• The few studies of HPV persistence showed a possible protective effect of fruits, vegetables, vitamins C and E, beta- and alpha-carotene, lycopene, luterin/zeaxanthin and cryptoxanthin.¹ Evidence for a protective effect of cervical neoplasia was probable for folate, retinol and vitamin E, and possibly for vegetables, vitamins C and B₁₂, alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin and cryptoxanthin. Evidence for an increased risk of cervical neoplasia associated with high blood homocysteine was probable, although the evidence is still inconclusive. Patients with an abnormal Pap smear should be advised to eat a diet rich in beta-carotene, vitamin C and folate (vitamin B₉) from fruits and vegetables.

• Exercise regularly.

• Reduce avoidable stress. Higher levels of perceived stress have been associated with impaired HPV-specific immune response in women with cervical dysplasia.²

ABNORMAL UTERINE BLEEDING

A normal menstrual cycle occurs every 21–35 days, with bleeding for 2–7 days. Normal blood loss is 20–60 mL per period, with > 80 mL described as heavy.

The process of normal regular menstruation requires:

• sufficient oestrogen to induce ‘follicular phase’ endometrium

• ovulation with formation of a corpus luteum, production of progesterone and induction of ‘secretory phase’ in the endometrium

• withdrawal of progesterone as the corpus luteum declines. Declining progesterone is the trigger for menstruation

• synchronous breakdown and repair of the endometrium at menses

• breakdown factors including prostaglandins, interleukin-1, matrix metalloproteinase (MMP)-1 and MMP-7

• endometrial repair factors including epidermal growth factor-alpha, endothelins and vascular endothelial growth factor (VEGF).³

FIGURE 52.5 The menstrual cycle and hormonal levels

TERMINOLOGY

Terms such as menorrhagia, metrorrhagia, polymenorrhoea, oligomenorrhoea and metropathia haemorrhagica should be replaced by descriptions of the frequency, heaviness and length of bleeding.

Abnormal uterine bleeding (AUB) covers all vaginal bleeding apart from regular ovulatory normal menses.

AETIOLOGY

Abnormal uterine bleeding is most common soon after menarche or in the years before menopause. It may be:

• anovulatory—without ovulation, a corpus luteum does not form. The resulting lack of progestogen and unopposed oestrogen stimulates the endometrium. Bleeding occurs when oestrogen levels fall or the endometrium becomes unstable:

• post-menarche—oestrogen levels rise but the immature hypothalamic-pituitary axis is unable to trigger ovulation. Menses may be infrequent but very heavy, often resulting in anaemia

• perimenopausal—ovarian follicle quality declines, resulting in variable oestrogen levels and variable menstrual flow. A dyssynchronous endometrium with irregular menstrual shedding results in prolonged menses with eventual amenorrhoea

• chronic anovulation—e.g. polycystic ovarian syndrome or hypothalamic dysfunction associated with low body weight, excessive exercise or stress. Oestrogen levels are variable. The corpus luteum does not form or is inadequate to maintain endometrial stability. Unopposed oestrogen stimulates the endometrium, which ultimately becomes unstable and bleeds irregularly

• ovulatory—periods are heavy but regular, due to:

• uterine pathology, e.g. fibroids

• abnormal endometrial function ⁴ or

• systemic causes, e.g. obesity (endogenous oestrogen), clotting disorders (including von Willebrand’s disease), hypothyroidism

• iatrogenic—an imbalance between oestrogen and progestogen associated with the oral contraceptive pill (OCP), hormone replacement therapy (HRT) or progestins results in abnormal bleeding:

• light or absent periods, often with irregular bleeding due to excess progestogen effect

• premenstrual bleeding with inadequate progestogen

• intermenstrual bleeding with triphasic contraceptives

• heavier periods with excess oestrogen effect

• midcycle bleeding with inadequate oestrogen.

Medications associated with bleeding include anticoagulants, selective serotonin reuptake inhibitors, antipsychotics, corticosteroids, tamoxifen.

Medications that interact with the OCP/HRT, including liver enzyme inducers, antibiotics, anti-tuberculous drugs and antifungals, may also cause bleeding.

Herbal substances associated with bleeding include ginseng, ginkgo and soy supplements.

Causes of abnormal uterine bleeding are listed in Box 52.1.

BOX 52.1 Causes of abnormal uterine bleeding

Endocrine:

• immature hypothalamic–pituitary axis

• menopause

• obesity

• polycystic ovarian syndrome

• premature ovarian failure

• Cushing’s disease

• hyperprolactinaemia

• endometrial or cervical polyps

• endometrial or cervical malignancy

• leiomyomas

Pregnancy:

• ectopic pregnancy

• incomplete abortion

Medications:

• oral contraceptive pill (especially low dose, missed pills or drug interactions)

• progestogen-only contraceptives

• intrauterine devices

• tamoxifen

• warfarin

Other conditions:

• bleeding disorders (including thrombocytopenia, von Willebrand’s disease)

HISTORY

The history should include:

• menstrual history—last menstrual period (LMP), flow, ‘accidents’, ‘flooding’, length of cycle, number of days of bleeding, frequency of pad/tampon changes (more than 2-hourly is heavy), limitations on daily activities, use of double pads, changing at night

• features of polycystic ovarian syndrome

• reproductive history—contraceptive use, pregnancies, fertility plans

• lifestyle factors—change in exercise, stress, weight

• symptoms of anaemia—tiredness, palpitations

• medical history—thyroid function, bleeding disorders

• drug history—anticoagulants, hormone use, aspirin, anticonvulsants, SSRIs, antibiotics, alternative and complementary therapies.

EXAMINATION

Examination may be normal but should include:

• signs of anaemia, thyroid disease, bleeding disorder, hyperprolactinaemia

FIGURE 52.6 Main causes of uterine bleeding: A Anovulatory endometrium with stromal breakdown; B Chronic endometriosis with numerous plasma cells (arrow); C Endometrial polyp; D Submucosal leiomyoma with attenuation of the endometrial lining (arrow)

• signs of polycystic ovarian syndrome (i.e. hyperandrogenism, hirsutism, acne, obesity and palpable enlarged ovaries; see Fig 7.7)

• speculum examination to exclude cervical and vaginal causes, especially if bleeding is post-coital

• bimanual examination to exclude fibroids and adnexal masses.

INVESTIGATIONS

Investigations include:

• pregnancy test

• Pap smear, STD screen

• haematology where loss is heavy:

• complete blood picture

• iron studies

• prothrombin time, activated partial thromboplastin time, von Willebrand screen—if bleeding heavy since menarche or suggestive history

• follicle-stimulating hormone, prolactin, thyroid-stimulating hormone

• transvaginal ultrasound—uterine lesions, polycystic ovarian syndrome (PCOS), retained products of conception, ovarian tumours. An endometrial thickness ≤ 4 mm virtually excludes endometrial cancer ⁵

• endometrial biopsy—does not allow visual inspection of cavity and will not allow removal of polyps, resection of fibroids or endometrial ablation

• hysteroscopy and curettage, if required—exclusion of malignancy, removal of endometrial polyp, resection of submucosal fibroid.

MANAGEMENT

Management depends on the cause of bleeding, the woman’s plans for fertility and the impact that periods have on her life. In addition to bleeding, periods may involve dysmenorrhoea, sore breasts, mood disorder, migraines or an aggravation of pelvic symptoms.

Some women may request minimal treatment. Others may wish to avoid periods entirely. Different women may choose very different treatment options.

Teenagers presenting acutely with prolonged heavy bleeding (anovulatory cycles):

• Exclude anaemia, iron deficiency, pregnancy, bleeding disorders (including von Willebrand’s disease).

• Consider options including:

• Vitex agnus castus (chaste tree) 1000 mg daily.⁶ Although few randomised controlled trials (RCTs) exist, Vitex is commonly prescribed for menstrual irregularities, based on data collected by the German Commission E.⁷ Menstrual cycle irregularities due to hyperprolactinaemia, corpus luteum insufficiency, oligomenorrhoea and secondary amenorrhoea have been effectively treated with Vitex extract in open-label, uncontrolled studies

• combined 30–35 μg OCP q.d. with antiemetic until bleeding stops (within 72 hours). Follow with 1 tablet daily without placebo for 3–6 weeks, then withdrawal bleed for 5 days, then OCP ⁸

• norethisterone 5–15 mg daily until bleeding stops, then 5–10 mg daily for 3–6 weeks

• IV conjugated oestrogen (Premarin®) 25 mg. Repeat 4-hourly until bleeding stops, usually within three doses. Follow with a combined OCP or progestin for 3–6 weeks ⁹

FIGURE 52.7 Polycystic ovaries: A Operative findings of classical enlarged polycystic ovaries. The uterus is located adjacent to the two enlarged ovaries. B Sectioned polycystic ovary with numerous follicles. C Histological section of a polycystic ovary with multiple subcapsular follicular cysts and stromal hypertrophy (low power, left). At higher power (×100, right), islands of luteinized theca cells are visible in the stroma.

FIGURE 52.8 Pathology of polycystic ovarian syndrome

FIGURE 52.9 Cervical polyp

• intracavity tamponade with 30–50 mL Foley catheter for 2–48 hours ¹⁰

• Iron therapy until ferritin level is in normal range and for 3 months after bleeding becomes normal.

Ovulatory, regular, heavy periods:

• Exclude anaemia, hypothyroidism, iatrogenic causes, uterine disease (ultrasound).

• Where dysmenorrhoea is present, consider endometriosis or adenomyosis.

Perimenopausal women with frequent irregular periods and variable flow:

• Exclude anaemia, hypothyroidism, hyperprolactinaemia, iatrogenic causes.

• Exclude uterine and cervical disease—ultrasound and cervical smear.

• Consider the woman’s general wellbeing—oestrogen/testosterone deficiency symptoms, increased exercise, dietary review, weight loss assistance, psychological support.

• Consider options:

• Vitex agnus castus 1000 mg daily

• low-dose OCP—if low risk, non-smoker < 50 years

• cyclical progestins, e.g. norethisterone 5 mg day 1–12 each calendar month until menses cease

• sequential HRT—especially with menopausal symptoms

• levonorgestrel IUD—will reduce volume but not change timing of periods

• hysterectomy.

DYSMENORRHOEA

Dysmenorrhoea can be considered ‘normal’ if:

• it is only present on day 1–2 of the cycle

• it resolves with the OCP, or anti-inflammatory medications, and

• the woman is nulliparous.

MANAGEMENT

Management options for ‘normal period pain’ include:

• acupuncture and acupressure

• vitamin B₁, 100 mg daily ¹¹

• magnesium supplement

• strenuous physical exercise.

ENDOMETRIOSIS

DEFINITION

Endometriosis is the presence of endometrial glands and stroma outside the uterus.

AETIOLOGY

The aetiology of endometriosis is unknown. It is increasing in prevalence. A tendency to develop endometriosis is inherited as a complex genetic trait influenced by environmental factors.¹³ Established lesions include inflammatory cells, fibrosis, neovascularisation and aberrant innervation. It has been associated with environmental toxins including organochlorines (polychlorinated biphenyls and dioxin-like compounds).¹⁴

Risk is increased with nulliparity and early menarche.¹⁵

SYMPTOMS

In the past, endometriosis was considered an uncommon condition of women in their thirties and forties. We now know it to be a common condition (5–10%) of women in their teens and twenties.

While some women are asymptomatic, common symptoms include:

• period pain resistant to OCP or anti-inflammatories

• period pain present for more than 1–2 days

• period pain felt on one side or in the lower back

• period-like pain during the month

• ovulation pain always felt on one side

• deep dyspareunia

• progression to chronic pelvic pain

• infertility—this is variable; many women become pregnant easily, so contraception is required

• fatigue.

Dysmenorrhoea is usually a combination of pain from the endometriosis and pain from the uterus. The endometrium of women with endometriosis has nerve fibres (pain receptors) not present in women without endometriosis.¹⁶ Optimal outcome requires management of both endometriotic lesions and the uterine component of pain.

HISTORY

Typical histories include:

• a teenager in whom periods have always been painful. Initial improvement on the OCP is followed by worsening pain resistant to NSAIDs

• a young woman with period pain on more than 1–2 days of a period, pain leading up to a period or pain that feels like period pain at other times of the cycle

• a woman who has had period pain for some time, but now has pain on most days (chronic pain), often with several different pain symptoms

• a woman whose severe period pain as a young woman did not resolve after pregnancy.

INVESTIGATIONS

CA 125

• Rarely used. Not useful for screening.

• Mildly elevated in some cases.

Ultrasound

• Usually normal unless endometriomas are present.

• Transvaginal ultrasound is preferred, except in virgins or where the vaginal probe would cause pain or distress.

• An endometrioma has a grey, homogeneous, ‘ground glass’ appearance.

• The differential diagnosis of an endometrioma is a haemorrhagic corpus luteum. Repeat scan in 2–3 months will show persistence of an endometrioma or resolution of a corpus luteum.

• 99% of women with an endometrioma on ultrasound will have additional peritoneal deposits found at laparoscopy.¹⁷

• An endometrioma may be a marker for severe peritoneal or rectosigmoid disease.

MRI

Rarely required. May be used to investigate rectosigmoid disease or diagnose coexistent adenomyosis.

Laparoscopy

• Required for definitive diagnosis and treatment.

• Lesions may be clear, pink, yellow, brown, white, red or bluish black. May show only as increased vascularity, white scarring or adhesions. Frequently under-diagnosed.

• Histological confirmation of lesions is required.

• Areas of inflammatory tissue are common, but rare in women without pain.

TREATMENT OPTIONS

The treatments chosen will depend on the woman’s individual symptoms, preference, desire for fertility and coexistent conditions.

Explanation and support

• Ensure she knows you believe in her pain. Many women have been told that their pain is exaggerated, it is all in their head or their pain is normal.

• Provide education regarding endometriosis, her specific situation and the treatment options.

• Provide a management plan for when pain is severe, to allow her to control her pain. Anticipation of severe uncontrolled pain causes distress and anxiety as the period approaches.

• Involve a psychologist/counsellor where possible. The psychological, educational, financial, employment and relationship sequelae of pain, low self-esteem and self-doubt are common.

Laparoscopy

Once the diagnosis has been made, options include:

• excision of the endometriosis lesions if an experienced laparoscopic surgeon is present. Conservation of the uterus and ovaries is usual unless the woman is older and removal of these organs has been discussed

• documentation of the lesions and referral to a laparoscopic surgeon for repeat laparoscopy with excision

• diathermy to the endometriosis lesions—this is suitable for superficial ovarian lesions and some superficial peritoneal lesions. It is less effective than excision as deep lesions are incompletely removed and lesions close to the bowel or ureter cannot be safely diathermied

• no surgical treatment, with consideration of medical therapies.

Dietary and complementary therapies

These aim to:

• reduce oestrogen dominance

• reduce inflammation

• block aromatase activity in the endometriosis lesion.

Management includes:

• reducing dietary saturated fats

• avoiding trans fats (found in many processed foods)¹⁸

• maintaining healthy weight range

• reducing caffeine and alcohol intake

• engaging in regular strenuous exercise.

Herbs and supplements:¹⁹

• Vitex agnus castus 1000 mg daily

• anti-inflammatory—Boswellia, cat’s claw, turmeric, bromelain

• magnesium

• vitamin C 500 mg daily, vitamin E 400 IU daily ²⁰

• fish oil 1–2 g daily

• traditional Chinese medicine ²¹—herbs often prescribed include corydalis, cnidium, bupleurum, dong quai and perilla, sometimes accompanied by acupuncture.