Secondary Amenorrhea Notes

SECONDARY AMENORRHEA

Secondary amenorrhea is a high-yield topic, especially its diagnostic algorithm.

Key topics include:

• Primary ovarian insufficiency (POI).
• Asherman syndrome.
• Prolactinomas.

Definitions

Primary Amenorrhea:

• 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.
  Secondary Amenorrhea:

• Absence of menstruation for 90 consecutive days (three months) in a female who was previously menstruating normally.

• Absence of menstruation for six months in a female with previously irregular cycles (e.g., PCOS).

Updates According to Williams Gynecology, Fourth Edition:

Primary Amenorrhea:

• Absence of menstruation by 15 years.
• Absence of menstruation within three years of telarche (breast budding).
• No menstruation by age 14 with signs of hirsutism, excessive exercise, or eating disorders. (ACUG 2017 guidelines).

Secondary Amenorrhea:

• Absence of menstruation for three months in a previously menstruating female.
• Less than nine cycles in a year (oligomenorrhea) should prompt investigation.

Categories of Amenorrhea

Based on gonadotropin and estrogen levels:

1. Hypergonadotropic Hypogonadism

• High LH and FSH, low estrogen.

• Defect lies in the ovary.
  Explanation:

  • Hypothalamus releases GnRH $(\rightarrow)$ anterior pituitary releases LH and FSH $(\rightarrow)$ ovary releases estrogen and progesterone.
  • Estrogen has negative feedback on FSH and GnRH.
  • If the ovary cannot synthesize estrogen, the negative feedback on FSH is lost, increasing FSH levels.
    Formula:
    $FSH \uparrow, LH \uparrow, Estrogen \downarrow$

2. Hypogonadotropic Hypogonadism

• Low LH and FSH, low estrogen.

• Problem in the hypothalamus or pituitary.
  Explanation:

  • Hypothalamus/pituitary problem $(\rightarrow)$ low GnRH $(\rightarrow)$ low LH/FSH $(\rightarrow)$ low estrogen.
    Formula:
    $FSH \downarrow, LH \downarrow, Estrogen \downarrow$

Note: FSH levels are measured, not LH, to differentiate. Also, be aware of hyperprolactinemia.

3. Eugonadotropic Condition

• Normal LH and FSH, normal to low-normal estrogen, but still amenorrhea.

Most common cause of secondary amenorrhea: Pregnancy (physiological).

Other physiological causes: Lactation.

• Pregnancy: High progesterone levels throughout pregnancy causing amenorrhea.
• Lactation: High prolactin inhibits GnRH $(\rightarrow)$ decreased LH/FSH $(\rightarrow)$ secondary amenorrhea.

HYPERPROLACTINEMIA

Prolactin's Negative Feedback:

Prolactin inhibits GnRH, which can cause hypogonadotropic amenorrhea.

Important Distinction:

• Hyperprolactinemia always leads to hypogonadotropic amenorrhea.
• However, hypogonadotropic amenorrhea doesn't always imply hyperprolactinemia (e.g., Sheehan syndrome).

Example: Sheehan Syndrome

• Pituitary gland necrosis leads to decreased LH/FSH (hypogonadotropic amenorrhea) and decreased prolactin levels.

Gyne-Physio Integration Concepts

Hypothalamus & Pituitary Hormones:

• Hypothalamus releases releasing hormones (CRH, TRH, GnRH) that positively affect pituitary hormone release (TSH, LH/FSH).
  Prolactin Exception:

• Hypothalamus releases dopamine, which inhibits prolactin release.

• Dopamine agonists are used to treat hyperprolactinemia.

Other Substances Affecting Prolactin:

• TRH, vasopressin, VIP, and acetylcholine increase prolactin release.

Dopamine Receptors:

• D1 and D2 receptors. Anterior pituitary cells primarily have D2 receptors.
• D2 receptor agonists (cabergoline) are more effective in treating hyperprolactinemia than non-specific drugs (bromocriptine).

Cabergoline vs. Bromocriptine:

• Cabergoline: Specific D2 receptor agonist, longer half-life, fewer side effects, preferred in non-pregnant females.
• Bromocriptine: Daily administration, more nausea and vomiting.

TRH & Prolactin:

• TRH acts on the pituitary to release both TSH and prolactin.
  Application: Hypothyroidism

• In Hashimoto's thyroiditis, hypothyroidism leads to decreased thyroid hormones $(\rightarrow)$ increased TRH $(\rightarrow)$ increased TSH and prolactin.

• Hypothyroidism frequently associated with hyperprolactinemia.

Clinical Implications

• Always measure TSH levels in patients with increased prolactin levels.
• Treat hypothyroidism first; hyperprolactinemia may resolve without specific treatment.

Causes of Hyperprolactinemia

Physiological:

• Pregnancy (highest levels).
• Sleep.
• Eating.
• Intercourse.

Chest Wall Stimulation:

• Suckling.
• Breast examination.
• Chest wall surgery.
• Herpes zoster infection.

Clinical Lesions:

• Cranial tumors.
• Radiations.
• Sarcoidosis.
• Tuberculosis.
• Hypothyroidism.
• Pituitary adenoma (prolactinoma).

Measuring Prolactin Levels

• Measure in the morning hours for uniformity.
• Normal levels: Less than 20-25 nanograms per ml.

Mildly Elevated Prolactin

Next Step:

• Repeat a second sample to confirm hyperprolactinemia before proceeding.

Confirmed High Prolactin

Next Step:

• Get an MRI to rule out prolactinoma and determine the size (microadenoma $<$ 1 cm, macroadenoma $>$ 1 cm).

Symptoms of Prolactinoma

• Most common: Amenorrhea (secondary) followed by infertility.
• Other: Delayed puberty, anovulation, oligomenorrhea, galactorrhea (due to decreased LH/FSH).

Prolactinoma Clinical Features

Symptoms of Increased Prolactin:

• Amenorrhea, infertility, delayed puberty, anovulation, oligomenorrhea, galactorrhea.

Symptoms Related to Invasion of Surrounding Structures:

• Visual defects (bitemporal hemianopsia due to pressure on optic chiasma).
• Cavernous sinus syndrome (headache, visual disturbances, cranial nerve III, IV, VI palsies).
• Headache (mass effect).

Release of Other Pituitary Hormones:

• Acromegaly or Cushing's disease symptoms based on which hormone is released.

Spontaneous Hemorrhage:

• Pituitary apoplexy.

Prolactinoma Management

Depends on:

• Whether it is asymptomatic or symptomatic.
• Whether it is a microadenoma or macroadenoma.

Asymptomatic Microadenoma

• Managed conservatively, includes serial MRIs and prolactin levels every 1-2 years.
• Patient advised to report any changes in menstrual cycle.
• Chances of progression to macroadenoma are less than 10%.

Indications for Management of Prolactinoma:

• Asymptomatic macroadenoma (due to potential pressure symptoms).

• Symptomatic prolactinoma of any size.

• Infertility due to increased prolactin levels.
  Medical Management (First Line):

• Dopamine agonist (cabergoline).

• If cabergoline is not available, use bromocriptine.
  Follow-Up:

• Check prolactin levels after one month.

• Continue same dose if levels are normal.

• Titrate dose if prolactin levels have not decreased, monitoring every month.

Indications for Surgical Management:

• Prolactin levels persistently raised (more than 50).
• Tumor does not shrink or increases in size after 4 months (assessed via MRI).

Prolactinoma During Pregnancy

Taught separately in OBGYN Course.

Physiological Causes of Secondary Amenorrhea

Most Common:

• Pregnancy.
  Lactation.

Post-Menopause:

• Normal age in India is 47 years, elsewhere 51 years.
  Premature menopause (ovarian failure less than 40 years) is now called Primary Ovarian Insufficiency (POI).

PRIMARY OVARIAN INSUFFICIENCY (POI)

Definition:

Ovarian failure happening at less than 40 years.

POI could be due to:

• Radiation exposure (ovary is most radiosensitive pelvic organ).
• Chemotherapeutic drugs (especially alkylating agents).
• Chromosomal anomalies.
• Autoimmune disorders.
• Mumps virus infection.
• Galactosemia.

Chromosomal Anomalies Leading to POI:

• Turner syndrome.
• Fragile X syndrome.
• CYP17 mutation.
• Perrault syndrome.

Fragile X Syndrome

• Triple repeat sequence of CGG.
• Most common inherited cause of mental retardation and autism.
• In females, leads to POI.

CYP17 Mutations

• Deficiency in 17-alpha-hydroxylase or 17,20-lyase.
• Decreased cortisol and androgen production.
• In female fetuses: No ambiguous genitalia, but decreased estrogen.
• Causes sexual infantilism (absent breast development, scanty axillary/pubic hair, infantile uterus).
• Increased ACTH $(\rightarrow)$ increased mineralocorticoids $(\rightarrow)$ increased BP and hypokalemia.

Perrault Syndrome

• Sensorineural hearing loss + ovarian dysfunction + neurological dysfunction.
• Ovarian dysfunction: Ranging from ovarian dysgenesis to primary amenorrhea to POI.
• Neurological dysfunction: Ranging from learning disability to cerebellar ataxia.

Confirming POI

• Measure FSH levels on two occasions one month apart.
• If FSH levels are more than or equal to 40 international units, POI is confirmed.

Other Investigations:

• Karyotyping (especially if POI is happening in a female less than thirty years).
• Bone mineral density (due to risk of osteoporosis).

Managing POI

HRT (Estrogen + Progesterone) until the age of normal menopause (47 years in India, 50-51 years internationally) + donor egg and IVF.

Infertility Management in POI

Donor egg + IVF.

Causes of Secondary Amenorrhea (Divided)

• Endocrine Problem.
• Anatomical Problem.

Anatomical Cause

• Asherman Syndrome (Intrauterine adhesions/synechiae).
• Normal hypothalamus, pituitary, and ovary $(\rightarrow)$ normal LH, FSH, and estrogen levels.

Endocrine Causes

• Hypogonadotropism.
• Hypergonadotropic Hypogonadism.
• Eugonadotropic Amenorrhea.

1. Hypogonadotropic Amenorrhea

• Problem in the hypothalamus or pituitary $(\rightarrow)$ low LH and FSH levels.

Hypothalamus Related:

• Excessive exercise.
• Stress.
• Eating disorders (bulimia, anorexia nervosa).
• Infiltrative lesions (tumors, radiations, infections).

Pituitary Related:

• Tumors, radiations.
• Sheehan Syndrome.
• Prolactinoma.

2. Hypergonadotropic Amenorrhea

• Site is the ovary. Problem is in the ovary, and that problem is a POI.
• Problem in the ovary $(\rightarrow)$ low estrogen $(\rightarrow)$ high FSH $(\geqslant$ 25 mIU/mL on two occasions).

3. Eugonadotropic Amenorrhea

• PCOS (FSH levels are normal, LH levels high).
• Non-classical congenital adrenal hyperplasia.
• Thyroid disorders.

Separate Category:

• Hyperprolactinemia (not included in above categories).

Investigations for Secondary Amenorrhea with Normal Pelvic Anatomy

• Pregnancy test.
• TSH, prolactin, and FSH levels.
• Ultrasound (assess estrogen levels and number of follicles).
• MRI (if prolactin levels are high).
• Estrogen levels assessment.

Excessive Exercise and Amenorrhea

Female Athlete Triad:

• Menstrual dysfunction, low energy availability, and low bone mineral density.

Mechanism:

• Excessive exercise $(\rightarrow)$ release of opioids (endorphins) $(\rightarrow)$ alters GnRH pulsatility $(\rightarrow)$ secondary amenorrhea.

Sheehan Syndrome

Definition:
Necrosis of the anterior pituitary gland due to excessive postpartum hemorrhage (PPH).

Pathophysiology:

• Abrupt severe hypotension due to PPH $(\rightarrow)$ necrosis of anterior pituitary (or pituitary apoplexy).

Hormonal Changes:

• All anterior pituitary hormones decrease (LH/FSH first, TSH last).

Clinical Presentation:

• Secondary amenorrhea.
• Failure to lactate.
• Loss of pubic and axillary hair.
• Hypothyroidism.

Pituitary Apoplexy:

• Sudden onset headache, nausea, visual defects, and hormonal dysfunction.

Asherman Syndrome

Definition:
Presence of intrauterine adhesions or synechiae due to destruction of the endometrium (up to the basal layer).

Pathophysiology:

• Excessive uterine curettage (especially in the postpartum period) or multiple D&Cs.
• Genital TB, schistosomiasis, uterine surgery.

Clinical Presentation:

• Menstrual irregularities (most common): amenorrhea, followed by hypomenorrhea.
• Infertility.
• Dysmenorrhea.
• Recurrent pregnancy loss.

Investigations

• Ultrasound (initial assessment).
• HSG (screening test): Moth-eaten appearance (multiple irregular filling defects).
• Hysteroscopy (diagnostic and for management).

Hysteroscopy Findings

• Dipping of the fundus and in drawing of the lateral walls of the uterus $\rightarrow$ distorted landmarks.

Management

Hysteroscopic adhesiolysis, insertion of pediatric Foley’s catheter or Cook's intrauterine balloon catheter, estrogen and progesterone

Details:

• Hysteroscopic adhesiolysis.
• Pediatric Foley's catheter insertion.
• Estrogen and progesterone (to rebuild endometrium).

Diagnosing Secondary Amenorrhea: Diagnostic Algorithm

1. Rule out pregnancy (urine pregnancy test).
2. Hormonal evaluation: TSH, prolactin, FSH, and estrogen levels.

Based on FSH Levels:

• High FSH (more than 25 international units) $(\rightarrow)$ POI.
• Low to normal FSH $(\rightarrow)$ Progesterone challenge test.

Progesterone Challenge Test

• Give medroxyprogesterone acetate 10 mg for 5 days, then stop.

Positive Test (Withdrawal Bleeding Present):

• Anovulation (normal estrogen levels, no progesterone).
• Causes: PCOS or late-onset congenital adrenal hyperplasia (check 17-hydroxyprogesterone levels).

Negative Test (No Withdrawal Bleeding):

• Check estrogen levels:

  • Normal estrogen levels: Asherman syndrome.
  • Decreased estrogen levels: Hypothalamus or pituitary problem (MRI to differentiate).

Alternate Approach (Estrogen + Progesterone Challenge Test):

• Give estrogen and progesterone for 21 days, then stop.

  • Negative Test (No Bleeding): Asherman Syndrome.
  • If bleeding occurs: Hypothalamus or the pituitary is the issue (MRI to differentiate).
    • MRI = Space occupying lesion $(\rightarrow)$ prolactinoma.
    • MRI = Empty Sella = Sheehan syndrome.
    • MRI = Normal = Hypothalamic Amenorrhea. Excessive exercise or eating too much or stress.

Overlapping Causes of Primary and Secondary Amenorrhea

• Primary ovarian insufficiency (POI).
• Pregnancy.
• PCOS.
• Increased prolactin levels.
• Thyroid disorders.
• Cushing's syndrome/disease.
• M. Cellar Tarsika syndrome.

Diagnosed POI

Further Testing:

• FMRI premutation.
• Karyotyping (all females with POI, Novak suggests).
• Testing for congenital adrenal hyperplasia.

Anti-Mullerian Hormones

• AMH decreased in POI (no follicles).
• AMH increased in PCOS (many follicles).

Primary Amenorrhea: Study in India

• Most common cause of primary amenorrhea in India, according to a study, is Mullerian malformation.
• Second most common cause is gonadal dysgenesis (Swyer syndrome more common than Turner syndrome).
• Genital TB can lead to primary amenorrhea in 6-8% of cases.