Primary amenorrhoea is a symptom with an extensive list of underlying causes, the majority of which are rare. According to the definition, it should present in adolescence, although some conditions are diagnosed in childhood may present with failure of menstruation. Many causes of secondary amenorrhoea can also present with primary amenorrhoea if they arise very early in life. A systematic, compartment based approach will cover the commoner causes of primary amenorrhoea and recommend a pragmatic but cost-effective approach to achieve a correct diagnosis. Treatment must be directed at the specific cause but has often wider implications for lifelong wellbeing like weight management, hormone replacement, sexual health, and fertility.
Amenorrhea is defined as the absence of menarche in females of reproductive age. Primary amenorrhea is defined as the failure of initiation of menses by age 14 in the absence of secondary sexual characteristics or the absence of menarche by age 16 regardless of the presence of normal growth and development of secondary sexual characteristics. In contrast, secondary amenorrhea is defined as the cessation of previous menses for more than 6 months.[rx]
Causes of Primary Amenorrhoea
The majority of cases of primary amenorrhea are caused by anatomical defects, elevated follicle-stimulating hormone (FSH) levels, hyperprolactinemia, hypothalamic amenorrhea, or polycystic ovary syndrome (PCOS).[rx]
Gonadal dysgenesis includes most commonly Turner syndrome, which makes up to 43% of primary amenorrhea cases.
- Anatomical Defects – When the uterus and vagina are partially or completely absent in the presence of otherwise normal female sexual characteristics, the diagnosis is typically Mullerian agenesis, which accounts for approximately 10% of primary amenorrhea cases. Other anatomical defects include imperforate hymen or transverse vaginal septum, both of which create a partial or complete vaginal blockage, and isolated absence of the vagina or cervix.[rx]
- Elevated FSH Levels – Elevated follicle-stimulating hormone levels can indicate gonadal dysfunction. In individuals with XX chromosomes, gonadal failure refers to ovarian failure.[rx]
- Hyperprolactinemia – Prolactin is a pituitary hormone that is involved in many reproductive functions. The secretion of prolactin causes an inhibition of the secretion of gonadotropin-releasing hormone, which negatively modulates the secretion of pituitary hormones that are responsible for the gonadal function.[rx]
- Hypothalamic Amenorrhea – This condition causes cessation or absence of menses due to a functional disorder of the hypothalamus.
- Polycystic Ovary Syndrome – PCOS is the most common cause of amenorrhea in females with evidence of androgen excess. It is a common reproductive and endocrinologic disorder. The three main characteristics of this syndrome are hyperandrogenism, polycystic ovaries, and ovulatory dysfunction.[rx]
- Hypopituitarism – weight loss, anorexia nervosa, and isolated gonadotropin-releasing hormone (GnRH) deficiency can also cause amenorrhea.
- Constitutional delay of puberty – as well as chronic systemic disease or acute illness, can also lead to amenorrhea.
- Primary amenorrhoea is much less frequently caused by
- imperforate hymen – a congenital disorder in which a hymen has no opening and completely obstructs the vagina
- transverse vaginal septum – a birth defect that results in a wall of tissue running horizontally across the vagina, blocking all or part of it
- enzymes deficiencies
- high prolactin levels due to a pituitary tumour
- congenital adrenal hyperplasia
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Pregnancy
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Hypogonadtrophichypogonadism:
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Endocrine lesions
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Congenital abnormalities
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Tumors
- hypothyroidism
- low energy availability (for example, due to decreased caloric intake, excessive energy use, eating disorders, excessive exercise, or being an elite athlete)
- stress.
The World Health Organization (WHO) categorized amenorrhea into three groups. WHO group I includes females with no evidence of endogenous estrogen production, normal or low follicle-stimulating hormone (FSH) levels, normal prolactin levels, and no evidence of lesions in the hypothalamic-pituitary region. WHO group II includes females who can produce estrogen and have normal levels of prolactin and FSH. WHO group III includes females with increased serum FSH, which indicates gonadal insufficiency or failure.[rx][rx]
Symptoms of Primary Amenorrhoea
In addition to the absence of menstrual periods, patients may have the following signs and symptoms of amenorrhoea:
- Headaches, visual disturbance or tiredness caused by diseases affecting the pituitary gland
- The spontaneous flow of milk from the breasts caused by excessive levels of a hormone called prolactin. This is called galactorrhoea
- Acne and/or excess body hair growing in male-pattern distribution caused by polycystic ovary syndrome
- Symptoms of premature menopause (premature ovarian failure) such as hot flushes, vaginal dryness, poor sleep or reduced libido
- Short stature and lack of secondary sexual characteristics (e.g. breast development) if premature ovarian failure is caused by the genetic condition of Turner syndrome.
- Milky nipple discharge
- Hair loss
- Headache
- Vision changes
- Excess facial hair
- Pelvic pain
- Acne
Diagnosis of Primary Amenorrhoea
History
The evaluation of amenorrhea begins with a thorough medical history and physical examination.
- It is important to first rule out pregnancy as a patient ovulates before their first period. Inquire about pubertal development or cyclic abdominal pain, which may be caused by an imperforate hymen, transverse vaginal septum, or cervical atresia.
- Any history of anosmia, galactorrhoea, headaches, and visual changes may be indicative of a central nervous system or pituitary disorder. Inquire about medical history, general health, and lifestyle, particularly to identify chronic illness or exposure to radiation.
- Current medications should be reviewed. A history of extreme weight loss should be noted. Delayed menarche or androgen insensitivity syndrome can often be hereditary.[rx][rx]
Physical examination
- Short stature and sexual infantilism are hallmarks of gonadal dysgenesis. Low body weight is associated with hypothalamic amenorrhea resulting from severe malnutrition or physical, psychological, or emotional stress. Breast tanner staging is a reliable indicator of estrogen production or exposure to exogenous estrogen.
- A goiter or thyroid nodule suggests thyroid disorder; both hypothyroidism and hyperthyroidism can be associated with amenorrhea. Stigmata of Turner’s syndrome should be explored, which include a webbed neck, widely spaced nipples, cubitus valgus, low hairline, high arched palate, multiple pigmented naevi, and short fourth metacarpals. Abdominal examination may reveal a mass that may result from hematometra or an ovarian neoplasm, but this is rare.
- A thorough examination of the external genitalia should be conducted. An imperforate hymen is diagnosed by the presence of a bulging membrane that distends during the Valsalva maneuver. A patent vagina and normal cervix exclude Mullerian vaginal agenesis, androgen insensitivity syndrome, and obstructive causes of amenorrhea such as an imperforate hymen or transverse vaginal septum. Rectal examination can detect any distended haematocolpos that may form above the obstruction when the uterus is present and functional.[rx][rx]
Lab tests
A variety of blood tests may be necessary, including
- Pregnancy test –This will probably be the first test your doctor suggests, to rule out or confirm a possible pregnancy.
- Thyroid function test – Measuring the amount of thyroid-stimulating hormone (TSH) in your blood can determine if your thyroid is working properly.
- Ovary function test – Measuring the amount of follicle-stimulating hormone (FSH) in your blood can determine if your ovaries are working properly.
- Prolactin test – Low levels of the hormone prolactin may be a sign of a pituitary gland tumor.
- Male hormone test – If you’re experiencing increased facial hair and a lowered voice, your doctor may want to check the level of male hormones in your blood.
- Hormone challenge test – For this test, you take a hormonal medication for seven to 10 days to trigger menstrual bleeding. Results from this test can tell your doctor whether your periods have stopped due to a lack of estrogen.
Imaging tests
Depending on your signs and symptoms and the result of any blood tests you’ve had your doctor might recommend one or more imaging tests, including:
- Ultrasound – This test uses sound waves to produce images of internal organs. If you have never had a period, your doctor may suggest an ultrasound test to check for any abnormalities in your reproductive organs.
- Computerized tomography (CT) – CT scans combine many X-ray images taken from different directions to create cross-sectional views of internal structures. A CT scan can indicate whether your uterus, ovaries and kidneys look normal.
- Magnetic resonance imaging (MRI) – MRI uses radio waves with a strong magnetic field to produce exceptionally detailed images of soft tissues within the body. Your doctor may order an MRI to check for a pituitary tumor.
- Scope tests – If other testing reveals no specific cause, your doctor may recommend a hysteroscopy — a test in which a thin, lighted camera is passed through your vagina and cervix to look at the inside of your uterus.
The evaluation should include
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Beta hCG – to rule out pregnancy, because pregnancy is the most common cause of amenorrhea
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Prolactin – level to rule out prolactinoma
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Thyroid hormones – since thyroid gland disturbances can lead to amenorrhea
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Testosterone and DHEAS – to rule out hyperandrogenism
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FSH and LH for hypothalamic amenorrhea – BMI (to look for malnutrition, anorexia nervosa, and excessively strenuous exercise)
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Pelvic ultrasound and adrenal CT – for androgen-secreting tumors and other anatomical defects like Mayor-Rokitansky-Kauser-Hauser syndrome
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MRI to assess – the hypothalamic-pituitary tract (eg prolactinoma)
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Progesterone challenge test – This test is performed to differentiate between the anovulation, anatomic, and estradiol deficiency as causes of amenorrhea. Progesterone is administrated to the patient in the form of intramuscular injection, and after the progesterone is withdrawn. If bleeding takes place within 2 to 7 days, the cause must be the anovulation, but if no bleeding takes place after progesterone withdrawal, the causes are other than anovulation or premature ovarian failure. These other causes can include estradiol deficiency or anatomic defects like cervical stenosis and Asherman syndrome.
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Karyotyping – is sometimes an important test for Turner and androgen insensitivity syndromes.
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Pelvic ultrasound – should be conducted to confirm the presence or absence of a uterus. Initial laboratory tests can determine the serum levels of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels unless the history and physical examination indicate otherwise. This can help to discern hypogonadotropic and hypogonadotropic forms of hypogonadism.
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If the screening FSH level is low – the diagnosis of hypogonadotropic hypogonadism can be confirmed. Other important blood investigations include measurement of serum thyroid-stimulating hormone level and serum prolactin level. Elevated serum FSH level indicates premature ovarian insufficiency or failure. A karyotype should be conducted in patients under 30-years-old.
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A karyotype – is also useful in the diagnosis of androgen insensitivity syndrome, Turner syndrome, Mullerian anomalies, and gonadal dysgenesis. Due to the association between Turner Syndrome and coarctation of the aorta, patients should have an echocardiograph conducted every 3 to 5 years. The presence of the Y chromosome, along with raised serum testosterone levels, point towards the diagnosis of androgen insensitivity.
If the karyotype is normal with an elevated FSH level, 17-hydroxylase deficiency should be considered as it can be life-threatening if left untreated. Testing can be done with serum measurement of 17 alpha-hydroxyprogesterone and deoxycorticosterone level. The diagnosis is established with an Adrenocorticotropic hormone (ACTH) stimulation test. Ultrasonography or MRI is useful to identify the Mullerian anomaly when the abnormality cannot be found by physical examination. Lesions of the central nervous system should be excluded through the use of imaging using CT or MRI, particularly if headaches, visual impairments, or galactorrhea are present.[rx][rx]
Treatment of Primary Amenorrhoea
For the treatment of congenital anomalies [rx][rx]
- (1) Treatment of imperforate hymen involves making a cruciate incision to open the vaginal orifice.
- (2) If a transverse septum is present, surgical removal is required.
- (3) Hypoplasia or absence of the cervix in the presence of a functioning uterus is more difficult to treat than other outflow obstructions. Surgery to repair the cervix is rarely successful, and hysterectomy is typically required. The ovaries should be retained to provide the benefits of estrogen and to allow for the possibility of future childbearing by removing mature oocytes for in vitro fertilization and transfer of embryos to a gestational carrier.
- (4) If the vagina is absent or short, progressive dilation is usually successful.
Females diagnosed with primary amenorrhea that is associated with all forms of gonadal failure and hypogonadotropic hypogonadism require cyclic estrogen and progestogen therapy for the initiation, maturation, and maintenance of secondary sexual characteristics.
- (1) Therapy can be initiated with conjugated estrogens per day or estradiol per day.
- (2) Females with short stature should not receive high doses of estrogen as this can cause the epiphyses to close prematurely.
- (3) Hyperplasia can occur due to unopposed estrogen stimulation of the endometrium. In order to prevent hyperplasia, estrogen can be provided daily in combination with progestogen.
- (4) Patients with gonadal streaks and mosaicism may be able to ovulate and conceive either following the initiation of estrogen therapy or spontaneously.
- (5) If the diagnosis of 17 alpha-hydroxylase deficiency is established, treatment can be initiated with exogenous corticosteroid replacement therapy with either hydrocortisone or dexamethasone.
Therapeutic measures should aim to target the underlying cause or primary amenorrhea.
- (1) Craniopharyngiomas may be resected either during craniotomy or with a transsphenoidal approach.
- (2) Germinomas are very radiosensitive; thus, surgery is seldom indicated.
- (3) Hyperprolactinemia and prolactinomas may respond to dopamine agonists.
- (4) Specific therapies can target underlying causes such as anorexia nervosa or malnutrition.
- (5) Individuals diagnosed with Kallman syndrome or with other etiologies for hypothalamic amenorrhea may be treated with hormone replacement therapy.
If a female’s karyotype contains the Y chromosome, for example, as in gonadal dysgenesis, gonad removal should be performed to prevent tumors.
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