Approach
Although history and physical examination frequently direct the clinician towards a working diagnosis, ancillary studies are often necessary. Most systemic disorders may be diagnosed with laboratory tests assessing neuroendocrine and ovarian function, and the majority of structural abnormalities are identified through pelvic examination or imaging studies.[1]
History
The mean age of pubertal development aids in deciding the timing of an amenorrhoea evaluation. Evaluation should take place with absent menstruation by age 15 years (if other pubertal development is noted), within 3 years of breast development, or with failure of breast development by age 13 years.[1][15][16] Thelarche ('breast budding') denotes previous or current oestrogen production. Age of onset or lack thereof may be used to determine when to begin an assessment. Early pubarche (appearance of pubic hair) may be associated with development of polycystic ovary syndrome (PCOS).[17]
Galactorrhoea: hyperprolactinaemia is more commonly associated with secondary amenorrhoea.
History of a traumatic head injury or central nervous system infection: a remote history may be elicited from the patient or parents.
Headache/visual field changes: suggest a central nervous system tumour (e.g., craniopharyngioma).[18]
Anosmia: suggests Kallman syndrome or a complete congenital gonadotrophin-releasing hormone (GnRH) deficiency.[19]
Chronic systemic illness: may present with fatigue, malaise, anorexia, and weight loss.
Family history: height should be documented and compared with that of other family members. Short stature is suggestive of Turner syndrome or hypothalamic-pituitary disease.[20] A history of familial delayed puberty, in addition to onset of menarche in the patient's mother and female siblings, should be elicited.
A diagnosis of functional hypothalamic amenorrhoea should only be made after excluding anatomical or organic pathology. An enquiry into a patient's health status, eating habits, and body image is necessary. Poor nutritional status due to systemic illness, an eating disorder, and/or low body fat may result in hypothalamic dysfunction.[21] Emotional stress or extreme athleticism can also result in a similar phenomenon.[22][23]
Physical examination
The patient's weight and height should be measured. Shortened height may suggest a chromosomal abnormality. Patients with gonadal dysgenesis and hypo-oestrogenaemia are at risk for shortened final adult height. Growth pattern should be documented and compared with that of first-degree relatives.
On initial examination, careful attention should be given to male pattern baldness, deepening of the voice, wide distribution of terminal hair (male pattern), acne, or oily skin, suggesting hyperandrogenaemia. These patterns may vary based on ancestry. If symptoms are slowly progressive, PCOS or non-classic congenital adrenal hyperplasia is possible. If acute and progressive, the patient may be harbouring an androgen-producing tumour (ovarian or adrenal).
Consider performing a neurological examination to assess for neurological findings such as peripheral vision changes, which suggests an intracranial mass impinging on the optic chiasm (e.g., pituitary adenoma, craniopharyngioma).
Careful examination of the breasts to elicit galactorrhoea should be performed in the event that prolactinoma is suspected.
On speculum and bimanual examination, most structural anomalies are identified. The hymen must be assessed first. A blind vaginal pouch will be noted in patients with Mullerian agenesis, transverse vaginal septum, or androgen insensitivity syndrome (the latter along with inguinal hernias). The uterine cervix should be noted on examination. Internal examinations are not always possible and the clinician may need to proceed with imaging options or an examination under anaesthesia.[Figure caption and citation for the preceding image starts]: Imperforate hymenLardenoije C, Aardenburg R, Mertens H. Imperforate hymen: a cause of abdominal pain in female adolescents. BMJ Case Reports 2009; doi:10.1136/bcr.08.2008.0722 [Citation ends].
Laboratory tests
All patients with primary amenorrhoea, regardless of physical examination findings, should have preliminary laboratory studies drawn, including follicle-stimulating hormone (FSH), estradiol, thyroid-stimulating hormone (TSH), and prolactin. Based on these results, other tests are ordered.
Patients with secondary sexual development should be assessed for pregnancy. A karyotype is indicated for patients with primary amenorrhoea and lack of secondary sexual development or those who are diagnosed with premature ovarian insufficiency (usually secondary amenorrhoea).[7][24]
FSH: in concert with estradiol levels, gonadotrophins help determine if amenorrhoea is due to gonadal failure, hypothalamic dysfunction, or systemic or functional causes. FSH is more useful as a single test than luteinising hormone (LH), and LH is not usually included in the initial investigations ordered.
Serum estradiol: low levels are suggestive of either primary ovarian failure (along with elevated FSH) or suppressed hypothalamic function (low FSH).
Serum prolactin: elevated levels of circulating prolactin (hyperprolactinaemia), whether idiopathic or due to a pituitary adenoma, result in hypogonadotrophic hypogonadism. For persistently elevated levels, neuroimaging is indicated to rule out intracranial neoplasm.[13]
TSH: is indicated to rule out (primary) hypothyroidism, more commonly associated with secondary amenorrhoea. Mild or sub-clinical hypothyroidism is unlikely to result in menstrual irregularities.[25] It is proposed that elevated thyrotrophin-releasing hormone (TRH) stimulates prolactin secretion from the pituitary, suppressing FSH production.[26]
Serum androgens: done for signs of hyperandrogenism. Androgens such as dehydroepiandrosterone sulphate (DHEAS) and free testosterone will be elevated in patients with PCOS, but higher levels are suggestive of an androgen-producing tumour and these patients should be referred for further investigation.[27][28]
Karyotype: helps to identify patients at risk for gonadal tumours, such as those with premature ovarian insufficiency (usually secondary amenorrhoea), androgen insensitivity syndrome, or gonadal dysgenesis.[1][6][14] A diagnosis of complete androgen insensitivity can be confirmed by a 46,XY karyotype, and a diagnosis of Turner syndrome by 45,X. Gonadal dysgenesis (streak gonads) can occur with normal XX and XY karyotypes.[1]
Physiological tests and imaging
Transabdominal or transvaginal ultrasound is performed if a pelvic examination is not possible. Ultrasound confirms normal anatomy and aids in the diagnosis of most structural abnormalities, as well as the presence of an ovarian or adrenal tumour. Transvaginal is the preferred modality, if possible and appropriate, to evaluate endometrial thickness.
MRI is the most effective tool for characterising specific structural abnormalities and may prevent the need for surgical diagnosis. On MRI, Mullerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome) or asymmetrical fusion defects of the Mullerian system (unicornuate uterus) can be identified as well as renal anomalies, which can occur in up to 30% of these patients.[29] A spine x-ray may reveal skeletal abnormalities, which have been reported in around 8% to 32% of patients with Mullerian agenesis.[30]
If prolactin levels are significantly elevated, cranial MRI is indicated to rule out pituitary adenoma.[13]
Bone density measurement may be indicated in selected patients.[24] Bone age is an additional test conducted in patients with delayed puberty.
Audiometric and ophthalmological testing is recommended in patients with Turner syndrome. A coeliac screen is also useful in these patients.
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