Normal menstruation and its disorders

Physiology of the menstrual cycle 502 Menstrual disorders: amenorrhoea 506 Menstrual disorders: oligomenorrhoea 508 Menstrual disorders: dysmenorrhoea 510

Dysfunctional uterine bleeding: scope of the problem 512 Dysfunctional uterine bleeding: diagnosis and investigations 514 Dysfunctional uterine bleeding: medical management 516 Dysfunctional uterine bleeding: surgical management 518 Premenstrual syndrome: overview 520

Premenstrual syndrome: management 522

502 CHAPTER 15 Normal menstruation and its disorders

Physiology of the menstrual cycle

The menstrual cycle involves the coordinated hormonal control of the endometrium allowing pregnancy or regular shedding (periods). Peptide hormones from the hypothalamus and pituitary direct the ovary to produce steroid hormones (HPO axis), which in turn control the endometrium (see Fig. 15.1). The process is complex and aspects of its initiation, control, and cessation are not fully understood. The average ages of menarche and menopause are 12.8 (falling) + 51, respectively. Day 1 of a cycle is the first day of fresh bleeding and this should always be clarified on history of LMP.

Follicular phase

•Pulsatile release of hypothalamic GnRH lanterior pituitary to produce FSH.

•FSH promotes ovarian follicular development lrecruitment of a dominant follicle containing oocyte.

•Follicular granulosa cells produce oestrogen lendometrial proliferation.

•iOestrogen levels l–ve feedback on the hypothalamo-pituitary (HP) axis (via follicular inhibin) to stop further FSH production.

Ovulation

Increasing dominant follicle oestrogen (positive feedback via follicular activin) l altered hypothalamic GnRH pulsatility l pituitary production of LH—LH surge 36h before ovulation.

Luteal phase

•The follicle collapses down to become the corpus luteum (CL) (‘yellow body’), which produces oestrogen and progesterone (from theca cells).

•Progesterone and oestrogen act on an oestrogen-primed endometrium to induce secretory changes lthickening and i vascularity.

•The corpus luteum has a fixed lifespan of 14 days (programmed cell death) before undergoing involution lcorpus albicans (‘white body’).

•If implantation occurs, hCG (luteotrophic) ‘rescue’ of the CL allows continued production of progesterone to support the endometrium.

•In the absence of pregnancy, CL degeneration la rapid fall in progesterone and oestrogen, initiating menstruation.

Fig. 15.1 The menstrual cycle. Reproduced from Sanders S, Dawson J, Datta S, et al. (eds) (2005). Oxford Handbook for the Foundation Programme. Oxford: OUP. By permission of Oxford University Press.

Menstrual phase

•Rapid din steroids lshedding of the unused endometrium.

•Inflammatory mediators (PGs, ILs, and tumour necrosis factor (TNF)) lvasospasm (approx. 24h) in spiral end arteries lhypoxia and endometrial devitalization.

•Vasodilatation and spiral artery collapse lloss of the layer and bleeding from vessels.

•Endometrium lost down to basalis layer (1/3 of loss reabsorbed).

•Complex vascular changes controlled by above secondary messengers, also lnatural haemostatic mechanisms including platelet plugs, coagulation cascade, and fibrinolysis.

•All steroid hormones now at basal level, negative feedback is lifted, and GnRH–FSH production can begin a new cycle.

504 CHAPTER 15 Normal menstruation and its disorders

Normal cycle or pathological?

•Ovulatory cycles vary, but are usually 21–32 days with a basically regular pattern.

•Ovulatory cycles that vary do so due to the follicular phase (luteal phase fixed).

•Shorter or longer cycles usually result from oligo-ovulation/ anovulation.

•After menarche, cycles often irregular for months or for several years until maturation of the HPO axis reliably triggers ovulation.

•Peri-menopausal periods are commonly irregular (usually icycle length) due to ovarian resistance to gonadotrophins and anovulatory cycles.

•1Do NOT blame erratic, chaotic, or constant bleeding in women >45yrs on ‘the menopausal change’—it needs further investigation to exclude genital tract cancer.

•Nearly all women will experience some menstrual irregularity in timing or flow at some stage—many cases are transient.

Bleeding and pain: what is normal?

•Bleeding can be for 1–7 days with an average of 3–5 days.

•Reported amount of blood loss is highly variable.

•Periods described as ‘heavy’ should always be viewed as such.

•Pain is ‘normal’ (vasospasm and ischaemia), but is highly variable.

1Pain interfering with normal functioning needs to be addressed.

1 Bleeding between periods (IMB), after intercourse (PCB), or totally erratic/constant bleeding is always abnormal.

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506 CHAPTER 15 Normal menstruation and its disorders

Menstrual disorders: amenorrhoea

•1° amenorrhoea is lack of menstruation by age 16 in the presence of ssexual characteristics or 14 in their absence.

•2° amenorrhoea is an absence of menstruation for 6mths.

Diagnosis

History

Emphasis on:

•Sexual activity, risk of pregnancy, and type of contraceptive used.

•Galactorrhoea or androgenic symptoms (weight gain, acne, hirsutism).

•Menopausal symptoms (night sweats, hot flushes).

•Previous genital tract surgery (intrauterine instrumentation or LLETZ).

•Issues with eating or excessive exercise.

•Drug use (especially dopamine antagonists for psychiatric conditions).

Examination

•BMI <17/>30, hirsutism, 2°sexual characteristics (Tanner staging).

•Stigmata of endocrinopathies (including thyroid) or Turner’s syndrome.

•Evidence of virilization (deep voice, male pattern balding, cliteromegaly).

•Abdominal: may show masses due to tumours or genital tract obstruction.

•Pelvic: imperforate hymen, blind ending vaginal septum, absence of cervix and uterus.

Management

Must be guided by the diagnosis and fertility wishes. Options include:

•Treat any underlying causes including attaining normal BMI.

•Cabergoline or surgery for hyperprolactinaemia.

•Cyclical withdrawal bleeds (COCP for PCOS).

•HRT for POF.

•Relief of genital tract obstruction: cervical dilation, hysteroscopic resection, incision of hymen.

•Specific treatment for endocrinopathies and tumours.

2 Major congenital abnormalities, AIS, etc. should be managed by multidisciplinary teams in specialist centres.

Common causes of amenorrhoea

Physiological causes

1Pregnancy must always be excluded.

•Lactation.

•Menopause.

Iatrogenic causes

•Progestagenic contraceptives: Depo-Provera®, Mirena IUS®, Nexplanon®, POP.

•Therapeutic progestagens, continuous COCP use, GnRH analogues, rarely danazol.

508 CHAPTER 15 Normal menstruation and its disorders

Menstrual disorders: oligomenorrhoea

When cycles are longer than 32 days they usually represent anovulation or intermittent ovulation. Transient oligomenorrhoea is common (‘stress’ or emotionally related causes are often cited) and usually self-limiting.

Causes of oligomenorrhoea

Similar to many of the causes of 2° amenorrhoea:

•PCOS is the commonest cause (see bPolycystic ovarian syndrome, p. 570).

•Borderline low BMI.

•Obesity without PCOS.

•Ovarian resistance leading to anovulation, e.g. incipient POF, is rare, but important,

•Milder degrees of hyperprolactinaemia need to be excluded as well as mild thyroid disease.

Management of oligomenorrhoea

What does the patient want? Regular periods or fertility?

•Provide reassurance.

•Treat any underlying causes as for amenorrhoea.

•It is not uncommon for no cause to be found, but serious pathology must be excluded.

•Attain normal BMI (weight loss or gain as appropriate).

•Provide regular cycles:

•COCP or cyclical progestagens

•for PCOS a minimum of 3 periods/yr is recommended to dthe risk of endometrial hyperplasia due to unopposed oestrogen.

•Full fertility screening should be performed if ovulation induction is required.

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510 CHAPTER 15 Normal menstruation and its disorders

Menstrual disorders: dysmenorrhoea

•pdysmenorrhoea: the pain has no obvious organic cause.

•sdysmenorrhoea: the pain is due to an underlying condition.

Pain is highly subjective and varies greatly between women. However, if a woman describes her periods as unacceptably painful, then they are!

Diagnosis

History

•Timing and severity of pain (including degree of functional loss): commonly premenstrual pain iin the first 1–2 days of bleeding, then eases.

•Pelvic pain and deep dyspareunia (may signify pelvic pathology).

•Previous history of PID or STIs.

•Previous abdominal or genital tract surgery (may cause adhesions).

Examination

•Abdominal exam to exclude pelvic masses.

•Pelvic exam; cervical excitation, adnexal tenderness, mobility, and masses.

Investigations

•STI screen (including Chlamydia swab).

•USS, endometriomata, PID sequelae, fibroids, congenital abnormalities.

•Laparoscopy is usually reserved for women with USS abnormalities, medical treatment failures, or those with concomitant subfertility.

2 When no disease is identified then ovulation suppression by tricycling COCP or GnRH analogues for up to 6–12mths will limit the number of ‘periods’ and therefore pain. This is an empirical trial of hormonal therapy.

2Pain clinic, psychological support, and self-help groups may be of benefit to some women who wish to maintain their fertility, especially when they have other pelvic pain symptoms.

MENSTRUAL DISORDERS: DYSMENORRHOEA 511

1° dysmenorrhoea

Pain in the menstrual cycle is a feature of ovulatory cycles and is due to uterine vasospasm and ischaemia, nervous sensitization due to PGs and other inflammatory mediators, and uterine contractions. A maternal or sibling history of dysmenorrhoea is very common and the problem usually starts soon after menarche. Theories accounting for 1° dysmenorrhoea include:

•Abnormal PG ratios or sensitivity.

•Neuropathic dysregulation.

•Venous pelvic congestion.

•Psychological causes.

2° dysmenorrhoea

Underlying causes include:

•Endometriosis.

•Adenomyosis.

•PID.

•Pelvic adhesions.

•Fibroids (though not always causal).

•Cervical stenosis (iatrogenic post-LLETZ or instrumentation).

•Asherman’s syndrome.

•Congenital abnormalities causing genital tract obstruction, e.g. non-communicating cornua.

Management of dysmenorrhoea

•Appropriate reassurance and analgesia may be all that is required.

•Symptom control:

•mefenamic acid 500mg tds with each period is effective

•COCP to abolish ovulation

•data on Mirena IUS® demonstrate benefit

•paracetamol, hot-water bottles, etc., may be helpful for some

•TENS, vitamin B1, and magnesium may be of benefit to some women.

•Treat any underlying causes:

•Endometriosis—COCP, progestagens, GnRH analogues

•antibiotics for PID

•relief of obstruction (usually surgical).

•Therapeutic laparoscopy—for above indications: gold standard for diagnosis + management of endometriosis/adhesions/complicated PID.

•Hysterectomy is now rare for this indication alone.

•Laparoscopic uterine nerve ablation (LUNA) is not currently recommended.

512 CHAPTER 15 Normal menstruation and its disorders

Dysfunctional uterine bleeding: scope of the problem

Dysfunctional uterine bleeding (DUB) is a diagnosis of exclusion and is defined as any abnormal uterine bleeding in the absence of pregnancy, genital tract pathology, or systemic disease.

•Menorrhagia is the commonest symptom and DUB will ultimately be the cause in 50–60% of women with this symptom.

•Menorrhagia is responsible for 15–20% of gynaecological referrals to hospital and an even higher proportion of GP gynae consultations.

1Objective measures of blood loss >80mL are clinically meaningless and should not be used outside research. If periods are reported as unacceptably heavy, then they are!

Aetiology

The exact causes of DUB are unknown. Proposed mechanisms at the endometrial level include:

•Abnormal PG ratios (+ other inflammatory mediators) favouring vasodilatation and platelet non-aggregation.

•Excessive fibrinolysis.

•Defects in expression/function of matrix metalloproteinases (MMPs), vascular growth factors, and endothelins.

•Aberrant steroid receptor function.

•Defects in the endomyometrial junctional zone.

The medical treatments tend to reflect the underlying pathologies (see b Dysfunctional uterine bleeding (DUB): diagnosis and investigations, p. 514).

DYSFUNCTIONAL UTERINE BLEEDING: SCOPE OF THE PROBLEM 513

DUB at a glance

•Menorrhagia is the commonest gynaecological symptom you will see, and most of these women will have DUB.

•DUB is an umbrella term and only diagnosed after exclusion of pathology.

•Women under 45 can safely be treated without investigation in the absence of erratic bleeding.

•TVS is the first-line investigation if the woman is >45yrs with failed medical therapy to identify endometrial polyps + fibroids (i.e. focal pathology).

•In the presence of erratic bleeding in women >45yrs an endometrial biopsy is required.

•The majority of women will respond to medical therapy, especially tranexamic ± mefenamic acid.

•The Mirena IUS® is an excellent treatment that significantly reduces the number of women requiring surgery.

•Surgery should only be used in women who have completed their family and have had failed adequate medical therapy.

•Endometrial ablation: microwave endometrial ablation (MEA), balloon ablation, or Novasure are easy to perform and should be offered before hysterectomy.

•Hysterectomy has higher morbidity and cost, but is a guaranteed cure, and long-term satisfaction rates are high.

514 CHAPTER 15 Normal menstruation and its disorders

Dysfunctional uterine bleeding: diagnosis and investigations

Diagnosis

Symptoms

•Heavy and/or prolonged vaginal bleeding (with clots and flooding): irregular, heavy periods usually occur at the extremes of reproductive life (post-menarche and peri-menopausal).

•May be associated with dysmenorrhoea.

•Systemic symptoms of anaemia and disruption of life due to bleeding.

•A smear history and contraceptive use are vital information.

1Totally erratic bleeding, IMB, or PCB should prompt a search for cervical or endometrial pathology.

Clinical signs

•Anaemia.

•Abdomino-pelvic examination is usually normal. If the uterus is significantly enlarged, fibroids are likely.

Differential diagnosis for DUB

•Submucous fibroids.

•Adenomyosis.

•Endometrial polyps, hyperplasia, or cancer.

•Very rarely, hypothyroidism or coagulation defects.

Investigations

1Pregnancy should always be considered and excluded.

•FBC (Hb + MCV).

•Ferritin, TFTs, and clotting screens are not routine investigations—only consider if clinically indicated.

•Cervical smears are not done opportunistically if smear history normal.

•STI screen including Chlamydia.

•The risk of endometrial pathology in women <45yrs is very small so no further investigation required—treat and await clinical response.

•If >45yrs, with risk factors for endometrial disease, or no clinical response:

•TVS USS—is good for identifying fibroids and polyps, and measuring endometrial thickness. The risk of endometrial pathology with a normal TVS USS is small, but it may be less accurate during menstruation

•pipelle endometrial biopsy to exclude hyperplasia or cancer

•hysteroscopy and biopsy (preferably outpatient) may be appropriate as above or if there is no response to initial medical treatment

•hysteroscopy is mandatory with erratic bleeding in a woman >45yrs if USS reveals focal pathology, e.g. polyp, or is unable to assess the whole endometrium, biopsy is inadequate, or bleeding is persistent or repeated.

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DYSFUNCTIONAL UTERINE BLEEDING: MEDICAL MANAGEMENT 517

Choice of management for DUB

This will depend on:

•Treatment being directed to symptom relief and improved QoL.

•A woman’s wishes for treatment being of prime importance.

•Her reproductive wishes and contraceptive needs.

•Whether her periods are regular or irregular.

2Many women may just need reassurance that there is no serious cause.

2 Women may continue medical treatments for as long as they are beneficial.

2 Anaemia should be corrected by treating the underlying cause of bleeding and using ferrous sulphate (or equivalent) to replace lost iron stores.

Further patient information

NICE. (2010). Heavy menstrual bleeding: understanding NICE guidance. NICE guideline CG44.

Mwww.nice.org.uk/CG044publicinfo

518 CHAPTER 15 Normal menstruation and its disorders

Dysfunctional uterine bleeding: surgical management

Surgery should be reserved for the minority of women who fail to respond to medical management.

1Women have to be certain their families are complete before surgery.

Endometrial ablation

Destruction of the endometrium down to the basalis layer is effective for most women and should be offered to all for consideration.

Methods include:

•Microwave (MEA).

•Thermal balloon (Thermachoice).

•Novasure (electrical impedance).

2Hysteroscopic resection, or rollerball ablation, are now used much less often due to ioperative complications.

1 Endometrial ablation is less effective if the endometrial cavity is >10cm.

Typical endometrial ablation results in normal size cavities:

•80–90% of women are significantly improved.

•30% will become amenorrhoeic.

•20% will need a second procedure by 5yrs.

•The newer procedures above are generally very safe and straightforward; however, there is a small risk of bleeding, infection, uterine perforation, and failed procedure.

•They are generally carried out under GA, but may occasionally be done under cervical block.

Hysterectomy

•Hysterectomy is the only guaranteed cure for DUB, but RCTs have shown higher morbidity, longer recovery, and financial costs compared

to endometrial ablation.

•Complications include haemorrhage; infection; and bladder, ureteric, or bowel injury (<1%). Death is extremely rare.

•Long-term satisfaction rates for hysterectomy are generally very high and regardless of method most women report improved sexual function—as one patient put it, ‘I actually have sex now I’m not bleeding all the time’.

DYSFUNCTIONAL UTERINE BLEEDING: SURGICAL MANAGEMENT 519

Current evidence regarding method of hysterectomy

•Vaginal hysterectomy is the route of choice over abdominal, where possible, as recovery, post-operative pain, and cost are reduced.

•Laparoscopic-assisted vaginal hysterectomy (LAVH) takes longer than abdominal or vaginal, and has higher rates of urinary tract injury. No evidence supports routine use of this method.

•Subtotal hysterectomy is quicker and has a lower risk of bladder injury, but the possible improved sexual satisfaction rates are as yet unproven. There is a small risk of continuing light menstruation if residual endometrial cells are left, and women will continue to require smear tests.

PREMENSTRUAL SYNDROME: OVERVIEW 521

DSM-IV criteria for premenstrual dysphoric disorder

At least 5 symptoms present for most of the late luteal phase with remission within a few days of onset of menses and absence of symptoms in the week post menses. At least one symptom must be from the following first four:

•Markedly depressed mood, feelings of hopelessness, or self-deprecation.

•Marked anxiety, tension (being ‘on edge’).

•Marked affective lability (e.g. feeling suddenly sad or tearful).

•Persistent and marked anger/irritability/increased conflicts.

•Decreased interest in usual activities (school, friends, hobbies).

•Subjective sense of difficulty in concentrating.

•Lethargy, easy fatiguability/lack of energy.

•Marked change in appetite, overeating, or specific food cravings.

•Hypersomnia or insomnia.

•Subjective sense of being overwhelmed or out of control.

•Other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sense of ‘bloating’, weight gain.

Further reading

National Association of Premenstrual Syndrome. Mwww.pms.org.uk

522 CHAPTER 15 Normal menstruation and its disorders

Premenstrual syndrome: management

Hormonal

Progesterone and progestogens

A meta-analysis suggests no benefit of progesterone pessaries, suppositories, depot injections, or oral formulations.

Ovulation suppression agents

•COCP: appears useful for some women. However, some women have PMS-type progestagenic side effects or symptoms during the pill-free interval. Yasmin® contains drospirenone with a better side

effect profile, and newer pills with a 2–4-day break or with no pill-free interval may be more therapeutic.

•Danazol: 4 RCTs report benefit for PMS, but there are significant masculinizing side effects. Treatment in luteal phase only is effective for breast tenderness.

•Oestrogen: transdermal oestrogen or implants at doses sufficient to suppress ovulation are not currently licensed, but they are a well established and accepted treatment of PMS. Estradiol patch 100 micrograms twice weekly with a progestogen (cyclical basis). Implants generally makes them unsuitable for those who may wish to conceive.

•GnRH analogues ± addback HRT: are of proven benefit for moderate to severe PMS, but with a licence for 6mths treatment only due to bone loss. Usually given with addback tibolone (fewer side effects and bone loss). ‘GnRH test’ useful for those considering hysterectomy and bilateral salpingo-oophrectomy (BSO) for severe symptoms.

Non-hormonal

•SSRIs/selective noradrenalin reuptake inhibitors: a meta-analysis confirms benefit for continuous and luteal phase only treatment. No current

licence in the UK so careful documentation is required as some women are reluctant to accept antidepressants. Side effects may be problematic, but are reduced by luteal phase only dosing.

• Antidepressants: tricyclics and anxiolytics have benefits for selected patients as indicated in at least 9 studies.

Surgery

Two trials have confirmed a benefit of removal of the ovarian trigger with the uterus to avoid the need for combined HRT as definitive treatment for severe PMS. However, it is generally recommended that a ‘GnRH test’ is performed to ensure that a benefit will be realized and/or another indication for hysterectomy is present.

PREMENSTRUAL SYNDROME: MANAGEMENT 523

Self-help techniques for managing PMS

Dietary alteration

Possible benefit with less fat, sugar, salt, caffeine, and alcohol, frequent starchy meals, more fibre, fruit, and vegetables, and 4-hourly

small snacks.

Dietary supplements

•Vitamin B6: possible benefit for PMS symptoms and depressive symptoms.

•Vitamin E: studies small, but promising.

•Calcium: two studies (1200–1600mg) revealed some improvement in symptoms.

•Magnesium: appears most beneficial for premenstrual anxiety.

•Evening primrose oil: of value for mastalgia only.

Exercise

Moderate regular aerobic exercise promoting cardiovascular work is beneficial (three controlled studies).

Stress reduction

Relaxation techniques, yoga, meditation, breathing techniques, and encouragement of healthier lifestyle may also help.

Cognitive behavioural therapy

Several studies have indicated a long-term benefit for women with PMS.

Complementary and alternative therapies used in PMS

•Acupuncture: several RCTs show positive data for dysmenorrhoea.

•Homeopathy: in a pilot study (n = 20), improvement in 90% compared to placebo.

•Progesterone and wild yam: no benefit demonstrated in many studies.

•Phytoestrogens: possible benefit for PMS symptoms (may be difficult to incorporate into a western diet).

•Herbal remedies:

•two good trials confirm benefit of Vitex agnus castus (20mg od)

•St John’s wort may also be of value due to its action as an SSRI; further studies awaited.

•Mind–body: aromatherapy, reflexology, photic stimulation, and magnotherapy may show some benefit, but data are sparse.

Further reading

Mwww.bms.org.uk

Mwww.pms.org.uk

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