Table 2 New issues not specifically assessed in the reference guideline [3] and considered potentially relevant from a clinical point of view. These new topics are presented as clinical questions

1.How to diagnose PCOS?

1a.EBR – The diagnosis of PCOS should be based on the presence of at least two of the following three criteria: (a) clinical and/or biochemical hyperandrogenism, (b) polycystic ovarian morphology, and (c) irregular menstrual cycles, after exclusion of other causes of hyperandrogenism and/or irregular menses. ❖❖❖⊕⊕⊕◯

2.Is hysteroscopic assessment needed in infertile patients with PCOS?

2a.CR – Hysteroscopic assessment should not be considered as routinary evaluation for diagnostic work-up in infertile patients with PCOS. ❖

2b.CR - Hysteroscopic assessment should be considered in infertile women with PCOS according to clinical data and ultrasonographic findings in consideration of the higher risk of endometrial premalignant/malignant diseases. ❖❖❖

3.Which are the protocols for administering CC, letrozole, and metformin?

3a.CR - CC should be administrated using an escalation regimen, starting from lowest up to highest doses (from 50 mg to 150 mg daily) for five days, starting in the early proliferative phase (2^nd - 3^rd day of the menstrual cycle). ❖❖❖

3b.CR - Letrozole should be administered in an escalation regimen, starting from lowest to the highest doses (from 2.5 mg to 7.5 mg daily) for five days, starting in the early proliferative phase (2^nd - 3^rd day of the menstrual cycle). ❖❖❖

3c.CR – Metformin is available as immediate- and extended-release formulation:

- immediate-release metformin could be taken at meals, beginning with 500 mg at dinner for 3–4 days, and then increasing by 500 mg every 3–4 days up to a maximal dosage of 2000 mg daily ❖❖

- extended-release metformin (1000 mg) could be taken with the evening meal and a second dose could be added after one week with breakfast up to a maximal dosage of 2000 mg daily. ❖❖

4.How to define CC and letrozole resistance?

4a.PP – CC resistance should be diagnosed when 150 mg daily of CC for 5 days is ineffective to induce ovulation.

4b.PP – Letrozole resistance should be diagnosed when 7.5 mg daily of letrozole for 5 days is ineffective to induce ovulation.

5.How to define CC and letrozole failure?

5a.EBR - CC failure should be diagnosed in case of reproductive failure after 6 ovulatory cycles. ❖❖❖⊕⊕◯◯

5b.PP – Letrozole failure should be diagnosed when reproductive failure occurs after 6 ovulatory cycles.

6.Should oral ovulation induction treatments be started after progesterone withdrawal bleeding?

6a.EBR – After pregnancy exclusion, oral ovulation inductors could be administered without progesterone-induced uterine bleeding. ❖❖⊕◯◯◯

7.Should oral ovulation induction treatments be monitored in women with PCOS?

7a.PP - Ovulation induction treatments with CC with or without metformin should be monitored to minimize the risk of multiple pregnancy.

7b.CR – Ovulation induction with gonadotropin for non-IVF cycles should be strictly monitored to cancel cycles with a multiple follicular growth (more than two follicles) and minimize the risk of multiple pregnancy. ❖❖❖

8.How many ovulatory cycles should be performed before moving on to the next therapeutic step?

8a.PP – Before considering an IUI or IVF program, a total of 6-12 ovulatory cycles should be completed according to clinical context, risks, benefits, costs, timing and patient’s individual preferences. Consider a period of 6 ovulatory cycles for women older than 35 years.

9.How to treat the infertile PCOS patient after failure of the ovulation induction?

9a.PP – Women with PCOS who did not achieve a pregnancy after 12 ovulatory cycles should be considered as patients with unexplained infertility, considering treatment options in relation to clinical context, risks, benefits, costs, timing and patient’s individual preferences.

10.Is it necessary to perform male and tubal factor assessments before ovulation induction in anovulatory women with PCOS?

10a.CR – Semen analysis should be considered before starting ovulation induction treatment in infertile patients with PCOS and anovulation. ❖❖❖

10b.CR – Tubal patency testing should be considered on an individual basis before starting ovulation induction treatment in infertile patients with PCOS and anovulation. ❖❖❖

11.Are there add-on treatments to improve oocyte and endometrial quality in infertile women with PCOS?

11a.EBR – No specific add-on treatments should be considered to improve oocyte and endometrial quality in infertile women with PCOS. ❖❖❖⊕⊕◯◯

12.Could letrozole be administrated in combination with metformin?

12a.EBR – Letrozole could be considered in women with PCOS under metformin administration. ❖❖⊕◯◯◯

13.Should all the PCOS diagnostic criteria be assessed in the PCOS infertile patient?

13a.PP - The assessment of all the diagnostic criteria of PCOS could be beneficial for optimizing counselling and management infertile patients with PCOS. AMH could be useful in infertility setting for driving specific strategies of treatment.

14.Are progestins administration useful for inhibiting the LH surge in women with PCOS undergoing IVF cycles?

14a.EBR – In IVF cycles, where freeze-all protocol (also called “cycle segmentation”) is planned, the administration of progestins could be considered to inhibit the LH surge, potentially reducing the costs. ❖❖⊕◯◯◯