Amenorrhea overview

# Overview
The first descriptions about disturbances in menstrual cycle are found in Papyrus Ebres , from New Kingdom period (1450-1550 B.C.). Amenorrhea may be classified according to etiology into three subtypes, including primary amenorrhea, secondary amenorrhea, and functional amenorrhea. Primary amenorrhea is basically refers to a young girl who have not experienced menarche, at all. Secondary amenorrhea reflects a woman who had ordinary menstruation cycles, experiencing at least 3 months of absence of menstruation cycle. Functional amenorrhea is a subtype of the amenorrhea caused by exaggerated different lifestyles. Primary and secondary amenorrhea are distinguished solely based on history. Mainly the pathophysiology of amenorrhea is described in many categories, include hypothalamic, pituitary, thyroid, adrenal, ovarian, uterine, and vaginal pathogenesis. About 25 various genes, in 3 different group of Kallmann syndrome related genes, hypothalamus-pituitary-gonadal (HPG) axis related genes, and obesity related genes, play role in amenorrhea. Common causes of amenorrhea include breastfeeding, pregnancy, menopause, and stress. Primary amenorrhea must be differentiated from other diseases that cause lack of menstrual cycle, such as Mullerian agenesis, 3-beta-hydroxysteroid dehydrogenase type 2 deficiency, androgen insensitivity syndrome, Kallmann syndrome, Turner syndrome, and 17-alpha-hydroxylase deficiency. In contrast, secondary amenorrhea must be differentiated from other diseases that cause menstrual cycle arrest, such as primary ovarian insufficiency, hypothyroidism, hyperprolactinemia, polycystic ovary syndrome, and Asherman's syndrome. The prevalence of amenorrhea is approximately 3,000 to 4,000 per 100,000 individuals worldwide. The most common risk factor in the development of primary amenorrhea is chromosomal disorder and the most common risk factor in the development of secondary amenorrhea is breastfeeding. If left untreated, all of patients with amenorrhea may progress to develop infertility and osteoporosis. Common complications of amenorrhea are based on the background disease that induced it. Prognosis is generally excellent and the mortality rate of patients with amenorrhea is approximately less than 1%, generally in amenorrhea due to brain lesions. The initial laboratory tests for evaluating amenorrhea are pregnancy test, thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), and prolactin (PRL). Second line laboratory tests include free and total testosterone, dehydroepiandrosterone sulfate (DHEAS), and also progesterone challenge test. There are no echocardiography findings associated with amenorrhea. However, an echocardiography may be helpful in the diagnosis of the diseases that can cause amenorrhea, such as Turner syndrome. Findings on an echocardiography suggestive of Turner syndrome include bicuspid aortic valve, elongation of transverse aortic arch, coarctation of aorta, and partial anomalous pulmonary venous return (PAPVR). There are no ultrasound findings associated with amenorrhea. However, an ultrasound may be helpful in the diagnosis of the diseases that can cause amenorrhea, such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency, androgen insensitivity syndrome, 17-alpha hydroxylase deficiency, and also anatomic genital defects. Pharmacologic medical therapy is recommended among patients with hypothalamic causes, pituitary causes, ovarian insufficiency, and chronic anovulation. The general principle of the treatment in amenorrhea is sex hormone replacement therapy, with suitable forms of estrogen and progesterone. The mainstay of treatment for amenorrhea is medical therapy. Surgery is usually reserved for patients with either hypothalamus or pituitary tumors, Turner syndrome, and genital anatomical defects (imperforate hymen or transverse vaginal septum). The surgical treatment for hypothalamus or pituitary tumors is tumor resection via endoscopic transsphenoidal surgery. Ovaries have to be excised in Turner syndrome to prevent malignant transformation. Small incision is the main surgery for imperforate hymen and septal excision is the main treatment for transverse vaginal septum.

# Historical Perspective
The ancient Egyptian belief honored "menstrual blood" as life-giving. The Mesopotamian mother goddess, named Ninhursag, is believed to have created mankind from loam and her "blood of life". The first descriptions about disturbances in menstrual cycle are found in Papyrus Ebres , from New Kingdom period (1450-1550 B.C.E). They described the patients as a "women who suffers from the side of her pubic region as an irregularity of her menstruation". In 1907, British Medical Journal, released an article about different types of treatments (mostly herbal and conservative) for amenorrhea. In 1911, some researchers evaluate the therapeutic methods presented 4 years ago and make some suggestions to manage amenorrhea better. The term amenorrhea is derived from Greek language , means lack of menstruation cycle in a woman.

# Classification
Amenorrhea may be classified according to etiology into three subtypes, including primary amenorrhea, secondary amenorrhea, and functional amenorrhea. Primary amenorrhea is basically refers to a young girl who have not experienced menarche, at all, classified as hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, and eugonadotropic state. Secondary amenorrhea reflects a woman who had normal menstruation cycles, experiencing at least 3 months of absence of menstruation cycle. It is classified as polycystic ovary syndrome, hypothalamic-pituitary dysfunction, hypothalamic-pituitary failure, and ovarian failure. Functional amenorrhea is a subtype of the amenorrhea caused by exaggerated different lifestyles, classified as stress, weight loss, and exercise related groups.

# Pathophysiology
Amenorrhea is defined as absence of menstrual cycle. The pathophysiology of amenorrhea include hypothalamic, pituitary, thyroid, adrenal, ovarian, uterine, and vaginal causes. About 25 different genes are involved in the pathogenesis of amenorrhea such as 3 different groups of Kallmann syndrome related genes, hypothalamus-pituitary-gonadal (HPG) axis related genes, and obesity related genes. On gross pathology, normal endometrium is the characteristic findings of amenorrhea. Patients of amenorrhea from craniopharyngioma have cystic mass filled with motor oil-like fluid on gross pathology. On microscopic histopathological analysis, craniopharyngioma presents as trabecular squamous epithelium surrounded by palisaded columnar epithelium, small-to-medium sized cells with moderate amount of basophilic cytoplasm, bland nuclei, and calcifications. On microscopic histopathological analysis, pituitary adenoma as a cause of amenorrhea presents as loss of fibrous stroma and nested cells of normal anterior pituitary (based on the type of adenoma).

# Causes
Common causes of amenorrhea are breastfeeding, pregnancy, menopause, and stress. Common causes of primary amenorrhea are craniopharyngioma, idiopathic gonadotropin deficiency, Kallmann's syndrome, Mayer-Rokitansky-Hauser Syndrome, Mullerian dysgenesis, and outflow tract disorders. Common causes of secondary amenorrhea are craniocerebral trauma, curettage, Cushing's syndrome, depression, diabetes mellitus, and drug side effects. Common causes of functional amenorrhea are stress, rapid weight loss, and excessive exercise.

# Differentiating Amenorrhea from Other Diseases
As amenorrhea manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. Primary amenorrhea must be differentiated from other diseases that cause lack of menstrual cycle, such as Mullerian agenesis, 3-beta-hydroxysteroid dehydrogenase type 2 deficiency, androgen insensitivity syndrome, Kallmann syndrome, Turner syndrome, and 17-alpha-hydroxylase deficiency. In contrast, secondary amenorrhea must be differentiated from other diseases that cause menstrual cycle arrest, such as primary ovarian insufficiency, hypothyroidism, hyperprolactinemia, polycystic ovary syndrome, and Asherman's syndrome.

# Epidemiology and Demographics
The incidence of primary amenorrhea is approximately 3,000 cases per 100,000 individuals, mostly due to hypothalamic amenorrhea. The incidence of secondary amenorrhea is approximately 3,300 per 100,000 individuals. The prevalence of amenorrhea is approximately 3,000 to 4,000 per 100,000 individuals worldwide. The prevalence of amenorrhea was estimated to be 13,400 cases per 100,000 female athletes. The mortality rate of amenorrhea is less than 1%, and seen in patients of pituitary macroadenomas or generally brain lesions which cause amenorrhea. Primary amenorrhea is initially diagnosed among adolescents, 16 years of age. There is no racial predilection for amenorrhea. Commonly, females in developed countries experience puberty and menarche earlier than females of developing countries. This can be attributed to nutritional and socioeconomic situation but since the age of diagnosis of primary amenorrhea is based on the society's mean age of puberty onset and menarche, there is not any difference between developing and developed countries in terms of prevalence of amenorrhea.

# Risk Factors
The most common risk factor in the development of primary amenorrhea is chromosomal disorder and the most common risk factor in the development of secondary amenorrhea is breastfeeding. Common risk factors in the development of amenorrhea include risk factors related to hypothalamus, pituitary, ovaries, and also functional amenorrhea. Most common hypothalamic risk factors are Kallmann syndrome and chronic disorders. Most common pituitary risk factors are hyperprolactinemia and pituitary microadenoma.

# Screening
According to the US Preventive Services Task Force (USPSTF), there is insufficient evidence to recommend routine screening for amenorrhea.

# Natural History, Complications, and Prognosis
If left untreated, all of patients with amenorrhea may progress to develop infertility and osteoporosis. Common complications of amenorrhea are based on the background disease that induced it. Prognosis is generally excellent and the mortality rate of patients with amenorrhea is approximately less than 1%, generally in brain lesions.

# Diagnosis

## Diagnostic Criteria
There are no established criteria for the diagnosis of amenorrhea. Diagnosis is based on delayed or absent menstrual cycle.

## History and Symptoms
The hallmark of primary amenorrhea is lack of menarche 15 years of age, while other secondary sexual characteristics are already appeared; or lack of menarche after 5 years of thelarche, if it is occurred before 10 years of age. The hallmark of secondary amenorrhea is menstrual cycle interruption for at least 3 months, however was regular before; or menstrual cycle interruption for at least 6 months, however was irregular before.

## Physical Examination
Physical examination of patients with amenorrhea is based on underlying disease. The presence of hirsutism and acne on physical examination is diagnostic of polycystic ovary disease. The presence of galactorrhea and vision loss on physical examination is diagnostic of hyperprolactinemia (prolactinoma). The presence of bulging in vulva and imperforated hymen on physical examination is highly suggestive of imperforate hymen.

## Laboratory Findings
The initial laboratory tests for evaluating amenorrhea are pregnancy test, thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), and prolactin (PRL). Second line laboratory tests include free and total testosterone, dehydroepiandrosterone sulfate (DHEAS), and also progesterone challenge test.

## Electrocardiogram
There are no ECG findings associated with amenorrhea.

## X-ray
There are no X-ray findings associated with amenorrhea, exclusively. There are no X-ray findings associated with most common causes of amenorrhea, like polycystic ovary syndrome (PCOS) and premature ovarian failure. However, an  X-ray may be helpful in the diagnosis of delayed puberty.

## Echocardiography/Ultrasound
There are no echocardiography findings associated with amenorrhea. However, an echocardiography may be helpful in the diagnosis of the diseases that can cause amenorrhea, such as Turner syndrome. Findings on an echocardiography suggestive of Turner syndrome include bicuspid aortic valve, elongation of transverse aortic arch, coarctation of aorta, and partial anomalous pulmonary venous return (PAPVR). There are no ultrasound findings associated with amenorrhea. However, an ultrasound may be helpful in the diagnosis of the diseases that can cause amenorrhea, such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency, androgen insensitivity syndrome, 17-alpha hydroxylase deficiency, and also anatomic genital defects.

## CT scan
There are no CT scan findings associated with amenorrhea. However, a CT scan may be helpful in the diagnosis of the diseases that can cause amenorrhea, such as Turner syndrome, androgen insensitivity syndrome and also anatomic genital defects.

## MRI
There are no MRI findings associated with amenorrhea. However, a MRI may be helpful in the diagnosis of the diseases that can cause amenorrhea, such as polycystic ovary syndrome (PCOS), androgen insensitivity syndrome, anatomic genital defects, and also pituitary adenoma.

## Other Imaging Findings
Hysterosalpingography (HSG) may be helpful in the diagnosis of the anatomic defects that can cause amenorrhea. Findings on a hysterosalpingography diagnostic of Asherman syndrome include multiple irregular linear (or lacunar) filling defects showing intrauterine adhesion, inability to distend the endometrial cavity, and totally non-filled uterine mostly in severe cases. Testicular scan can diagnosis the intra-abdominal or inguinal testes in androgen insensitivity syndrome.

## Other Diagnostic Studies
Karyotyping is used to diagnose amenorrhea caused by chromosomal disorders, such as Turner syndrome. University of Pennsylvania Smell Identification Test (UPSIT), consist of microencapsulated odorants released by scratching standardized odor-impregnated questionnaires, is used to detect hyposmia or anosmia in Kallmann syndrome.

# Treatment

## Medical Therapy
Pharmacologic medical therapy is recommended among patients with hypothalamic causes, pituitary causes, ovarian insufficiency, and chronic anovulation. The general principle of the treatment in amenorrhea is sex hormone replacement therapy, mostly with suitable forms of estrogen and progesterone.

## Surgery
The mainstay of treatment for amenorrhea is medical therapy. Surgery is usually reserved for patients with either hypothalamus or pituitary tumors, Turner syndrome, and genital anatomical defects (imperforate hymen or transverse vaginal septum). The surgical treatment for hypothalamus or pituitary tumors is tumor resection via endoscopic transsphenoidal surgery. Ovaries have to be excised in Turner syndrome to prevent malignant transformation. Small incision is the main surgery for imperforate hymen and septal excision is the main treatment for transverse vaginal septum.

## Primary Prevention
Based on US Preventive Services Task Force (USPTSF), there are no established measures for the primary prevention of amenorrhea.

## Secondary Prevention
Effective measures for the secondary prevention of functional hypothalamic amenorrhea include oral contraceptive pills (OCPs), androgen therapy, recombinant insulin like growth factor 1 (IGF-1), recombinant leptin, bisphosphonates, and increasing calorie intake.