Treatment of Infertility

Summary

The management of infertility encompasses a stepwise approach beginning with ovulation induction, proceeding to intrauterine insemination, and ultimately to in vitro fertilization with or without ICSI depending on the underlying cause. Advances in reproductive medicine, particularly IVF and genetic testing, have significantly improved outcomes, with millions of births worldwide attributed to assisted reproductive technologies. Careful patient selection, individualized treatment planning, and awareness of risks are essential to optimize success while minimizing complications.

Ovulation Induction

Ovulation induction is indicated in women with absent or infrequent ovulation, most commonly due to polycystic ovary syndrome (PCOS) or hypothalamic amenorrhea. Before initiating treatment, other specific causes of anovulation should be excluded, and baseline levels of TSH, FSH, and prolactin should be within the normal range.

Clomiphene Citrate

A selective estrogen receptor modulator (SERM), is the first-line therapy for unexplained infertility and anovulation, with a success rate of approximately 86%. It acts by blocking estrogen receptors in the hypothalamus, reducing negative feedback, and increasing GnRH secretion, thereby stimulating FSH and LH production to promote follicular growth and ovulation.

• Administration: Given orally from day 3–5 of the follicular phase for 5 days, with ovulation typically occurring 5–12 days after the last dose.

• Adverse effects: Multiple gestation, ovarian hyperstimulation syndrome (OHSS), abnormal uterine bleeding, vasomotor symptoms (hot flushes), mood changes, visual disturbances, gastrointestinal upset, and rarely, hair loss.

• Limitations: Ineffective in women with premature ovarian insufficiency (POI).
  
  

Gonadotropins (Human Menopausal Gonadotropins, FSH, or LH)

Gonadotropins may be used when clomiphene fails or in women with pituitary or hypothalamic dysfunction (e.g., Sheehan syndrome). They stimulate follicular growth by directly replacing FSH and LH, with success rates of 80–90%. Administration is intramuscular during the follicular phase, with estrogen levels and ultrasound monitoring required to avoid excessive response.

Letrozole

Letrozole, an aromatase inhibitor, is increasingly used as an alternative to clomiphene, particularly in PCOS. By reducing estrogen synthesis, it increases GnRH pulsatility and gonadotropin release, thereby enhancing ovulation.

Assisted reproductive technology

Intrauterine Insemination (IUI)

IUI involves the introduction of washed sperm directly into the uterine cavity at the time of ovulation, often combined with controlled ovarian hyperstimulation (COH). This enhances the number of motile sperm available at the fertilization site and is widely used for unexplained infertility, mild male factor infertility, and cervical factor infertility.

• Compared with IVF, IUI is less invasive, less costly, and carries a lower risk, although pregnancy rates are generally lower.

 

In Vitro Fertilization (IVF)

IVF is the most advanced and widely used assisted reproductive technique. It involves aspirating mature oocytes transvaginally under ultrasound guidance, fertilizing them with sperm in the laboratory, and transferring the resulting embryos into the uterine cavity.

Indications

IVF is indicated when other treatments are ineffective or inappropriate, including:

• Tubal factor infertility (blocked or damaged fallopian tubes)

• Severe male factor infertility (azoospermia, oligospermia, asthenozoospermia, anti-sperm antibodies)

• Endometriosis-associated infertility

• Ovulatory dysfunction unresponsive to ovulation induction

• Age-related infertility with diminished ovarian reserve

• Unexplained infertility after failed simpler interventions

• Genetic disorders, where preimplantation genetic testing (PGT) is needed
  
  

Ovarian Reserve Testing (ORT)

ORT is primarily used in women ≥35 years to assess ovarian capacity to produce viable oocytes. Diminished ovarian reserve is characterized by normal cycles but reduced oocyte quality and number, leading to decreased fecundability. As estradiol and inhibin production decline, FSH levels rise, and day 3 FSH testing is a common method to evaluate ovarian function and predict IVF response.

IVF Procedure (The IVF Cycle)

1. Patient selection and evaluation

2. Suppression of natural hormonal cycles with GnRH agonists/antagonists

3. Controlled ovarian stimulation with gonadotropins

4. Oocyte retrieval via transvaginal aspiratio

5. Semen preparation and fertilization (standard IVF or ICSI in severe male infertility)

6. Embryo culture and transfer to the uterus

7. Cryopreservation of surplus embryos for future use
   
   

Embryo Transfer

• Generally, 1–2 embryos are transferred to balance success rates with the risk of multiple pregnancy.

• In women <35 years, typically up to 2 embryos are transferred, whereas in women >35, up to 3 may be considered.

• The risk of multiple pregnancy and its complications increases with the number of embryos transferred.
  
  

Success Rates

• <35 years: 40–50%

• 35–37 years: 33–35%

• 38–40 years: 23–27%

• 41 years: 13–20%
  Overall outcomes depend strongly on maternal age and infertility etiology.
  
  

Complications

• Ovarian hyperstimulation syndrome (OHSS)

• Multiple pregnancy

• Miscarriage and ectopic/heterotopic pregnancy

• Emotional and psychological stress

• Cycle failure

 

Intracytoplasmic Sperm Injection (ICSI)

ICSI involves injecting a single motile sperm directly into the cytoplasm of an oocyte, bypassing natural barriers to fertilization. It is especially valuable in cases of severe male factor infertility or azoospermia, where sperm may be retrieved surgically from the epididymis or testes (e.g., TESE). ICSI has revolutionized IVF outcomes for male infertility and is now a standard adjunct to IVF in many centers.