Abnormalities of Menstruation

Published on 10/03/2015 by admin

Filed under Obstetrics & Gynecology

Last modified 22/04/2025

Print this page

This article have been viewed 3232 times

Chapter 6 Abnormalities of Menstruation

Normal and Physiological Changes in the Menstrual Cycle 88

Amenorrhoea 88

Menarche 88

Physiological Amenorrhoea 89

Pregnancy 89

Lactation 89

Menopause 89

Causes of Amenorrhoea 89

Uterine and Lower Genital Tract Disorders 90

Imperforate Hymen or Transverse Vaginal Septum 90

Asherman’s Syndrome 91

Müllerian Agenesis 91

Congenital Androgen Insensitivity 91

Ovarian Disorders 92

Gonadal Dysgenesis 92

Premature Ovarian Failure 93

Resistant Ovary Syndrome 93

Polycystic Ovarian Syndrome 94

Pituitary Disorders 97

Hyperprolactinaemia 97

Hypothalamic Disorders 101

Diagnosis 101

Causes 101

Investigation of Amenorrhoea 102

Investigation 102

Hirsutism 105

Aetiology 105

Physiology of Testosterone 105

Virilisation 106

Clinical Features 106

Investigation 106

Management of Hirsutism 107

Local Treatment 107

Drug Treatment 108

Menstrual Disorder 109

Dysfunctional Uterine Bleeding 110

Clinical Features 110

Estimation of Blood Loss 110

Investigation of the Endometrium 111

Outpatient Procedures 111

Investigations of Endometrium 112

Methods of Endometrial Biopsy 112

Dilatation and Curettage 112

Investigations of Endometrium – Complications 113

Management of Heavy Menstrual Bleeding 114

Medical Management 114

Surgical Management 115

Endometrial Ablation Techniques 115

Dysmenorrhoea 120

Nature of the Pain 120

Aetiology 120

Clinical Features of Primary Dysmenorrhoea 121

Management 121

Drug Treatment 121

Adenomyosis 122

Pathology 122

Microscopic Appearances 122

Premenstrual Syndrome 129

Clinical Features 129

Investigations 129

Treatment 130

Management Options for Severe PMS 130

Normal and physiological changes in the menstrual cycle

Normal menstrual cycles have a length of 21–35 days (mean 28 days). A normal period lasts for 3–7 days. Menstrual blood loss of 30–50 ml/month is normal. Menstrual blood loss is considered as excessive when it is greater than 80 ml/month. It is, however, rarely measured in clinical trials, and heavy menstrual loss should be defined clinically.

Amenorrhoea

Amenorrhoea is the absence of menstruation for 6 months in a woman who had previously menstruated normally (sometimes called 2° amenorrhoea)

amenorrhoea is the term given when a girl has failed to menstruate by the age of 16 (sometimes called 1° amenorrhoea).

In practice, the distinction between 1° and 2° amenorrhoea is not generally helpful in making a diagnosis. A similar process of investigation should be carried out whether or not the patient had previously menstruated. Amenorrhoea occurs in a number of physiological conditions, and these should be borne in mind when initiating investigation.

Menarche

Menarche is the onset of menstruation at puberty. The median age at which menarche occurs (13 y) is relatively late in the events occurring around puberty. For most young women, the growth spurt and secondary sexual characteristics, such as breast development (thelarche) and the growth of pubic and axillary hair, usually precede the onset of menstruation by about 2 years.

Absent or late puberty may present with amenorrhoea. If a girl over the age of 14 presents with amenorrhoea, investigations should depend on whether or not other signs of puberty are present.

Physiological amenorrhoea

Pregnancy

During pregnancy, the levels of oestrogen and progesterone remain high, thus ensuring the integrity of the endometrium, and causing amenorrhoea. Initially, the corpus luteum is the source of oestrogen and progesterone. Later in pregnancy, the production of oestrogen and progesterone is taken over by the placenta. Pregnancy should be considered in the differential diagnosis of all women who present with amenorrhoea.

Lactation

Soon after delivery, prolactin is secreted in large quantities by the anterior pituitary. There is partial suppression of luteinising hormone (LH) production so that ovarian follicles may grow, but ovulation does not occur, and amenorrhoea is the result. If the mother does not breast feed, menstruation will return in 2–3 months, but if she does breast feed, the period of amenorrhoea will be prolonged.

Menopause

The menopause is the cessation of menstruation (mean age 51 y) due to exhaustion of the supply of ovarian follicles. Oestrogen production therefore falls. This fall in oestrogen production is accompanied by a rise in follicle stimulating hormone (FSH) levels, which continues for a considerable time. In a proportion of women, menstruation ceases abruptly, but in many, the menstrual cycles alter. Frequently, they become shorter initially, but later they lengthen and tend to be irregular, before ceasing entirely. This phase is known as the menopause transition, and the final period is recognised only in retrospect, after 1 year of amenorrhoea. See Chapter 18.

Causes of amenorrhoea

Amenorrhoea may be classified in a number of ways. One of the most helpful classifications is shown below:

1. Uterine or lower genital tract causes

2. Ovarian causes

3. Pituitary causes

4. Hypothalamic causes.

Uterine and lower genital tract disorders

Imperforate hymen or transverse vaginal septum

This condition usually presents with primary amenorrhoea. There is no visible bleeding although the usual cyclical symptoms are present. In that there is no flow of blood, the term amenorrhoea can be used, but the cause is an obstruction by a vaginal septum or an imperforate hymen rather than a functional abnormality.

Three degrees are recognised.

Haematocolpos. Only the vagina is distended by altered blood.

Haematometra. The uterus is also distended.

Haematosalpinx. In long-standing cases the tubes are also involved.

Asherman’s syndrome

In Asherman’s syndrome, the uterine cavity is obliterated by adhesions. The condition is usually caused by uterine surgery: most commonly curettage, for example during termination of pregnancy. In developing countries, infections such as tuberculosis and schistosomiasis are commoner causes of Asherman’s syndrome.

The adhesions should be broken down hysteroscopically. High dose oestrogens are used to stimulate endometrial proliferation following the procedure. Some authorities advocate the use of a Foley catheter placed in the uterus for a short time after adhesiolysis to prevent recurrence. Pregnancy rates following treatment are in the order of 80%. Such pregnancies may be complicated by abnormal placentation, for example by placenta accreta.

Müllerian agenesis

See Chapter 1

The Müllerian ducts fuse by the 10th week of gestation to form the fallopian tubes, uterus and upper portion of the vagina. Agenesis or lack of development of the Müllerian ducts (the Mayer–Rokitansky–Kuster–Hauser syndrome) leads to absence of these structures. Absence or hypoplasia of the vagina is a constant feature, but the uterine abnormalities vary. Provided there is a cavity lined by endometrium, menstruation can be normal.

The diagnosis of Müllerian agenesis is made in women with primary amenorrhoea and an absent vagina, but normal female chromosomes. Ovarian function is normal.

Congenital androgen insensitivity

Previously known as testicular feminisation syndrome, congenital androgen insensitivity is the third commonest cause of primary amenorrhoea. The individual is phenotypically female although the uterus is absent. The karyotype is 46XY (see p. 62).

Ovarian disorders

1. Gonadal dysgenesis

2. Premature ovarian failure

3. Resistant ovary syndrome

4. Disorders of ovulation such as polycystic ovarian syndrome

5. Hormone-producing tumours, such as granulosa cell tumours (oestrogen-producing) or Leydig cell tumours (androgen-producing).

Gonadal dysgenesis

Women with gonadal dysgenesis have abnormal ovarian development, leading to absent or streak ovaries. The number of germ cells that migrate to the ovary during intrauterine life is reduced. These woman present with primary or secondary amenorrhoea, and have persistently elevated gonadotrophins on testing.

In women under 30 years of age at the time of presentation, a karyotype should be performed. Turner’s syndrome (p. 60) is the classic form of gonadal dysgenesis, but other karyotypes, including 46XX are also found. If a Y chromosome is present, consideration should be given to gonadectomy because of the risk of neoplasia.

Premature ovarian failure

In this condition, ovarian follicles are depleted from the ovary before the normal age of the menopause, and a premature menopause ensues. In addition to amenorrhoea, the patient may complain of menopausal symptoms such as hot flushes, loss of libido, etc. This condition is not uncommon: 1% of women will have ovarian failure by the age of 40. Premature ovarian failure is found in around 10% of women with amenorrhoea.

Cause

The majority of women with premature ovarian failure have no obvious cause for their condition. It is associated with chromosomal abnormalities such as Turner’s syndrome (XO). It may occur in association with autoimmune disease, following infections such as mumps, or following chemotherapy or pelvic radiotherapy.

Diagnosis

The diagnosis is made by finding elevated serum FSH levels (>20 IU/L). As FSH levels are elevated physiologically mid-cycle, at least two FSH levels should be obtained at six weekly intervals. If a high FSH level is followed 2 weeks later by menstruation, the cause of the elevated FSH may be more likely to represent ovulation rather than menopause.

Treatment

Women with premature ovarian failure should be advised that they are likely to be infertile, although spontaneous pregnancies have been reported. Pregnancy can be achieved by IVF (in vitro fertilisation) with donor oocytes.

Oestrogen replacement should be considered to reduce the risk of osteoporosis and cardiovascular disease. A progestogen is also required to protect the endometrium from the stimulatory effects of oestrogen. This can be in the form of hormone replacement therapy, but, alternatively, the combined oral contraceptive pill would be a suitable option and may be more acceptable to young women.

Resistant ovary syndrome

In this condition, the ovarian follicles fail to develop, despite high circulating levels of gonadotrophins. The clinical and biochemical features are that of premature ovarian failure. An ovarian biopsy will reveal ovarian follicles, and thus distinguish the condition from premature ovarian failure. In practice, this is not helpful; it may stimulate adhesion formation and the absence of follicles can be reliably determined only after the entire ovary has been examined. The treatment is the same as for premature ovarian failure.

Polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is a functional derangement of the hypothalamo–pituitary ovarian axis associated with anovulation. The pathophysiology of PCOS remains poorly understood. Insulin resistance is a feature, and a genetic element to the disorder has been proposed. Women with PCOS are more at risk of developing Type II diabetes.

In women with PCOS, LH levels are relatively high and FSH levels are relatively low, leading to an elevated LH:FSH ratio. Oestradiol levels tend to be within the normal range. Production of androgens is stimulated by the elevated levels of LH; increased levels of testosterone, androstendione and DHA are secreted by the ovary. Some of these androgens are converted to oestrogen in peripheral tissues. In response to high androgen levels, sex hormone binding globulin (SHBG) is reduced by about 50%, leading to an increase in the proportion of unbound, active, androgens. Hence, androgenic side effects are common, despite only a modest rise or even normal levels of total serum testosterone levels.

Clinical Features

The clinical features of PCOS are variable. In the classic ‘Stein Leventhal’ syndrome, described in 1935, the presenting features are oligomenorrhoea, hirsutism and obesity. Other manifestations are common, however, and include menstrual disorders ranging from amenorrhoea to menorrhagia and signs of androgen excess, such as hirsutism, acne and infertility.

Diagnosis

No specific features of polycystic ovarian syndrome are diagnostic of the condition. According to the Rotterdam criteria, the diagnosis can be made if two out of three of the following criteria are present:

1. Oligoamennorhoea

2. Ultrasound

Ultrasound will show multiple follicular cysts up to 6–8 mm diameter within the ovary. This is described as a necklace of pearls appearance. The volume of the ovarian subcortical stroma is increased. Such findings on ultrasound support rather than confirm a diagnosis of PCOS, as 25% of normal women will demonstrate these features on ultrasound.

3. Elevated free testosterone levels

A modest increase in total testosterone is accompanied by a decrease in SHBG resulting in an increase in free testosterone levels.

An elevated LH:FSH ratio may occur but is no longer a diagnostic criteria. A physiological raised LH level occurs during the LH surge.

Long-term Effects of PCOS

1. Women with PCOS who are anovulatory are at increased risk of endometrial hyperplasia and subsequent endometrial cancer (×3) because of the high oestrogen and low progesterone levels.

2. The hyperinsulinaemia associated with insulin resistance leads to an increased risk of diabetes mellitus.

3. Women with PCOS who are obese and insulin resistant have an increased risk of hypertension and cardiovascular disease.

Treatment of PCOS

The treatment for PCOS is aimed at relieving symptoms and preventing adverse long-term effects. For women who are overweight, weight loss should be strongly supported as it reduces the clinical features of the condition and provides long-term health benefits.

1. Infertility

Anovulatory women with infertility should be treated with clomiphene in the first instance. Women who fail to respond may require gonadotrophins ± gonadotrophin releasing hormone (GnRH) analogues.

2. Amenorrhoea

Women with amenorrhoea may be treated with the combined oral contraceptive pill if contraception is required, or cyclical gestogens (e.g. medroxyprogesterone acetate 10 mg daily from day 15 to 25) if contraception is not required. The prevention of amenorrhea is important in PCOS to reduce the risk of endometrial carcinoma. The Mirena IUS is also useful to reduce the long-term risk of endometrial hyperplasia.

3. Hirsutism

See p. 106.

Pituitary disorders

1. Hyperprolactinaemia

2. Pituitary adenoma

3. Craniopharyngioma

4. Other tumours such as meningioma

5. Pituitary necrosis (Sheehan’s syndrome/Simmond’s disease).

Pituitary tumours are normally benign. However, as they grow in a confined space, they may cause symptoms by compressing surrounding tissue and structures. Functioning pituitary tumours may exert effects because of the hormones they release. The commonest of these are prolactin secreting pituitary tumours, accounting for 50% of all pituitary adenomas.

‘Double floor’ appearance of the pituitary fossa due to tumour

Hyperprolactinaemia

Prolactin is secreted from the anterior pituitary, and the normal blood level is between 150 and 600 mU/L depending on the laboratory. During pregnancy, there is a 10-fold increase in serum prolactin levels. Non-physiological hyperprolactinaemia, which occurs when the woman is non-pregnant, can cause amenorrhoea or galactorrhoea (inappropriate lactation) or both. Hyperprolactinaemia is the principal cause of amenorrhoea in around 20% of women with this condition.

Control of prolactin release

Aetiology

1. Pituitary tumour

microadenoma <10 mm diameter

macroadenoma >10 mm diameter

2. Hypothyroidism

Thyroid function tests should be performed on all women with hyperprolactinaemia. In primary hypothyroidism, TRH is increased. As TRH stimulates pituitary prolactin production, hyperprolactinaemia results.

Treatment with L-thyroxine should restore prolactin levels to normal.

4. Idiopathic

Diagnosis of Hyperprolactinaemia

The diagnosis of hyperprolactinaemia can be made on a single serum measurement. In the presence of oligo- or amenorrhoea, a serum prolactin of 800 mU/L or greater is likely to be of pathological significance. In the absence of an obvious alternative cause, radiological examination such as computerised tomography (CT) scanning or magnetic resonance imaging (MRI) should be performed to exclude a pituitary tumour.

Treatment

Medication

Dopamine is the prolactin release inhibiting factor produced by the hypothalamus, and medical treatment for hyperprolactinaemia is based around dopaminergic stimulation.

1. Bromocriptine

This is a semi-synthetic ergot alkaloid. Side effects include nausea and giddiness with fainting (syncope). Side effects may be minimised by commencing with a small dose and increasing gradually.

Effect of bromocriptine on serum prolactin. Duration 12–16 h.

2. Quinagolide

Quinagolide, a dopamine agonist, is given daily and may be tolerated better than bromocriptine.

3. Cabergoline

Cabergoline is a dopamine agonist with a long half-life. It is administered weekly.

Surgery

Transnasal

Trans-sphenoidal surgery can be used to resect both micro- and macroadenomas. Symptoms of hypopituitarism, particularly diabetes insipidus, may be a long-term consequence of surgery. The results of treatment vary greatly between centres. Knowledge of local data can be used to determine whether surgery or medical treatment is most appropriate for each patient.

Hypothalamic disorders

Intermittent release of GnRH (gonadatrophin releasing hormone) stimulates production of FSH and LH by the anterior pituitary. Increased concentration of endogenous dopamine and opioids can affect the release of GnRH. This can be provoked by a number of conditions, detailed below.

Disorders of the hypothalamus result in hypogonoadotrophic hypogonadism, and hence amenorrhoea.

Diagnosis

The diagnosis is made by exclusion. These patients have low gonadotrophins, normal prolactin levels, a normal pituitary gland on radiological evaluation, and they fail to bleed in response to progesterones.

Causes

1. Anorexia nervosa

This is an eating disorder characterised by low body weight. It is much more common in women than in men and usually starts in the mid-teen years. The patient’s weight is more than 15% below normal for her age and height.

In moderate to severe disease, it is important to treat the psychological cause of the condition and this is best done by referral to a psychiatrist. Treatment with hormone replacement therapy will relieve symptoms of oestrogen deprivation and initiate the resumption of menstrual periods.

2. Exercise

Female athletes are commonly amenorrhoeic, and the mechanism is one of suppression of GnRH production. This condition is related to the much reduced body fat (although not necessarily body weight), stress and to exercise itself. Again, oestrogen replacement (with added cyclical gestogens) should be considered.

3. Kallmann’s syndrome

This is a rare condition of congenital hypogonadotrophic hypogonadism in association with anosmia. Secondary sexual characteristics are absent. Ovulation can be induced with gonadotrophins.

Investigation of amenorrhoea

In most cases, the failure to menstruate is due to some abnormality in the control mechanism involving the hypothalamic–pituitary pathway. A careful history and physical examination is essential and may provide pointers to likely abnormalities.

The history should include the following:

change in weight

presence of galactorrhoea

presence of hirsutes (excess body or facial hair)

presence of stress

questions about excessive exercise.

A full physical examination should be performed. This should include the following:

assessment of patient’s body mass index (BMI) (weight in kg²/height in m)

presence of galactorrhoea

presence of hirsutes

blood pressure

urinalysis

assessment of secondary sexual characteristics

assessment of external genitalia

pelvic examination to assess internal genitalia.

In women who are virgo intacta, a pelvic examination should not be performed. If necessary, information about the presence of a uterus can be gained from ultrasound or MRI. However, inspection of external genitalia can still be performed and may reveal a condition such as cliteromegaly.

Investigation

The simplified scheme of investigation shown will identify which compartment is responsible for the amenorrhoea. In practice, estimation of serum prolactin and thyroid stimulating hormone (TSH) is performed concurrently with a progesterone challenge test.

The progesterone challenge test involves giving a progesterone, for example, medroxyprogesterone acetate 10 mg daily for 5 days. It is essential to exclude pregnancy first. If the woman bleeds after progesterone is withdrawn, this indicates firstly that a uterus is present, and secondly that there is some circulating oestrogen. If the progesterone challenge test is negative, it is appropriate to give oestrogen and progesterone, (e.g. 1.25 mg of conjugated oestrogens for 21 days, with the addition of a progesterone for the last 5 days). Failure to bleed in response to this treatment confirms a uterine problem.

If the results of these tests are inconclusive, it suggests that the cause lies between the pituitary and ovaries, and further laboratory exploration must be undertaken.

Hirsutism

Hirsutism in the female means an excessive production of hair with a tendency to male distribution. ‘Excessive’ is defined as beyond social acceptability or causing embarrassment to the patient.

Normal pattern hair is of two types:

(i) fine downy, vellus hair which is non-pigmented.

(ii) coarser pigmented terminal hair as in the axilla and pubis.

About one-third of women have some visible pigmented hair on the upper lip, and 5% have it on the chin and sides of the face.

Aetiology

1. Rise in secretion of free androgens.

2. Reduction in SHBG.

3. Increased end organ sensitivity to androgens.

SHBG level falls when testosterone production increases, and probably also in the case of drug-induced hirsutism. Oestrogen increases the levels of SHBG and lowers the amount of free androgen.

Physiology of testosterone

The three principal androgens are dihydrotestosterone, testosterone and androstenedione; the last mentioned is the least potent but is converted to dihydrotestosterone in the follicle cells.

Causes:

1. Idiopathic hirsutism

By far the commonest, it has no apparent androgen increase, and is probably due to increased local testosterone production at the target organ.

2. Polycystic ovary disease

There is usually a higher level of free active testosterone because of reduced SHBG. See page 95.

3. Androgen-producing tumours

These may arise in the ovary or adrenal glands. They should be considered if serum testosterone is greater than 5 nmol/L or if the history is of sudden onset.

4. Congenital adrenal hyperplasia

This is an adrenal disease, caused by an enzyme defect (commonly 21-hydroxylase deficiency) resulting in elevated androgens.

17-hydroxyprogesterone is elevated.

androgen-containing compounds

Virilisation

Masculinisation and virilisation are terms for extreme androgen effects.

Clinical features

The symptoms and signs include the following:

male pattern balding

cliteromegaly

deepening of the voice

increased muscle mass

male body habitus.

These symptoms are more likely to represent an androgen secreting tumour, but mild symptoms such as male pattern balding can occur with PCOS.

Investigation

serum testosterone

serum dehydroepiandrosterone sulphate (DHAS)

(elevated in adrenal disease)

17-hydroxyprogesterone (17-OHP)

(elevated in congenital adrenal hyperplasia)

24 h urinary free cortisol if Cushing’s syndrome is suspected.

If the testosterone levels are significantly elevated, an androgen secreting tumour of the ovary or adrenal gland is likely. Ultrasound, CT scanning and perhaps even laparoscopy may be required to make the diagnosis.

Management of hirsutism

If the woman is untroubled by her symptoms, no treatment is needed. Women who are overweight should be advised to lose weight.

Local treatment

Ferriman Galwey Charts

These charts provide a semi-objective scoring system for hirsutism. If they are completed at each patient visit, the change in symptoms may be assessed.

Shaving

This method has to be repeated frequently.

Electrolysis

Decomposition of the hair follicle by the passage of an electric current. Low galvanic current is used through a fine electrode. The hair is electrolysed after about 10 s and plucked out painlessly.

Diathermy

The follicle is coagulated instantly and the hair pulled out.

Electrical destruction of individual hairs is permanent, but prolonged treatment is tedious and expensive and may cause scarring.

Depilatory Creams

These are alkaline solutions, which dissolve the hairs and allow them to be wiped away. They will injure the skin if left on too long.

Depilatory Waxes

The wax is melted and spread on to the skin. When it sets, it is pulled off, plucking the hairs with it. This is painful and leaves the skin tender and reddened.

Drug Treatment

1. Combined oral contraceptive pill (COCP)

These drugs act firstly by suppressing LH production and thereby attenuating ovarian androgen synthesis. Secondly, the oestrogens stimulate SHBG production by the liver. The effect of the progestogen component can vary as some such as norethisterone and levonorgestrel have an androgenic derivation. Some of the available preparations contain antiandrogenic progestogens, these include Cyproterone Acetate and Drospirenone.

2. Antiandrogens

As mentioned above, cyproterone is a progesterone, which inhibits LH production. It also binds to the androgen receptor and therefore acts as an antiandrogen. It can either be administered as with ethinyloestradiol (the contraceptive pill ‘Dianette’) or daily from days 5–14, with ethinyloestradiol on days 5–25 (the ‘reverse sequential’ regimen).

Other antiandrogens include flutamide, a non-steroidal, and finasteride, a 5α reductase inhibitor. Finasteride inhibits the conversion of testosterone to dihydrotestosterone.

3. Insulin sensitising agents

Metformin will improve insulin sensitivity and reduces free androgens in women with PCOS.

4. Dexamethasone

Dexamethasone inhibits adrenal androgen production, and is useful in hirsutism caused by adrenal disease.

5. GnRH analogues with addback hormone replacement therapy (HRT)

This treatment is expensive, but has been shown to be effective in clinical trials.

6. Eflornithine cream locally slows hair growth by inhibiting the enzyme orthinine decarboxylase.

NB. With all of the above, it may be 3 months or more before an improvement in symptoms can be expected, and the patient should be counselled regarding this.

Menstrual disorder

Heavy menstrual bleeding is one of the commonest reasons why women in the Western world consult a gynaecologist. The vast majority of these women have benign or no pathology; however, the illustration demonstrates that for a minority of women there will be a malignant pathology.

Clearly, the age of the patient has a major influence on the likely cause of bleeding, for example, endometrial carcinoma is uncommon in premenopausal women and, similarly, endometriosis is uncommon in postmenopausal women.

Careful history taking is crucial in the assessment of menstrual disorder. Women with heavy regular bleeding and no additional symptoms of concern such as intermenstrual or postcoital bleeding are most likely to have dysfunctional uterine bleeding. Benign pathologies such as fibroids are a common cause of heavy menstrual bleeding. See Chapter 11.

Dysfunctional uterine bleeding

Dysfunctional uterine bleeding is one of the commonest causes of excessive menstrual bleeding in women of reproductive age.

Dysfunctional uterine bleeding is the term applied to cases of excessive bleeding where no organic lesion can be found. Presumably the cause lies in an abnormal function of the ovarian and endometrial control mechanisms associated with the menstrual cycle.

Where appropriate investigation may be required. This will depend on the age of the patient and any additional symptoms.

Pelvic ultrasound (ideally transvaginal) should be performed. Hysteroscopy and endometrial biopsy may be required, depending on scan findings, age of the woman, and presenting symptoms.

Clinical features

The patient will complain of heavy and/or irregular bleeding. Normal menstrual cycles have a length of 21–35 days (mean 28 days). A normal period lasts for 3–7 days. Menstrual blood loss of 30–50 ml/month is normal. Menstrual blood loss is considered as excessive when it is greater than 80 ml/month. It is however rarely measured during clinical trials, and heavy menstrual loss should be defined clinically.

Estimation of blood loss

1. Subjective methods

The subjective estimation of menstrual blood loss is often difficult. What is normal to one woman may be regarded as abnormal by another. The simplest method of determining excessive menstrual loss is to ask the patient about the number of sanitary pads and/or tampons used daily. The use of pictures to indicate the amount of staining on each pad/tampon may improve accuracy. The passage of significant clots usually indicates excessive menstrual loss. The social effect of heavy menstrual loss can be considerable and symptoms such as flooding through sanitary protection are important.

2. Objective methods

Haemoglobin measurements will indicate if the patient is anaemic. An estimation of serum ferritin may show a depletion in iron stores. Whilst the detection of anaemia has important clinical implications, many women with a good diet are able to maintain normal haemoglobin levels, despite excessive menstrual loss.

The optimum method of assessing menstrual blood loss accurately is to ask the patient to collect her used pads and tampons over the course of one menstrual period. These can then be soaked in sodium hydroxide, and the optical density compared to a known standard. This technique is generally only used as a research tool, but reveals that many women who complain of menorrhagia have a menstrual loss within the normal range. A blood loss of 80 ml is thought to represent the upper limit of a ‘normal’ period. Studies have also shown that some women with a blood loss of greater than 80 ml do not perceive that they have heavy periods.

Investigation of the endometrium

Transabdominal scanning can be useful and should be used for women who have never been sexually active (virgo intacta). The bladder requires to be full so that overlying bowel is moved away to optimise the view of the pelvis. Even with a full bladder, views of the endometrium may be limited and particularly difficult to obtain in obese patients.

Transvaginal ultrasound scan This technique offers a close view of the uterus and adnexae.

Features noted during transvaginal scanning of the pelvis

Thickness and regularity of the endometrium; in postmenopausal women, the endometrial thickness (ET) is less than 3 mm in an AP diameter. A thickened endometrium may represent a polyp or endometrial hyperplasia; however, the normal endometrial thickness varies in premenopausal women during the menstrual cycle, and it may be physiological.

Presence of uterine fibroids The size and site of fibroids are important. Small fibroids of less than 3 cm are very common and usually do not change the treatment options.

Adnexal pathology can also be visualised in detail.

Outpatient procedures

Hysteroscopy

Hysteroscopy is a technique used to visualise the endometrium under magnification. Abnormal areas of the endometrium can be seen, and a targeted biopsy taken. The procedure may be performed as an outpatient procedure if a sufficiently narrow hysteroscope and distension media are available. The distension media can be fluid: saline or dextrose or CO₂ gas.

Investigation of the Endometrium

The main purpose of endometrial biopsy is to assess for endometrial hyperplasia or identify endometrial carcinoma. The risk of endometrial cancer in premenopausal women is very low, but biopsy should be performed for women over 45 with menstrual disorder. In women under 45, the need for biopsy (possibly with hysteroscopy) should be guided by other factors including intermenstrual or irregular bleeding, and scan findings. See page 201 hyperplastic conditions of the uterus.

Methods of endometrial biopsy

Pipelle de Cornier

The Pipelle is inserted into the uterine cavity and the plunger withdrawn to produce a vacuum. A small sample of endometrium is thereby sucked into the tube and subsequently expelled into fixative.

Vabra Curettage

This method of obtaining material for histological examination can be done in the outpatient clinic. Adequate specimens can be obtained, but the procedure is painful.

Dilatation and curettage

As a sole procedure, dilatation and curettage is now considered to be an outdated procedure; however, occasionally it may be required to provide a better sample of the endometrium. It is usually accompanied by hysteroscopic assessment of the cavity prior to sampling. It is often necessary to dilate the cervical canal in order to pass the curette. This procedure is normally performed under general anaesthesia as an inpatient.

Technique

The dilator must be held firmly in one hand and pressed into the canal against traction in the opposite direction exerted by the other hand. Resistance must be overcome slowly, and the dilator must not be passed farther than the length of the uterine cavity measured by the sound.

Curettage

Dilatation of the cervix is followed by curettage of the endometrium. The endometrium can then be examined histologically. Hysteroscopy and endometrial biopsy are largely diagnostic tools, but in the uncommon situation in which pathology such as an endometrial polyp is present, they may be therapeutic.

Investigations of Endometrium – Complications

1. Trauma to cervix

The volsellum forceps may tear the anterior lip of cervix if pulled on too forcibly.

2. Perforation of the uterus or cervix

This is not an uncommon occurrence and usually no ill-effects result. The usual site is the midline of the fundus, and it becomes evident when the curette passes farther than the length of the cavity as shown by the uterine sound. Immediate laparoscopy and/or laparotomy is required if there is any suspicion of damage to extrauterine viscera. This risk is higher during pregnancy as the uterus is softer.

3. Uterine synechiae

Over-vigorous curettage may remove all the endometrium from areas of anterior and posterior walls, permitting the myometrium to heal together forming adhesions – Asherman’s syndrome. This is diagnosed and treated hysteroscopically.

Management of heavy menstrual bleeding

Medical management

Tranexamic Acid

Administration: tranexamic acid 1 g qds during menstruation.

Mode of action: inhibits clot breakdown within endometrial vasculature.

Side effects are usually mild but can include nausea, vomiting and diarrhoea.

Up to 40% reduction in menstrual loss can be achieved.

Prostaglandin Synthetase Inhibitors

Administration: for example mefenamic acid, 500 mg tid during menstruation.

Mode of action: alters imbalance of vasodilator prostaglandin PGE2 and the vasoconstrictor prostaglandin PGF2a.

Side effects can include, diarrhoea, rashes, thrombocytopenia and haemolytic anaemia.

A 25% reduction in menstrual loss can be achieved.

Combined Contraceptive Pill

Administration: usual contraceptive regimen.

Mode of action: suppression of ovulation limits hormonal stimulation of the endometrium.

A reduction in menstrual loss can be seen in women both with and without menorrhagia.

Levonorgestrel Intrauterine System (LNG-IUS) Mirena

Administration: intrauterine system releasing 20 μg of levonorgestrel daily.

Mode of action: inhibits endometrial proliferation.

This device was originally designed as a contraceptive agent but is one of the most effective medical methods for reducing menstrual blood loss. One year after insertion, menstrual blood loss is reduced to 5% of the original amount. The main side effect of treatment is irregular bleeding in the first 3–6 months after insertion.

Progesterone

This is most useful for anovulatory bleeding.

Cyclical gestogens.

Administration: for example norethisterone 5 mg bd from days 5–26 of the menstrual cycle.

Mode of action: thought to provide progestogenic support to the endometrium when endogenous progesterone is lacking.

Endometrial Ablation Techniques

These techniques use a variety of energy sources and can either be performed under hysteroscopic guidance or as a blind procedure. Endometrial ablation does not guarantee amenorrhoea, but symptoms are improved in most women. The major advantage of endometrial ablation over abdominal hysterectomy is the shorter inpatient stay and recovery associated with this operation. Complications of the procedure include excessive fluid absorption and uterine perforation with damage to intra-abdominal organs.

Endometrial ablation is only appropriate for women who have completed their family and effective contraception should be continued following the procedure.

Hysteroscopic Procedures

Trans-cervical resection of endometrium (TCRE)

Using an operating hysteroscope, the uterine cavity is distended with a glycine solution and either a wire loop diathermy instrument is used to cut strips of endometrium and underlying myometrium or a ‘roller ball’ electrode is used to coagulate the endometrium. These techniques are performed under direct vision.

Second Generation Techniques

These techniques use a variety of thermal energies and are not performed under direct vision. They are relatively simple to perform; however, if the instrument is displaced, there is a risk of thermal injury to extrauterine structure, for example, bowel injury. The common techniques are microwave (MEA), a fluid filled balloon that is heated, Thermachoice and electrical energy, Novasure. There are a variety of safety mechanisms that these techniques employ; however, none of them is infallible, and recent advice has recommended that hysteroscopy should be performed prior to the procedure and that ultrasound should be used to confirm that the device is within the endometrial cavity during treatment.

An endometrial biopsy to exclude endometrial carcinoma is essential as part of any endometrial ablation procedure.

Subtotal Hysterectomy

Subtotal hysterectomy involves removal of the body of the uterus only. The cervix is conserved. The operation is easier and safer than total hysterectomy, particularly if there are adhesions around the cervix (e.g. from previous caesarean section). The risk of ureteric damage is much less than with total hysterectomy. The major disadvantage of subtotal hysterectomy is that cervical smears continue to be required as there remains a risk of cervical cancer. There is a small risk of persistent light bleeding from the remnant of endocervix.

Vaginal Hysterectomy

In vaginal hysterectomy, the uterus and cervix are removed via a vaginal approach. The operation is technically difficult in women without some degree of uterine prolapse. This approach avoids the need for an abdominal scar, and recovery is usually more rapid; however, the risk of major complications is slightly higher than with an abdominal procedure. There are a number of factors that may make an abdominal procedure the better option, for example, large fibroids, severe endometriosis.

Vaginal hysterectomy

Laparoscopically Assisted Vaginal Hysterectomy (LAVH)

A laparoscopically assisted hysterectomy procedure allows the ovaries to be removed; this is difficult with a standard vaginal hysterectomy. The broad ligaments, including the ovarian vessels, the round ligaments, and the uterine arteries may be ‘clamped and cut’ by an endoscopic device which inserts multiple rows of stainless steel staples and divides the tissues. Alternatively, diathermy may be used to coagulate the tissues prior to division. The uterus is then removed vaginally and the vaginal vault closed per vaginam.

Total Laparoscopic Hysterectomy

The entire procedure is completed laparoscopically, and the uterus is removed per vaginam.

Dysmenorrhoea

Dysmenorrhoea implies pain during menstruation, and most women experience some degree of pain at least on the first day of the period, when the loss is heaviest.

Cramp may occur premenstrually; if this is severe, it may be more likely to suggest underlying pathology, such as endometriosis.

The pain may be secondary to organic disease such as endometriosis or infection, but primary dysmenorrhoea, which is being discussed here, occurs in the presence of a normal genital tract.

Nature of the pain

It is usually described as having two components: a continuous lower abdominal pain attributed to vascular congestion, which radiates through to the back and sometimes down the thighs, and an intermittent cramping pain.

Aetiology

There is increased myometrial activity during the periods in women with dysmenorrhoea and uterine blood flow is reduced, especially during intense contractions. It is thought that this hyperactivity is the result of excessive quantities of prostaglandins synthesised during the breakdown of the premenstrual endometrium.

Clinical features of primary dysmenorrhoea

This condition is typically present from the time when ovulation is established, usually the late teens.

Prostaglandin (PG) synthetase inhibitors have been shown experimentally to abolish uterine contraction and ischaemia and the pain that accompanies them.

Management

In mild or moderate disease, treatment can be commenced after a full history and examination. In severe or unresponsive disease, investigation should be performed. A transvaginal scan and possibly laparoscopy should be considered.

Drug treatment

1. The contraceptive pill. Dysmenorrhoea is very unlikely in the absence of ovulation, probably because of the pseudo-atrophy of the endometrium. The disadvantages of this efficacious treatment are the well-known side effects and perhaps the prevention of pregnancy.

2. Prostaglandin synthetase inhibitors such as mefenamic acid inhibit prostaglandin production, reduce uterine contractions, and thereby alleviate dysmenorrhoea. In controlled studies, up to 90% of women report an improvement of symptoms with mefenamic acid.

3. Levonorgestrel intrauterine system MIRENA

Progesterone is a smooth muscle relaxant and intrauterine administration will significantly reduce dysmenorrhoea.

Adenomyosis

This is an infiltration of the myometrium by ectopic deposits of endometrium. It is usually only diagnosed once the uterus is examined histologically following hysterectomy. It can be visualised with ultrasound but MRI is better at differentiating adenomyosis from fibroids.

Pathology

The gross appearances are quite striking. The uterus is usually enlarged and this may be quite marked.

Microscopic appearances

The appearance of the endometrial deposits within the myometrium varies. In many cases, they consist of typical glands and stroma although the stroma may be more prominent than the glands. Cyclical changes may be observed, but this is not common. More often, the endometrium is of immature type, and if it does react, it usually shows only proliferative changes. Clinical features are pain and menstrual upset.

Endometrial deposits in the myometrium. Note the non-secretory gland epithelium. The surrounding myometrium undergoes moderate hyperplasia.

Endometriosis

Endometriosis is a condition where deposits of endometrium develop outside the uterine cavity. Its manifestations are very variable and often bear no relation to the extent of the disease.

Pathology

The gross appearance shows ectopic deposits, which can vary in number from a few in one locality to large numbers distributed over the pelvic organs and peritoneum.

The commonest sites of these deposits are the following:

• Ovary

• Peritoneum of the rectovaginal cul-de-sac of the Pouch of Douglas

• Sigmoid colon

• Broad ligament

• Uterosacral ligaments.

Less common are the following sites:

The commonest appearance of a typical lesion is that of a round protruding vesicle that shows a succession of colours from blue to black to brown. The variation in colour is due to haemorrhage with subsequent breakdown of the haemoglobin. Ultimately the area of haemorrhage heals by the formation of scar tissue. The result is a puckered area on the peritoneum. Commonly, however, the haemorrhage results in adhesion to surrounding structures. These adhesions are more apt to form between fixed structures such as the broad ligament, ovary, sigmoid colon, or the posterior surfaces of the vagina and cervix.

The ectopic deposits of endometrial tissue vary in size from pin-point to 5 mm or more. It is these larger deposits which tend to rupture leading to adhesions. These adhesions over the ovary can lead to the formation of quite large haemorrhagic cysts due to continued bleeding from deposits, the blood being unable to escape.

Investigation has shown that many lesions do not have a ‘typical’ appearance. The following is a list of other appearances which have been described.

• White, slightly raised opacities due to retroperitoneal deposits.

• Red flame-like or vascular swellings, more common in the broad ligament or uterosacral ligament.

• Small excrescences like the surface of normal endometrium.

• Adhesions under the ovary or between the ovary and the ovarian fossa peritoneum.

• Café-au-lait patches often in the Pouch of Douglas, broad ligament or peritoneal surface of the bladder.

• Peritoneal defects on uterosacral ligament or broad ligament.

• Areas of petechiae or hypervascularisation usually on the bladder and the broad ligament.

Secondary pathology

This is due to the adhesions between the endometriotic deposits and adjacent organs. In long-standing cases, the pelvic cavity is obliterated by these adhesions. Retroversion of the uterus can occur as the adhesions form.

Histology

While the deposits consist of endometrial elements, rarely do they mirror the appearance of normal endometrium, especially in their architecture. In place of the compact orderly arrangement of glands and stroma, there are scattered patches of gland formations with some surrounding stroma. Sometimes gland formations predominate; occasionally only stromal cells can be seen.

Sometimes the deposits show evidence of cyclical activity, but the activity does not always coincide with what is happening in the uterine endometrium.

Clinical findings

The incidence of endometriosis has been estimated at 3–7% of women, but the true incidence is unknown. Quite often, deposits are found incidentally in women who have no symptoms of endometriosis and are undergoing laparoscopy or laparotomy for some other condition. In addition, as indicated in the section on pathology, many peritoneal changes now known to be due to endometriosis were undiagnosed in the past.

The prevalence of endometriosis peaks between the ages of 30 and 45 years. As ectopic endometrium is stimulated by the same ovarian steroid hormones as the endometrium lining the uterine cavity, endometriosis is almost never found outside the reproductive years.

Symptomatology

A. Pain affects more than 80% of women with endometriotic deposits. The pain tends to begin premenstrually, reaching a peak during menstruation and subsiding slowly.

The character of pain may vary as does its apparent origin. It may be generalised throughout the abdomen and pelvis like the pain of severe dysmenorrhoea. Alternatively, pain may be localised to a particular site within the pelvis. Deep dyspareunia affects around 40% of women with endometriosis.

B. Menstrual disturbance Menstrual disturbance affects around 20% of women with endometriosis. It may take the form of premenstrual ‘spotting’, menorrhagia or infrequent periods. Lesions in the wall of the bladder may result in ‘menstrual haematuria’.

C. Infertility Endometriosis is found more commonly in women undergoing investigation for infertility than in the ‘normal’ population. It is not clear which condition arises first. Approximately 30% of patients with endometriosis complain of infertility. When endometriosis is extensive, and both fallopian tubes are occluded, the mechanism by which endometriosis prevents conception is obvious. However, milder forms of endometriosis are also associated with subfertility, and here the pathophysiology is less clear. The most likely mechanism appears to be that immunological factors within the peritoneal cavity inhibit normal gamete function, thus reducing fertilisation rates.

Physical examination

Endometriosis cannot be diagnosed by physical examination alone. However, enlargement of the ovaries, fixed retroversion of the uterus, and tender nodules within the pelvis may each raise the suspicion of the disease. Endometriosis should always be considered when patients have symptoms referable to the pelvic cavity.

Laparoscopy

Laparoscopic examination is the gold standard investigation for endometriosis. The lesions can be seen and their number and location estimated. Endometriosis of long standing may be very difficult to diagnose because of obliteration of the pelvic cavity by adhesions.

Imaging techniques

Ultrasound, CT and MRI may suggest the presence of endometriosis (e.g. by the demonstration of a particular type of ovarian cyst) but are by themselves insufficiently reliable to make the diagnosis.

Differential diagnosis

Owing to the mixture of symptoms and the variation in appearance of the pelvic structures, conditions such as pelvic inflammatory disease and tumours of the ovary and bowel must be considered and eliminated.

Histogenesis

There are three theories:

1. Retrograde spill of menstrual debris through the tubes. Retrograde menstruation takes place in most women, but it is unclear why some women should develop endometriosis while others are unaffected.

2. Metaplasia of embryonic cells. These are derived from the primitive coelom and may remain in and around the pelvis and differentiate into Müllerian duct tissue.

3. Emboli of endometrial tissue may travel by lymphatics or blood vessels and become established in various sites.

The first of these theories is the most favoured.

Treatment

Medical Treatment

Any treatment must be aimed at treating symptoms. As ovarian hormones are responsible for growth and activity in endometrium, many medical therapies are designed to reduce ovarian steroid production or oppose their action.

1. Progestogens

Progestogens in a relatively high dose (e.g. medroxyprogesterone acetate 10 mg tid) induce decidualisation, and sometimes resorption of ectopic endometrium. Side effects include weight gain, bloating and irregular vaginal bleeding.

2. Combined contraceptive pill

The combined oral contraceptive pill also induces decidualisation of ectopic endometrium. It may be given continuously for up to 3 months.

3. Danazol

Danazol is a steroid hormone closely related to testosterone, which inhibits pituitary gonadotrophins, and is antioestrogenic, antiprogestational, slightly androgenic, and anabolic. It is an effective treatment but is now outdated as irreversible androgenic effects such as hirsutism and deepening of the voice are common.

4. Gonadotrophic releasing hormone analogues (GnRH analogue)

GnRH analogues are administered by depot injection or nasal spray. Their mode of action is shown above. These drugs are generally effective in treating symptoms caused by endometriosis; however, menopausal side effects are common. Add-back hormone replacement therapy will usually prevent the vast majority of vasomotor symptoms without stimulating endometriosis. These preparations are licensed for 6 months of use as there is concern that long-term use will increase the risk of osteoporosis and other effects of oestrogen deprivation.

Conclusion

As with medical therapies for other conditions, the optimum treatment is dictated by the side effect profile which is most acceptable to the patient. None of the drug treatments described will prevent recurrence of endometriosis once therapy has been stopped, although there may be a period of some months between stopping treatment and the re-emergence of symptoms. No medical treatment has been shown to improve subsequent fertility.

Surgical Treatment

Where the woman has completed her family, radical surgery to remove both ovaries is likely to provide a lasting cure for endometriosis as it removes the oestrogenic stimulus to endometrial growth.

In many cases, the patient wishes relief from pain but also desires to retain the possibility of future pregnancy. In these circumstances, only conservative surgery can be employed.

The intentions in conservative surgery are the following:

1. To ablate as many endometrial deposits in the pelvic cavity as possible.

2. To restructure the pelvic anatomy by destroying adhesions that interfere with ovarian and tubal function.

3. To destroy endometrial deposits in the ovaries.

Premenstrual syndrome

The premenstrual syndrome (PMS) includes a large group of symptoms, which appear regularly and predictably in the week before the onset of menstruation. The symptom pattern varies with the individual, but 95% of women are likely to acknowledge at least one of the symptoms listed below. Symptoms resolve completely by the end of menstruation. The severity can vary significantly and it has been classified as follows:

Mild – does not interfere with personal/social and professional life.

Moderate – interferes with personal/social and professional life, but the woman is still able to interact, although may be suboptimally.

Severe – unable to interact personally/socially/professionally – withdraws from social and professional activities.

Water retention	Pain	Autonomic reactions
Weight gain (up to 7lb)	Headache	Dizziness/faintness
Painful breasts	Backache	Cold sweats
Abdominal distension	Tiredness	Nausea/vomiting
Feeling of bloatedness	Muscle stiffness	Hot flushes
Mood changes	Loss of concentration	Miscellaneous
Tension	Forgetfulness	Feelings of suffocation
Irritability	Clumsiness	Chest pains
Depression	Difficulty in making decisions	Heart pounding
Crying spells	Poor sleeping	Numbness, tingling