Premature Ovarian Insufficiency (POI) and Mullerian Malformations😊

Premature Ovarian Insufficiency (POI)

• Physiology
• FSH stimulates granulosa cells
• Inhibits inhibin B, estrogen, AMH
• Levels decrease
• LH stimulates theca cells
• Stimulates androgens

Tests for Ovarian Reserve

• Day 2-3 of cycle:
• Inhibin B: decreased d/t decreased follicles
• FSH:
• M/c used
• 4 - 10 IU
• Increased
• > 15 → Poor reserve
• > 20 → Suggestive of POI
• d/t loss of negative feedback from inhibin
• Antral follicle count:
• <10 (in both ovaries)

• Any day:
• AMH:
• Glycoprotein hormone
• Gene for MIS/AMH
• Chromosome 19
• Produced by
• Sertoli cells at 7 weeks
• Granulosa cells of preantral and small antral follicles
• Function: Regression of Mullerian Duct in males.
• Best test for Ovarian reserve
• Done any day
• 1 - 3 = Normal
• High AMH
• > 3: PCOS
• > 3.3: High risk of OHSS
• Good outcome of IVF
• Low AMH
• <1 = Suggestive of POI (Poor Ovarian reserve)
• <0.5 = Diagnostic of POI

Note

• Outdated test: Clomiphene citrate challenge

• Test not done for ovarian reserve:
• S. progesterone levels > S. estradiol levels
• It can be used to check ovulation

Indications for Ovarian Reserve Testing

• Age > 35 years

• Family history of POI

• History of radiotherapy/chemotherapy

• Unexplained infertility

Management

• Donor eggs + IVF

Mullerian Malformations

Overview of Mullerian Duct Development

• Formation of Internal Genital Organs:
• From Mullerian ducts (MDs).
• Right MD
• Left MD

• Derivatives of Mullerian Ducts:
• Fallopian Tube
• Uterus
• Cervix + Upper 1/2 of Vagina

• Developmental Process:



• Fusion of MDs occurs from below upwards.
• Leads to septa formation.
• Septa typically resolves by 20 weeks of intrauterine life.
• Resulting fundus is dome-shaped.

• Definition of Malformations:
• Defect in any of these steps results in Mullerian malformations / Lateral Fusion Defects.

Classification of Mullerian Malformations/
Lateral Fusion Defects

Class I: Mullerian Agenesis (Both Mullerian Ducts Absent)

Class II: Unicornuate Uterus (Only one MD present + Rudimentary Horn)

• Not seen: Transverse lie

• Associated with (A/W):
• Ectopic ovary
• Ectopic pregnancy
• Rupture uterus
• Unilateral dysmenorrhea (U/L dysmenorrhea)
• A/W U/L renal anomalies (most common)

• Known as Banana Uterus.

• HSG Image Characteristics:
• Single Fallopian Tube (FT)
• Banana-shaped uterus

• Structures Present:
• FT: 1
• Uterus: 1/2
• Cervix: 1/2
• Upper Vagina: 1/2

Class III: Uterus Didelphys (Both MDs present but fail to fuse)

• Key Features:
• Either fail to fuse, OR
• Fuse only in vagina

• Structures Present:
• FT: 2
• Uterus: 2
• Cervix: 2 (distinguishing feature)
• Vagina: 2 (Or 1 if only vagina is fused)

• HSG Image Characteristics:
• Seen with two Leech-Wilkinson cannulas

• Not seen: Transverse lie

• M/c A/w Vaginal Septum
• Leads to endometriosis via retrograde spread

Class IV: Bicornuate Uterus

• Both MDs fuse in vagina and cervix but not in uterus

• Key Features:
• Distinguishing feature: Fundus of uterus is divided (separate vs. bicornuate).
• Note: On HSG, the fundus of the uterus cannot be seen (cannot differentiate from septate uterus).

• Structures Present:
• FT: 2
• Uterus: 2
• Cervix: 1
• Vagina: 1

Additional Information:

• HSG is not a good investigation for these anomalies.

• Ideal Investigations:
• Hysteroscopy + Laparoscopy.
• Then MRI.
• Then 3D USG.

Differentiation between Bicornuate and Septate Uterus (by MRI):

Feature	Septate Uterus	Bicornuate Uterus
Endometrium	Split	Split
Outer Surface	Smooth (not split)	Split
Angle of Horns	Small	Bigger

HSG Image Characteristics:

• Angle between uterine horns: Obtuse

• Distance between horns: ≥4 cm

Class V: Septate Uterus

• Both MDs fuse, septa forms but fails to resolve in uterus

• Key Features:
• From outside: Uterus appears normal
• From inside: Septum present
• Note: Fundus of uterus fused (undivided)

• HSG Image Characteristics:
• Angle between uterine horns: Acute
• Distance between horns: <4 cm
• To differentiate b/w septate and bicornuate uterus:
• Fundus of uterus (undivided in septate, divided in bicornuate).
• Angle of separation is small.

• Structures Present:
• FT: 2
• Uterus: 2
• Cervix: 1
• Vagina: 1

Class VI: Arcuate Uterus

• Everything is normal, MDs fuse, septa forms and resolves

• Problem: Fundus of uterus is flat.

• Best reproductive outcome.

Class VII: In utero exposure to Diethylstilbestrol (DES)

• Cause: Synthetic estrogen given to pregnant women (now discontinued).

• Features: Teratogenic

• Associated with (A/W):
• Most common malignancy: Clear cell cancer of cervix and vagina
• Most common uterine malformation: Hypoplastic uterus (T-shaped uterus)
• DES exposure does not lead to renal anomalies in female fetuses.

Investigations for Mullerian Malformation

1st Investigation:

• Recurrent abortion: Transvaginal Ultrasound (TVS)

• Infertility: Hysterosalpingography (HSG)

Investigation of Choice (IOC): 

• 3D Ultrasound

• Gold Standard Investigation: MRI

• Last / Best Resort: Laparoscopy + Hysteroscopy

HSG-Based Diagnosis Flowchart

Number of FT:

• 1: Unicornuate

• 2:
• Number of Leech-Wilkinson Cannulae:
• 2: Didelphys
• 1:
• Angle b/w Uterine Horns:
• Obtuse (or distance b/w horns ≥ 4 cm): Bicornuate
• Acute (or distance b/w horns < 4 cm): Septate

Important PYQ (Previously Asked Questions)

• Most common Mullerian Anomaly: Septate uterus > Bicornuate uterus

• Most common clinical features: Recurrent abortion

• Septate uterus
• Most common uterine malformation A/W
• 2nd trimester abortions > 1st trimester:
• Infertility
• Worst reproductive outcome
• Surgery:
• Indications: Recurrent abortion
• Hysteroscopic / Transcervical resection of septum (Metroplasty)
• Outdated surgery for septate uterus: 
• Tompkins metroplasty
• Jones metroplasty

• Outdated surgery for bicornuate uterus: 
• Strausman metroplasty
• Jones septal ring → outdated
• 2 straws → outdated

• Surgery for didelphys uterus and bicornuate uterus: 
• Unification surgery

• 2nd trimester abortion
1. Cervical insufficiency
2. Mullarian malformation

• Best Outcome: Arcuate uterus > Didelphys uterus

• Uncommon in Didelphys: Transverse lie

• Maximum associated with renal anomalies: Unicornuate uterus > Mullerian Agenesis

Gynaecological Complications with Mullerian Malformation

• Outflow Tract Obstruction: 
• leading to Hematometra

• Endometriosis: 
• If pubertal female has endometriosis,
• rule out Mullerian malformation.

• Dysmenorrhea

• Infertility: (Rare)

Malpresentations in Mullerian Malformation

Transverse Lie (Mnemonic: SSB) seen in:

• Septate uterus

• Sub-septate uterus

• Bicornuate uterus

Breech:

• Uterus didelphys

Transverse Lie not seen in:

• Unicornuate

• Didelphys

Obstetric Complications with Mullerian Malformation

• Recurrent Pregnancy Loss (RPL)
• Most common complication overall

• Preterm Labor

• Malpresentation