Clinical Topic A-Z Clinical Speciality

Amenorrhoea

Amenorrhoea
D000568Amenorrhea
Sexual healthWomen's health
2009-10-19Last revised in October 2009

Amenorrhoea - Summary

Amenorrhoea is the absence or cessation of menses. It may be physiological, pathological, or iatrogenic.

Primary amenorrhoea is generally defined as the failure to establish menstruation by 16 years of age in girls with normal secondary sexual characteristics, or by 14 years of age in girls with no secondary sexual characteristics.

Secondary amenorrhoea is generally defined as the absence of menstruation for at least 6 consecutive months in women with previously normal and regular menses, or for 12 months in women with prior oligomenorrhoea.

Causes of primary amenorrhoea include:

Physiological causes: pregnancy and constitutional.

Pathological causes associated with normal secondary sexual characteristics. The most common are genito-urinary malformations, including imperforate hymen, transverse septum, absent vagina, or absent uterus.

Pathological causes associated with no secondary sexual characteristics. The most common are ovarian failure (for example in Turner's syndrome) and hypothalamic-pituitary dysfunction (for example caused by weight loss, or excessive exercise).

Causes of secondary amenorrhoea include:

Physiological causes: pregnancy, lactation, menopause.

Iatrogenic/illicit drugs: progestogen methods of contraception, radiotherapy, cocaine.

Uterine causes: cervical stenosis, Asherman's syndrome.

Ovarian causes: premature ovarian failure, chemotherapy.

Hypothalamic dysfunction: weight loss, eating disorders, excessive exercise, stress, depression, chronic systemic illness.

Pituitary causes: prolactinoma, hypopituitarism, Sheehan's, sarcoidosis, cranial irradiation.

Thyroid disease: hypothyroidism, hyperthyroidism.

Endocrine causes: polycystic ovary syndrome, Cushing's syndrome, late-onset congenital adrenal hyperplasia.

Androgen-secreting tumours of the ovary or adrenal gland.

Referral for investigation of primary amenorrhoea is recommended for girls:

Who have not started menstruating by 14 years of age and have no secondary sexual characteristics.

With normal secondary sexual characteristics who have not started menstruating by 16 years of age.

Assessment of women with secondary amenorrhoea in primary care includes:

Clinical evaluation when amenorrhoea has persisted for 3–6 months.

Laboratory investigations when 6 months have elapsed since the last menstrual period (pregnancy test, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), prolactin, total testosterone and sex hormone-binding globulin, and thyroid-stimulating hormone).

Referral should be arranged, or specialist advice sought for women with secondary amenorrhoea lasting 6 months (or earlier if clinically indicated) in whom the cause cannot be established or requires confirmation, or if secondary care treatment is required.

Referral to a gynaecologist should be arranged if the woman has any of the following: elevated FSH and LH levels (and younger than 40 years of age); recent history of uterine or cervical surgery or severe pelvic infection; infertility; suspected polycystic ovary syndrome (if diagnosis is not feasible in primary care).

Referral to an endocrinologist should be arranged if the woman has any of the following: hyperprolactinaemia; low FSH and LH; an increased testosterone level not explained by polycystic ovary syndrome; features of Cushing's syndrome or late-onset congenital adrenal hyperplasia.

Referral should be considered to a:

Psychiatrist/ psychologist if an eating disorder is suspected.

Dietitian if she is underweight.

Have I got the right topic?

120months3060monthsFemale

This CKS topic covers the causes, initial assessment, investigation, and initial management of primary and secondary amenorrhoea. It also covers the management of hypothalamic amenorrhoea and the management of osteoporosis risk in women with amenorrhoea associated with low oestrogen levels.

This CKS topic does not cover in detail the management of the specific causes of amenorrhoea. It also does not specifically cover oligomenorrhoea, although many of the causes, and the initial assessment and management, of oligomenorrhoea are the same as amenorrhoea.

There are separate CKS topics on Infertility, Menopause, and Polycystic ovary syndrome.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in October 2009

July to October 2009 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

There are no major changes to the recommendations.

Previous changes

March 2009 — minor update to include hypopituitarism following traumatic brain injury as a cause of amenorrhoea. Issued in April 2009.

July–September 2006 — reviewed. Validated in December 2006 and issued in January 2007.

October 2005 — minor technical update. Issued in November 2005.

February 2005 — updated to include prescribing advice from the Committee on Safety of Medicines on the effect of depot medroxyprogesterone acetate contraception on bones. Issued in February 2005.

July 2003 — reviewed. Validated in September 2003 and issued in October 2003.

January 2000 — written. Validated in March 2000 and issued in May 2000.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 June 2009.

HTAs (Health Technology Assessments)

No new HTAs since 1 June 2009.

Economic appraisals

No new economic appraisals relevant to England since 1 June 2009.

Systematic reviews and meta-analyses

No new systematic review or meta-analysis since 1 June 2009.

Primary evidence

No new randomized controlled trials published in the major journals since 1 June 2009.

New policies

No new national policies or guidelines since 1 June 2009.

New safety alerts

No new safety alerts since 1 June 2009.

Changes in product availability

No changes in product availability since 1 June 2009.

Goals and outcome measures

Goals

To make an appropriate assessment, including the appropriate use of investigations, in order to identify the cause and/or refer to secondary care

To offer advice and treatment in the primary care setting to women and girls with hypothalamic amenorrhoea

To manage osteoporosis risk in women with amenorrhoea associated with low levels of oestrogen

Background information

Definition

What is it?

Amenorrhoea is the absence or cessation of menses [Balen, 2000; Practice Committee of the American Society for Reproductive Medicine, 2008].

It may be physiological (before puberty or due to pregnancy, lactation, or menopause), pathological, or iatrogenic (for example due to contraceptives or surgery).

Primary amenorrhoea is generally defined as the failure to establish menstruation by 16 years of age in women and girls with normal secondary sexual characteristics, or by 14 years of age in women and girls with no secondary sexual characteristics [Baird, 1997; McIver et al, 1997; Garden, 1998; Balen, 2000; Edmonds, 2007a].

Secondary amenorrhoea is generally defined as the absence of menstruation for at least 6 consecutive months in women with previously normal and regular menses, or for 12 months in women with prior oligomenorrhoea [Kiningham et al, 1996; McIver et al, 1997; Ledger and Skull, 2004; Balen, 2007; Alberta Medical Association, 2008].

Oligomenorrhoea (not covered in this topic) is defined as menses occurring less frequently than every 35 days [Balen, 2004].

Prevalence

How common is it?

The prevalence of amenorrhoea not due to pregnancy, lactation, or menopause is approximately 3–4% in women of reproductive age [Kiningham et al, 1996; Practice Committee of the American Society for Reproductive Medicine, 2008].

Causes

What causes it?

Causes of primary amenorrhoea

What are the causes of primary amenorrhoea?

Physiological causes

Pregnancy.

Constitutional delay (physiologically delayed puberty) is a common cause.

There is no anatomical abnormality, and maturation usually occurs spontaneously by 18 years of age. The condition is frequently familial.

Diagnosis is by exclusion of pathological causes [Reindollar and McDonough, 1981; Thomas and Rebar, 1997; Garden, 1998; Crouch and Creighton, 2004; Master-Hunter and Heiman, 2006; Edmonds, 2007a; Clark, 2009].

Pathological causes (see Table 1)

The most common pathological causes associated with normal secondary sexual characteristics are genito-urinary malformations, including imperforate hymen, transverse septum, absent vagina, or absent uterus [Garden, 1998; Crouch and Creighton, 2004; Edmonds, 2007a].

One example of genito-urinary malformation is Meyer–Rokitansky–Kuster–Hauser syndrome, or complete Mϋllerian agenesis, where the external female genitalia are normal but uterine development is rudimentary or absent, the vagina is short, and renal anomalies may be present (in 40% of women with the condition) [Garden, 1998; Edmonds, 2007a].

The most common pathological causes associated with no secondary sexual characteristics are ovarian failure (for example in Turner's syndrome) and hypothalamic-pituitary dysfunction (for example caused by chronic systemic illness, weight loss, or excessive exercise) [Reindollar and McDonough, 1981; Garden, 1998; Wilson et al, 2005].

Most of the causes of secondary amenorrhoea can also cause primary amenorrhoea if they occur before the menarche.

Table 1 . Pathological causes of primary amenorrhoea.
Secondary sexual characteristics* usually present Secondary sexual characteristics* usually absent Ambiguous external genitalia
Genito-urinary malformation: imperforate hymen, transverse vaginal septum, absent vagina, absent uterus. Androgen insensitivity syndrome (previously known as 'testicular feminization'): 46XY female (breast development present but reduced, and pubic/axillary hair absent). Endocrine disease: hypothyroidism, hyperthyroidism, hyperprolactinaemia (for example caused by prolactinoma or drugs), Cushing's syndrome. Polycystic ovary syndrome. Ovarian failure: gonadal dysgenesis (as in Turner's syndrome, 46XO), gonadal agenesis (46XX or 46XY), premature ovarian failure, chemotherapy, pelvic irradiation. Hypothalamic dysfunction: chronic systemic illness (including uncontrolled diabetes, severe renal and cardiac disorders, coeliac disease, cancer, and infections such as tuberculosis), eating disorders, weight loss, excessive exercise, stress, depression. Other causes of gonadotrophin deficiency: head injury, infection, cranial irradiation, tumours of the hypothalamus and pituitary, hydrocephalus, Kallman's syndrome (congenital gonadotrophin deficiency characterized by anosmia and other cranial anomalies), empty sella syndrome, Laurence–Moon–Biedl syndrome, Präder–Willi syndrome. 5-alpha-reductase deficiency. The external genitalia are female, but the internal genitalia are male. Characteristically, virilization becomes apparent at puberty. Androgen-secreting tumour. This is rare and results in extreme virilization characterized by temporal balding, clitoral enlargement, deepening of the voice, and extreme hirsutism. Congenital adrenal hyperplasia. As a result of an enzyme deficiency, the adrenal gland produces too much androgen, resulting in female babies developing male characteristics. The degree of virilization varies and can be of late onset.
* Secondary sexual characteristics: puberty is divided into five stages (Tanner stages), each stage representing the extent of breast and pubic hair growth. † In girls with anorexia nervosa, the growth spurt usually occurs, but secondary sexual characteristics are absent [Edmonds, 2007a].
Data from: [Reindollar and McDonough, 1981; Strubbe et al, 1994; Baird, 1997; McIver et al, 1997; Garden, 1998; Balen, 1999; Pletcher and Slap, 1999; Scholes et al, 1999; Warren and Stiehl, 1999; Khalaf, 2003; Edmonds, 2007a; Klose et al, 2007; Golden and Carlson, 2008; Practice Committee of the American Society for Reproductive Medicine, 2008; Heiman, 2009; Sabatini, 2009]

Causes of secondary amenorrhoea

What are the causes of secondary amenorrhoea?

Causes of secondary amenorrhoea are listed in Table 1, categorized according to the presence or absence of androgen excess.

Always consider pregnancy. Also consider other physiological causes, including lactation and menopause, and certain contraceptive methods, such as depot medroxyprogesterone and the levonorgestrel intrauterine system.

The most common pathological causes are polycystic ovary syndrome, hypothalamic suppression (by weight loss, excessive exercise, or chronic systemic illness), premature ovarian failure, and hyperprolactinaemia [Reindollar et al, 1986; Balen, 2000].

Table 1 . Secondary amenorrhoea classified according to the presence or absence of androgen excess.
No features of androgen excess present Features of androgen excess present
Physiological: pregnancy, lactation, menopause (40 years of age or older). Endocrine causes: polycystic ovary syndrome, Cushing's syndrome, late-onset congenital adrenal hyperplasia.
Iatrogenic/illicit drugs: progestogen methods of contraception (depot medroxyprogesterone acetate contraceptive injection, levonorgestrel intrauterine system, subdermal progestogen-only contraceptive implant, desogestrel progestogen-only pill); radiotherapy, chemotherapy, and surgery (oophorectomy, hysterectomy, endometrial resection); drugs causing hyperprolactinaemia (antipsychotics, metoclopramide, methyldopa, cimetidine, opiates, cocaine). Tumour: androgen-secreting tumours of the ovary or adrenal gland.
Uterine causes: cervical stenosis, Asherman's syndrome (intrauterine adhesions).
Ovarian causes: premature ovarian failure, resistant ovary syndrome*, chemotherapy or pelvic irradiation, mosaic Turner's syndrome.
Hypothalamic dysfunction: weight loss, eating disorders, excessive exercise, stress, depression, chronic systemic illness (for example severe cardiac, renal, or liver disease; inflammatory bowel disease; coeliac disease; AIDS; or cancer), idiopathic.
Other hypothalamic causes: central nervous system tumours (such as craniopharyngiomas or metastases), cranial irradiation.
Pituitary causes: prolactinoma, other hormone-secreting pituitary tumours, head injury, hypopituitarism (for example after traumatic brain injury), Sheehan's syndrome (pituitary infarction after major obstetric haemorrhage), sarcoidosis, tuberculosis, cranial irradiation.
Thyroid disease: hypothyroidism, hyperthyroidism.
* Some consider resistant ovary syndrome to be a variant of premature ovarian failure.
Data from: [Reindollar et al, 1986; Baird, 1997; McIver et al, 1997; Garden, 1998; Balen, 2000; Balen, 2004; Practice Committee of the American Society for Reproductive Medicine, 2008; Heiman, 2009]

Complications

What are the complications?

Women with amenorrhoea may have the following complications, depending on the underlying cause.

Osteoporosis

Evidence from observational studies indicates that women with amenorrhoea associated with oestrogen deficiency (in particular premature ovarian failure, weight loss, anorexia nervosa, and excessive exercise) are at increased risk of osteoporosis. This increased risk persists even if normal menses are resumed. Oestrogen deficiency is of particular concern in adolescents, as a desirable peak bone mass may not be attained [Davies et al, 1990; McGee, 1997; Warren and Stiehl, 1999; Master-Hunter and Heiman, 2006; Csermely et al, 2007; Golden, 2007].

Cardiovascular disease

Women with amenorrhoea associated with oestrogen deficiency may be at increased risk of cardiovascular disease. Although this has not been studied specifically, the increased risk associated with a low oestrogen state in postmenopausal women is well documented [Kiningham et al, 1996; Fogel, 1997; McIver et al, 1997].

Infertility

Women with amenorrhoea do not usually ovulate, but, with some causes of amenorrhoea, unpredictable spontaneous ovulation may occur; therefore, contraception should be used if pregnancy is to be avoided. Pregnancy can be achieved by many women either by treatment of the underlying disorder or by specialized infertility treatment [Baird, 1997; McIver et al, 1997]. Between 10% and 20% of women with infertility have amenorrhoea [Franks, 1987].

Psychological distress

Amenorrhoea often causes considerable anxiety, altered self-image, and loss of self-esteem. Many women have concerns about loss of fertility, loss of femininity, or unwanted pregnancy. The diagnosis of Turner's syndrome, androgen insensitivity syndrome, or developmental anomaly can be traumatic for both girls and their parents [Fogel, 1997; Rees, 2003].

The following conditions may be associated with specific complications:

Polycystic ovary syndrome, a common cause of secondary amenorrhoea, is associated with infertility, increased risk factors for cardiovascular disease, and increased risks of Type 2 diabetes and endometrial hyperplasia.

Polycystic ovary syndrome is not associated with an increased risk of osteoporosis.

See the CKS topic on Polycystic ovary syndrome.

Women with a Y chromosome are at increased risk of gonadal tumours.

Gonads (residual testes) should be removed either at diagnosis or, in women with androgen insensitivity, after puberty [Ledger and Skull, 2004; Practice Committee of the American Society for Reproductive Medicine, 2008].

Diagnosis

Diagnosis

Diagnosis - primary amenorrhoea

Diagnosis of primary amenorrhoea

Diagnosis of primary amenorrhoea

How do I make a diagnosis of primary amenorrhoea?

Ask about, and examine for, the development of secondary sexual characteristics, using the Tanner stages of pubertal development as a guide.

Diagnose primary amenorrhoea:

In girls up to 14 years of age who have no secondary sexual characteristics.

In girls up to 16 years of age with normal secondary sexual characteristics.

Basis for recommendation

Basis for recommendation

Evaluating for secondary sexual characteristics

The recommendation to evaluate for secondary sexual characteristics is based on expert opinion from narrative reviews and specialist textbooks [Kiningham et al, 1996; Garden, 1998; Boothroyd, 2002; Crouch and Creighton, 2004; Ledger and Skull, 2004; Master-Hunter and Heiman, 2006; Edmonds, 2007a; Hayden and Balen, 2007; Heiman, 2009].

The presence or absence of secondary sexual characteristics helps to determine when to investigate or refer women and girls with primary amenorrhoea, and facilitates identification of the underlying cause.

When to diagnose primary amenorrhoea

The recommendation on when to diagnose primary amenorrhoea is based on expert opinion in published narrative reviews and specialist textbooks [Baird, 1997; McIver et al, 1997; Garden, 1998; Balen, 2000].

Two more recent US narrative reviews recommend reducing the thresholds for further assessment to 15 years of age for girls with secondary sexual characteristics and 13 years of age for girls without secondary sexual characteristics [Golden and Carlson, 2008; Practice Committee of the American Society for Reproductive Medicine, 2008]. This is on the basis that these ages are two standard deviations above the means of onset of menarche and puberty in the US population.

CKS identified no UK publications that recommend similar reductions in the age criteria for diagnosing primary amenorrhoea.

This recommendation is also broadly supported by CKS expert reviewers.

Tanner stages of pubertal development

What are the Tanner stages of pubertal development?

This information is also available in a list format for users of mobile devices.

Table 1 . Pubertal development according to the staging system developed by Tanner.
Tanner stages Breast development Pubic hair growth
Stage 1 Pre-pubertal Pre-pubertal
Stage 2 Breast buds form Few long, downy hairs at the labia majora
Stage 3 Breast buds larger Pubic hair growth continues, but mainly central
Stage 4 Breasts in a 'mound' form Pubic hair in the triangular adult shape, but smaller
Stage 5 Breasts fully formed Pubic hair adult in shape, quantity, and type, and spread to the inner thighs
Data from: [Marshall and Tanner, 1969]

Tanner stages - for mobile devices

Tanner stages - for mobile devices

Stage 1: pre-pubertal breast development and pubic hair growth.

Stage 2: breast buds form, and there are a few long, downy hairs at the labia majora.

Stage 3: breast buds are larger and pubic hair growth continues, but is mainly central.

Stage 4: breasts are in a 'mound' form and pubic hair is in the triangular shape, but smaller.

Stage 5: breasts are fully formed and pubic hair is adult in shape, quantity, and type, and spread to the inner thighs.

[Marshall and Tanner, 1969]

Basis for recommendation

Basis for recommendation

The Tanner stages of pubertal development are derived from a longitudinal study of 192 white British girls that classified the girls into five stages of development, originally described by Tanner in 1962 [Marshall and Tanner, 1969].

Assessment to identify underlying cause

How do I identify the underlying cause of primary amenorrhoea?

Exclude pregnancy.

Enquire about:

Cyclical lower abdominal pain (suggesting haematocolpos caused by a genital tract malformation).

Stress, depression, weight loss, disturbance of perception of weight or shape, level of exercise, and chronic systemic illness (suggesting hypothalamic dysfunction).

Headache, visual disturbance, or galactorrhoea (suggesting prolactinoma).

Sexual history.

Age at menarche of mother and sisters (family history of late menarche suggests constitutional delay).

Family history of genetic anomalies (for example androgen insensitivity [46XY female], which can be caused by an X-linked defect in peripheral androgen receptor function).

Medication (such as antipsychotics), previous chemotherapy or radiotherapy, and illicit drug use (in particular opiates and cocaine).

Measure height and body weight, and calculate body mass index.

Examine for:

Hirsutism.

Clitoromegaly (indicating virilization) if hirsutism is present.

Galactorrhoea if appropriate. It is important not to examine the breasts before prolactin estimation, as the level may then be falsely elevated.

Haematocolpos (if there is a history of cyclical lower abdominal pain — separation of the labia reveals a bulging blue-coloured membrane and a pelvic mass may be palpable).

Features of Turner's syndrome (short stature, web neck, shield chest with widely spaced nipples, wide carrying angle, and scoliosis).

Features of androgen insensitivity (absence of axillary and pubic hair with normal breast development; testes may be palpable in the inguinal canal or labia).

Signs of thyroid and other endocrine disease.

Pelvic examination

This is inappropriate in young girls who are not sexually active; ultrasonography can be done to assess pelvic anatomy.

In older women presenting with primary amenorrhoea, it may be appropriate to do a pelvic examination, for example to look for an absent uterus.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion from narrative reviews and specialist textbooks [McIver et al, 1997; Garden, 1998; Master-Hunter and Heiman, 2006; Golden and Carlson, 2008; Heiman, 2009].

Pregnancy may be the cause of primary amenorrhoea; although the first few menstrual cycles after menarche are often anovulatory, this is not always the case [McIver et al, 1997].

Investigations

What investigations should I do for primary amenorrhoea?

Test for pregnancy if indicated.

Although investigations for primary amenorrhoea are usually done by a specialist, some primary healthcare professionals may wish to carry out the following preliminary investigations to facilitate diagnosis (see also Interpretation of investigation findings):

Pelvic ultrasonography (if the presence of a vagina and uterus cannot be confirmed by physical examination).

Prolactin.

It is important not to examine the breasts before prolactin estimation, as the level may then be falsely elevated. Delay blood tests for at least 48 hours.

Thyroid-stimulating hormone.

Follicle-stimulating hormone and luteinizing hormone.

If there are features of androgen excess:

Total testosterone.

If chronic illness is suspected:

Investigate according to clinical findings.

Interpretation of investigation findings

Interpretation of investigation findings

Referral to a specialist is likely to be needed regardless of the result of investigations, but the following information may guide referral, speed up diagnosis, and aid explanation to the girl or woman and her family about the possible cause of amenorrhoea (pending specialist opinion).

Pelvic ultrasonography

Uterus present

In girls with normal secondary sexual characteristics, causes include outflow obstruction (for example imperforate hymen or transverse vaginal septum) and causes of secondary amenorrhoea (such as polycystic ovary syndrome).

In girls with no secondary sexual characteristics, causes include Turner's syndrome (46XO; 'streak' ovaries only), gonadal agenesis (46XX or 46XY), and hypothalamic or pituitary causes.

Uterus absent or abnormal

Causes include androgen insensitivity (46XY genotype, female phenotype) and Meyer–Rokitansky–Kuster–Hauser syndrome (complete Mϋllerian agenesis).

Prolactin level

The normal prolactin level is less than 500 mIU/L.

Prolactin levels greater than 1000 mIU/L usually warrant further investigation by an endocrinologist (usually magnetic resonance imaging of the pituitary fossa is required). Causes include pituitary adenoma, empty sella syndrome, hypothyroidism, and drugs (in particular antipsychotics).

Prolactin levels of 500–1000 mIU/L:

Repeat the measurement, as persistent moderate elevations can be due to pituitary adenomas (imaging is needed).

Other causes include stress, recent breast examination, venepuncture, drugs (antipsychotics, antidepressants, antihypertensives, H2-receptor antagonists, opiates, and cocaine), renal or liver failure, hypothyroidism (prolactin level usually greater than 700 mIU/L), and polycystic ovary syndrome (rare cause of primary amenorrhoea).

Thyroid-stimulating hormone — see the CKS topic on Hypothyroidism.

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

If secondary sexual characteristics are absent, karyotyping in secondary care will be necessary in some women:

Short stature and high FSH and LH levels suggest Turner's syndrome.

Short stature and low FSH and LH levels suggest an intracranial lesion (for example hydrocephalus, trauma to skull, or craniopharyngioma) or empty sella syndrome.

Normal height and high FSH and LH levels suggest ovarian failure (normal karyotype) or 46XY (abnormal karyotype).

Normal height and low FSH and LH levels suggest constitutional delay, weight loss, anorexia nervosa, or excessive exercise. These findings may also occur in Kallman's syndrome, but the diagnosis is usually known before primary amenorrhoea is identified.

If normal secondary sexual characteristics are present:

The LH level may be mildly elevated in polycystic ovary syndrome, although this is a rare cause of primary amenorrhoea.

Total testosterone level

High levels of total testosterone (5.0 nanomol/L or greater) warrant investigation to exclude androgen insensitivity (46XY genotype, female phenotype), late-onset congenital adrenal hyperplasia, Cushing's syndrome, or an androgen-secreting tumour.

A moderately increased testosterone level (2.5–5.0 nanomol/L) may be seen in polycystic ovary syndrome.

Basis for recommendation

Basis for recommendation

Choice of investigations

These recommendations are based on expert opinion in narrative reviews and specialist textbooks [Kiningham et al, 1996; Baird, 1997; McIver et al, 1997; Garden, 1998; Fraser, 2000; Ledger and Skull, 2004; Wilson et al, 2005; Master-Hunter and Heiman, 2006; Edmonds, 2007a; Hayden and Balen, 2007; Golden and Carlson, 2008; Heiman, 2009], although there is no consensus on the choice of first-line investigations.

Some authors recommend a step-wise approach to the investigation of primary amenorrhoea, taking into account clinical features (such as the presence of secondary sexual characteristics and height) and the results of pelvic ultrasonography (the presence or absence of a uterus). A list of investigations is recommended here for the purpose of clarity.

Total testosterone measurement is not recommended by any authors as a first-line investigation, but it is generally recommended either if it is clinically indicated or as a second-line investigation. It may be useful to detect androgen insensitivity (46XY), late-onset congenital adrenal hyperplasia, Cushing's syndrome, and polycystic ovary syndrome (all relatively rare causes of primary amenorrhoea) in women and girls with hirsutism.

Sex hormone-binding globulin is usually used together with total testosterone to aid diagnosis of polycystic ovary syndrome [RCOG, 2007], but it has not been included here on the basis that polycystic ovary syndrome is a rare cause of primary amenorrhoea, one CKS expert reviewer stated that it is expensive and unnecessary, and referral to secondary care is recommended.

Interpretation of investigations

Pelvic ultrasonography

Interpretation is based on expert opinion from narrative reviews and specialist textbooks [McIver et al, 1997; Master-Hunter and Heiman, 2006; Edmonds, 2007a; Hayden and Balen, 2007; Golden and Carlson, 2008].

Prolactin

Interpretation is based on expert opinion from narrative reviews and specialist textbooks [Aloi, 1995; Kiningham et al, 1996; Balen, 2004; Master-Hunter and Heiman, 2006; Hayden and Balen, 2007; Practice Committee of the American Society for Reproductive Medicine, 2008; Heiman, 2009].

Follicle-stimulating hormone and luteinizing hormone

Interpretation is based on expert opinion from a narrative review [McIver et al, 1997] and a specialist textbook [Edmonds, 2007a].

Total testosterone

Interpretation is based on a specialist textbook [Edmonds, 2007b] and on a guideline from the Royal College of Obstetricians and Gynaecologists on the diagnosis of polycystic ovary syndrome [RCOG, 2007].

Diagnosis - secondary amenorrhoea

Diagnosis of secondary amenorrhoea

When to evaluate

When should I evaluate a woman with secondary amenorrhoea?

Evaluate the woman when amenorrhoea has persisted for 3–6 months.

This also applies to women with amenorrhoea after stopping the combined oral contraceptive, who should be evaluated for an underlying cause.

For most women, arrange laboratory investigations when 6 months have elapsed since the last menstrual period.

This can be done earlier if it is clinically indicated (for example if hirsutism is present) or if the woman is anxious.

For women who are amenorrhoeic after cessation of an injectable progestogen, investigate 9 months after the last injection.

Basis for recommendation

Basis for recommendation

There is no consensus in the published literature on the definition of secondary amenorrhoea, or when to evaluate. The recommendation to evaluate after 3–6 months is inclusive of all opinions.

Some authors and guidelines define secondary amenorrhoea as the absence of menstruation for at least 6 months in women with previously normal and regular menses, or for 12 months in women with previous oligomenorrhoea [Kiningham et al, 1996; McIver et al, 1997; Ledger and Skull, 2004; Alberta Medical Association, 2008].

Others define secondary amenorrhoea as the absence of menses for 3 months in women with previously normal menstruation, or for 9 months in women with previous oligomenorrhoea [NHS Scotland, 2005; Master-Hunter and Heiman, 2006; Practice Committee of the American Society for Reproductive Medicine, 2008; Heiman, 2009].

Regional Scottish referral guidelines suggest clinical assessment at 3 months, delaying investigations until 6 months have elapsed since the last menstrual period [NHS Lothian, 2009a].

The recommendations on when to evaluate women with amenorrhoea after stopping the combined oral contraceptive and when to investigate women with amenorrhoea after stopping depot medroxyprogesterone are based on expert opinion from narrative reviews [Rees, 2003; Warren and Hagey, 2004] and CKS expert reviewers.

Assessment to identify underlying cause

How do I identify the underlying cause of secondary amenorrhoea?

Exclude pregnancy and other physiological causes, such as lactation or menopause (in women 40 years of age or older).

Elicit the woman's concerns (for example about infertility — see the CKS topic on Infertility).

Enquire about:

History of infertility.

History of contraceptive use.

Hot flushes and vaginal dryness (suggesting premature ovarian failure).

Headache, visual disturbances, or galactorrhoea (for a pituitary tumour).

Acne and hirsutism.

Weight loss or gain (for eating disorders and polycystic ovary syndrome).

Stress or depression (for stress-related hypothalamic amenorrhoea).

Exercise level (for exercise-associated hypothalamic amenorrhoea).

Symptoms of thyroid and other endocrine disease.

Menstrual, obstetric, and surgical history (such as endometrial curettage, which may suggest intrauterine adhesions — Asherman's syndrome).

Medical history, including: chemotherapy; pelvic radiotherapy (which can cause premature ovarian failure); and cranial radiotherapy, head injury, or major obstetric haemorrhage (which can cause hypopituitarism).

Medication (such as antipsychotics) and illicit drug use (in particular cocaine and opiates).

Family history of cessation of menses before 40 years of age (for premature ovarian failure), diabetes (associated with polycystic ovary syndrome), and autoimmune disorders (associated with premature ovarian failure).

Measure height and body weight, and calculate body mass index.

Examine for:

Galactorrhoea, if appropriate.

Signs of excess androgens (hirsutism, acne) or virilization (hirsutism, acne, deep voice, temporal balding, increase in muscle bulk, breast atrophy, and clitoromegaly).

Acanthosis nigricans (associated with polycystic ovary syndrome).

Signs of thyroid disease.

Signs of Cushing's syndrome (striae, buffalo hump, significant central obesity, easy bruising, hypertension, and proximal muscle weakness).

Perform fundoscopy and assess visual fields if a pituitary tumour is suspected.

Consider whether to do any investigations in primary care.

Basis for recommendation

Basis for recommendation

These recommendations are based on Scottish referral guidelines [NHS Lothian, 2009a; NHS Lothian, 2009b] and on expert opinion from published narrative reviews and specialist textbooks [Kiningham et al, 1996; McIver et al, 1997; Balen, 2000; Rees, 2003; Balen, 2004; Ledger and Skull, 2004; Warren and Hagey, 2004; Wilson et al, 2005; Master-Hunter and Heiman, 2006; Dickerson et al, 2009; Heiman, 2009].

Investigations

What investigations should I do for secondary amenorrhoea?

See Interpretation of investigation findings.

Consider testing for pregnancy in all women who present with secondary amenorrhoea.

Obtain the following measurements:

Follicle-stimulating hormone and luteinizing hormone.

Prolactin.

Total testosterone and sex hormone-binding globulin.

Thyroid-stimulating hormone.

Interpretation of investigation findings

Interpretation of investigation findings

See Table 1 for laboratory findings in common causes of secondary amenorrhoea.

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

High FSH levels (greater than 20 U/L) and high LH levels (greater than 40 U/L) on two occasions suggest premature ovarian failure (in women younger than 40 years of age).

Normal or low FSH levels (20 U/L or less) and normal or low LH levels (40 U/L or less) suggest hypothalamic causes (most commonly weight loss, excessive exercise, or stress, or, rarely, a hypothalamic or pituitary tumour).

Normal FSH levels and normal or moderately increased LH levels may be found in polycystic ovary syndrome.

Prolactin level

The normal prolactin level is less than 500 mIU/L.

Prolactin levels greater than 1000 mIU/L warrant further investigation by an endocrinologist (usually magnetic resonance imaging of the pituitary fossa is required). Causes include pituitary adenoma and hypothyroidism.

If prolactin levels are 500–1000 mIU/L:

Repeat the measurement; if these levels persist, pituitary adenoma may be the cause (imaging is needed).

Other causes include stress, recent breast examination, venepuncture, medication (antipsychotics, antidepressants [tricyclics, monoamine oxidase inhibitors], antihypertensives [calcium-channel blockers, methyldopa], H2-receptor antagonists [cimetidine], metoclopramide and domperidone, opiates, and cocaine), ectopic production (for example teratoma or renal cell carcinoma), renal or liver failure, hypothyroidism (prolactin level usually greater than 700 mIU/L), and polycystic ovary syndrome.

Thyroid-stimulating hormone

See the CKS topic on Hypothyroidism.

Total testosterone and sex hormone-binding globulin

High levels of total testosterone (5.0 nanomol/L or greater) warrant investigation to exclude other causes, such as Cushing's syndrome, late-onset congenital adrenal hyperplasia, or an androgen-secreting tumour.

Calculate the free androgen index: normal value is less than 5. This is the total testosterone level (in nanomol/L x 100) divided by the sex hormone-binding globulin level (in nanomol/L).

A free androgen index greater than 5 with a normal or moderately increased testosterone level (less than 5.0 nanomol/L) is seen in polycystic ovary syndrome.

Table 1 . Laboratory findings in common causes of secondary amenorrhoea.
State FSH LH Prolactin Testosterone
Hyperprolactinaemia Normal/low Normal/low High Normal
Polycystic ovary syndrome Normal Normal/slightly increased in 40% Normal/slightly increased in 5–30% Normal/moderately increased Free androgen index increased
Ovarian failure High High Normal Normal
Hypothalamic (for example weight loss, excessive exercise, or stress) Low/normal Low/normal Normal Normal
FSH, follicle-stimulating hormone; LH, luteinizing hormone. Data from: [Aloi, 1995; Kiningham et al, 1996; Baird, 1997; McIver et al, 1997; Balen, 1999; Rees, 2003; Warren and Hagey, 2004; Practice Committee of the American Society for Reproductive Medicine, 2008]

Basis for recommendation

Basis for recommendation

Choice of investigations

These recommendations are based on reports of the relative frequencies of underlying causes of secondary amenorrhoea [Reindollar et al, 1986; Balen, 2000; Balen, 2004], Scottish referral guidelines [NHS Scotland, 2005; NHS Lothian, 2009a], recommendations from the American Society for Reproductive Medicine [Practice Committee of the American Society for Reproductive Medicine, 2008], and expert opinion from narrative reviews and specialist textbooks [Kiningham et al, 1996; Baird, 1997; McIver et al, 1997; Balen, 2000; Ledger and Skull, 2004; Wilson et al, 2005; Master-Hunter and Heiman, 2006; Dickerson et al, 2009; Heiman, 2009].

Excluding pregnancy is widely recommended; in particular, one expert notes that 'it is common to see one or two patients a year who are pregnant despite denying the possibility' [Balen, 2000].

Polycystic ovary syndrome (PCOS), premature ovarian failure, hyperprolactinaemia, and hypothalamic suppression (due to weight loss, stress, or excessive exercise) are the most common causes of secondary amenorrhoea [Reindollar et al, 1986; Balen, 2000; Balen, 2004]. Total testosterone, sex hormone-binding globulin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin measurements are appropriate first-line tests for these conditions.

There is no consensus in the published literature on the most appropriate first-line investigations for secondary amenorrhoea.

All of the cited studies recommend testing for pregnancy and assessing serum prolactin. Most also recommend FSH, LH, and thyroid-stimulating hormone (TSH) measurement, although thyroid disease appears to be a relatively rare cause of secondary amenorrhoea and some experts recommend TSH measurement only if the woman has features of thyroid disease.

The routine measurement of total testosterone and sex hormone-binding globulin are recommended on the basis that:

PCOS is a common cause of secondary amenorrhoea [Reindollar et al, 1986; Balen, 2000; Balen, 2004].

There is some evidence that women conceal hirsutism [Balen et al, 2005].

These tests are recommended for the investigation of PCOS in a Royal College of Obstetricians and Gynaecologists guideline [RCOG, 2007].

The UK-based authors of a review paper recommend that GPs perform several initial investigations before the woman is seen in secondary care [Ledger and Skull, 2004]. They state that, although amenorrhoea has traditionally been investigated using a step-wise approach, this is likely to lead to an increased number of visits to complete each stage of investigation, and thus increase expense.

Oestradiol measurement is not recommended on the basis that the result is unreliable (as levels tend to fluctuate), and levels can be normal or low in both PCOS and hypothalamic amenorrhoea [Practice Committee of the American Society for Reproductive Medicine, 2008].

Interpretation of investigation findings

Prolactin

Interpretation is based on a Scottish referral guideline [NHS Scotland, 2005], narrative reviews [Aloi, 1995; Kiningham et al, 1996; Wieck and Haddad, 2003; Ledger and Skull, 2004; Master-Hunter and Heiman, 2006; Practice Committee of the American Society for Reproductive Medicine, 2008; Heiman, 2009], and a specialist textbook [Balen, 2004].

FSH and LH

Interpretation is based on expert opinion from narrative reviews and a specialist textbook [McIver et al, 1997; Balen, 2000; Master-Hunter and Heiman, 2006], and on a Canadian guideline on endocrine testing in amenorrhoea [Alberta Medical Association, 2008].

Total testosterone and sex hormone-binding globulin

Interpretation is based on guidelines from the Royal College of Obstetricians and Gynaecologists on the diagnosis of PCOS [RCOG, 2007] and on expert textbook opinion [Edmonds, 2007b].

Management

Management

Scenario: Primary amenorrhoea : covers the treatment and referral of women and girls with primary amenorrhoea.

Scenario: Secondary amenorrhoea : covers the treatment and referral of women and girls with secondary amenorrhoea.

Scenario: Primary amenorrhoea

Scenario: Management of primary amenorrhoea

120months3060monthsFemale

Management

How should I manage a woman or girl with primary amenorrhoea?

Consider whether to refer to a specialist. In general, refer:

Girls who have not started menstruating by 14 years of age and have no secondary sexual characteristics.

Girls with normal secondary sexual characteristics who have not started menstruating by 16 years of age.

Treat the underlying cause in women and girls confirmed by a specialist as having hypothalamic amenorrhoea secondary to the following causes:

Chronic systemic illness.

Eating disorders — see the CKS topic on Eating disorders.

Exercise-associated amenorrhoea — advise modification of the exercise programme, along with attention to diet and weight.

Stress-induced amenorrhoea — refer for counselling or psychological therapy where appropriate.

If amenorrhoea persists, consider whether osteoporosis prophylaxis is required. This is covered in Managing osteoporosis risk in Scenario: Secondary amenorrhoea.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion from narrative reviews and textbooks [McIver et al, 1997; Garden, 1998; Edmonds, 2007a; Hayden and Balen, 2007].

See also Basis for recommendation in Referral.

Referral

When should I refer a woman or girl with primary amenorrhoea?

In general, refer for specialist investigation:

Girls who have not started menstruating by 14 years of age and have no secondary sexual characteristics.

Girls with normal secondary sexual characteristics who have not started menstruating by 16 years of age.

Earlier referral (at an earlier age than stated above) is appropriate if an abnormality is suspected — for example, in girls and women with:

Symptoms and signs of androgen excess (such as hirsutism) or thyroid disease.

Galactorrhoea or growth retardation.

Suspected genital tract malformation, intracranial tumour (for example prolactinoma), chromosomal anomaly (for example Turner's syndrome or androgen insensitivity), or anorexia nervosa.

Puberty lasting 5 years without menarche (for example presenting at 15 years of age when pubic hair and breast development started at 10 years of age).

Referral to a gynaecologist (preferably with a special interest in adolescent gynaecology) is appropriate for most girls and women.

Refer to an endocrinologist those women and girls with hyperprolactinaemia, thyroid disease, or signs of androgen excess.

Basis for recommendation

Basis for recommendation

The recommendation to refer all women and girls with primary amenorrhoea is based on expert opinion from Canadian regional guidelines [Alberta Medical Association, 2008], narrative reviews [Crouch and Creighton, 2004; Hayden and Balen, 2007; Golden and Carlson, 2008], and a primary care gynaecology textbook [Chamberlain and Bowen-Simpkins, 2000]. In general, few authors make recommendations on when to refer.

When to refer

The criteria for referral based on age and the presence or absence of secondary sexual characteristics are extrapolated from expert opinion in published narrative reviews and specialist textbooks on when to evaluate a woman or girl with primary amenorrhoea [Baird, 1997; McIver et al, 1997; Garden, 1998; Balen, 2000].

Two recent US narrative reviews recommend reducing the thresholds for assessment to girls 15 years of age or older with secondary sexual characteristics, and girls 13 years of age or older without secondary sexual characteristics [Practice Committee of the American Society for Reproductive Medicine, 2008]. This is on the basis that these ages are two standard deviations above the means for the onset of puberty and menarche in the US population.

CKS identified no UK papers that recommend similar reductions in the age criteria for diagnosing primary amenorrhoea, and so has not adopted the US recommendations.

This recommendation is also broadly supported by CKS expert reviewers.

Secondary care management is recommended so that the following investigations and treatment can be conducted, if appropriate [McIver et al, 1997; Garden, 1998; Balen, 2004; Crouch and Creighton, 2004; Ledger and Skull, 2004; Master-Hunter and Heiman, 2006; Edmonds, 2007a]:

Karyotyping.

Computed tomography or magnetic resonance imaging.

Specialist endocrine tests.

Progesterone and oestrogen/progesterone challenge tests (sometimes used to evaluate the level of endogenous oestrogen and the competence of the outflow tract).

Surgery for genital tract malformations and obstruction.

Induction of puberty.

Referral to specialists

One narrative review recommends referral to an endocrinologist if the girl is 14 years of age and showing no secondary sexual characteristics, and referral to a gynaecologist if the girl has secondary sexual characteristics but has not commenced menstruation by 16 years of age [Crouch and Creighton, 2004].

However, given that the most common pathological cause of primary amenorrhoea in women and girls without secondary sexual characteristics is ovarian failure (often caused by a chromosomal anomaly) [Reindollar and McDonough, 1981; Garden, 1998; Wilson et al, 2005], referring all girls 14 years of age showing no sexual characteristics to an endocrinologist may not be appropriate, as ovarian failure may be better dealt with by a gynaecologist.

Scenario: Secondary amenorrhoea

Scenario: Management of secondary amenorrhoea

120months3060monthsFemale

Management

How should I manage a woman with secondary amenorrhoea?

Consider whether to refer to secondary care or manage in primary care.

In general, refer if the cause cannot be established or requires confirmation, or treatment in secondary care may be required.

The following conditions may be managed in primary care, depending on clinical judgement:

Polycystic ovary syndrome (see the CKS topic on Polycystic ovary syndrome).

Hypothalamic amenorrhoea caused by weight loss, excessive exercise, or stress, after assessment by an endocrinologist to exclude a hypothalamic or pituitary tumour.

Hypothyroidism — menses may take several months to resume with treatment (see the CKS topic on Hypothyroidism).

Menopause (women 40 years of age or older, see the CKS topic on Menopause).

If the woman has persistent hyperprolactinaemia and is taking a drug known to cause high prolactin levels (see Interpretation of investigation findings), consider stopping the drug.

If the woman is taking an antipsychotic, refer to her psychiatrist.

For other drugs, contact an endocrinologist for advice, as it may still be necessary to exclude prolactinoma.

If infertility is an issue, see the CKS topic on Infertility.

Offer contraceptive advice if desired, as a small number of women with secondary amenorrhoea will become pregnant — see the CKS topic on Contraception - assessment.

Manage the risk of osteoporosis in women with amenorrhoea associated with low oestrogen levels (premature ovarian failure, hypothalamic amenorrhoea, hypopituitarism, and hyperprolactinaemia) — see Managing osteoporosis risk.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion from narrative reviews and a specialist textbook [McIver et al, 1997; Balen, 2000; Rees, 2003; Master-Hunter and Heiman, 2006; Practice Committee of the American Society for Reproductive Medicine, 2008; Heiman, 2009].

The statement that treatment of hypothyroidism should restore menses, but may take several months to do so, is based on expert opinion from a narrative review [Master-Hunter and Heiman, 2006].

Regarding women with persistent hyperprolactinaemia who are taking drugs known to cause increased prolactin levels:

The recommendation to refer the woman to her psychiatrist if she is taking an antipsychotic is pragmatic, supported by a CKS expert reviewer.

The recommendation to seek specialist advice from an endocrinologist in relation to other drugs is based on evidence in narrative reviews of a poor correlation between prolactin levels and the presence of a tumour [Master-Hunter and Heiman, 2006; Practice Committee of the American Society for Reproductive Medicine, 2008]. See Interpretation of investigation findings.

The recommendation to offer contraception, if desired, is based on evidence that women with premature ovarian failure have a 5–10% chance of natural conception, owing to intermittent ovarian function [Balen, 2000; Master-Hunter and Heiman, 2006; Practice Committee of the American Society for Reproductive Medicine, 2008; Heiman, 2009], and on expert opinion that women with hypothalamic amenorrhoea should be advised to use contraception [Fogel, 1997; Rees, 2003].

Referral

When should I refer a woman with secondary amenorrhoea?

Refer, or seek specialist advice for those women with secondary amenorrhoea lasting 6 months (or earlier if it is clinically indicated) if any of the following apply:

The cause cannot be established.

The cause requires confirmation (for example premature ovarian failure).

Secondary care treatment may be required (for example for infertility or a suspected tumour).

Refer the woman to a gynaecologist if she has any of the following:

Persistently elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels — which suggest premature ovarian failure in women younger than 40 years of age.

Recent history of uterine or cervical surgery (such as endometrial curettage, Caesarean section, or myomectomy) or severe pelvic infection (endometritis), suggesting Asherman's syndrome or cervical stenosis (normal FSH and LH levels).

Infertility — see the CKS topic on Infertility.

Suspected polycystic ovary syndrome, if diagnosis and management are not feasible in primary care — see the CKS topic on Polycystic ovary syndrome.

Refer the woman to an endocrinologist if she has any of the following:

Hyperprolactinaemia: serum prolactin level greater than 1000 mIU/L, or 500–1000 mIU/L on two occasions. This includes women with both hyperprolactinaemia and hypothyroidism, who should be investigated by an endocrinologist.

Low FSH and LH levels (to exclude hypopituitarism or a pituitary tumour, although stress, excessive exercise, or weight loss are more likely cause).

An increased testosterone level that is not explained by polycystic ovary syndrome (suggesting an androgen-secreting tumour, late-onset congenital adrenal hyperplasia, or Cushing's syndrome).

Other features of Cushing's syndrome or late-onset congenital adrenal hyperplasia (besides an increased testosterone level).

Consider referring the woman to a psychiatrist or psychologist if an eating disorder is suspected — see the CKS topic on Eating disorders.

Consider referring the woman to a dietitian if she is underweight (body mass index less than 19 kg/m2).

Basis for recommendation

Basis for recommendation

Recommendations are based on whether further investigation or treatment is needed in secondary care to identify and manage likely underlying causes of secondary amenorrhoea. Explicit recommendations on when to refer are lacking in the published literature. Of the authors that do comment, most recommend referral if the underlying cause cannot be identified or treatment can only be given in secondary care [Latthe, 2003; Wilson et al, 2005]. Scottish regional referral guidelines have also been used to guide the recommendations [NHS Lothian, 2009b].

Referral to a gynaecologist

Women with suspected premature ovarian failure require:

Confirmation of the diagnosis and identification of the underlying cause, which may include karyotyping in women younger than 30 years of age (for Y chromosome, mosaic Turner's syndrome, short arm deletion, fragile X syndrome, or sex chromosome translocation, as appropriate).

Screening for other autoimmune disease (present in up to 40% of women); the most common is thyroiditis.

Monitoring and prophylaxis or treatment of osteoporosis.

Treatment for infertility, if desired [Balen, 2000; Balen, 2004; Ledger and Skull, 2004; Master-Hunter and Heiman, 2006; Practice Committee of the American Society for Reproductive Medicine, 2008].

Women with suspected Asherman's syndrome require hysteroscopy [Balen, 2000; Practice Committee of the American Society for Reproductive Medicine, 2008].

Referral to an endocrinologist

The recommendation to refer the woman if the serum prolactin level is greater than 1000 mIU/L, or 500–1000 mIU/L on two occasions, is based on a Scottish referral guideline [NHS Scotland, 2005] and on expert opinion from narrative reviews and specialist textbooks that such findings can be caused by a pituitary adenoma, which requires imaging of the pituitary fossa and secondary care medical or surgical treatment [Aloi, 1995; Kiningham et al, 1996; Balen, 2004; Master-Hunter and Heiman, 2006; Practice Committee of the American Society for Reproductive Medicine, 2008; Heiman, 2009].

The recommendation that women with both hyperprolactinaemia and hypothyroidism should be investigated by an endocrinologist is based on the opinion of CKS expert reviewers.

The recommendation to refer women with an increased testosterone level that is not explained by polycystic ovary syndrome is based on a guideline from the Royal College of Obstetricians and Gynaecologists on the diagnosis of polycystic ovary syndrome [RCOG, 2007] and on expert textbook opinion [Edmonds, 2007b], which recommend that an androgen-secreting tumour, late-onset congenital adrenal hyperplasia, and Cushing's syndrome should be excluded. This is likely to require secondary care expertise.

The recommendation to refer women with low follicle-stimulating hormone and luteinizing hormone levels to exclude hypopituitarism or a pituitary tumour is based on opinions of several CKS expert reviewers.

Referral to a psychiatrist or psychologist

The recommendation to refer women in whom an eating disorder is suspected is based on expert opinion [Balen, 2000].

Referral to a dietitian

The recommendation to consider referring women who are underweight to a dietitian is based on expert opinion [McIver et al, 1997]. The definition of underweight is based on expert opinion that amenorrhoea can occur when body mass index is less than 19 kg/m2 [Ledger and Skull, 2004].

Managing hypothalamic amenorrhoea

How should I manage a woman with hypothalamic amenorrhoea?

Refer women with suspected hypothalamic amenorrhoea to an endocrinologist to exclude a hypothalamic or pituitary tumour.

After exclusion of a hypothalamic or pituitary tumour, women with the following may initially be managed in primary care:

Amenorrhoea due to systemic illness

Treat the underlying illness, which may restore menstruation.

Weight-related amenorrhoea

Encourage weight gain (which commonly restores menses). Refer to a dietitian if necessary.

If an eating disorder is suspected, consider referral to a psychiatrist. See the CKS topic on Eating disorders.

Exercise-induced amenorrhoea

Advise reducing exercise, increasing calorie intake, and weight gain.

Consider referral to or liaison with a sports physician, if available.

Stress-related amenorrhoea

Consider measures to manage stress and improve coping strategies, such as cognitive behavioural therapy.

Inform the woman that hypothalamic amenorrhoea may increase the risk of osteoporosis and cardiovascular disease because of low oestrogen levels — see Managing osteoporosis risk.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion from narrative reviews [Hobart and Smucker, 2000; Berga, 2001; Ledger and Skull, 2004; Warren and Hagey, 2004; Adis International Ltd., 2006; Berga and Loucks, 2006] and a specialist textbook [Balen, 2000], and on evidence from a small randomized controlled trial (RCT) of cognitive behavioural therapy (CBT) [Berga et al, 2003].

A small RCT in 16 women with functional hypothalamic amenorrhoea suggests that CBT aids recovery of ovarian activity compared with no treatment [Berga et al, 2003].

Functional hypothalamic amenorrhoea was defined according to levels of progesterone and luteinizing hormone, mildly increased energy expenditure or mildly decreased energy intake, and characteristic personality features (including high levels of perfectionism, high need for social approval, and altered attitudes toward eating). Women with depression, eating disorders, or any psychiatric disorders other than personality disorders were excluded, as were underweight women and those who ran 10 miles or more per week or who exercised for 10 hours or more per week.

Women who received 16 sessions of CBT over 20 weeks had significantly higher rates of full or partial recovery of ovarian activity (defined in terms of oestrogen and progesterone levels) than women who received no treatment (87.5% compared with 25%; p = 0.03).

The recommendation to consider referring to a sports physician, if available, those women with exercise-related amenorrhoea is based on the recognition in published literature on sports medicine of a condition known as the 'female athlete triad': disordered eating, amenorrhoea, and osteoporosis [Otis et al, 1997; American Academy of Pediatrics, 2000; Birch, 2005]. However, there are concerns both about the wider implications of the use of the term 'female athlete triad' [DiPietro and Stachenfeld, 2006], and that its components do not identify all women at risk [Burrows et al, 2007].

Managing osteoporosis risk

How should I manage the risk of osteoporosis?

For women with premature ovarian failure (younger than 40 years of age), hypothalamic amenorrhoea, or hyperprolactinaemia (women with amenorrhoea associated with low oestrogen levels who are at increased risk of developing osteoporosis):

Treat the underlying cause, if possible.

Advise an adequate intake of calcium (1500 mg/day) and vitamin D (400 IU/day).

Bisphosphonates are not currently recommended.

Consider offering oestrogen replacement (off-label use) if amenorrhoea persists for more than 12 months.

Consider measuring bone mineral density before treatment.

Offer cyclical combined hormone replacement therapy (at the doses used for menopause) or, particularly if contraception is needed, a combined oral contraceptive. See the CKS topics on Menopause and Contraception - combined hormonal methods for prescribing information.

In women with eating disorders, treat only after discussion with the woman's psychiatrist. The resumption of menses may reinforce denial that weight loss is contributing to amenorrhoea.

Review treatment at least annually. For women with amenorrhoea due to reversible causes (such as weight loss or excessive exercise), oestrogen replacement should be periodically stopped (for example after 12 months of treatment, for 6 months) to see whether menses will resume off treatment.

For women with amenorrhoea due to the following causes, management of the possible increased osteoporosis risk is covered in other CKS topics:

Menopause (women 40 years of age or older) — see the CKS topic on Menopause.

Depot medroxyprogesterone — see the CKS topic on Contraception - progestogen-only methods.

Women with polycystic ovary syndrome are not at increased risk of osteoporosis — see the CKS topic on Polycystic ovary syndrome.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion from narrative reviews and specialist textbooks [Hergenroeder, 1995; Baird, 1997; McIver et al, 1997; Balen, 2000; Balen, 2004; Ledger and Skull, 2004; Practice Committee of the American Society for Reproductive Medicine, 2008].

Identifying women at risk

Evidence from observational studies indicates that women with amenorrhoea associated with low oestrogen levels are at increased risk of osteoporosis [Davies et al, 1990; McGee, 1997; Warren and Stiehl, 1999; Master-Hunter and Heiman, 2006; Csermely et al, 2007; Golden, 2007].

Treating the underlying cause

This is a pragmatic recommendation, based on very low-quality evidence that increased calorie intake increases bone mineral density in women with anorexia- or exercise-associated amenorrhoea.

Calcium and vitamin D intake

This recommendation is based on expert opinion [Hergenroeder, 1995; Baird, 1997; McIver et al, 1997; Balen, 2000; Balen, 2004; Ledger and Skull, 2004; Practice Committee of the American Society for Reproductive Medicine, 2008].

Bisphosphonates are not recommended

Limited evidence from two small randomized controlled trials indicates that bisphosphonates increase bone mineral density in women with anorexia nervosa compared with placebo. There is no evidence in women with other forms of functional hypothalamic amenorrhoea. However, bisphosphonates are not widely recommended in the published literature, and there are concerns about possible teratogenicity [Master-Hunter and Heiman, 2006].

Hormone replacement therapy and combined oral contraceptives

Evidence of the benefits of hormone replacement therapy (HRT) or combined oral contraceptives (COCs) in preventing or treating osteoporosis in women with premature ovarian failure or hypothalamic amenorrhoea is limited, conflicting, and of low quality. Nonetheless, there is a consensus of expert opinion in the published literature that oestrogen replacement should be initiated to prevent excessive bone loss in women with hypothalamic amenorrhoea or premature ovarian failure [Hergenroeder, 1995; Baird, 1997; McIver et al, 1997; Balen, 2000; Balen, 2004; Ledger and Skull, 2004; Practice Committee of the American Society for Reproductive Medicine, 2008].

There is no consensus on which (HRT or COCs) is preferable. One expert recommends HRT (unless contraception is required) because of the lower oestrogen dose [Balen, 2004], whereas another states that the doses of oestrogen in HRT are insufficient to improve bone mineral density in teenagers and young adults [Hergenroeder, 1995].

In a consensus statement, the British Menopause Society says that the results of the Women's Health Initiative and the Million Women Study (showing an increased risk of breast cancer associated with HRT) are not necessarily relevant to younger postmenopausal women taking appropriate doses of different regimens [British Menopause Society, 2008]. It recommends that women with premature menopause should normally be offered HRT until the average age of the menopause (52 years). This could be extrapolated to women with premature ovarian failure and other causes of amenorrhoea which are associated with low oestrogen levels.

Caution over the use of oestrogen replacement to induce menses in women with anorexia nervosa is also expert opinion [Balen, 2004].

The recommendation on monitoring is based on expert opinion [Balen, 2004].

The recommendation to periodically stop treatment is pragmatic and is based on a study of 93 women with hypothalamic amenorrhoea due to stress, exercise, or weight loss, in which more than 70% recovered some ovarian function over 8 years [Falsetti et al, 2002].

Opinions in the published literature differ on the period of amenorrhoea after which oestrogen replacement is recommended, varying from 6–12 months [Hergenroeder, 1995; Baird, 1997; McIver et al, 1997; Balen, 2000; Balen, 2004; Ledger and Skull, 2004; Practice Committee of the American Society for Reproductive Medicine, 2008]. CKS recommends 12 months, to allow time for treatment of the underlying cause to be effective.

Evidence

Evidence

Supporting evidence

Interventions for loss of bone density

Evidence on interventions for loss of bone density

Increased calorie intake

Evidence on increased calorie intake in hypothalamic amenorrhoea

Very low-quality evidence suggests that increased calorie intake increases bone mineral density (BMD) in women with anorexia- or exercise-associated amenorrhoea.

A systematic review (search date: 1960 to January 2007) of strategies to reverse bone loss in women with functional hypothalamic amenorrhoea identified no randomized controlled trials of increased calorie intake [Vescovi et al, 2008]. This is probably because it would be unethical to perform them, particularly in women with eating disorders. The review identified four uncontrolled intervention studies in women with anorexia-associated amenorrhoea, and one small observational study and two case reports in women with exercise-associated amenorrhoea.

The review was limited by:

Failure to assess the quality (internal validity) of the included studies, or use quality as a criterion for inclusion.

The use in the included studies of change in BMD as a surrogate measure of the main outcome of interest: fracture risk (either acutely or later in life).

Results:

Six studies in 107 women reported increases in BMD at the hip, femoral neck, proximal femur, or lumbar spine of 1.1–25.5% over 2 months to 12 years with increased calorie intake.

One study in 26 women reported no change in BMD at any site after 12 months with increased calorie intake.

Oral contraceptives

Evidence on oral contraceptives in hypothalamic amenorrhoea

The evidence regarding the effects of combined oral contraceptives (COCs) on bone mineral density (BMD) is conflicting and of low-to-moderate quality. There is limited, low-quality evidence for a beneficial effect of COCs on BMD in premenopausal women with oligomenorrhoea or amenorrhoea (in particular women with hypothalamic amenorrhoea), and very limited, very low-quality evidence for their effectiveness in women with anorexia nervosa. Because placebo-controlled trials are lacking, it remains uncertain whether COCs protect against further bone loss, let alone whether they can restore BMD to normal levels, in women with hypothalamic amenorrhoea. Furthermore, change in BMD is a surrogate measure of the main outcome of interest: fracture risk (either acutely or later in life).

A systematic review (search date: up to March 2005) identified 17 studies of oral contraceptives in premenopausal women with amenorrhoea, oligomenorrhoea, or anorexia nervosa. Most of the studies were of low quality (observational) or small [Liu and Lebrun, 2006].

Premenopausal women with amenorrhoea or oligomenorrhoea (10 studies)

A positive effect was found in seven studies in 379 women: two randomized controlled trials (RCTs) in 88 women with hypothalamic amenorrhoea or oligomenorrhoea and five cohort studies in 291 women.

No effect was found in two studies in 64 women: one RCT in 34 women with hypothalamic amenorrhoea and one cohort study in 30 women.

A negative effect was found in one case study of one athlete.

Anorexic premenopausal women (seven studies)

A positive effect was found in two cross-sectional studies in 483 women.

No effect was found in five studies: three RCTs in 159 women, one cohort study in 50 women, and one case series in 38 women.

A negative effect was found in one cohort study in 4 women.

A subsequent systematic review (search date: 1960 to January 2007) identified no additional studies and made similar conclusions [Vescovi et al, 2008].

HRT

Evidence on hormone replacement therapy in hypothalamic amenorrhoea

There is conflicting, low-quality evidence on the effect of hormone replacement therapy (HRT) at doses used for menopause on bone mineral density (BMD) in women with anorexia- or exercise-associated amenorrhoea. Because placebo-controlled trials are lacking, it is not known whether HRT is effective in preventing fracture, preventing osteoporosis, or treating low BMD in women with amenorrhoea. Furthermore, most studies use change in BMD as a surrogate measure of the clinical outcome of interest: fracture risk (either acutely or later in life).

A systematic review (search date: 1960 to January 2007) identified six studies on the effects of oestrogen therapy in women with functional hypothalamic amenorrhoea [Vescovi et al, 2008]. The review was limited by the failure to assess the quality (internal validity) of the included studies, or use quality as a criterion for inclusion.

No randomized, placebo-controlled trials were identified.

Two controlled trials in 89 women with exercise-associated amenorrhoea found either no change in BMD with treatment, or no difference between treatment and control.

Two intervention studies in 44 women with anorexia-associated amenorrhoea found no change in BMD with treatment.

One cross-sectional study in 58 women with anorexia-associated amenorrhoea found increased BMD in the lumbar spine and femoral neck in treated compared with untreated women.

The result of a case study of a woman with anorexia nervosa was not reported.

Bisphosphonates

Evidence on bisphosphonates in hypothalamic amenorrhoea

Limited evidence from two small placebo-controlled, randomized controlled trials (RCTs) suggests that bisphosphonates increase bone mineral density (BMD) in women with anorexia nervosa. CKS identified no evidence in women with other forms of functional hypothalamic amenorrhoea.

A systematic review (search date: 1960 to January 2007) of strategies to reverse bone loss in women with functional hypothalamic amenorrhoea identified two small RCTs of bisphosphonates in women with anorexia nervosa [Vescovi et al, 2008]. It also identified a small uncontrolled study in women with anorexia nervosa who had osteopenia. The review was limited by the failure to assess the quality (internal validity) of the included studies or use quality as a criterion for inclusion, and by the use in the included studies of change in BMD as a surrogate measure of the main outcome of interest: fracture risk (either acutely or later in life).

One RCT compared etidronate with either calcium and vitamin D or placebo in 41 women with anorexia nervosa.

After 3 months, midshaft tibial BMD (as assessed by ultrasonography) increased in the etidronate group by 1.1% and in the calcium/vitamin D group by 0.8%, but decreased in the placebo group by 0.1%. Statistical significance was not reported in the review.

Another RCT compared alendronate, vitamin D, and calcium with placebo in 32 women, 12–21 years of age, with anorexia nervosa.

At 12 months, lumbar spine and femoral neck BMD increased more in the treatment group compared with control (by 2.2% and 2.3%, respectively), but the differences were not significant (p > 0.4).

The result may have been biased by co-intervention of multidisciplinary treatment for the eating disorder, which led to mean increases in body mass of 13.5% in the treatment group and 16.2% in the control group.

An uncontrolled intervention study found a 4.9% increase in lumbar BMD in 10 women with anorexia and osteopenia treated with risedronate, calcium, and vitamin D after 8 months.

Search strategy

Scope of search

A literature search was conducted for guidelines and background reviews on the primary care management of amenorrhoea, with additional searches in the following areas:

Management of osteoporosis risk, cardiovascular risk, and risk of endometrial hyperplasia in women with chronic amenorrhoea (2006–)

Etiology of primary and secondary amenorrhoea (1950–)

Search dates

Guidelines/background reviews: January 1990 – June 2009

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline and these were adapted for other databases. Further details are available on request.

exp amenorrhea/, amenorrhoea.tw, amenorrhea.tw

exp osteoporosis/, exp cardiovascular diseases/, exp endometrial hyperplasia/, exp risk factors/, exp risk/

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSH subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Topic specific literature search sources

American Society for Reproductive Medicine

Royal College of Obstetricians and Gynaecologists

Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

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