The mathematics of oogensis & how to maximize the sucess of IUI

NORMAL   OOGENESIS. & Tips on improving success in IUI ??

a)              Follicles can be imaged when follicular dia becomes 2-3 mm and not lesser diameter can be imaged.  A dominat follicle is noticeable by Day 8-12, speed of growth of follicle is 2mm /day.  E2 levels at ovulation are usually 150-400 pg/ml.

b)             Shape of the follicle: - Type A follicle: - Mostly in the shape of a cone and tip of cone points to O-C complex. Type B follicle—echo free space around the follicle. and become artistic

c)                Fluid in OD may be present prior to Ovulation due to transudation

: How we can optimize the effectiveness and safety of OI with oral drugs more so if IUI is contemplated.

Tips on IUI: -Q.1.  To modify the starting day of Ov induction as per day 3 estradiol and progesterone levels. Not to day of initiation of CC/Letrozole/ Tamoxifene (TMX)   by menstrual day alone as we commonly do but reliance should be made more on day 3 estradiol and progesterone levels.

 Q.2.-Be flexible on strength (weight) f the starting dose:-Not to be under the preformed idea of starting dose of CC (100 mg)/Letroz (2.5 mg) or HMG of 75 IU, - Instead   time has come when we should assess the initial dose by body weight.

 Issue 3:- If  midluteal progesterone level, preovulatory follicular and endometrial response are monitored by ultrasound and drugs, then one may add Arginine, oestrogen , hMG or any  other agents may  be added / supplemented .

d) Timing of IUI:-When to schedule the process of IUI?? When preovulatory ultrasound and estradiol level indicate that follicle development is sufficiently advanced . Additionally, the day and time of IUI or timed intercourse can be regulated to fit patient and clinic schedules

e) Timing of Trigger –when??

By triggering ovulation with HCG when the preovulatory ultrasound and estradiol level indicate that follicle development is sufficiently advanced.

  Issue 1. :_Use of estradiol and progesterone levels to choose the starting day : To initiate  stimulating only when serum estradiol levels ≥ 50 pg/mL  in cases of CC/Let & Only when serum Prog is > 0.9 ng/ml.

 Firstly, CC and TMX require serum estradiol levels ≥ 50 pg/mL to be effective.

Secondly, ipsilateral follicle development is inhibited when the serum progesterone level is ≥ 0.9 ng/mL.  Initiating OI with CC or TMX before these levels are attained will result in no or reduced follicle development.

Thirdly, In PCOS or persistent corpus luteum cysts there will be delay to return to achieve such low hormonal profile enabling one to initiate CC/Letroz. Though such an thought process seems irrational in day to day clinic practice but in IUI cycles it will be wise to adhere to such dictum before asking her to initiate the CC/Letroz tablets. So in PCO by and large, one should preferably initiate letroz/ CC a bit later in the cycle .If arbitrary i.e. one avoids estimation of E2 & Progesterone then a day 5 start will be most rational approach & helpful. Though few PCO will achieve such criteria and  such optimum levels for initiation on the third menstrual cycle day, but may PCO subfertile women require seven days or longer in patients with PCOS or persistent corpus luteum cysts.

Fifthly:-Back to physiology:-If say on day 3 serum Progesterone  is 1.8 ng /ml –then should we go on estimating P levels daily on day 4/day 5 to assess the exact day when P comes down to 0.9 ng/ ml only and  then start initiating CC/Letroz? Ans: No such practice of daily blood testing is not feasible, advisable or neither affordable:-Instead one can  rely more on the formula which states that Serum estradiol levels normally double every two days, and progesterone levels normally decrease 50% per day during the early follicular phase of the cycle. Therefore it is needless to get Serum P & E2 rechecked unless they would require more than three days reaching the level required to start.

Therefore, delaying the start of Letrozole / CC or TMX until hormone levels are in the desired range will increase the chance of successful stimulation.

 Issue 2:-Use of body weight to select the initial dose of CC or TMX: - Do we do it in our day to day practice?

The dose of CC and by inference TMX, necessary to induce ovulation is proportional to body weight. A starting dose of 100 mg CC or 60 mg TMX is recommended for patients who weigh > 75kg. By contrast, a starting dose of 25 mg CC or 10-20 mg TMX is recommended for women who weigh < 45kg. Women with other weights should be started on 50 mg CC or 20-40 mg TMX.

 Issue  3:-- Routine progesterone suppl or selective Prog suppl if warranted. There is one school who routine supplement Vaginal Prog after IUI procedure assuming LPD . There is another group who feel that if serum P is less on day 18  then only P suppl will be sufficient .  If routine P suppl is advocated then she may be after IUI with an instruction to report after the onset of period in case this cycle appears futile :

Another group insist Prog suppl on demand: Such women are asked to report on day 18 of period and asses P level and supplement P. : This group claim that they can  prescribe Vag P with confidence after diagnosing LPD no matter how costly   and how repeated clinic visit is!!  Use of mid-luteal progesterone to select the dose of CC or TMX

A)             What is the optimum level of progesterone for successful outcome??  :-Progesterone levels in the mid-luteal phase of CC cycles that result in term pregnancies averages 37 ng/mL, compared to 22 ng/mL in spontaneous cycles. .Progesterone levels in the mid-luteal phase, 5-7 days after ovulation, that are less than 18 ng/mL are evidence of possible luteal insufficiency. Levels less than 15 ng/mL are rarely associated with ongoing pregnancy.

B)             In next cycle we should increase the dose of CC/Letroz to improve Follicular stage & thereby correct LPD as was evidenced in previous cycle.:-When progesterone levels are less than 18 ng/mL following CC in midluteal phase then oral or vaginal supplementation should be considered in the current cycle, and the dose of CC or TMX should be increased in 50 mg and 20 mg increments respectively in subsequent cycles until progesterone levels are ≥ 18 ng/mL.

  Issue 4:- To cut your cloth according to measurements of Coat: The effect of increasing the dose of CC or additional days of treatment ?  Any adverse effect ?

Increasing the dose of CC from 50 mg in the first cycle to 100 mg in the next cycle results in minimal increases in average number of small, medium and large follicles (≥ 12 mm follicles  from 2.4 to 2.6, ≥ 15 mm follicles from 1.7 to 1.9, ≥ 18 mm follicles from 1.2 to 1.3).

Extending the number of days that 50 mg of CC is taken to 8 or 10 days has been shown to result in ovulation in patients who did not respond to 200 or 250 mg CC for five days in a small series. The benefit of increasing the dose of CC or number of days CC is taken must be balanced against the possibility of increased antiestrogen effect on the endometrium and cervical mucus.

 The effects of increasing the dose of TMX or extending the length of TMX treatment have not been reported, but they would not be expected to have an adverse effect on endometrium or cervical mucus. When additional numbers of follicles are desired, increasing the dose of CC or TMX will have little effect compared to adding or substituting gonadotropins.

  Issue 5:- How useful is Use of preovulation ultrasound (USG) to predict ovulation and multiple pregnancies?

Preovulatory USG performed 5-7 days after the last CC or TMX allows the ovulation day to be predicted for timed IUI or intercourse, and the number of preovulatory follicles to be assessed in order to cancel cycles if an excessive number of preovulatory follicles are present.

   In CC and TMX cycles the lead follicle is usually 18-20 mm in diameter on the day of spontaneous LH surge and 20-24 mm on the day of ovulation. The dominant follicle and others destined to ovulate ordinarily increase at a rate of 2 mm per day from cycle day 10 until ovulation.

Prediction of spont LH surge –How?? The size of the leading follicle on cycle day 12-14 can be used to predict when a spontaneous LH surge and ovulation will occur. If predicted to occur at an inconvenient time for performing IUI, ovulation can be induced by HCG (5,000 or 10,000 IU) or rhCG 250 mg if the lead follicle is at least 16 mm and estradiol concentration is consistent with the number of follicles. The serum estradiol level should be 180-250 pg/mL per mature follicle.

   Issue 6:- How best to avoid multiple pregnancies? The possibility of multiple pregnancies can be estimated from the number of follicles expected to be ≥ 10-12 mm on the day of spontaneous LH surge or HCG injection. This allows sufficient time to prescribe intercourse or cancel IUI if there is risk of triplet and higher-order multiple pregnancies or a desire to avoid a twin pregnancy.  

How best to guess that the CC cycle is going to be effective?? The probability of any pregnancy in CC cycles is most closely related to the number of follicles ≥ 15 mm, rather than or smaller or larger sizes. Multiple pregnancy rates in CC and TMX cycles are most closely related to the number of follicles ≥ 12 mm on the day of spontaneous LH surge or HCG injection, but follicles as small as 10 mm on the day of HCG can result in pregnancy . Pregnancy rates do not increase appreciably when there are more than four follicles ≥ 15 mm in CC cycles .

Use of preovulatory ultrasound (US) to evaluate endometrial receptivity

Preovulatory US enable evaluation of endometrial receptivity by measurement of endometrial thickness and observation of the endometrial pattern. Ideally, endometrial thickness will be ≥ 9 mm, and endometrial pattern will be triple line on the day of LH surge or HCG injection . If the endometrial thickness is < 9 mm on preovulation ultrasound, administration of HCG should be delayed. If the LH surge has already started, vaginal estrogen (2 mg micronized estradiol tablets or the equivalent twice daily), or oral estrogen (2 mg micronized estradiol tablets or the equivalent four times daily), can be used provided that hCG is given to induce ovulation, lest the estrogen suppresses the LH surge, whether adding estrogen increases endometrial thickness is unproven. Thickness normally increases at a rapid rate in the late proliferative phase of CC cycles as the endometrium escapes the antiestrogen effect of CC, and eventually equals or surpasses thickness in spontaneous cycles . In subsequent cycles endometrial thickness may be improved by using a lower dose of CC, by switching to TMX, or by taking oral or vaginal estrogen (2 mg daily) concurrently with and following CC.

Use of serum LH monitoring to predict ovulation day ?

If a baseline LH has been measured at the start of the cycle, a repeat LH measurement on cycle day 12-14 will provide an indication of how soon spontaneous ovulation will occur. Ovulation normally occurs within 24 hours from the time that LH levels are twice the baseline level. A smaller increase above baseline level indicates the beginning of the LH surge and ovulation in 36 hours. A sharp dip in serum LH is often seen one day before the start of LH surge and ovulation in 36 hours. A sharp dip in serum LH is often seen one day before the start of LH surge. In PCOS patients, LH levels are often ≥ 20 mIU/mL during the early follicular phase but decrease to < 10 mIU/mL one or two days before ovulation and rise again at the beginning of the LH surge. Repeated LH determinations combined with US and estradiol levels may be needed to determine when the LH surge starts in PCOS patient if one likes to achieve maximum success in IUI..

Use of human chorionic gonadotropin (HCG) or recombinant  HCG (rhCG)

Use of HCG or rhCG in CC and TMX cycles is seldom necessary to induce ovulation. But this in  CC and TMX cycles may be beneficial for planning time most convenient for IUI or TI. Use of HCG or rhCG does not increase the incidence of multiple pregnancies