Clinical Obstetrics and Gynaecology, 3ed.

8

Amenorrhoea

Introduction

Primary amenorrhoea

Secondary amenorrhoea

Summary of clinical management

Introduction

Amenorrhoea may be defined as the failure of menstruation to occur at the expected time.

It may be considered in two categories:

1. Primary amenorrhoea, when menstruation has never occurred.

2. Secondary amenorrhoea, when established menstruation ceases for 6 months or more.

Primary amenorrhoea

Failure to menstruate by the age of 16 is referred to as ‘primary amenorrhoea’. The likely cause of primary amenorrhoea depends on whether secondary sexual characteristics are present or not. If secondary sexual characteristics are absent, then the cause is most likely delayed puberty (see p. 45). If pubertal development is normal, then an anatomical cause should be suspected. The main ‘anatomical’ causes are:

icon01.gif congenital absence of the uterus; this is due to a failure of the Müllerian ducts to develop

icon01.gif imperforate hymen; the menstrual blood is retained within the vagina (a haematocolpos) causing cyclical lower abdominal pain each month at the time of menstruation (cryptomenorrhoea). Inspection of the vulva reveals a distended hymenal membrane through which dark blood may be seen and treatment by incision, usually under anaesthesia, is all that is required (Fig. 8.1).

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FIG. 8.1Imperforate hymen (A) before and (B) after incision.

Failure to menstruate may also be physiological delay, in other words, the development is normal but there is an inherent delay in the onset of menstruation. There is often a family history of the same delay in the mother. A progestogen challenge test is useful to identify constitutional menstrual delay. A progestogen (e.g. norethisterone) is given orally for 5 days, and withdrawal should lead to a vaginal bleed. If such a bleed occurs, it is reasonable to offer reassurance that spontaneous menstruation is likely to occur. An abdominal ultrasound may be reassuring to confirm that the uterus and ovaries are normal.

Low body weight and excessive exercise are also associated with primary amenorrhoea. The other causes listed in Table 8.1 are rare, although a few are outlined under the ‘secondary amenorrhoea’, discussion below (see also Chapters 5 and 6).

Table 8.1

Causes of primary amenorrhoea

System

Problem

Incidence

Chromosomal

XO – Turner syndrome

Rare

 

46,XY DSD

Rare

 

Ovotesticular DSD

Rare

Hypothalamic

Physiological delay

Common

 

Weight loss/anorexia/heavy exercise

Common

 

Isolated GnRH deficiency

Rare

 

Congenital CNS defects

Rare

 

Intracranial tumours

Rare

Pituitary

Partial/total hypopituitarism

Rare

 

Hyperprolactinaemia

Rare

 

Pituitary adenoma

Rare

 

Empty sella syndrome

Rare

 

Trauma/surgery

Rare

Ovarian

True agenesis

Rare

 

Premature ovarian failure

Rare

 

Radiation/chemotherapy/autoimmune

Rare

 

Polycystic ovaries

Common

 

Virilizing ovarian tumours

Rare

Other endocrine

Primary hypothyroidism

Rare

 

Adrenal hyperplasia

Rare

 

Adrenal tumour

Rare

Uterine/vaginal

Imperforate hymen

Not uncommon

 

Uterovaginal agenesis

Rare

Secondary amenorrhoea

Secondary amenorrhoea means the cessation of established menstruation. It is defined as no menstruation for 6 months in the absence of pregnancy. A full list of causes is given in Table 8.2, but the commonest are weight loss, polycystic ovary syndrome (PCOS) and hyperprolactinaemia. The more common conditions are discussed below.

Table 8.2

Causes of secondary amenorrhoea

System

Problem

Incidence

Physiological

Pregnancy

Common

 

Lactation

Common

 

Menopause

Common

Hypothalamic

Weight loss/anorexia

Common

 

Heavy exercise

Common

 

Stress

Common

Pituitary

Hyperprolactinaemia

Not uncommon

 

Partial/total hypopituitarism

Rare

 

Trauma/surgery

Rare

Ovarian

Polycystic ovary syndrome

Common

 

Premature ovarian failure

Uncommon

 

Surgery/radiotherapy/chemotherapy

Uncommon

 

Resistant ovary syndrome

Rare

 

Virilizing ovarian tumours

Rare

Other endocrine

Primary hypothyroidism

Rare

 

Adrenal hyperplasia

Rare

 

Adrenal tumour

Rare

Uterine/vaginal

Surgery – hysterectomy

Common

 

Endometrial ablation

Common

 

Progestogen intrauterine device

Common

 

Asherman syndrome

Rare

Causes

Physiological

The commonest causes of amenorrhoea during the reproductive phase of life are physiological – pregnancy and lactation. Pregnancy should therefore be excluded in all sexually active women presenting with amenorrhoea.

The high postpartum level of prolactin associated with breastfeeding suppresses ovulation and gives rise to lactational amenorrhoea. The mechanism is probably related to reduced gonadotrophin-releasing hormone (GnRH) production as a result of changes in the sensitivity of the hypothalamic–pituitary axis to oestrogen. Amenorrhoea usually persists throughout the time that the infant is fully breastfed, but with the introduction of supplementary feeding, and therefore reduction in the frequency of suckling, prolactin levels fall and ovarian activity is resumed. This hypo-oestrogenic state may lead to atrophic vaginitis, and occasionally to painful intercourse.

Hypothalamic

Hypothalamic amenorrhoea (‘hypogonadotrophic hypogonadism’) is frequently associated with stress, for example, leaving home for higher education, and in such cases, the condition usually resolves spontaneously. Physical stress in the form of athletic training can also result in suppression of the hypothalamo–pituitary–ovarian axis. There are low levels of pituitary gonadotrophins in association with low levels of prolactin and oestrogen.

If hypothalamic amenorrhoea is not related to low body weight (see below), treatment will depend on whether or not the woman wants to conceive. If pregnancy is not desired, oestrogen replacement therapy is advisable, and is conveniently provided in the form of the oral contraceptive pill. If the woman wishes to become pregnant, ovulation may be induced with pulsatile GnRH therapy or exogenous gonadotrophins (p. 75).

The hypothalamus is also sensitive to changes in body weight, and weight loss, even to only 10–15% below the ideal, may be associated with amenorrhoea. Anorexia nervosa should be considered. Restoration of the body weight results in the return of ovulatory function, although there may be a significant time interval between the attainment of the ideal body weight and the resumption of ovarian activity. Ovulation induction therapy is not recommended prior to the restoration of body weight, as pregnancy, if it occurs, carries the risk of growth restriction of the fetus and increased perinatal mortality.

Pituitary

Prolactin stimulates breast development and subsequent lactation. The secretion of prolactin, a polypeptide hormone produced by the lactotrophs of the anterior pituitary, is inhibited by dopamine from the hypothalamus. High levels of prolactin, which may be either physiological (during lactation) or pathological (see below), in turn suppress ovarian activity by interfering with the secretion of gonadotrophins.

Mildly elevated prolactin levels are common and can be due to stress (e.g. of venepuncture). Sustained higher levels can result in amenorrhoea and galactorrhoea unrelated to pregnancy. Galactorrhoea occurs in < 50% of those with hyperprolactinaemia, and < 50% of those with galactorrhoea have an elevated prolactin level. The causes of hyperprolactinaemia are given in Box 8.1.

Box 8.1

Causes of hyperprolactinaemia

Pituitary adenoma

icon01.gif microadenomas

icon01.gif macroadenomas

Secondary to other causes

icon01.gif primary hypothyroidism

icon01.gif chronic renal failure

icon01.gif pituitary stalk compression

icon01.gif PCOS

icon01.gif drugs (phenothiazines, haloperidol, metoclopramide, cimetidine, methyldopa, antihistamines and morphine)

icon01.gif idiopathic

Adenomas occur in the lateral wings of the anterior pituitary and are usually soft and discrete with a pseudocapsule of compressed tissue (Fig. 8.2). If the prolactin is more than 1000 mU/L, then imaging with CT or (ideally) MRI should be carried out. A microadenoma is < 10 mm in diameter and a macroadenoma > 10 mm. Visual fields should be checked as optic chiasma compression may lead to bitemporal hemianopia. One-third of adenomas regress spontaneously and fewer than 5% of microadenomas become macroadenomas. Serum levels correlate well with tumour size, so that if the tumour is relatively large and the prolactin level only modestly elevated, then pituitary stalk compression from a non-secreting macroadenoma or other tumour is possible (e.g. a craniopharyngioma). It is possible that apparently idiopathic hyperprolactinaemia may be caused by microadenomas which are too small to be picked up by an MRI scan.

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FIG. 8.2CT scan of a pituitary macroadenoma.

All patients should have pituitary imaging before treatment. This treatment is usually with a dopamine agonist, either bromocriptine or cabergoline, which suppresses the prolactin level and also induces regression of the prolactinoma. Transnasal transsphenoidal microsurgical excision of an adenoma is only rarely required.

Ovarian

Premature ovarian failure

The menopause (with cessation of ovarian function) normally occurs around the age of 50. The term ‘premature ovarian failure’ is usually used to describe cessation of ovarian function before the age of 40. As in the natural menopause, failure is usually due to depletion of primordial follicles in the ovaries.

Premature ovarian failure occurs in 1% of women and may be due to surgery, viral infections (e.g. mumps), cytotoxic drugs or radiotherapy. It may also be idiopathic and is occasionally associated with chromosomal abnormality (XO mosaics or XXX). A low oestrogen level, very high follicle-stimulating hormone (FSH) and the absence of any menstrual activity are poor prognostic signs for recovery. Pregnancy by in-vitro fertilization (IVF) with donor oocytes may be possible. There is an association with other autoimmune disorders. Hormone replacement therapy is required to relieve postmenopausal symptoms and minimize the risk of osteoporosis.

Polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome is associated with menstrual disturbance, and is the most common form of anovulatory infertility. It is estimated to affect up to 20% of women in the UK. It is characterized by the presence of at least two out of the following three criteria:

icon01.gif oligo- or amenorrhoea

icon01.gif ultrasound appearance of large-volume ovaries (> 10 cm3) and/or multiple small follicles (12 or more < 10 mm) (Fig. 8.3)

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FIG. 8.3Polycystic ovaries.

These are classically bilaterally enlarged with multiple peripherally situated cysts ‘like a ring of pearls’ in a dense stroma: (A) ultrasound scan; (B) surgical dissection; (C) pathological preparation.

icon01.gif clinical evidence of excess androgens (acne, hirsutism) or biochemical evidence (raised testosterone).

The aetiology of the condition is unknown, but recent evidence suggests that the principal underlying disorder is one of insulin resistance, with the resultant hyperinsulinaemia stimulating excess ovarian androgen production. Associated with the prevalent insulin resistance, there is a characteristic dyslipidaemia and a predisposition to non-insulin-dependent diabetes and cardiovascular disease in later life. PCOS may therefore be considered to be a systemic metabolic condition rather than one primarily of gynaecological origin (Fig. 8.4).

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FIG. 8.4Pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome can be considered to be a disorder primarily of insulin resistance, with the resultant hyperinsulinaemia stimulating excess ovarian androgen production. There may also be dyslipidaemia and a predisposition to later non-insulin-dependent diabetes and cardiovascular disease.? = uncertain relationship between insulin and the adrenal gland.

Treatment depends on whether the presenting problem has been menstrual irregularity, hirsutism or infertility. The combined oral contraceptive pill has been used to regulate the menses. Hirsutism may be treated by cosmetic measures such as waxing or laser treatment. Hirsutism may also be treated with the combined oral contraceptive pill since it suppresses ovarian androgen production, or with the antiandrogen cyproterone acetate. Women taking an antiandrogen should use effective contraception during and for at least 3 months after treatment, due to the potential risk of teratogenicity (feminization of a male fetus) with antiandrogen therapy. Clomifene is used to induce ovulation in women with anovulatory infertility (p. 74). If clomifene does not work, ovulation may be induced by injections of gonadotrophins, or by laparoscopic laser or diathermy to the ovary.

The cornerstone to management, however, is weight reduction, which reduces insulin resistance, corrects the hormone imbalance and promotes ovulation. Although initial small studies of insulin-sensitizing agents (e.g. metformin) as a therapeutic option in the management of anovulation and other symptoms of PCOS were promising, recent larger trials have failed to demonstrate benefit.

Long term, there is an increased risk of endometrial hyperplasia and endometrial carcinoma as a consequence of the effects of anovulation with unopposed oestrogen stimulation of the endometrium. There is also an increased risk of non-insulin-dependent diabetes mellitus and cardiovascular disease. Individuals may gain benefit from early screening for cardiovascular risk factors, particularly hypertension and glucose intolerance.

Other endocrine causes

These are rare. Women with thyrotoxicosis may have amenorrhoea. Primary hypothyroidism is also associated with amenorrhoea, as thyrotrophin-releasing hormone stimulates prolactin secretion. The most common of the rare adrenal problems is late-onset congenital adrenal hyperplasia. This is usually due to a deficiency of the enzyme 21-hydroxylase (Fig. 6.4), and treatment with a low dose of corticosteroids is usually sufficient to re-establish ovulatory function by suppressing adrenal function. Androgen-secreting adrenal tumours can also occur.

History

Asherman syndrome was first described in 1894 by Heinrich Fritsch and further characterized by the gynaecologist Joseph Asherman (1889–1968). It is also known as Fritsch syndrome, or Fritsch–Asherman syndrome.

Uterine

Excessive uterine curettage – usually at the time of miscarriage, termination of pregnancy or secondary postpartum haemorrhage – may remove the basal layer of the endometrium and result in the formation of uterine adhesions (synechiae), a condition known as Asherman syndrome (Fig. 8.5) (see History box). It may rarely also result from severe postpartum infection. Treatment involves breaking down the adhesions through a hysteroscope with or without inserting an IUD to deter reformation.

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FIG. 8.5Rarely, adhesions can form within the uterine cavity.

If so severe that they obstruct the menstrual flow, the condition is referred to as Asherman syndrome.

Summary of clinical management

Initial management:

icon01.gif exclude pregnancy

icon01.gif ask about perimenopausal symptoms (e.g. flushings, vaginal dryness)

icon01.gif take a history, including weight changes, drugs, medical disorders and thyroid symptoms

icon01.gif carry out an examination, looking particularly at height, weight, visual fields and the presence of hirsutism or virilization; also carry out a pelvic examination, unless this is contraindicated

icon01.gif check serum for LH, FSH, prolactin, testosterone, thyroxine and thyroid-stimulating hormone (TSH)

icon01.gif arrange a transvaginal ultrasound scan, looking for polycystic ovaries

icon01.gif review with the results (Table 8.3).

Table 8.3

Further management based on test results

Ultrasound scan

A scan showing large-volume ovaries (> 10 cm3) and/or multiple small follicles (12 or more < 10 mm)

If pregnancy desired, clomifene or gonadotrophins. If pregnancy not desired, consider the combined oral contraceptive pill

Elevated PRL level

If PRL > 1000 mU/L on at least two occasions, the diagnosis is hyperprolactinaemia

Arrange MRI or CT of the pituitary. Treat with dopamine agonist

Elevated FSH

If FSH > 30 U/L, repeat 6 weeks later. If still elevated and the patient > 40 years old, the patient is menopausal. If less than 40, the diagnosis is premature ovarian failure

Consider HRT. Pregnancy with oocyte donation is possible

Abnormal TFTs

If the TFTs are abnormal, treat as appropriate

 

FSH, follicle-stimulating hormone; HRT, hormone replacement therapy; LH, luteinizing hormone; PRL, prolactin; TFTs thyroid function tests.

If the tests listed in Table 8.3 are normal, consider the following causes:

icon01.gif weight loss

icon01.gif depression, emotional disturbance and extreme exercise

icon01.gif Asherman syndrome

icon01.gif idiopathic amenorrhoea.

In the majority of patients who present with secondary amenorrhoea, investigations will fail to demonstrate any significant endocrine abnormality – idiopathic amenorrhoea. It is probable that there is a disturbance of the normal feedback mechanisms of control. Undue sensitivity of the hypothalamus and pituitary to the negative feedback suppression of endogenous oestrogen may result in impaired gonadotrophin secretion which is inadequate to stimulate follicular development, and results in cycle initiation failure. Those requiring ovulation usually respond well to an anti-oestrogen such as clomifene.

Key points

• The commonest causes of primary amenorrhoea (when menstruation has never occurred) are physiological delay, weight loss, heavy exercise and an imperforate hymen.

• Secondary amenorrhoea is said to have occurred when established menstruation ceases for 6 months or more. Outside pregnancy, lactation and the menopause, the commonest causes are the polycystic ovary syndrome, stress, weight loss and hyperprolactinaemia.

• Polycystic ovary syndrome is the commonest cause of anovulatory infertility.