For doctors: ovulation induction without OHSS, from letrozole to knowing when to refer
For doctors: much of OHSS risk is decided by us long before she feels unwell. Confirm the tubes and semen first, prefer letrozole in PCOS, scan every cycle, start gonadotropins low and step up slowly, never trigger with hCG when the response is excessive, freeze rather than transfer fresh in a high responder, and refer on time.
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Who this article is for
A continuing medical education (CME) article for young gynaecologists starting out in fertility practice, written colleague to colleague and first recorded for World IVF Day. In the video Dr Mayur Pai names drugs and gives his practical numbers; this page leaves doses out, because patients read it too. Treat it as a starting framework, not a prescription: the decision belongs to you and the woman in front of you. Patients will find our guides to PCOS and fertility and follicle scans more useful.
What should you check before starting induction?
Confirm that the tubes are open and the semen analysis is adequate. Dr Pai still meets women given months of tablets before anyone checked either.
Why letrozole before clomiphene in PCOS?
Letrozole, an aromatase inhibitor, lowers oestrogen early in the cycle; the pituitary answers with more of her own FSH, and that rise grows the follicle. Accumulating androgens probably also sensitise the follicle to FSH. Either way, it works with her own feedback loop.
Clomiphene blocks oestrogen receptors widely, including at the endometrium and cervical mucus, so some women get a good follicle and a thin lining. Letrozole clears quickly, usually spares the lining and tends to give fewer follicles. In PCOS, trial evidence has favoured letrozole for live birth, and the international guideline now places it first. In several countries this use is off label, so know your own position.
How should you start it, and how closely should you scan?
Start letrozole in the first five days of her period, on day two, three, four or five. If that window has passed, do not start late. Watch the cycle as a natural one, to see whether she ovulates on her own, and begin properly next cycle. Starting late does not rescue a cycle; it only confuses your reading of it.
Induction without a scan is not treatment, it is hoping. Scan at baseline, then track her; if you cannot yet scan yourself, ask your radiology colleagues. If you meant to make one follicle and you are looking at four, that cycle has changed its nature, and so must your plan.
What is the extended letrozole protocol?
Polycystic ovaries hold a large pool of small antral follicles sitting very close to their FSH threshold. Push a little too hard and many wake together; push too gently and nothing happens.
In the extended protocol, you do not stop the tablet after five days. You continue it daily, scanning her, until you see a follicle of 12 to 14 mm, then stop. Let that follicle mature, trigger, and go ahead with timed intercourse or IUI. Her own FSH is lifted gently and held, coaxing one follicle across the threshold rather than a cohort. Be honest about the evidence: the studies are small and this is not settled standard of care.
Dr Pai uses it in PCOS after a standard short course has failed, before injections, because gonadotropins in a young woman with PCOS and a high antral count are exactly where ovarian hyperstimulation syndrome (OHSS) happens: the ovaries swell and fluid leaks into the abdomen and chest. The benefit is not treating OHSS well, but not creating the cycle that causes it.
HMG, urinary FSH or recombinant FSH: does the choice matter?
HMG comes from urine and carries FSH and LH activity, much of the LH-like activity coming from hCG added to standardise the vial. Highly purified urinary FSH is the same source with most of the LH removed. Recombinant FSH is made in cell culture, pure FSH with no LH; its strength is consistency.
In hypogonadotropic hypogonadism she needs LH activity, and FSH alone grows a follicle poorly. Otherwise live-birth differences are small, so cost is a genuine clinical variable: several affordable cycles may serve her better than one she cannot repeat.
While you are finding your feet, stay with the lowest-strength preparations: larger vials and pens make it far too easy to give more than you meant. And do not start gonadotropins in isolation: stay in touch with an IVF specialist and an IVF lab.
How do you run an OHSS-free clinic?
You cannot bring the risk to zero, but a large part of it is decided by us. What not to do:
- Do not start injections where you cannot scan her repeatedly. A two-hour journey or a shared machine rules them out.
- Do not give everyone the same starting dose. Weigh her age, AMH, antral follicle count, weight and past response. The young, lean woman with PCOS and a high antral count is your high responder: say so on day one.
- Do not be impatient. Start low, go up in small steps and give each step time. Dr Pai has more than once traced a severe case to a dose raised too early.
- Do not watch only the lead follicle. Count the small and mid-sized ones and follow the oestradiol trend.
- Do not trigger with hCG when the response is excessive. It lingers for days and keeps driving the leak. In an antagonist protocol (your default in a high responder), you can trigger with a GnRH agonist instead, whose short LH surge clears in hours; then freeze the embryos, with no hCG for luteal support.
- Do not transfer a fresh embryo into a high responder. Freeze everything and transfer later in a calm cycle; pregnancy itself makes hCG.
- Do not proceed with IUI or a timed cycle when too many follicles have grown. Set your cancellation number before the cycle starts and do not move it on the day.
What if the cycle overshoots?
With an IVF lab within reach, an overshot cycle need not be thrown away: convert it to an emergency oocyte retrieval and freeze or fertilise the eggs. That removes the engine of OHSS, and the drugs, injections and leave already spent are not lost. Send every woman home knowing the warning signs: worsening bloating, breathlessness, passing much less urine, rapid weight gain or severe abdominal pain, with a number where a human being answers.
When should you offer laparoscopy and hysteroscopy?
Think of hysteroscopy when the scan or HSG suggests something in the cavity (a polyp, a fibroid bulging into the cavity, a septum or adhesions) and in repeated implantation failure. Think of laparoscopy for suspected endometriosis, adhesions, past pelvic infection or surgery, or doubtful tubes.
When there is a clear indication for either, Dr Pai does both in one sitting with chromopertubation, and treats what he finds, with consent for the operative step taken beforehand. Infertility is one system, and she gets one anaesthetic, one admission and one recovery. But this is indication driven: diagnostic laparoscopy for every woman is not recommended, and for many couples the right answer is IVF rather than an operation.
When should you stop and refer?
Have a ladder with a clock on it: a few cycles of induction with timed intercourse, then two or three cycles of IUI, then refer onward for IVF. Not eventually; then. Years spent on a ninth or tenth cycle of tablets cannot be given back; her eggs age the whole time. Referring on time is not losing a patient; it is the most respectful thing you can do. See also how many IUI cycles before IVF.
About the author
This guide is by Dr Mayur Pai, MBBS, MS (Obstetrics & Gynaecology), a fertility and laparoscopy specialist. He practises at Pai Hospital in Goa, which has its own IVF laboratory, and shares this article colleague to colleague. A companion CME article covers myomectomy.
Colleagues who would like to discuss a cycle or refer a couple can message us on WhatsApp at +91 95185 02773. Consultations are by appointment; to book one for a patient, call reception on +91 95459 20817. Patients: your first online consultation is free (one session). This article is for education only and is not personal medical advice; please consult your doctor about your own situation.
Questions colleagues ask
Why is letrozole preferred to clomiphene in PCOS?
Clomiphene blocks oestrogen receptors at the endometrium and cervical mucus, so some women get a good follicle with a thin lining. Letrozole clears quickly, usually spares the lining and tends to give fewer follicles. In PCOS, trial evidence has favoured it for live birth, and the international guideline places it first.
What is the extended letrozole protocol?
The daily tablet is continued beyond the usual five days, with serial scans, until a follicle of 12 to 14 mm is seen, then stopped; the follicle matures, is triggered, and timed intercourse or IUI follows. The studies are small and it is not settled standard of care.
Why avoid an hCG trigger when the response is excessive?
hCG stays in the body for days and keeps driving the vascular leak of OHSS. In an antagonist protocol, a GnRH agonist trigger gives a short LH surge that clears in hours. Then freeze the embryos, and give no hCG for luteal support.
What can be done when an induction cycle overshoots?
Do not proceed with IUI or timed intercourse. With an IVF lab available, convert the cycle to an emergency oocyte retrieval and freeze or fertilise the eggs. That removes the engine of OHSS and saves the couple's investment in the cycle.
When should ovulation induction stop and IVF be considered?
Have a ladder with a clock on it: a few cycles of induction with timed intercourse, then two or three cycles of IUI, and if she is still not pregnant, refer her for IVF. Do not spend years of her fertility proving a treatment is not working.
Or call +91 95185 02773
This page is for general education and is not personal medical advice. Treatment depends on your own examination and reports, so please speak to a doctor about your situation. We do not carry out or offer sex determination of any kind.