Amenorrhea

A 17 year old female presents with absence of menstruation. She has normal breast development but complains of cyclic lower abdominal pain every month. Physical examination reveals normal pubic hair and a bulging bluish membrane at the vaginal introitus. Pregnancy test is negative. Diagnosis?

Diagnosis is primary amenorrhea due to imperforate hymen causing outflow tract obstruction.

1. Initial Evaluation of Amenorrhea

Step 1: Pregnancy Test

Most Important First Step

1. Serum or urine β-hCG should always be performed first
2. Pregnancy is the most common cause of secondary amenorrhea

If hCG Positive

Diagnosis

• Pregnancy

If hCG Negative

Proceed with:

1. TSH
2. Prolactin level

2. Thyroid Disease and Hyperprolactinemia

Hyperprolactinemia

Pathophysiology

1. Elevated prolactin suppresses GnRH secretion
2. Leads to decreased LH and FSH secretion
3. Results in hypogonadotropic hypogonadism and amenorrhea

Causes

1. Prolactinoma
2. Antipsychotics
3. Hypothyroidism
4. Pituitary stalk compression

Clinical Clues

1. Galactorrhea
2. Infertility
3. Headache
4. Visual field defects

Thyroid Disease

Both hypothyroidism and hyperthyroidism may cause menstrual irregularities and amenorrhea

3. Primary Amenorrhea Algorithm

Critical Next Step

Assess:

1. Breast development
2. Presence or absence of uterus

4. Breast Development Present

Indicates:

1. Estrogen exposure is present
2. Ovarian estrogen production is functioning

4.1 Uterus Present

Outflow Tract Obstruction

Suspect:

1. Imperforate hymen
2. Transverse vaginal septum

Clinical Clues

1. Cyclic pelvic pain
2. Hematocolpos
3. Primary amenorrhea with normal secondary sexual characteristics

4.2 Uterus Absent

Next Steps

1. Karyotype
2. Testosterone level

46,XX with Normal Female Testosterone

Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome

Features

1. Congenital absence of uterus and upper vagina
2. Normal ovaries
3. Normal pubic and axillary hair
4. Normal breast development
5. Renal anomalies may coexist

46,XY with Male-Range Testosterone and Sparse Pubic Hair

Androgen Insensitivity Syndrome (AIS)

Features

1. Androgen receptor resistance
2. Female external genitalia
3. Blind-ending vagina
4. Absent uterus
5. Intra-abdominal testes
6. Sparse or absent pubic and axillary hair
7. Normal breast development due to aromatization of testosterone

LH may be normal or mildly elevated

5. Breast Development Absent

Suggests:

1. Hypoestrogenism
2. Delayed puberty

Next step:

• Measure FSH and LH

5.1 Elevated FSH/LH

Hypergonadotropic Hypogonadism

Indicates ovarian failure or gonadal dysgenesis

Turner Syndrome (45,XO)

Features

1. Short stature
2. Webbed neck
3. Shield chest
4. Streak ovaries
5. Primary amenorrhea
6. Coarctation of aorta may occur
7. Bicuspid aortic valve may occur

Swyer Syndrome (46,XY Gonadal Dysgenesis)

Features

1. Phenotypic female
2. Streak gonads
3. Uterus present
4. Lack of secondary sexual characteristics
5. Increased gonadoblastoma risk

Prophylactic gonadectomy is recommended

5.2 Low or Normal FSH/LH

Hypogonadotropic Hypogonadism

Causes:

1. Functional hypothalamic amenorrhea (most common)
2. Kallmann syndrome
3. Pituitary tumors
4. Hyperprolactinemia
5. Chronic systemic illness

Functional Hypothalamic Amenorrhea (FHA)

Pathophysiology

1. Reduced GnRH pulsatility causes decreased LH and FSH secretion

Common Causes

1. Stress
2. Excessive exercise
3. Eating disorders
4. Low BMI

Kallmann Syndrome

Features

1. GnRH deficiency
2. Anosmia or hyposmia
3. Delayed puberty

6. Secondary Amenorrhea Algorithm

After excluding:

1. Pregnancy
2. Thyroid disease
3. Hyperprolactinemia

Next step:

• Progesterone challenge test

7. Progesterone Challenge Test

Withdrawal Bleeding Present

Indicates:

1. Adequate endogenous estrogen is present
2. Endometrium is functional
3. Outflow tract is intact

Most common pathologic cause:

• Anovulation due to PCOS

Polycystic Ovary Syndrome (PCOS)

Clinical Features

1. Irregular menstruation
2. Hirsutism
3. Acne
4. Obesity
5. Insulin resistance

No Withdrawal Bleeding

Next step:

• Estrogen plus progesterone challenge test

8. Estrogen + Progesterone Challenge Test

Bleeding Occurs

Indicates:

1. Endometrium and outflow tract are intact
2. Problem is estrogen deficiency

Causes

1. Hypothalamic dysfunction
2. Pituitary disease
3. Premature ovarian insufficiency

No Bleeding Occurs

Indicates:

1. Endometrial damage
2. Outflow tract obstruction

Asherman Syndrome

Cause

• Intrauterine adhesions due to uterine instrumentation

Clinical Clues

1. History of dilation and curettage (D&C)
2. Reduced menstrual flow followed by amenorrhea

9. Final Classification Using FSH/LH

Elevated FSH/LH

Ovarian Failure

Causes:

1. Premature ovarian insufficiency
2. Menopause
3. Gonadal dysgenesis

Low or Normal FSH/LH

Central Causes

1. Functional hypothalamic amenorrhea
2. Pituitary adenoma
3. Hyperprolactinemia
4. CNS lesions

10. Important Investigations

1. Pregnancy test
2. TSH
3. Prolactin
4. FSH and LH
5. Estradiol
6. Pelvic ultrasound
7. MRI pituitary if hyperprolactinemia suspected
8. Karyotype analysis when indicated

11. Key Clinical Insight

Primary amenorrhea with normal breast development requires evaluation of the uterus and outflow tract, while absent breast development requires evaluation of gonadotropins and estrogen status

12. Key Exam Points

1. Pregnancy test is always the first step in amenorrhea evaluation
2. Functional hypothalamic amenorrhea is the most common cause of hypogonadotropic amenorrhea
3. PCOS is the most common pathologic cause of secondary amenorrhea due to anovulation
4. Imperforate hymen causes cyclic pelvic pain with hematocolpos
5. MRKH syndrome presents with absent uterus but normal ovaries and normal pubic hair
6. AIS presents with absent uterus, sparse pubic hair, intra-abdominal testes, and male-range testosterone
7. Turner syndrome causes hypergonadotropic hypogonadism with streak ovaries
8. Progesterone withdrawal bleeding indicates adequate estrogen and intact outflow tract
9. Asherman syndrome is caused by intrauterine adhesions after uterine instrumentation
10. Elevated FSH/LH suggests ovarian failure, while low or normal FSH/LH suggests hypothalamic or pituitary disease