid that was to be converted to a prostaglandin via the action of cyclo-oxygenase can be utilised by an alternative biosynthetic route, leading to increased formation of leukotrienes. Alternatively, the second cyclo-oxygenase enzyme (COX-2), which is generally induced under pathological conditions, may be involved. Many of the currently available NSAIDs are relatively poor inhibitors of COX-2, and if some of the prostaglandins in these uterine disorders are produced via the action of this form of cyclo-oxygenase, then it is not surprising that the NSAIDs are not 100% effective. Celecoxib and etoricoxib have been shown to be effective, although none is currently licensed for use in dysmenorrhoea.

A small study has investigated the use of the leukotriene receptor antagonist montelukast (Singulair®) in the treatment of dysmenorrhoea (Fujiwara et al., 2010). The results suggest blockade of leukotriene receptors alleviate pain and reduce NSAID usage, and this appears to be most effective in women without endometriosis.

It has been estimated that approximately 50% of primary dysmenorrhoea sufferers will gain relief from taking the oral contraceptive pill, although, as this is a condition afflicting young girls, there may be attitudinal problems to the use of these products either in the patient or her parents. The oral contraceptive pill inhibits ovulation and thereby prevents increased luteal phase prostaglandin synthesis and so decreases uterine contractility. However, not all women are suitable candidates for COC use because of the potential problems associated with exogenous oestrogen. Contraindications include high blood pressure, obesity and a significant personal or family history of venous thromboembolism. Progestogenic preparations (e.g. dydrogesterone 10 mg twice daily from day 5 to 25 of cycle, norethisterone 5 mg three times daily from day 5 to 24 of the cycle) or progestogen-only pills may be useful if they inhibit ovulation. For pain relief, there appears to be no significant difference between the various formulations. Antispasmodics such as hyoscine butylbromide and propantheline bromide have a very limited role in the treatment of dysmenorrhoea, not least because of their poor oral bioavailability. Related compounds such as atropine also have negligible effects upon the human uterus. A summary of the treatment options for dysmenorrhoea is presented in Table 45.1. Future therapy may involve use of vasopressin antagonists. Clinical trials have shown these compounds to be effective and well tolerated and they do not affect bleeding patterns.

Table 45.1 Summary of treatment options for dysmenorrhoea

Drug	Side effects
NSAIDs	Gastric irritation, which can be minimised by taking with or after food or selecting an agent with less gastrotoxicity, for example, ibuprofen. Hypersensitivity reactions, particularly bronchospasm. Headache, dizziness, vertigo, hearing problems (e.g. tinnitus) and haematuria. NSAIDs may adversely affect renal function and provoke acute renal failure
Combined oral contraceptives	Many side effects are dose related and so the development of the ultra-low-dose preparations (i.e. those containing 20 μcg ethinylestradiol) is beneficial. An alternative to the oral preparations is the low-dose transdermal combined contraceptive which releases 20 μcg ethinylestradiol and 150 μcg of norelgestromin (active metabolite of the third-generation progestogen, norgestimate). The most serious potential adverse effect is the increased risk of thromboembolism due to a decrease in circulating levels of antithrombin III while increasing serum levels of some clotting factors. This risk increases with age and smoking. Analysis of current data suggests that the risk of breast cancer is not increased for most women who use the combined oral contraceptive for the major portion of their reproductive years. Use of the combined oral contraceptive also conveys several health benefits besides being an effective contraceptive. The progestogenic side effects are discussed as follows
Progestogen-only preparations	Use of these agents may cause menstrual disturbances, for example, breakthrough bleeding. Other adverse effects relate to the selectivity of the synthetic hormone, for example, norethisterone is a first-generation progestogen and has some affinity for steroid receptors other than progesterone and so possesses androgenic, oestrogenic and antioestrogenic activity. The third-generation progestogens (gestodene, norgestimate and desogestrel) have the least androgenic activity. This should be advantageous as it is the androgenicity of the compounds that correlates with the decrease in high-density lipoproteins

For secondary dysmenorrhoea, the best treatment lies in finding the underlying cause and then taking an appropriate therapeutic route. For example, if some form of PID is diagnosed that can be attributed to a causative organism, then antimicrobial therapy is appropriate. PID is most commonly caused by the presence of a sexually transmitted infection. The most frequent causative organisms are Chlamydia trachomatis and Neisseria gonorrhoeae. In addition, any procedure that may compromise the mucus barrier of the cervix, for example, insertion of an intrauterine device, may also increase the risk of contracting PID. Treatment of endometriosis will often reduce symptoms of dysmenorrhoea. Surgical treatment for secondary dysmenorrhoea such as hysterectomy is also possible for those women who do not want to become pregnant.

Non-pharmacological management options have recently been reviewed and include high-frequency transcutaneous nerve stimulation (TENS) and acupuncture (Proctor et al., 2002). Both of these therapies showed some potential benefit. There is limited evidence to support the use of uterine nerve ablation and presacral neurectomy, to interrupt the sensory nerve fibres near the cervix blocking the pain pathway. Dietary therapies such as vitamin and mineral supplementation have also been investigated. One study identified that vitamin B₁ 100 mg daily may be effective in relieving pain (Proctor et al., 2002). Magnesium supplementation also shows promising results. Unfortunately, evidence is still lacking to support use of other herbal and dietary therapies, for example, omega-3 fatty acids. Some Chinese herbal medicines have shown interesting results but trial quality is poor.

Menorrhagia

Blood loss is considered to be excessive if it exceeds 80 mL per period, although both women themselves and clinicians find it difficult to objectively quantify blood loss. In practice, it is defined by the woman’s subjective assessment of blood loss. Any change in menstruation, whether real or perceived, may be disturbing with respect to social, occupational or sexual activities and can lead to other problems including depression and concern about an undiagnosed problem such as cancer. Physically excessive blood loss will precipitate iron deficiency anaemia (haemoglobin <12 g/dL) which, if left undiagnosed and untreated, will compound the problems outlined earlier.

If a patient has any intermenstrual or postcoital bleeding, then referral to a gynaecologist for endometrial biopsy is essential to exclude intrauterine pathology. Up-to-date cervical cytology is also required. It should also be noted that hormonal contraceptives may cause some irregular spotting or breakthrough bleeding, but this is generally a tolerance effect. Non-oral methods, particularly implants, depots and intrauterine systems decrease bleeding with continued use (see later). WHO recommends a 90-day reference period for reporting vaginal bleeding.

Epidemiology

In the UK, about 30% of women complain of heavy menstrual bleeding, and about 1 in 20 women aged 25–44 years consult their primary care doctor about this problem. Historically, once referred to a gynaecologist, 60% of women could expect to have a hysterectomy within 5 years. Recent changes in the management of women with menorrhagia and new treatment options, particularly endometrial ablations and the levonorgestrel intrauterine contraceptive devices (LNG-IUS), have significantly reduced hysterectomy rates for menorrhagia to a third of the number 10 years ago.

Aetiology and investigation

The aetiology of menorrhagia can be divided into three categories: underlying pelvic pathology, systemic disease and dysfunctional uterine bleeding (Box 45.3). The typical symptoms suggestive of underlying pelvic pathology are presented in Box 45.4. Pelvic pathologies associated with menorrhagia include myomas (fibroids, common benign tumours of the myometrium), endometriosis, adenomyosis (penetration of endometrial tissue into the myometrium), endometrial polyps, polycystic ovarian disease and endometrial carcinoma. Although endometrial cancer is more typically seen in postmenopausal women, approximately 50% of those patients diagnosed with it premenopausally will have associated menorrhagia. Systemic diseases from which menorrhagia may stem include hypothyroidism, disorders involving the coagulation system such as elevated endometrial levels of plasminogen activator and systemic lupus erythematosus. Very few women fall into this group. About 60% of menorrhagia sufferers have no underlying systemic or pelvic pathology and have ovulatory cycles. These patients are said to have dysfunctional uterine bleeding and local uterine mechanisms appear to be important in the control of menstrual blood loss. Occasionally, cycles may be anovulatory, with heavy blood loss because the endometrium has become hyperplastic under the influence of oestrogen. In addition, use of an intrauterine contraceptive device may also increase menstrual blood loss.

Box 45.4 Symptoms suggestive of underlying pelvic pathology

Irregular bleeding

Sudden change in blood loss

Intermenstrual bleeding

Prostaglandins appear to play a role in the aforementioned local mechanisms and have been implicated in menorrhagia. Studies have suggested an association between the type and quantity of endometrial prostaglandin synthesis and the degree of menstrual blood loss. In the mid-1970s, it was discovered that women with heavy periods had raised endometrial levels of PGF_2α and PGE₂ and that blood loss could be reduced by the use of drugs inhibiting prostaglandin formation. More studies suggested that, in menorrhagic women, there is a shift towards increased biosynthesis of PGE₂, which is known to dilate uterine vasculature and/or increase the number of membrane receptors for this prostanoid. The availability of arachidonic acid, a substrate for prostaglandin synthesis, is also greater in women with menorrhagia. Levels of the vasodilators or their metabolites, PGI₂ and nitric oxide (NO), are also increased in the menstrual blood collected from women with excessive blood loss. It has been suggested that menorrhagia is an angiogenesis-related disease associated with changes in the pattern of vascular fragility involving the upregulation of various vascular endothelial growth factors.

Excessive menstrual blood loss is the most common cause of iron deficiency anaemia in women of reproductive age. In an otherwise healthy, well-nourished woman, it has been estimated that menstrual blood loss would have to exceed 120 mL to precipitate iron deficiency anaemia. Objective measurement of menstrual blood loss is difficult, so measurement of full blood count (including red blood cell indices and serum ferritin levels), and in particular, haemoglobin concentration, gives some indication of blood loss. Thyroid function should also be assessed. If fibroids are suspected, then pelvic ultrasound may be required. Endometrial biopsy is needed if there is an associated irregularity of menstruation or if intermenstrual or postcoital bleeding is present. In the case of regular menses, however, investigation of the uterine cavity would usually only be required in women over the age of 35 years or if medical treatment fails to alleviate symptoms. Young women presenting with dysfunctional uterine bleeding may have underlying coagulopathies such as von Willebrand’s disease or Christmas disease, which should be excluded.

Treatment

The management of menorrhagia depends upon the cause of the condition and a woman’s desire to conceive. Treatment can be either surgical or medical (Table 45.2). The effectiveness of drug therapy is obviously influenced by the accuracy of the diagnosis. Drug treatment is also influenced by a woman’s contraceptive needs; for example, COCs can reduce menstrual blood loss by up to 50%, but in women over 35 years of age who smoke, this form of therapy would need careful consideration. Low-dose luteal phase progestogens are no longer recommended for treatment of heavy but regular periods as they increase menstrual blood loss in this situation. However, they may be of value in women with an irregular cycle. Long-term, long-acting progestogens, however, may render a woman amenorrhoeic. Other hormonally based therapies include the GnRH analogues, although their propensity to induce a hypo-oestrogenic state with long-term use may be problematic (a 6-month course would reduce trabecular bone density by 5–6%). Danazol can reduce menstrual blood loss but its use is generally prohibited by its side-effect profile. However, in 2009, a local vaginal treatment of 200 mg a day was investigated in 55 women (Luisi et al., 2009). Results showed danazol to be effective in reducing blood loss and few adverse effects were reported. A trial of ormeloxifene, a selective estrogen receptor modulator (similar to raloxifene), 60 mg twice weekly has been used successfully to reduce blood loss with relatively few side effects (Kriplani et al., 2009).

Table 45.2 Summary of drug treatment options for menorrhagia

Drug	Comments
Combined oral contraceptive	See Table 45.1. These preparations are taken for 21 days with a 7-day pill-free (or placebo) period to allow for a withdrawal bleed
Progestogen-only preparations	See Table 45.1. Compounds such as norethisterone can be used, for example, 5 mg three times daily or 10 mg twice daily for the latter half of the cycle. Ten days of therapy should be sufficient from day 15 of the cycle in ovulatory cycles. However, if the cycles are anovulatory, then a minimum of 12 days’ therapy is more appropriate. Progestogens for 12 days are also required to prevent endometrial hyperplasia in peri- and postmenopausal women taking oestrogen. When progestogens such as norethisterone are used, the dosage required is higher than that used in the combined oral contraceptive pill, and the adverse effects associated with the synthetic progestogens, particularly the 19-nortestosterone derivatives, may be more pronounced
Intrauterine progestogen-only contraceptive	The levonorgestrel-releasing intrauterine device (LNG-IUS) typically releases 20 μcg of levonorgestrel/24 h. Unlike non-medicated IUCDs, which may increase menstrual blood loss, this device appears to reduce it, as a result of the local endometrial actions of the progestogen. The device also offers contraceptive cover without many of the side effects associated with the non-medicated IUCDs. Progestogen-related side effects should be minimised because of the low dose of levonorgestrel employed. Initially, bleeding patterns may be disrupted, but menstrual blood loss should become lighter within three menstrual cycles
Danazol	Danazol suppress the pituitary–ovarian axis. Side effects include amenorrhoea, hot flushes, sweating, changes in libido, vaginitis and emotional lability. Danazol also causes androgenic side effects such as acne, oily skin and hair, hirsutism, oedema, weight gain, voice deepening and decreasing breast size. Danazol has to be taken daily
GnRH analogues (gonadorelin)	After an initial period of stimulation, these agents suppress the pituitary–ovarian axis. As result of inducing a hypo-oestrogenic state, these compounds should only be used for 6 months because they may decrease trabecular bone density
NSAIDs	These agents only need to be taken for the first 3–4 days of menses
Tranexamic acid	This drug appears well tolerated, but can produce dose-related gastro-intestinal disturbances. Patients who may be predisposed to thrombosis are at risk if given antifibrinolytic therapy. This compound is usually only taken for the first 3 days of menses

IUCDs, intrauterine contraceptive devices; GnRH, gonadotrophin-releasing hormone.

Prostaglandins have been implicated in the aetiology of several forms of menorrhagia. Therefore, NSAIDs may be of use in some patients, especially if there is pain associated with menstruation. The NSAIDs appear to be most effective in women with the heaviest blood loss, for example, mefenamic acid 500 mg three times daily from day 1 until heavy flow ceases.

Women with menorrhagia have greater endometrial fibrinolytic activity, hence the use of antifibrinolytic drugs, which are plasminogen activator inhibitors. Tranexamic acid became available for purchase over the counter in UK pharmacies in 2010 as Cyklo-F®. This can be sold to women aged 18–45 years old with a history of regular heavy menstrual bleeding over several consecutive menstrual cycles. Tranexamic acid reduces menstrual blood loss by up to 50% (Lethaby et al., 2000), the recommended dose being 1 g three times daily starting on the first day of menses for up to 4 days. Agents such as tranexamic acid carry a risk of unwanted thrombogenesis, but this does not appear to be translated into practice as increased numbers of deep vein thromboses. This class of drugs decreases menstrual blood loss better than NSAIDs and oral luteal phase progestogen (Lethaby et al., 2005). However, tranexamic acid should be stopped if it has produced no benefit after three cycles.

The levonorgestrel intrauterine contraceptive devices (also known as intrauterine systems or LNG-IUS) can be left in place for up to 5 years following insertion. They reduce menstrual blood loss by up to 90% after 12 months of use. The levonorgestrel-releasing intrauterine system provides relief from dysmenorrhoea, effective contraception and long-term control of menorrhagia. A study showed that the levonorgestrel-releasing intrauterine device was the most cost-effective treatment followed by ablation surgery (Clegg et al., 2007). In addition, other slow-release progestogenic devices such as nesterone implants and vaginal rings also reduce menstrual blood loss and promote amenorrhoea.

Hysterectomy has been the traditional surgical treatment for menorrhagia, with either an abdominal or vaginal approach used (Marjoribanks et al., 2006). Newer alternatives to hysterectomy include endometrial ablation, which can be done by electrosurgical, laser, microwave or thermal techniques. Endometrial ablation is less invasive than hysterectomy, but recurrence of menorrhagia can occur and amenorrhoea cannot be guaranteed. There is evidence that pretreatment with a single dose of a GnRH agonist before the ablation procedure gives a better result. These preparations cause an initial stimulation of gonadotrophin release which then suppresses the hypothalamic–pituitary axis, producing a hypo-oestrogenic state. If circulating levels of oestrogen are low, then endometrial growth will not be stimulated; thus, it will be thinner, making the surgical endometrial destruction more effective. With GnRH pretreatment, modern techniques such as microwave ablation have achieved amenorrhoea rates of about 50% and patient satisfaction rates of 90%.

Endometriosis

Endometriosis is a condition in which endometrial tissue is found outside the uterus. These so-called ectopic endometrial foci have been found outside the reproductive tract in the gastro-intestinal tract, the urinary tract and even the lungs.

Aetiology

Aetiology remains unclear, although retrograde menstruation, when shed endometrial cells migrate up through the fallopian tubes, would appear to be involved. This may occur because abnormalities in uterine innervation cause disruption in the usual patterns of myometrial contractility with consequent loss of the usual fundocervical polarity. Endometriosis is found in women in whom the normal route for the menstrual flow is disrupted, such as when there is some genital tract abnormality. Women who have frequent and heavier periods also seem to be more likely to suffer from endometriosis. Familial predisposition may also be a factor and several gene polymorphisms have been identified.

Studies suggest that endometrium from endometriosis sufferers tends to be more invasive. This may reflect either biological or genetic differences in the peritoneal milieu and may be explained by the upregulation of certain types of metalloproteinase responsible for the degradation of basement membrane. Endometrial tissue from women with endometriosis has aromatase activity which can be stimulated by PGE₂. Therefore, ostensibly the endometriotic lesions have their own oestrogen supply as aromatase converts androgenic precursors into oestrogen and oestrogen stimulates biosynthesis of PGE₂; thus, the cycle is self-perpetuating. In vitro studies have shown that eutopic and ectopic endometrial explants have different lipidomic profiles in terms of their prostaglandin release and the myometrium from endometriosis suffers is more acontractile during menses. Pilot studies in the USA using aromatase inhibitors, such as anastrozole and letrozole, are ongoing.

Epidemiology

Endometriosis was previously considered to be a disease affecting women in their 30s onwards, but increasing use of laparoscopy has revealed that it can occur at any time throughout a woman’s reproductive life. The condition is dependent upon oestrogen stimulation, and as such, it does not occur before the menarche or after the menopause. The exact incidence of the disease is unknown, but it is believed to be about 10% in the general female population of reproductive age. One study has found a positive correlation between a menarche before 13 years and increased risk of developing endometriosis.

Symptoms

Although not all women with endometriosis are symptomatic, the pelvis is the most commonly affected site. Consequently, most of the symptoms of endometriosis relate to this region. Symptoms take the form of dysmenorrhoea and pelvic pain. However, the severity of the pain does not necessarily reflect the extent of the disease because women with severe pain may have few lesions, and vice versa. Dyspareunia often with postcoital discomfort is also common. There may also be menstrual irregularities.

The link between endometriosis and infertility is recognised, but the mechanisms involved have not been established. If the ovaries or fallopian tubes themselves are directly affected by the endometriotic lesions, then fertility may be compromised by purely mechanical means. However, the situation is less clear when the endometriosis does not cause any anatomical distortions. In this case, some of the postulated causes of infertility associated with endometriosis include ovulation disorders such as luteinised unruptured follicle syndrome, anovulation, premature ovulation; hyperprolactinaemia; and changes in the peritoneal environment such as extrauterine endometrial material which, like normal endometrium, is subject to control by the ovarian steroids and like its uterine counterpart is also capable of producing prostaglandins. Prostaglandin levels, along with macrophage concentrations, are raised in the peritoneal fluid of women with endometriotic explants, and these may alter tubular and uterine motility within the abdomen.

Outside the reproductive tract, endometrial deposits can be found along the urinary and gastro-intestinal tracts. If the former is involved, then the patient may suffer from cyclical haematuria, dysuria or even ureteric obstruction. If there is gastro-intestinal tract involvement, then symptoms could include dyschezia, cyclical tenesmus and rectal bleeding or even obstruction. Very occasionally, the lesions are found at more distant sites such as the lungs, where they could cause cyclical haemoptysis. A reduction in bone mass in women with endometriosis has also been reported.

Treatment

The aims of treatment in endometriosis are to relieve symptoms and improve fertility if pregnancy is desired. Treatment can be either surgical or medical. Surgery is increasingly performed laparoscopically and can be employed to restore normal pelvic anatomy, divide adhesions or ablate endometriotic tissue using either laser treatment or electrodiathermy. Medical treatment utilises the fact that endometriotic tissue is oestrogen dependent, and any drug therapy that will oppose the effects of oestrogen should, among other things, inhibit the growth of the endometriotic tissue. Hence, the choices of drug treatment are as follows.

• GnRH analogues such as buserelin, goserelin, leuprorelin and nafarelin. These initially stimulate the hypothalamic–pituitary–ovarian axis but thereafter induce a hypo-oestrogenic state by paradoxically inhibiting follicle-stimulating hormone (FSH) and LH release.

• Low-dose COC (20–30 μcg of ethinylestradiol) monophasic preparations have been found to be as effective as GnRH analogues, and they may slow down disease progression in young women and preserve future fertility.

• Compounds with androgenic activity such as danazol also inhibit pituitary gonadotrophin release by interfering with the negative feedback and cause atrophy of endometrial tissue.

• Progestogens such as dydrogesterone, medroxyprogesterone acetate and norethisterone initially cause decidualisation of the endometrial tissue followed by glandular atrophy.

None of the aforementioned drug therapies are free from side effects. Use of the GnRH analogues may evoke menopausal symptoms such as hot flushes, decreased libido, vaginal dryness (topical vaginal lubricants may be helpful), mood changes and headache. The problems associated with the hypo-oestrogenic state limit the long-term use of GnRH analogues. Although lipoprotein levels are not affected adversely, bone mass is, and this loss of bone density may not be entirely reversible after cessation of therapy. Various ‘add-back’ hormone replacement therapies have been successfully used to minimise bone demineralisation, for example, low-dose oestrogen/progestogen combinations used continuously. Such regimens protect against osteoporosis and other hypo-oestrogenic side effects without apparently affecting clinical efficacy. Pain associated with endometriosis was relieved similarly by gosarelin and a low-dose oral contraceptive (Prentice et al., 1999). However, side-effect profiles differed, for example, hot flushes and vaginal dryness with the former agent and headache and weight gain with the latter.

The androgenic compounds, because of their very nature, are associated with hirsutism, weight gain and acne. Side effects associated with synthetic progestogens relate again to androgenicity, although dydrogesterone is free from virilisation. However, using a levonorgestrel-releasing intrauterine device ensures the low dose of levonorgestrel is delivered locally and the more direct pelvic distribution may be useful in the management of endometriosis. Recent results suggest this device causes the downregulation of endometrial cell proliferation and increased apoptotic activity. Longer-term studies, over 5 years, need to be undertaken to determine how long this effect is maintained and also effectiveness on symptoms such as dyspareunia and dyschezia.

Researchers have also found that certain dietary changes may be beneficial and reduce symptoms. A decreased intake of glycaemic carbohydrates such as sugar, rice and potatoes in addition to reducing/eliminating caffeine and increasing the intake of omega-3 oils such as flax seed oil may also be helpful. In addition, one study found that women with endometriosis tended to have a lower body mass index than those without the condition.

Total pelvic clearance, including the removal of the ovaries, is practical in women who have completed their family. This tends to be a last resort treatment but it is usually effective. However, surgery may be difficult if multiple lesions are present. There is no evidence that hormonal suppression improves surgical outcome.

Neither surgical nor medical management is effective in all cases. Studies suggest that pain associated with endometriosis responds well to both surgical and medical treatment, but symptoms of recurrence occur in about 50% of patients within 5 years of stopping treatment. Fertility may be increased by the use of surgery to remove endometriotic foci causing anatomical distortion. The same benefit is not associated with medical treatment.

Case studies

1. In young girls, it is worthwhile trying non-hormonal treatment options first as they will tend to have a lower side-effect profile than hormonal treatment. Tranexamic acid at a dose of 1 g three times a day should be taken while bleeding. This is a very simple and effective option with few side effects and a reported 50% reduction in menstrual blood loss. Another option would be to try a non-steroidal preparation such as mefanamic acid (500 mg three times daily from first day of bleeding until period ends), especially if associated dysmenorrhoea is a significant problem. Tranexamic acid and an NSAID can be taken together if required.

2. Cyclical norethisterone (5 mg three times daily from day 5 to day 25 of cycle) can be helpful if the periods are irregular, but it is not recommended for heavy regular periods. Progestogenic side effects such as nausea and bloating can limit use. The COC pill can be very effective at relieving menorrhagia and dysmenorrhoea, provided that there are no contraindications. Sometimes, parents can raise concerns about the use of a contraceptive agent, some parents perhaps believing that it may promote promiscuity.

Case 45.2

A 33-year-old woman has been diagnosed with endometriosis having presented with severe dysmenorrhoea. She has visited the gynaecology clinic to discuss treatment options but is very concerned about her fertility. She does not wish to conceive at the present time but would certainly plan to try for a baby in the next couple of years.

Questions

1. What effect does endometriosis and its treatment have on fertility?

2. What treatment options could be considered?

Answers

1. Severe endometriosis with significant distortion of the pelvic anatomy can cause tubal blockage and hence cause tubal factor infertility. Most patients will have much less severe endometriosis which, although not causing any anatomical abnormality, is associated with a reduction in fertility. Such couples tend to take longer to conceive perhaps because the endometrial deposits create an unfavourable milieu for the egg and sperm. Surgical treatment such as diathermy or laser destruction or excision of endometriotic deposits may improve fertility, although such surgery can be complicated. Medical treatments are not associated with an improvement in fertility rates as many treatment options are contraceptive in themselves and should not be used if women wish to try to conceive. In this situation, symptom control with analgesia may be the best option.

2. As this patient is not wishing to conceive, a trial of medical therapy should be considered. Surgery for endometriosis is a highly skilled procedure which has a significant risk of complications. Medical treatment options include GnRH analogues, the COC pill or a prolonged course of progestogens such as medroxyprogesterone acetate. All have different side effects and contraindications but are all equally effective at reducing symptoms of endometriosis. Currently, the most popular option is a 6-month course of a GnRH analogue which is generally well tolerated. Vasomotor symptoms can be treated with add-back hormone replacement therapy with a continuous combined preparation or tibolone. Treatment is limited to a 6-month course because of the bone loss associated with the GnRH-induced hypo-oestrogenism. The COC pill can be taken in a conventional way, but anecdotal experience supports tricycling, that is, taking 3 packets back to back and only having a withdrawal bleed after the third packet. Clearly, the usual contraindications to taking a COC pill apply. Progestogens are often poorly tolerated with side effects such as bloating and nausea.

1. Before considering treatment, the patient should have a pelvic examination, primarily to exclude large fibroids which are unlikely to respond to medical therapy. Current advice is to recommend a levonorgestrel-releasing intrauterine device as first line for heavy menstrual bleeding (NICE, 2007). If the patient declines this, other options would include tranexamic acid and/or a non-steroidal NSAID such as mefenamic acid taken at the onset of the period. The COC pill could be considered if not contraindicated. Cyclical norethisterone may be of benefit if the menstrual cycle is irregular. Hysterectomy should be reserved as the last option and if medical therapy fails. Consideration should be given to an endometrial ablative procedure before resorting to major surgery.

2. If pelvic examination is normal, the only investigation recommended for this lady is a full blood count to exclude anaemia. If examination suggests the possibility of a pelvic mass, an ultrasound scan should be organised. Further endometrium investigation, by hysteroscopy or endometrial biopsy, in women under 45 with heavy menstrual bleeding and no intermenstrual bleeding, is not indicated unless medical treatment options fail.

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