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.[10][11]

Physical examination includes measurement of height, weight, and BMI. 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.[10][12]

To determine the reason for amenorrhea, a pregnancy test should first be conducted. To determine whether secondary sexual characteristics are present, the Tanner scale should be used to stage pubertal development. The absence of secondary sexual characteristics indicates that a woman has never been exposed to estrogen. 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 hypergonadotropic and hypogonadotropic forms of hypogonadism. 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. 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.[13][14]

For the treatment of congenital anomalies:[15][14]

(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 hypergonadotropic 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.

The differential diagnoses are as follows: 

• Primary hypothalamic amenorrhea 
• Emotional/physical stress 
• Female athlete triad 
• Hypogonadotropic hypogonadism (Kallman syndrome)
• Malnutrition 
• Chronic disease state
• Constitutional delay
• PCOS
• Outflow tract obstruction 

Primary amenorrhea is not a life-threatening disease but can result in some complications.

If primary amenorrhea is associated with decreased estrogen levels, it can cause an increased risk of bone fractures due to reduced bone density from osteoporosis.[16]

Due to the diversity of etiologies that can lead to primary amenorrhea, patient education should be individualized to the underlying cause. Females nearing the age of puberty should be educated on normal menstrual periods and when to follow-up with a physician. Patients being treated for primary amenorrhea should regularly follow up with their physician.

Primary amenorrhea poses a diagnostic dilemma. These patients present with specific signs and symptoms which point toward the underlying etiology. A detailed history and thorough physical examination help in reaching the diagnosis in most cases. However, diagnosis is further supported in some of the patients by an array of laboratory investigations, which includes serum measurement of thyroid function tests, FSH, LH and prolactin, radiological imaging, and karyotype. Treatment is aimed at correcting the primary cause of amenorrhea. Treatment is primarily surgical in which congenital anomalies are found to be the cause of primary amenorrhea. Cyclic hormonal therapy is instituted in all cases of premature ovarian failure and gonadal dysgenesis. Clinicians, nurses, and pharmacists must work together in educating the patient and monitoring treatment.[11]