Comprehensive Notes on Amenorrhea

Amenorrhea

It is essential to review normal sexual development, disorders of sexual development, and puberty before studying amenorrhea. Amenorrhea is broadly divided into primary and secondary amenorrhea.

Primary Amenorrhea

Definition

• No menarche by 15 years of age in the presence of secondary sexual characteristics (breast budding).
• No menarche by 13 years of age in the absence of secondary sexual characteristics (delayed puberty).

Causes

1. Gonadal Dysgenesis:
   • Most common cause.
   • Turner's Syndrome (45, XO) is the most common type.
2. Mullerian Agenesis (MRKH Syndrome):
   • Second most common cause.
3. Hypothalamic Failure:
   • Example: Kallmann Syndrome
4. Anterior Pituitary Issues:
   • Example: Craniopharyngioma
5. Uterine Problems:
   • Mullerian Agenesis or Androgen Insensitivity Syndrome.
6. Outflow Tract Obstruction (Cryptomenorrhoea):
   • Imperforate Hymen
   • Vaginal Agenesis
   • Transverse Vaginal Septum

Algorithm for Primary Amenorrhea

1. Physical Examination:
   • Breast examination and Tanner staging.
   • Pubic and axillary hair assessment.
   • Per rectal examination to check for the presence of the uterus.
   • Examination of external genitalia and inguinal area (for undescended testes).
2. Urine Pregnancy Test (UPT):
3. Pelvic Ultrasound:
   • To assess the presence or absence of the uterus and the state of the gonads.
4. LH and FSH Levels:
5. Karyotyping:
   • Confirmatory investigation.
   • 45, XO indicates Turner Syndrome.
   • 46, XY indicates Swyer Syndrome or Androgen Insensitivity Syndrome.

Primary Amenorrhea with Uterus Present

Differential diagnoses include:

1. Kallmann Syndrome (46, XX)
2. Gonadal Dysgenesis
   • Turner Syndrome (45, XO)
   • Swyer Syndrome (46, XY)
3. Cryptomenorrhoea (46, XX)

Primary Amenorrhea with Uterus Absent

Differential diagnoses include:

1. Mullerian Agenesis (46, XX).
2. Complete or Partial Androgen Insensitivity Syndrome (46, XY).

Secondary Amenorrhea

Definition

• Absence of menstruation for 90 consecutive days (three months) in a female with previously normal menstrual cycles.
• In females with previously irregular cycles (e.g., PCOS), absence of menstruation for six months.

Causes

• Most Common: Pregnancy (due to high progesterone levels).
• Most Common Pathological Cause: Polycystic Ovary Syndrome (PCOS).

Understanding Menstruation

Menstruation requires:

1. Normal Hypothalamus
2. Normal Anterior Pituitary
3. Normal Ovary
4. Normal Uterus
5. Normal Outflow Tract

The hypothalamus releases $GnRH$ in a pulsatile manner, stimulating the anterior pituitary to release $FSH$ and $LH$. These act on the ovary to produce estrogen and progesterone, which affect the uterine endometrium. Menstruation is the shedding of the endometrium, requiring a normal outflow tract.

Kallmann Syndrome

Genetics and Pathophysiology

• Chromosome number is 46, XX (female).
• Failure of migration of $GnRH$ neurons from the olfactory epithelium to the hypothalamus.
• Defect in the $CAL1$ gene.
• Inherited as an X-linked recessive disorder (more common in males).

Hormonal Profile

• Low $GnRH$, $LH$, $FSH$, and estrogen levels (hypogonadotropic hypogonadism).

Clinical Features

• Primary amenorrhea.
• Primary infertility.
• Anosmia (lack of smell).
• Normal height.
• Normal female external genitalia.
• Uterus, cervix, and vagina are present but infantile or hypoplastic.

Management

• Pulsatile $GnRH$ administration to increase $LH$, $FSH$, and estrogen.

Gonadal Dysgenesis: Turner Syndrome

Genetics and Pathophysiology

• Genotype: 45, XO.
• Absence of the Y chromosome results in ovaries. However, the single X chromosome leads to accelerated atresia of the ovary, resulting in streak gonads.
• Mutation in the $SHOX$ gene.

Hormonal Profile

• High $LH$ and $FSH$ levels, low estrogen levels (hypergonadotropic hypogonadism).

Clinical Features

• Short stature.
• Webbing of the neck, low posterior hairline, shield-shaped chest, and widely spaced nipples.
• Cubitus valgus.
• Congenital heart disease (bicuspid aortic valve, coarctation of the aorta).
• Autoimmune diseases (diabetes, Hashimoto's thyroiditis).
• Short fourth metacarpal.
• Infantile or hypoplastic uterus.

Management

• Estrogen replacement for breast development, followed by estrogen and progesterone for hormone therapy.
• Growth hormone to increase height.
• Ovaries do not have chances of malignancy, so no gonadectomy is performed (unless mosaicism with Y chromosome).
• IVF with donor egg if pregnancy is desired.
• Pregnancy is contraindicated if there are cardiac complications like coarctation of the aorta or bicuspid aortic valve.

Gonadal Dysgenesis: Swyer Syndrome

Genetics and Pathophysiology

• Genotype: 46, XY.
• Inactivation of the $SRY$ gene, leading to dysgenetic testes.
• Increased risk of malignancy in dysgenetic testes.

Hormonal Profile

• High $LH$ and $FSH$ levels due to non-functioning Sertoli and Leydig cells.
• Absent testosterone, preventing conversion to estrogen.

Clinical Features

• Female external genitalia.
• Uterus, fallopian tubes, cervix, and upper vagina are present due to the absence of Mullerian-inhibiting substance.

Management

• Gonadectomy as soon as possible to prevent malignancy.
• Estrogen replacement for breast development, followed by estrogen and progesterone.

Gonadal Dysgenesis: Pure Gonadal Dysgenesis

Genetics and Pathophysiology

• Genotype: 46, XX.
• Streak gonads despite the normal XX karyotype.

Clinical Features

• Similar to Turner Syndrome, but without short stature or additional features.
• High $LH$ and $FSH$ due to non-functioning ovaries.

Management

• Similar to Turner Syndrome (estrogen and progesterone replacement)

Common Features of all Gonadal Dysgenesis Types

• Decreased estrogen levels, resulting in absent breast development and infantile uterus.
• High $LH$ and $FSH$ levels.
• External genitalia are female.

Cryptomenorrhoea

Definition

• Menstrual blood fails to exit due to outflow tract obstruction.

Causes

• Imperforate hymen (most common).
• Transverse vaginal septum.
• Vaginal agenesis.

Hormonal Profile

• Normal $LH$ and $FSH$ levels.
• Normal estrogen and ovarian function.

Clinical Features

• Cyclical abdominal pain without menstruation.
• Urinary retention.
• Enlarged uterus (hematocolpos and/or hematometra).
• Imperforate hymen: Tensed bluish bulging hymen and cough impulse.
• Transverse vaginal septum: Thicker membrane than bulging hymen; cough impulse absent.

Management

• Cruciate incision on the hymen for imperforate hymen.

Hymen Classifications

Images to understand various types of Hymen:

• Imperforate Hymen: No opening.
• Sieve Hymen/Cribriform Hymen: Sieve-like openings.
• Septate Hymen.
• Annular Hymen.

Differentiating Conditions

• Kallmann Syndrome: Decreased $LH$ and $FSH$.
• Gonadal Dysgenesis: High $LH$ and $FSH$.
• Cryptomenorrhoea: Normal $LH$ and $FSH$.

Primary Amenorrhea with Uterus Absent: Mullerian Agenesis vs. Androgen Insensitivity Syndrome

Mullerian Agenesis (MRKH Syndrome)

• Genotype: 46, XX.
• Gonads: Ovaries (normal function).
• Hormones: Normal estrogen levels.
• Defect: Absence of both Mullerian ducts.
• Breast Development: Normal (Tanner stage 4 or 5).
• Pubic/Axillary Hair: Normal (Tanner stage 4 or 5).
• Internal Genital Organs: Uterus is absent, complete vaginal agenesis.
• External Genital Organs: Female.
• Testosterone Levels: Equivalent to normal female levels.
• $LH$/$FSH$: Normal.
• Management: Vaginoplasty before/after marriage (McIntoy, YKT, or Davidoff technique). IVF followed by surrogacy for pregnancy.

Androgen Insensitivity Syndrome

• Genotype: 46, XY.
• Gonads: Testes (normal function producing testosterone).
• Hormones: Normal testosterone production, but resistant to testosterone.
• Defect: Resistance to testosterone.
• Breast Development: Normal (Tanner stage 4 or 5) due to conversion of testosterone to estrogen.
• Pubic/Axillary Hair: Sparse (Tanner stage 1 or 2).
• Internal Genital Organs: Uterus is absent (due to anti-Mullerian hormone), blind vaginal pouch.
• External Genital Organs: Complete AIS - Female; Partial AIS - Ambiguous.
• Testosterone Levels: Higher than normal female levels.
• $LH$: Increased; $FSH$: Normal.
• Management: Female gender assignment. Gonadectomy after puberty (16-18 years) due to malignancy risk. Estrogen HRT after gonadectomy. Adoption.

Indications for Gonadectomy

• Complete AIS (around 16-18 years).
• Partial AIS (as soon as possible).
• Swyer Syndrome (as soon as possible).
• Turner Syndrome (only if mosaicism with Y chromosome).