Cycle monitoring in Ovulation induction : Methodology ?

 

Evaluation Cycle- Before initiation of CC/ TNX and more so Gonadotrophins-a through Sonological assessment and endocrine evaluation will be prudent to minimise futile cycles.

 

What information we can gather?? Before initiation of Ov induction one  ideally should perform USG on Cycle day 3-5 of regular or induced menses: Ultrasound is performed to evaluate the 1) endometrium, 2) to determine the number of antral follicles and 3) to rule out ovarian (clear cysts larger than 1 cm, solid or complex cysts of any size).But quite often this golden rule is omitted for financial reason. International agreement for simple ovulation induction –Nil. Some center does it on day 8 of cycle after initiating Letrozole //TMX  .but it is true that   most carry out this basal   scan for Gondo cycles as each cycle is costly.

·      Additionally, endometrial thickness should ideally be  < 6mm because an overtly thick endometrium found on cycle day 3-5 will ordinarily shrink to < 6 mm in 2-4 days. Failure to do so is an indication for further evaluation.

·      Antral follicle counts greater than 8-10 per ovary signify increased probability of triplet or higher-order pregnancy and the need to start with a low dose of Letrozole 2.5 mg/ CC (some considers 25 mg even) or TMX(20 mg instead of 40 mg)  and repeat US before ovulation.

·      If a corpus luteum cyst larger than 1 cm is present, serum progesterone should be measured. Initiating OI when progesterone is > 0. 9 ng/mL will result in fewer preovulatory follicles. If no significant cysts are present, and endometrium is < 6 mm, a single Letrozole 2.5 mg /  50 mg tablet of CC or 20 mg tablet of Tamoxifene (TMX) is taken daily for five days.

·      Couples are advised to have sexual relations every other day beginning on the tenth cycle day.

·      If unable to afford Fol monitoring and couple is young and live in rural areas unable to report to town for USG at regular intervals the how do we know that ovulation has occurred?? They are too illiterate to purchase and interpret LH kit. But , if menses occur within the usual time frame cycle day 26-32-ovulation is assumed to have occurred and the same dose is repeated for two additional cycles.

·      If ovulation does not occur and there are no side effects, the dose is increased by one tablet each succeeding cycle to a maximum of 3 tab of Letrozole (daily 7.5 mg) /  three tablets (150 mg CC, 60 mg TMX). All tablets are taken at the same time each day. But common sense demands that at least second cycle should be monitored may be at subsidy.

·      Side effects of CC are hot flashes (11% of patients) and visual symptoms (2% of patients) .Visual symptoms may be blurring or spots and flashes (scintillating scotomata) but more a theoretical issue . CC and TMX should be discontinued immediately if visual symptoms occur, but can be restarted at a lower dose in the next cycle.

 

Use of preovulation USG to avoid multiple pregnancy and to time timed intercourse (TI) or IUI

·      USG are performed 5-7 days after the last tablet of Letrozole /CC or Tamoxifene (TMX) .

·      If no more than two follicles are ≥ 12 mm and the lead follicle is at least 18 mm, 5,000-10,000 IU of human chorionic gonadotropin (HCG) or 250 μg recombinant HCG (rhCG) may be given for IUI or timed intercourse (TI) 30-36 hours later.

·      If more than two follicles are ≥ 12 mm and age is < 38 years, the cycle is cancelled to avoid triplet or higher order pregnancy. The couple is warned not to have unprotected sexual relations for five days.

Use of LH testing for TI and IUI

·      Patients are instructed to begin LH monitoring on the 10th cycle day using a home LH test kit. When the LH test indicated that ovulation is imminent by a change in color, usually on the 12th or 13th day, the IUI patient notifies the clinic or office and arrangements are made to perform IUI within 24 hours. Alternatively, TI couples should have sexual relations soon after initiation of surge twice daily for 48 hours. To maximize the chance of conception.

Notes regarding the basic protocol

·      Whether to start the third or fifth day is based on the length of the patient’s untreated cycle, with the aim of maintaining a minimum of six days between the last pill and ovulation, in order to negate the antiestrogen effect of CC. thus patients with 28-day cycles are started on the third day and patients with 30-day or longer cycles are started on the fifth day. In case of Letrozole however day 3 start   is all right and seems sensible,

·      Because Tamoxifene (TMX) does not have an antiestrogen effect on cervical mucus or endometrium, it is not necessary to start as early as Letrozole / CC. So, Tamoxifene can be started as late as the seventh day.

·      How safely one can induce withdrawal bleed in sec ameno prior to Ov induction ??   Use Duphaston or Micronized Progesterone in patients who are amenorrheic or have a prolonged time between cycles, it may be necessary to induce menses before starting OI. Inducing menses with oral contraceptive (OC) pills or medroxyprogesterone acetate (MPA) is no longer acceptable due to the possibility of fetal masculinization or birth defect if a patient is pregnant. Unmodified progesterone is effective in inducing menses if the endometrial thickness is 6 mm or greater, and will support rather than harm an early pregnancy.

·      How safely one can induce withdrawal bleed in sec ameno??   Progesterone can also be administered as a single injection of 50-100 mg in oil, as a vaginal gel or as tablets 90-100 mg 1-3 times daily for 7-14 days, or as 200 mg micronized oral tablets 3-4 times  daily for 7-14 days. Menses should occur within 14 days of injection or two days following the last vaginal or oral progesterone.

·      The preovulation LH surge normally occurs by the 16th cycle day, or nine days after the last oral pill (Letrozole/CC/TMX) . If the patient does not detect a change in urine or Cervical   mucus (may be fallacious in CC cycles) within the expected time, the OI drug may have failed A)  to induce follicular development, B)  follicular development may be delayed but be otherwise satisfactory, C)  or the patient may have failed to detect the LH change. Which of these has happened can be determined by performing a pelvic USG and measuring serum LH, estradiol and progesterone if affordable. In some cases IUI is still possible if trying time is > 5 years and they can afford for serum Prog , while in others the information will be used to plan treatment in the next cycle.

·      When IUI is planned, the basic protocol calls for insemination twice, six and eight days after the last pill. When IUI is timed by LH monitoring or HCG administration, only a single IUI is needed.

Unless it is a planned IUI cycle, a postcoital test should be performed during the first CC cycle and should be repeated in subsequent cycles if the CC dose is increased. IUI can be strongly advised if the PCT test is abnormal