Infertility😍

Infertility

• Definition: Inability to conceive after 1 year of unprotected intercourse.

• WHO grade 2
• No man’s land in flexor tendon → Zone 2
• Infertility workup → WHO grade 2 is most common

• Investigations (Following unprotected Intercourse):
• Age of female
• <35 years: 1 year
• ≥35 years: 6 months
• ≥45 years: 3 months

• Basic Ix:
• Semen analysis.
• Test for ovulation: S. Progesterone on Cycle Day 22.
• Test for tubal patency: Hysterosalpingography b/w D7 - D10.

Causes of Female Infertility

1. Ovarian (m/c) reversible
• Anovulation

2. Tubal: 2nd m/c

3. Uterine
• Submucosal fibroid
• Endometrial polyp
• Asherman syndrome
• DES exposure
• Mullerian malformation

4. Cervical (Unexplained)
• Antisperm Abs (Immunological)
• Cervicitis

• Note: Male infertility
• M/C cause: Testicular causes → Abnormal spermatogenesis.
• M/C reversible cause: Varicocele.

WHO Classification of Ovarian Causes

• Not classified: Hyperprolactinemia.

Cervical & Uterine Causes of Infertility

Cervical/Immunological Cause

• Etiology: Antisperm antibodies in cervix

• Tests:
• Sims test/post coital test/Huhner test: Day 12-14 of cycle
• Outdated as treatment is same as unexplained infertility

• Management: CC + IUI (3 cycles)

Uterine Causes

• Most common cause: Submucosal fibroid
• Type 0, 1: Hysteroscopic myomectomy
• Type 2: Laparoscopic myomectomy

• Mullerian malformation: Septate uterus (most common)

• Asherman's syndrome

Note: Timing of Tests

Tubal Causes of Infertility

Causing tubal block

• Genital TB

• Pelvic inflammatory disease

• Endometriosis

Investigations

• HSG (Hysterosalpingography):
• Imaging for tubal blocks
• Dye: Urograffin

• HSG is always f/b Lap chromopertubation → gold standard for confirmation
• Laparoscopic chromo pertubation:
• Dye: Methylene blue, Indigocarmine dye

Management

• Unilateral (U/L) block:
• Managed Like unexplained infertility
• IUI + CC

• Bilateral (B/L) block:

B/L Cornual block (better outcome):



• Most common cause: Physiological spasm

• Most common pathological cause: Genital TB

• (before Lap chromopertubation → perform hysteroscopic cannulation)
• Hysteroscopic cannulation
• Passing thin wire: Relieves physiological spasm

• If block persists after laparoscopic chromopertubation:
• Genital TB treatment → IVF

Distal block:



• Imaging: B/L distal block →
• Laparoscopic chromopertubation →
• Mild: Fimbrioplasty
• Severe → Hydrosalpinx:
• Fluid in hydrosalpinx is embryotoxic
• Retort shaped / Sausage shaped
• Indicate PID → other signs
• Cogwheel sign
• Waist sign
• Beads on string sign
• Salpingectomy, then → IVF

 

Salpingitis isthmica Nodosa

Classification of Male Infertility on FSH, LH, and Testosterone

1. Hypogonadotropic Hypogonadism

• FSH: ↓

• Testosterone: ↓

• Organs Involved: Hypothalamus/Pituitary
• Kallmann syndrome.
• Hypothyroidism.
• ↑Prolactin.

2. Hypergonadotropic Hypogonadism

• FSH: ↑

• Testosterone: ↓

• Organ Involved: Testis
• Klinefelter’s syndrome.
• Mumps orchitis.
• Exposure to heat (miners).

3. Normogonadotropic Normogonadism

• FSH: Normal

• Testosterone: Normal

• Organs Involved: Sperm pathway
• Vasectomy.
• Cystic fibrosis.
• Varicocele.
• Retrograde ejaculation.

Note: Sperm Pathway

• Testis: Spermatogenesis.

• Epididymis.

• Vas deferens.

• Seminal vesicle (SV): Secretions  majority of semen, fructose.

• Ejaculatory duct.

• Prostate: Secretions make semen acidic.

• Bulbourethral/Cowper’s gland: Secretions released only during intercourse.

Sertoli Cell vs Leydig Cell

Cells	Notes
Sertoli Cell	• Contains receptors for FSH and androgens • Forms blood-testis barrier → Tight junction • “Nurse cells of testis” ↳ Nourishes and protects developing sperm cells Functions • Inhibin → Inhibit FSH • Androgen-binding protein (ABP) → Bind to testosterone • AMH (MIS) → causes regression of Müllerian ducts • Aromatase enzyme → converts testosterone to estradiol • Phagocytic function → Ingest dead sperms
Leydig Cell	• Contains LH receptors • Synthesizes cholesterol de novo • Acquires cholesterol via LDL & HDL receptors ↳ (scavenger receptor) • Expresses high levels of 3β-HSD ↳ (converts androstenedione to testosterone) • Testosterone diffuses into seminiferous tubules • In tubules, aromatase of Sertoli cells converts testosterone into estradiol

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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

Scrotum Temperature

• Scrotum temperature is 1-2°C less than body temperature

• This lower temperature favors spermatogenesis.

Sperm Development during Puberty

• During puberty, cells transform into sperms.

• Sperm structure includes:
• Head
• Midsection
• Tail

• Sperm continues to develop in the epididymis for 2 to 4 weeks (20 days)

Sperm Capacitation

• Occurs after ejaculation into female genital tract.

Events Before Fertilisation

• Capacitation:
• Ability of sperms to fertilize ova
• Time: 6-8 hours.
• Site:
• Begin → cervix
• Completed → fallopian tube

• Acrosomal reaction:
• Head of sperm enters cortex of 2˚ oocyte
• Due to hyaluronidase released by acrosomal cap
• Penetrate Zona pellucida
• Zona pellucida:
• Acellular layer
• Has ZP3 Glycoprotein (most abundant)
• Main receptor for sperm
• Mnemonic: ZP3 → Zperm
• Influx of calcium

• Zona reaction >> Cortical reaction:
• Prevents: Polyspermy
• Release of enzymes by cortex of 2˚ oocyte
• Zona pellucida made impermeable to other sperms

Semen Components (Fluid)

Produced by:

• Seminal vesicle (60%):
• Fructose: Energy source (GLUT-5 mediated).
• Vit C: Antioxidant.
• Prostaglandin: Makes cervical mucus penetrable by sperm.
• Phosphorylcholine:
• Detected via Florence test (Test for seminal stain in rape cases).

• Prostate (30%):
• Fibrinolysin: Liquefaction of semen in 15-30 min.
• Acid phosphatase
• Spermine: Detected via Barberio's test.
• Zinc

• Vas deferens (10%):
• Bicarbonate.
• Phosphate.

• Buffers: Bicarbonate, phosphate.

• Mnemonic: Barber (Barberio) Sperm (Spermine) edth Flower (Florence) nte Purath (Phosphorylcholine) itt

Semen Analysis

Overview

• Done after 2-7 days of abstinence.

• Sample should reach lab within 1 hr.

• Analysis done on liquified sperm (liquefaction time: 20-30 mins).

Sperm Characteristics (Proximal/Distal Epididymis)

• Sperms attain maturity: Proximal part of epididymis.

• Sperms attain motility: Distal part of epididymis.

WHO Criteria for Analysis (2022)

• WHO semen analysis provides minimum criteria for conception (not average values).

• Most important parameters:
• Morphology >
• Motility >
• Concentration.

• Parameters that remained unchanged (2010 vs 2022):
• Total sperm count: 39 million/ejaculate.
• Sperm morphology: 4% (Tygerberg criteria).

• Abnormal Semen Analysis Table (2022 Criteria)

Sperm Disorders

Causes

• Azoospermia
• Cystic fibrosis:
• B/L absence of vas deferens & seminal vesicles.
• Klinefelter’s syndrome:
• Testes: Small & hypoplastic
• Spermatogenesis defective → Azoospermia
• Tall men, long limbs
• Gynecomastia
• Tremors, Low IQ, Osteoporosis
• Autoimmune
• DM/RA/SLE
• Sertoli cell only Syndrome / Del Castillo Syndrome
• Cause
• Idiopathic (M/c)
• Y chromosome microdeletion
• Sertoli cell do not function
• as there is no interaction with germ cell
• No Inhibin B release ⇒ ↑↑ FSH
• Leydig cells are present
• Testosterone levels may be normal

• Asthenospermia
• Kartagener’s syndrome: immotile cilia syndrome
• Varicocele

• OATS (Oligospermia/Asthenospermia/Teratozoospermia)
• Smokers
• Varicocele

Obstructive Azoospermia

Work-up

• FSH, LH, HP axis
• FSH (next best step)
• Normal → Obstructive
• ↑↑↑ → Non Obstructive
• m/c → Primary hypogonadism
• Best test: Testicular biopsy

• Best prognosis

Assessment based on Semen Volume and Fructose

• ↓ Semen Volume & ↓ Fructose
• Causes:
• Absent seminal vesicle (Cystic Fibrosis)
• Block in ejaculatory duct
• Retrograde ejaculation
• Diagnostic Approach: Transrectal USG
• SV absent: CFTR gene testing
• SV present:
• Dilated: Blocked
• Normal: Retrograde ejaculation

• Normal Semen Volume & Normal Fructose
• Block above level of SV:
• Vas deferens
• Epididymis
• Diagnostic Approach: Scrotal USG

Management of Abnormal Semen Analysis

Azoospermia

• Repeat semen analysis:
• Minimum gap of 1 week, ideal gap of 1 month.

• If Azoospermia persists, check FSH, LH, and testosterone.

• FSH > Testosterone for evaluating azoospermia

Treatment of Infertility in males

Treatments by Condition

Intrauterine Insemination (IUI)

• Prerequisite
• Sperm count: Minimum 10 million/mL

• Process
• Processed sperm (increased quality) injected into female uterus with catheter

• Indications
• Mild oligospermia (≥10 million/mL)
• Minimum to mild endometriosis
• Unexplained infertility
• Female vaginismus
• Cervical factor infertility
• Failure of erection in males

In Vitro Fertilization (IVF)

• Prerequisite
• Sperm count: Minimum 5 million/mL
• Per oocyte: 50,000-1 lakh

• Process
• Drugs used for hyperovulation: HMG

• Indications
• B/L tubal block
• Mullerian agenesis (management: IVF followed by surrogacy)
• Low ovarian reserve
• Severe endometriosis
• Genital TB: Distorted anatomy
• Male: Oligospermia where sperm count is 5-10 million/mL

• Contraindications (C/I)
• Sperm count <5 million/mL
• Azoospermia
• Asthenospermia

Intracytoplasmic Sperm Injection (ICSI)

• Prerequisite
• Sperm needed per oocyte: 1

• Indications
• Indications and contraindications for IVF
• Severe oligospermia

• Fertilisation rate: 60 - 80%

Management of Testicular Azoospermia

• Surgical procedures to retrieve sperm
• TESA: Testicular sperm aspiration
• TESE: Testicular sperm extraction
• PESA: Percutaneous epididymal sperm aspiration
• MESA: Microsurgical epididymal sperm aspiration

• followed by ICSI

Tests for Ovulation

History

• Ovulatory cycles
• Regular cycles
• Mittelschmerz syndrome (C/O midcycle pain)
• Dysmenorrhea
• Premenstrual syndrome

• Anovulatory cycles
• Painless, irregular, heavy bleeding.
• Note: Due to estrogen breakthrough, not progesterone withdrawal.

Basal Body Temperature

• Midcycle ↑ temperature (Biphasic graph).

Hormonal Study

• Progesterone levels D22 of cycle: >10 ng/mL (Best & easiest).

Cervical Mucous Study

ㅤ	Estrogen	Progesterone
Consistency	Profuse, watery, elastic	Thick, scanty, viscous
Known as	Spinnbarkeit (Stretching ⊕) Spin → Loose	Tack (Stretching ⊝) Tack → katti
ㅤ	ㅤ	ㅤ

Ferning

• Seen under microscope on D8
• ↳ Proliferative phase

• Disappears by D18 of cycle

• If ferning persist by D18, indicates Anovulation

Endometrial Glands

• Endometrial Biopsy → Not commonly done for ovulation.

• Timing: D26 (Pre-menstrual phase).

 

Stages	Features
Early proliferative ↳ Estrogen	• Simple tubular glands • Telescoping of gland • Pseudostratification (Nuclei at different levels)
Early secretory ↳ Progesterone	• Subnuclear vacuolation: First sign of ovulation on biopsy (D17 - D18)
Late secretory ↳ Progesterone	• Corkscrew glands • Sawtooth appearance • Secretions in gland

Urinary LH Surge

• Occurs 24 hrs before ovulation
  (Blood LH surge occurs 32-36 hrs before ovulation).

Follicular Monitoring

• M/C done.

• TVS done from D10 on alternate days.

• Ovulation:
• ≥17 mm follicular size →
• Sudden decrease in size +
• Fluid in POD & Triple layered endometrium.

• Note: Follicle grows 1-2 mm/day.

USG

• Early proliferative phase: Single white line in endometrium.

• Late proliferative > Ovulatory phase: Trilaminar endometrium.

• Secretory phase:
• Thick endometrium.
• Posterior enhancement.

Management for Anovulation

Ovulation Timing:

• Around day 14 of menstrual cycle.
• Related to hormonal peaks:
• After Estradiol rise: ~83 hours. (80)
• After Estradiol peak: 24 to 36 hours. (30)
• After LH surge starts: 24 to 36 hours (Ganong) or 34 to 36 hours (Obstetrics). (30-35)
• After LH peak: ~9 hours (Ganong) or 10 to 12 hours (Dutta). (10)
• After Progesterone rise: ~8 hours. (8)
• Mnemonic:
• Granpa (estrogen)
• His peak was at 30
• But his emotions rised in 80
• Lady (LH)
• Her peak was at 10 yrs
• But her emotions rised at 30-35
• Both projected (Progesterone) their love for 8 hours

Hysterosalpingography (HSG)

Procedure

• Dye: Urograffin used (iodinated water soluble)

• Dye passed into uterus using Leech Wilkinson's cannula

• Imaging: B/L spillage of radiopaque dye

Timing

• Done in pre-ovulatory phase: Day 7-10
• Doing after 14 days may cause abortion if pregnant

Contraindications

• Pregnancy

• Active PID

• Active genital TB

Uses of HSG

1. Mullerian malformations:
• Coincidental findings

2. In case of Genital TB:
• After T/T if HSG is done
• In fallopian tubes:
• B/L cornual block
• Beaded appearance
• Cotton wool appearance
• Golf stick appearance
• Lead pipe appearance
• Tobacco pouch appearance
• In uterine cavity:
• Multiple filling defects + irregular borders
• (due to Asherman syndrome)

• IOC:
• For tubal patency
• Tubal block seen

• Filling defect seen:
• If smooth:
• Fibroids
• Polyp
• If multiple with moth-eaten appearance:
• Asherman syndrome