PCOS Infertility Treatment: Letrozole, Weight Loss and IVF

PCOS infertility treatment proceeds in steps. Women with polycystic ovary syndrome (PCOS) start on oral ovulation induction with letrozole or clomiphene, usually alongside metformin and weight reduction. If that fails, the next step is gonadotropin injections or laparoscopic ovarian drilling, and only then IVF, which the WHO guideline prefers to expectant management once drug treatment has failed. For overweight women, Dr. Hrishikesh Pai now uses weight-loss medicines before fertility treatment.

Dr. Hrishikesh Pai, Director of Fortis Bloom IVF Centre, described PCOS as simple to recognise and weight loss as central to treating it. This article covers his drug choices, his doses and his approach to obesity, including the newer GLP-1 medicines. The diagnostic thresholds he uses for PCOS are explained in the WHO infertility workup article, and the guideline as a whole in the complete guide to the WHO infertility guidelines.

Recognising PCOS before treating it

Women with PCOS typically do not ovulate regularly. Dr. Pai looks for ovaries carrying many small follicles arranged like a necklace on ultrasound, with an antral follicle count above 15, and an anti-Müllerian hormone (AMH) level above 3.5 ng/mL, which he regards as more accurate than the follicle count. Formal diagnosis under the 2023 international PCOS guideline needs two of three features: irregular ovulation, androgen excess, and polycystic ovaries on ultrasound or a raised AMH. Many women with PCOS are also overweight, which is why weight management runs alongside every other step.

The WHO ladder for PCOS infertility treatment

The guideline sets out an escalating sequence, and Dr. Pai follows it:

1. Oral ovulation induction. Clomiphene citrate or letrozole, combined with metformin, with IUI or timed intercourse, and weight reduction running in parallel.
2. Gonadotropins or laparoscopic ovarian drilling for women who do not conceive with oral drugs.
3. IVF. For women with PCOS in whom drug treatment, including gonadotropins, or laparoscopic drilling has not worked, WHO suggests IVF rather than continued expectant management.

Letrozole or clomiphene? Matching the drug to the ovary

Asked whether letrozole is more effective than clomiphene, Dr. Pai answered that it depends on the patient. He calls clomiphene a "master drug" and uses it widely, but chooses the stimulation drug according to ovarian reserve:

• Hyper-responders (the PCOS pattern): antral follicle count above 15 and AMH above 3.5 ng/mL. He uses letrozole.
• Normal responders: antral follicle count of 7 to 15 and AMH between about 1.5 and 3.5 ng/mL. He uses clomiphene, or clomiphene combined with human menopausal gonadotropin (HMG), and pure HMG for IVF.
• Poor responders: antral follicle count below 7 and AMH below 1.5 ng/mL. He uses clomiphene combined with HMG.

The reason for keeping women with PCOS away from HMG in IUI cycles is safety. Their ovaries respond strongly, and gonadotropins can cause ovarian hyperstimulation syndrome (OHSS), in which the ovaries enlarge and fluid collects in the abdomen. In IVF, the move from gonadotropin-releasing hormone (GnRH) agonist protocols to GnRH antagonist protocols, combined in high responders with a GnRH agonist trigger and freezing of all embryos, has made severe OHSS very rare.

Metformin dose for PCOS and how to build it up

Metformin, an inexpensive and widely available anti-diabetic drug, is one Dr. Pai pairs with ovulation induction in PCOS. His titration:

• Start with one 500 mg tablet, taken after food.
• Once it is tolerated, increase by 500 mg each week.
• Aim for 2,000 mg a day, split between morning and evening, going up to 2,500 mg a day where needed.

Gastrointestinal upset is the main problem with metformin, which is the reason for the gradual increase.

Weight loss and fertility: the factor that changes everything

Body mass index (BMI) is weight in kilograms divided by the square of height in metres. Obesity lowers the chance of conception and reduces success even with IUI or IVF. In Dr. Pai's experience, bringing weight down can raise the success rate by about 5 to 10%. A healthy diet and regular activity come first, but for overweight women his practice now is to prescribe medication.

The three classes of weight-loss medicine

Three generations of drugs have arrived, Dr. Pai explained:

1. GLP-1 (glucagon-like peptide-1) receptor agonists, of which the main example is semaglutide.
2. Combined GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) agonists, of which the example is tirzepatide. From a weight-loss standpoint, he considers it the more effective drug.
3. A triple GLP-1, GIP and glucagon agonist, which was close to release at the time of the session.

These drugs act on the brain and slow the emptying of the stomach, so patients do not feel like eating. Dr. Pai described semaglutide as cardioprotective and protective of the liver and kidneys, and called it a superb drug that he believes is worth using aggressively against obesity.

How semaglutide is given

Semaglutide comes as an injection or as a tablet. The injection starts at 0.25 mg once a week for the first month, after which the dose is increased step by step; the tablet has to be taken every day. Semaglutide has been in use in the United States since its approval in 2017, and general practitioners there prescribe it. In India, Dr. Pai explained, the first consultation has to be with a physician or endocrinologist, although gynaecologists prescribe it in follow-up.

Side effects in proportion

Pancreatitis and sudden loss of vision have been reported, and the labelling carries a warning about a thyroid tumour seen in animal studies, but Dr. Pai stressed that serious effects are very rare; acidity and difficulty eating are the common day-to-day complaints. He dismissed most of what circulates online as misinformation. Excess weight carries its own heavy toll on the heart, kidneys, liver and joints, as well as psychological and urinary problems, and in his judgement the drugs' risks are small by comparison. Every drug, he pointed out, has complications that must be weighed against its benefits.

Cost and access

Price has been the barrier, and it is falling. Dr. Pai put the cost of tirzepatide in the United States at about $1,000 a month, against 15,000 to 20,000 rupees a month in India, roughly one-sixth of the price. At the time of the session in February 2026, semaglutide's market exclusivity in India was due to end in March, and he understood that nearly 11 companies planned to release it in April. He encouraged doctors in Africa to use these medicines where they are available, and even to start obesity clinics. Participating doctors' questions on these drugs are answered in the masterclass Live Discussion.

Stopping semaglutide or tirzepatide before pregnancy

Weight-loss medicines are not used in pregnancy, and women should not conceive while taking them. Dr. Pai's protocol separates the two phases:

1. Use the medicine to bring weight down; some patients lose 40 kg or more.
2. Stop the medicine once the target weight is reached.
3. Start ovarian stimulation within about a month, allowing time for the drug to wash out.
4. Retrieve the eggs, create embryos and freeze them.
5. Transfer the embryos about a month later.

Freezing the embryos and transferring them later widens the interval between the last dose and conception. Product labelling for semaglutide advises stopping it at least two months before a planned pregnancy.

Bariatric surgery for severe obesity

For the small group of women with severe obesity, a BMI above 35, Dr. Pai considers bariatric surgery. He put its cost in India at about $4,000. Patients typically lose around 40 kg, and many then conceive without any fertility treatment. Indicative prices are on the bariatric surgery cost page.

Gonadotropins or ovarian drilling when oral drugs fail

For women with PCOS who do not conceive with letrozole or clomiphene, the guideline offers two routes: gonadotropin injections, or laparoscopic ovarian drilling, in which small punctures are made in the ovary through a laparoscope to restore ovulation.

Dr. Pai uses drilling where a clinician is wary of gonadotropins and their hyperstimulation risk, or where a patient is unlikely to comply with injections and monitoring. The technique has become more conservative: where surgeons once made around 20 punctures, he now makes three or four per ovary. He then leaves the patient alone for six months, because many women conceive spontaneously after drilling. Any fibroids found at the same operation can be removed.

For international patients this fits a short visit. The laparoscopy is done in India, the patient returns home, and if she has not conceived within six months she comes back for IVF.

When to move to IVF

IVF is the final step for PCOS: after oral drugs, gonadotropins or drilling have failed. Women with PCOS respond strongly to stimulation, so the protocol choice matters, which is why Dr. Pai's preference for antagonist protocols is relevant here. Success rates by age, embryo freezing and genetic testing are covered in the treatment pathway from IUI to IVF, and costs on the IVF and fertility treatment cost page. More on women's health across Jivo Healthcare's partner hospitals is collected under obstetrics and gynaecology.