Male Infertility Notes

Male Infertility

Spermatogenesis Revision

• Spermatogenesis begins at puberty.
• Site for spermatogenesis: seminiferous tubules in the testes.
• Time taken for spermatogenesis: 70-74 days.
• Additional time for sperms to travel in the epididymis and ductal system: 12-21 days.
• Daily sperm production: 100-200 million.

Hormonal Support for Spermatogenesis

• High local level of testosterone is needed.
• Testosterone is produced by Leydig cells.
  • First stimulus for Leydig cells to produce testosterone in intrauterine life is given by hCG.
  • LH takes over the function of stimulating testosterone production after the initial hCG stimulus.
• FSH acts on Sertoli cells.
  • Sertoli cells release inhibin B and androgen-binding protein (ABP).
  • ABP binds to testosterone to maintain high local levels.
  • FSH induces LH receptors on Leydig cells.
• Main hormone needed for spermatogenesis: testosterone.
• Additional contributory roles are played by LH and FSH.

Factors Affecting Spermatogenesis

• Adequate body temperature: lower than body temperature.
• Occupation of the male partner can affect spermatogenesis if it involves high temperatures.
• Febrile illness can affect sperm count.
• Testicular volume:
  • Normal: 15-25 ml.
  • Normal length: 4 cm.
  • Small testes indicate defective spermatogenesis.
• Y chromosome is essential for spermatogenesis.
• Klinefelter syndrome ($47, XXY$) or microdeletion of Y chromosome can result in defective spermatogenesis.

Karyotyping

• Should be done in patients with severe oligospermia (sperm concentration less than 5 million per ml) or non-obstructive azoospermia.

Semen Analysis

• Basic investigation for evaluating the male partner.
• Sample obtained by masturbation after an abstinence period of 2-7 days.
• Sample should reach the lab within 1 hour.
• Analysis has to be done on a liquefied sample.
• Liquefaction time range: 5-20 minutes.

WHO Parameters for Semen Analysis (Minimum Criteria for Conception)

• pH: $\geq 7.2$
• Volume: $\geq 1.5$ ml
• Total sperm count: $\geq 39 \times 10^6$ per ejaculate
• Sperm concentration: $\geq 15 \times 10^6$ per ml
• Total motility: 40%
• Progressive motility: 32%
• Morphology (strict Kruger criteria): 4%
• Vitality: 58%
• WBC count: < 1 \times 10^6 per ml
• Average sperm count: 50-100 million per ml
• Most important criteria: sperm morphology followed by motility and concentration.

Terminology for Abnormal Semen Analysis

• Aspermia: no semen.
• Oligospermia: sperm concentration < 15 \times 10^6 per ml.
• Severe oligospermia: sperm concentration < 5 \times 10^6 per ml.
• Azoospermia: no sperms in semen.
• Asthenospermia: decreased sperm motility.
• Teratospermia/Teratozoospermia: abnormal sperm morphology.
• Necrospermia: increased non-viable sperms.
• Leukocytosis: WBC count > 1 \times 10^6 per ml (seen in chronic prostatitis and epididymitis).
  • Management: Doxycycline $100$ mg twice daily for two weeks.

Conditions Associated with Terminology

• Azoospermia
  • Klinefelter syndrome: defective spermatogenesis (non-obstructive azoospermia).
  • Cystic fibrosis: congenital bilateral absence of vas deferens and seminal vesicles (obstructive azoospermia).
• Asthenospermia
  • Kartagener's syndrome (immotile cilia syndrome).
  • Prolonged abstinence period.
  • Genital tract infection.
  • Varicocele.
• Varicocele & Smokers:
  • Asthenospermia, oligospermia, and teratospermia.

Sperm Pathway

• Testes (seminiferous tubules) → Epididymis (attains motility and maturity) → Vas Deferens (seminal vesicles pour seminal fluid) → Ejaculatory Duct → Urethra.
• Seminal vesicles: major contributor to semen and adds fructose.
• Prostate gland: pours secretions into the semen, containing acidic enzymes for liquefaction.
• Bulbourethral gland: gives secretions at the time of ejaculation.
• Imaging
  • Scrotal ultrasound: visualizes testes and epididymis.
  • Transrectal ultrasound: visualizes seminal vesicles and ejaculatory duct.
  • MRI: preferred modality for imaging male sex glands and defects.

Semen Composition

• Sperms
• Seminal vesicle fluid (major contributor, contains fructose)
• Prostatic fluid
• Bulbourethral gland fluid

Abnormal Semen Analysis - Next Steps

• Repeat semen analysis after a week.
• If repeat semen analysis shows azoospermia or oligospermia, then hormonal evaluation.
• Hormonal Evaluation:
  • FSH.
  • Testosterone.
  • TSH.
  • Prolactin.

Hormonal Tests and Spermatogenesis

• Hypothalamus releases GnRH → Pituitary releases LH and FSH → Testes produce testosterone (helps in spermatogenesis).

Types of Problems

1. Pretesticular (Hypothalamus/Pituitary).
2. Testicular.
3. Post-testicular (Sperm pathway obstruction).

Negative Feedback Mechanism

• Testosterone has a negative feedback on GnRH, LH, and FSH secretion.

Pretesticular Azoospermia (Secondary Hypogonadism)

• Problem in hypothalamus or pituitary.
• Low FSH levels, Low testosterone levels.
• Causes:
  • Hypothalamic failure (Kallmann syndrome).
  • Hypothyroidism.
  • Increased prolactin levels.

Testicular Azoospermia (Primary Hypogonadism)

• Problem in the testes.
• High FSH levels, Low testosterone levels.
• Most common cause of azoospermia.
• Causes:
  • Klinefelter syndrome.
  • Mumps orchitis.
  • Varicocele.
  • Mumps.
  • Minors.

Reifenstein Syndrome

• Variety of partial androgen insensitivity syndrome.
• Testosterone levels are normal or high.
• FSH levels are normal (due to inhibin).
• LH levels are high (males are resistant to testosterone).

Post-Testicular Azoospermia (Obstructive Azoospermia)

• Problem in the sperm pathway.
• Normal FSH and testosterone levels.
• Causes:
  • Congenital bilateral absence of vas deferens (CBAVD) seen in cystic fibrosis.

Key Points

• In couples with infertility, do TSH and prolactin levels.
• Most common cause of male infertility: primary hypogonadism.
• Azoospermia with best prognosis: obstructive azoospermia.
  • Hormones are normal.

Klinefelter Syndrome

• Genotype: $47, XXY$.
• Seen in 1 in 500 men.
• Tall, under-virilized, gynecomastia.
• Small and firm testes.
• Defective spermatogenesis.
• Prader orchidometer used to measure testes size.
• Karyotyping should be done to rule out Klinefelter syndrome and microdeletion of Y chromosome.

Testicular Biopsy

• To determine presence of viable sperms in testes.
• Not the first investigation.
• Surgically retrieve sperms from the testes by procedures like TESA, TESE, or PESA.
  • TESA: Testicular Sperm Aspiration.
  • TESE: Testicular Sperm Extraction.
  • PESA: Percutaneous Epididymal Sperm Aspiration.
• After retrieval, perform ICSI (intracytoplasmic sperm injection).

Intracytoplasmic Sperm Injection (ICSI)

• Inject a single sperm into the cytoplasm of the oocyte.

Management of Male Infertility Based on Sperm Concentration

• Oligospermia ($10-15 \times 10^6$ per ml): IUI.
• Oligospermia ($5-10 \times 10^6$ per ml): IVF.
• Severe oligospermia (< 5 \times 10^6 per ml), azoospermia, or asthenospermia: ICSI.

Obstructive Azoospermia Management

• Obstruction above the level of seminal vesicles (epididymis or vas deferens).
  • Semen has fluid from seminal vesicles, prostate gland, and bulbo urethral gland.
  • Normal semen volume, fructose present, alkaline pH.
• Obstruction below the level of seminal vesicles.
  • Semen has fluid from prostate and bulbo urethral gland.
  • No sperms, no seminal vesicle fluid, low volume, no fructose, acidic pH.
• Cystic Fibrosis
  • No sperm, low volume, and semen will be acidic
• Approach to Obstructive Azoospermia
  • Check the CFTR gene mutation if low volume.
• Ejaculatory Duct Obstruction
  • Perform Transrectal Ultrasound (TRUS).
  • A seminal vesicles AP diameter > 15mm is considered dilated.
  • If no seminal vesicles dilation look for retrograde ejaculation

Semen Characteristics and Obstructive Azoospermia

• Low semen volume, decreased fructose, acidic pH:
  • Congenital bilateral absence of seminal vesicles (cystic fibrosis).
  • Obstruction in ejaculatory duct.
• Low semen volume, absence of fructose and acidic pH
  • Go for a CFTR Gene Mutation
• Normal semen volume, fructose present, alkaline pH:
  • Obstruction above the level of seminal vesicles (epididymis or vas deferens).
• Management: resection and anastomosis (relieve the obstruction).

IUI (Intrauterine Insemination)

• Semen from the male partner is processed and put into the female's uterus via a soft catheter, bypassing the cervix.

Minimum Sperm Concentration

• $10 \times 10^6$ per ml.

Indications and Timing

• Cervical factor infertility: Timing determined by urinary LH kit.
• Unexplained infertility/male factor infertility: Supraovulation with clomiphene citrate (day 2-5), follicular monitoring; give injection hCG when follicle $\geq 17$ mm, do IUI 32-36 hours after hCG.
• Retrograde ejaculation: Sperms collected and processed from a voided urine specimen after ejaculation; give sodium bicarbonate half an hour before ejaculation.

IVF (In Vitro Fertilization)

• Controlled ovarian stimulation with injection HMG.
• Follicular monitoring from day 10.
• Injection hCG when follicle $\geq 17$ mm.
• Egg retrieval 32-36 hours after injection hCG.
• Oocyte pickup under local or short GA with special needles under ultrasound guidance.
• Incubate oocytes with sperms (50,000-100,000 sperms per oocyte) at 37°C, 5-20% oxygen for 12-18 hours.
• Check for fertilization (two polar bodies, two pronuclei).
• Embryo transfer on day 3 (cleavage) or day 5 (blastocyst) under ultrasound guidance, 2 cm below the fundus.

IVF Key Points

• 50,000-100,000 sperms needed per oocyte for IVF.
• IVF cannot be done in males with azoospermia or asthenospermia.

ICSI (Intracytoplasmic Sperm Injection)

• Same as IVF until oocyte retrieval.
• Inject one sperm into the cytoplasm of each oocyte.
• ICSI can be done in case of severe oligospermia, azoospermia, and/or asthenospermia.

Indications for IVF, ICSI, IUI based on sperm concentration

• Oligospermia (10 to 15 million/ml): IUI
• Oligospermia (five to ten million/ml: IVF
• Severe oligospermia, azoospermia, or asthenospermia: ICSI

IVF over IUI (or in addition to IUI)

• Tubal infertility (tubal blockage).
• Mullerian agenesis (IVF plus surrogacy).
• Decreased ovarian reserve (IVF with donor eggs).
• Multiple IUI failures.
• Male sperm concentration 5 million/ml to 10 million/ml.

IUI Indications (in addition to IVF)

• Cervical factor infertility.
• Vaginismus.
• Unexplained infertility (clomiphene citrate plus IUI).
• Male ejaculatory problems (hypospadias, epispadias, retrograde ejaculation, etc.).
• Oligospermia with sperm count 10 million/ml to 15 million/ml.

Indications for ICSI

• All indications for IVF plus severe oligospermia, azoospermia and asthenospermia.

Success Rates

• IVF and ICSI success rate is 20-30%.

Complications of Assisted Reproductive Techniques (IVF and ICSI)

• Increased chances of PIH, placenta previa, and placental abruption.
• Multi-fetal gestation (including monozygotic twins).
• Prematurity, low birth weight, IUGR.
• Embryonal hepatic adenoma in IVF conceived offsprings.
• No increased risk of congenital anomalies.

Gamete Intra Fallopian Transfer (GIFT)

• Egg retrieval, then egg and sperms placed in the fallopian tube.
• Used earlier for unexplained infertility, now mostly replaced by IVF.

Preimplantation Genetic Testing (PGT)

• To identify chromosomal abnormalities or for HLA typing before embryo transfer.
• PGT-A: aneuploidy.
• PGT-M: monogenic/single gene defect.
• PGT-SR: chromosomal structural rearrangements.

Material for PGT

1. Polar body: Advantage is avoiding removal of cells from developing embryo; disadvantage is only maternal chromosomes, so genetic abnormalities of paternal origin cannot be detected.
2. Cleavage embryo.
3. Trophoectoderm (blastocyst stage): preferred

• Can also be done on cell-free fetal DNA amplified using spent embryo media (SEM).