Primary Amenorrhea

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).[2]

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.[3]

Elevated FSH Levels

Elevated follicle-stimulating hormone levels can indicate gonadal dysfunction. In individuals with XX chromosomes, gonadal failure refers to ovarian failure.[3]  

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 responsible for the gonadal function.[4]  

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.[5]

Hypopituitarism, weight loss, anorexia nervosa, and isolated gonadotropin-releasing hormone (GnRH) deficiency can also cause amenorrhea.

Constitutional delay of puberty and chronic systemic disease or acute illness can also lead to amenorrhea. 

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.[6][7]

The incidence of primary amenorrhea is less than 1% in the United States. No variation is seen in the overall prevalence of primary amenorrhea according to the ethnic group or national origin.

The menstrual cycle is a series of coordinated hormonal changes controlling the ovaries and endometrium that stimulate the growth of a follicle to release an egg and prepare the endometrium for implantation if fertilization should occur. Conversely, if the egg released is not fertilized, menstruation occurs due to the shedding of the functional layer of the endometrium. The basic requirements for normal menstrual function include four anatomically and functionally distinct structural components: the genital outflow tract, including the uterus, the ovaries, the pituitary gland, and the hypothalamus. If any of the components are non-functional, bleeding cannot occur.[8][9]

History and Physical

The evaluation of amenorrhea begins with a thorough medical history and physical examination. It is important first to 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, or visual changes may indicate 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, including 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]

Evaluation

In assessing the reason for amenorrhea, a pregnancy test should first be conducted. The Tanner scale should be used to stage pubertal development to determine whether secondary sexual characteristics are present. 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 diagnosing 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 levels. 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]

Treatment / Management

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 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. 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 other etiologies for hypothalamic amenorrhea may be treated with hormone replacement therapy. 

If a female's karyotype contains the Y chromosome, such as gonadal dysgenesis, gonad removal should be performed to prevent tumors.

Differential Diagnosis

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 

Prognosis

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

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]