Amenorrhea – Causes, Symptoms, Diagnosis, Treatment

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Amenorrhea not due to pregnancy, lactation, or menopause is a relatively common abnormality of the reproductive years and indicative of a defect somewhere in the hypothalamic-pituitary-ovarian-uterine axis. This chapter considers the various causes of amenorrhea and their treatment. It also considers the diagnosis and treatment of abnormal uterine bleeding at all stages of life.

The female menstrual cycle normally comprises a 28 to 30-day cycle, which contains 2 phases, the proliferative phase, and the secretory phase. At the end of the cycle, the uterine lining starts shedding off which is a normal phenomenon of female menstruation.

The absence of menstruation during the female during the reproductive ages of approximately 12 to 49 years is known as amenorrhea. There are primary and secondary causes of amenorrhea.

Amenorrhea is defined by the transient or permanent absence of menstrual flow. Amenorrhea can be divided into primary and secondary presentations. Primary amenorrhea is diagnosed when there is no menarche by 13 years of age in those without the development of secondary sexual characteristics, or by 15 years of age in those with secondary sexual characteristics []. Secondary amenorrhea is defined as discontinuation of previously regular menses for 3 months or previously irregular menses for 6 months []. The prevalence of primary amenorrhea is less than 0.1%, and secondary amenorrhea is more common with an incidence of about 4.0% [,].

Causes of Amenorrhea

Primarily amenorrhea is classified into 2 types determined by pathogenesis.Primary amenorrhea is the absence of initiation of menses, and secondary amenorrhea is an absence of menses in a previously normal menstruating female. There are many other types of classification of amenorrhea based on the anatomy of female reproductive organs, but this is the most accepted form of classifying the causes of amenorrhea.

Causes of primary amenorrhoea

Primary amenorrhoea is usually due to a genetic or anatomical abnormality. However, everything that causes secondary amenorrhoea can present as primary amenorrhoea.

Turner’s syndrome is the most common cause of primary amenorrhoea (43 per cent).

Other less common causes of primary amenorrhoea are:

  • Müllerian agenesis (15 per cent of cases) – a lack of development of the vagina, with or without the uterus, which occurs in early development in the foetus
  • delay of puberty (14 per cent) – this is more common in boys than girls and can be associated with chronic or acute illness
  • polycystic ovarian syndrome (7 per cent)
  • functional hypothalamic amenorrhoea (5 per cent).

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
  • Pregnancy
  • Hypogonadtrophichypogonadism:
  • Endocrine lesions
  • Congenital abnormalities
  • 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.

Causes of secondary amenorrhoea

A range of factors can affect how the hypothalamus works and cause amenorrhoea, including

  • emotional stress
  • losing weight, eating disorders and nutritional deficiencies (such as can occur with coeliac disease)
  • exercising too much (elite athletes)
  • certain medication used to treat mental health conditions
  • disorders of the endocrine system, such as hypothyroidism (having an underactive thyroid gland).

Other disorders that can cause amenorrhoea to include

  • Low body weight – Excessively low body weight — about 10 percent under normal weight — interrupts many hormonal functions in your body, potentially halting ovulation. Women who have an eating disorder, such as anorexia or bulimia, often stop having periods because of these abnormal hormonal changes.
  • Excessive exercise – Women who participate in activities that require rigorous training, such as ballet, may find their menstrual cycles interrupted. Several factors combine to contribute to the loss of periods in athletes, including low body fat, stress and high energy expenditure.
  • Stress – Mental stress can temporarily alter the functioning of your hypothalamus — an area of your brain that controls the hormones that regulate your menstrual cycle. Ovulation and menstruation may stop as a result. Regular menstrual periods usually resume after your stress decreases.
  • polycystic ovarian syndrome – the ovaries develop clusters of ovarian follicles, or eggs, which look like small cysts. Symptoms include irregular periods and added hair growth. Women with polycystic ovarian syndrome are more at risk of amenorrhoea when they put on weight
  • hyperandrogenaemia – the body makes high levels of male sex hormones, which can affect the reproductive system. This can be caused by tumors of the ovary or adrenal gland, or certain conditions present at birth
  • hyperprolactinemia – the body makes high levels of the breastfeeding hormone prolactin. Levels rise because the pituitary gland may be overactive or there may be a tumor on the gland
  • ovarian failure or early menopause (known as premature ovarian insufficiency) – low levels of oestrogen causing ovulation to stop, and stopping the menstrual cycle.
  • Weight loss
  • Chronic ovulation
  • Pituitary tumor
  • Cushing syndrome
  • Ovarian tumors
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Anatomic Causes

  • Pregnancy
  • Müllerian agenesis or dysgenesis (uterine, cervical, or vaginal)
  • Cervical stenosis
  • Various disorders of sexual differentiation
  • Intrauterine adhesions (Asherman syndrome)
Ovarian Failure Causes
  • Menopause
  • Genetic abnormalities
  • X chromosomal causes
  • Structural alterations, mutations in, or absence of an X chromosome
  • Gonadal dysgenesis with stigmata of Turner syndrome (most 45,X)
  • Gonadal dysgenesis without stigmata of Turner syndrome
  • Pure gonadal dysgenesis (46,XX)
  • Premature ovarian failure with mutations in the X chromosome
  • Mutations in POF1 (Xq26-q28)
  • Mutations in POF1 together with Fragile X (FMR1) premutations
    (Xq27.3)
  • Mutations in POF2A or 2B (Xq22 or Xq21)
  • Mutations in POF4 together with mutations in bone morphogenetic
    protein 15 (Xp11.2)
  • Trisomy X with or without mosaicism
  • Mutations with a 46, XY karyotype (Pure gonadal dysgenesis)
  • Mutations in Xp22. 11-21.2 (Swyer syndrome)
  • Mutations in 5 cen
  • Autosomal causes
  • In association with myotonia dystrophica or other abnormalities
  • Mutations involving enzymes with reproductive effects
  • 17α-Hydroxylase deficiency (CYP17A)(10q24.3
  • Galactosemia (Galactose- 1 – phosphate uridyltransferase deficiency)(9p13)
  • 20,22-Lyase (P450scc) and aromatase (P450arom) deficiency
  • Mutations involving reproductive hormones, their receptors, and actions
  • Mutations inactivating LH or FSH (theorectical)
  • Mutations in inhibin A (INHA)
  • Receptor mutations
  • FSH receptor (2p21-p16)
  • LH receptor (2p21)
  • Mutations in the hormone action pathways
  • Known genetic alterations of other specific genes
  • FOXL2 (a forkhead transcription factor associated with the
    blepharophimosis/ptosis/epicanthus inverse syndrome)
  • ELF2B (a family of genes associated with CNS leukodystrophy and ovarian
    failure)
  • BMP15 (bone morphogenetic factor 15, involved with folliculogenesis)
  • PMM2 (phosphomannomutase)
  • AIRE (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
    syndrome)
  • STAG3 (encoding a meiosis-specific subunit of cohesion)(7q21.3-22.2)
  • Immune Dysfunction
  • Association with other autoimmune disorders (15-20% of cases, 4% with
    steroidogenic cell autoimmunity)
  • Isolated
  • In association with congenital thymic aplasia
  • Physical Insults
  • Chemotherapeutic (especially alkylating) agents
  • Ionizing radiation
  • Viral agents
  • Surgical extirpation
  • Gonadotropin-Secreting Pituitary Tumors (Extremely Rare)
  • Idiopathic
Chronic Anovulation
  • Hypothalamic
  • Psychogenic, including pseudocyesis
  • Exercise-associated
  • Eating disorders, nutritional
  • 2□ to systemic illness
  • Hypothalamic neoplasms
  • Some forms of isolated (idiopathic) hypogonadotropic hypogonadism (including
    Kallmann syndrome)
  • Pituitary
  • Some forms of isolated (idiopathic) hypogonadotropic hypogonadism (including
    Kallmann Syndrome)
  • Hypopituitarism
  • Pituitary neoplasms, including mucroadenomas
  • With inappropriate steroid feedback
  • Functional androgen excess (PCOS)
  • Adrenal hyperplasia
  • Neoplasms producing androgens or estrogens
  • Neoplasms producing hCG (including trophoblastic disease)
  • Liver and renal disease
  • Obesity
  • Other endocrine disorders
  • Thyroid dysfunction
  • Adrenal hyperfunction

Symptoms of Amenorrhea

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 Amenorrhea

During the history and physical examination,

  • clinicians first need to ask about the age of a patient and at what age the patient started menses at puberty (menarche). This information is important to determine and differentiate between primary and secondary amenorrhea. If the patient was not menstruating at all, then it must be primary amenorrhea. All other cases will be secondary amenorrhea.
  • After the chronological age, the most important thing to determine is the psychosocial age of the patient, as well as their intelligence quotient (IQ) to rule out any chromosomal cause of primary amenorrhea. After that, clinicians should inquire about the other aspects of growth like breast bud development, because an absence of breast bud by the age of 13 to 14 years indicates estradiol deficiency, and there is a need for further investigation.
  • To rule out secondary amenorrhea, physicians need to determine the time frame of the absence of menses in the previously normal menstruating female. The most important cause of secondary amenorrhea is pregnancy, so it should be ruled out first. They should then ask about previous surgeries for Asherman syndrome.
  • History of night sweats, sleep disturbance, and hot flushes for premature ovarian failure, history of chemotherapy, and radiation therapy for neoplasm should be obtained because these can also cause ovarian failure in young females. Polycystic ovary syndrome (PCOS) should be ruled out in accordance with Rotterdam criteria.
  • A vision test and sense of smell should be performed for pituitary adenoma and Kallman syndrome. A history of medication is very important because antipsychotics are one of the most common causes of high prolactin levels which lead to amenorrhea. The use of contraception, cocaine, opioids, antiepileptics can cause the failure of menstruation to occur, dieting, strenuous exercise, history of weight loss, and anorexia nervosa can be determined by proper history taking to ascertain the cause of amenorrhea.
  • History of neurosarcoidosis, hemochromatosis, and presence of any chronic illness should be detected to determine the exact reason as these diseases greatly affect the hypothalamic-pituitary axis which plays a vital role in controlling of the female menstrual cycle.
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Physical examination includes the general physical examination which can be used to determine causes like malnutrition or hepatomegaly. The examination also should include:

  • Measuring height, weight, and fat index of the patient to look for the presence of any chronic illness
  • Checking body mass index (BMI) to rule out anorexia nervosa and malnutrition,
  • Checking for dental erosion,
  • Looking for metacarpophalangeal calluses or bruises
  • Checking the skin for hirsutism, hair loss, or acne to investigate possible hyperandrogenemia

Acanthosis nigricans (skin condition) can also provide the clue for PCOS. Examing the breasts, pubic hair, and the clitoral index is also an important part of the physical examination in the female with amenorrhea. Turner syndrome can be ruled out through a normal chest examination. Clinicians should also perform a fundal examination to rule out pregnancy and a vaginal examination to check for hematocolpos in an imperforate hymen.

FindingsAssociations
History
Chemotherapy or radiationImpairment of specific organ or structure, (e.g., brain, pituitary, ovary)
Family history of early or delayed menarcheConstitutional delay of puberty
GalactorrheaPituitary tumor
Hirsutism, acneHyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome
Illicit or prescription drug useMultiple associations, consider effect on prolactin
Loss of smell (anosmia)Kallman syndrome (GnRH deficiency)
Menarche and menstrual historyPrimary vs. secondary amenorrhea
Sexual activityPregnancy
Significant headaches or vision changesCentral nervous system tumor, empty sella syndrome
Temperature intolerance, palpitations, diarrhea, constipation, tremor, depression, skin changesThyroid disease
Vasomotor symptoms (e.g., hot flashes or night sweats)Primary ovarian insufficiency, natural menopause
Weight loss, excessive exercise, poor nutrition, psychosocial distress, dietsFunctional hypothalamic amenorrhea
Hypertension and hirsutism17-hydroxylase/17,20-lyase deficiency
Physical examination
Abnormal thyroid examinationThyroid disorder
Acanthosis nigricans or skin tagsHyperinsulinemia (PCOS)
Anthropomorphic measurements; growth chartsMultiple associations; Turner syndrome, constitutional delay of puberty
Body mass indexHigh: PCOS
Low: Functional hypothalamic amenorrhea
BradycardiaFunctional hypothalamic amenorrhea (e.g., anorexia nervosa)
Breast development (normal progression)Presence of circulating estrogen*
Dysmorphic features (e.g., webbed neck, short stature, low hairline)Turner syndrome
Male pattern baldness, increased facial hair, acneHyperandrogenism, PCOS, ovarian or adrenal tumor, nonclassic CAH, Cushing syndrome
Pelvic examination
Absence or abnormalities of cervix or uterusRare congenital causes including Müllerian agenesis or androgen insensitivity syndrome
ClitoromegalyAndrogen-secreting tumor; CAH; 5α-reductase deficiency
Presence of transverse septum or imperforate hymenOutflow tract obstruction
Reddened or thin vaginal mucosaDecreased endogenous estrogen
Sexual maturity rating abnormalTurner syndrome, constitutional delay of puberty, rare causes
Striae, buffalo hump, central obesity, hypertensionCushing syndrome

Laboratory and radiographic testing in the evaluation of amenorrhea

FindingsAssociations
Laboratory testing (refer to local reference values)
17-hydroxyprogesterone level (collected at 8:00 AM)High: nonclassic CAH
Anti-Müllerian hormoneHigh: Functional hypothalamic amenorrhea, PCOS
Low: Primary ovarian insufficiency
Complete blood count and metabolic panelAbnormal: chronic disease (e.g., elevated liver enzymes in functional hypothalamic amenorrhea)
EstradiolLow: Poor endogenous estrogen production (suggestive of poor current ovarian function)
Follicle-stimulating hormone and luteinizing hormoneHigh: primary ovarian insufficiency; Turner syndrome, FSH receptor mutation
Low: functional hypothalamic amenorrhea
Normal: PCOS; intrauterine adhesions; multiple others
Free and total T, DHEA-SHigh: hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome
T/DHT ratio (normal <30:1)High: 5-α-reductase deficiency
At puberty, serum LH, and THigh: androgen insensitivity syndrome
KaryotypeAbnormal: turner syndrome, rare chromosomal disorders
ProlactinHigh: pituitary adenoma, medications, hypothyroidism, other neoplasm
Thyroid-stimulating hormoneHigh: hypothyroidism
Low: hyperthyroidism
Radiographic testing
Dual-energy X-ray absorptiometryEvaluation of fracture risk
MRI of the adrenal glandsAndrogen-secreting adrenal tumor
MRI of the brain (including sella)Tumor (e.g., microadenoma)
Pelvic organ ultrasonography or MRIMorphology of pelvic organs, polycystic ovarian morphology, androgen-secreting ovarian tumor

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.
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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:
  • Beta hCG to rule out pregnancy, because pregnancy is the most common cause of amenorrhea
  • Prolactin level to rule out prolactinoma
  • Thyroid hormones since thyroid gland disturbances can lead to amenorrhea
  • Testosterone and DHEAS to rule out hyperandrogenism
  • FSH and LH for hypothalamic amenorrhea, BMI (to look for malnutrition, anorexia nervosa, and excessive strenuous exercise)
  • Pelvic ultrasound and adrenal CT for androgen-secreting tumors and other anatomical defects like Mayor-Rokitansky-Kauser-Hauser syndrome
  • MRI to assess the hypothalamic-pituitary tract (eg prolactinoma)
  • 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.
  • Karyotyping is sometimes an important test for Turner and androgen insensitivity syndromes.

Treatment / Management

Treatment mainly depends on the cause of amenorrhea.

  • If the cause of amenorrhea is estrogen deficiency, estrogen can be administered.
  • If amenorrhea is due to malnutrition, a proper diet plan can cure the patient successfully. Women who are very underweight through not eating enough or exercising too much often do not have periods; this may be resolved by putting on weight and/or exercising less
  • For anorexia nervosa and stress-induced amenorrhea, cognitive-behavioral therapy and SSRIs can help. Dopamine agonist drugs like cabergoline can treat prolactinoma, and if large, surgery can provide a full cure.
  • The appropriate surgical procedure can treat anatomical causes of amenorrhea. PCOS can be handled by combined oral contraceptives and metformin.
  • SSRI can treat Stress-induced hypothalamic amenorrhea.
  • There is good evidence that patients with menstrual irregularities are at high risk for bone fractures and hence osteoporosis prevention should be the next step. Patients should be offered vitamin D and calcium supplements.
  • Because amenorrhea can also affect self-esteem, a mental health consult is necessary.
  • Surgery and/or medication may be required for pituitary conditions. Women with tumors producing excess prolactin are usually treated with a class of drugs called ‘dopamine agonists’, which reduce prolactin levels
  • prescribing the missing hypothalamic or pituitary hormones that regulate reproduction for women who want to become pregnant. surgery may be required in patients with uterine or vaginal abnormalities dating from birth.

Women with stress, eating disorders should undergo behavior modification.

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK482168/
  2. https://www.ncbi.nlm.nih.gov/books/NBK279144/
  3. https://www.ncbi.nlm.nih.gov/books/NBK554469/
  4. https://www.ncbi.nlm.nih.gov/books/NBK278939/
  5. https://www.ncbi.nlm.nih.gov/books/NBK282/
  6. https://www.ncbi.nlm.nih.gov/books/NBK470216/
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790874/
  8. https://en.wikipedia.org/wiki/Amenorrhea
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