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Problem in stimulation

Dear Colleagues

Age 27, G-0
Menses normal until Feb 2013, then no menses till May, and Progesterone withdrawal bleeding is successful.
June menses normal, July very little (spotting) only.

I first saw her on 23/8, and US showed PCO like ovaries (but volume less than 9cc) and thin endometrium. On 1/8 FSH 6.9, LH 5.7, and E2 81pmol.

On 11/9, she had spotting and light bleeding and 13/9 FSH 5.6 LH 2.0 E2 v low <20pg, prolactin 5.9ng, TSH 2.37 mIU/L. She came back a few times for USD but there was no follicular growth. On 26/10, having found her E2 to be 47 pg, and Prog of 0.3, and US showing PCO, I started a course of clomid 50mg for 6 days. It showed some promise, and by 6/11, day 14, the leading follicle was 16mm. I gave her a boost of FSH 75U for two days, and Ovidrel on day 16 (8/11)
15/11 P4 1.0 repeated Ovidrel 500mc.

Then blood tests:

15/11 LH 18.4 HCH 16 P4 1.0
18/11 LH 14.7 HCG 55 P4 2.0
22/11 LH 2.4 HCG 7 P4 1.0

So I am entirely baffled. Its not the HCG, she just simply dont respond!
What shall I do? I am thinking of doin IVF and trigger with agonist, but what do you think is the endocrine problem here?

Thank you

Milton Leong HK

View Answers

Answer by Carlo Bulletti

Anovulatory cycles associated with PCO that does not respond to clomiphene. The abnormal case is mainly due to the dissociation between E2 serum levels in august > 40 pg/ml (82) and the following failure of clomid strategy. I would not surprise in seeing poor responsive endometrium because of low levels Of E2 and the PCO presence. The Leon's perspective for future treatment ( carefull use Of gonadotropin and LH for triggering) is correct, I Was wonder if the BMI Of Leon's patient is adequate , if not I suggest a restore Of adequate BMI under Medical control before to start the above mentioned Medical strategy.

My best regards,
Carlo Bulletti, MD, Italy

Answer by Pedro N Barri

We should evaluate her hormonal levels deeply including AMH, glucose, insulin, androgens. Information on BMI is mandatory
With all these results and assuming that the tubes are patent and the male factor is normal, you will be able to treat this patient with low dose slow FSH protocol.
Just in case of no apropriate response we will propse her an IVF cycle with OCs, GnRH antagonist, FSH stimulation and GnRH agonist triggering
Good luck!
Pedro N Barri,Spain

Answer by Gab Kovacs

I would try and Keep it Short and Simple (KISS) . I cannot explain the transient hCG rise,and I would ignore it, but I guess she is just PCOS with oligo/anovulation. I would give her another cycle of Clomephene citrate at 100 mg, NOT combine it with FSH, maybe even see if she has a spontaneous LH rise, with regular intercourse.
If that does not work- no ovulation - not good folliculogenesis- I would try on clomiphene 150, and if that fails, daily FSH on the usual OI protocol.
Her problem appears to be anovulation, and if you get her ovulating (sperm and tubes permitting) she should not need IVF.

Professor Gab Kovacs

Answer by Johan Smitz

Dear Milton,

Did you check AMH ? I guess it's high.... if yes this is the endocrine problem. Does she have high basal androgens
Maybe you triggered her too quickly with HCG, and she could still have benefitted from her clomid. Obviously she did not luteinise, so perhaps the follicle was not large enough when you triggered.
Let's give her a second chance , monitor with E2 and ultrasound and wait until follicle is somewhat larger (20 mm).
Sometimes the follicle comes up late ... days after stopping the clomid.
I wouldn't put her directly into IVF : she's young still and we have still time here.
In UZBrussels she would be directed towards IVM :-) ! I guess that after IVM aspiration of all follicles she starts to have normal cycles again. With IVM , and with a course of " days of 150 IU HP-HMG , she has a cumulative chance of 28 % to become pregnant from these IVM embryos ( cumulative means : 1 good day3 embryo in fresh cycle, followed by 1 or 2 embryos transferred of warmed vitrified D3 embryos)..... and ZERO risk for OHSS . In contrast : if you use now slow step up FSH protocol, she can also reach 20 % , but at a risk of developing OHSS and multiple pregnancy.
Hope it helps !

Johan Smitz, Belgium

Answer by John Yovich

Dear Milton

The clinical scenario requires consideration of Hypo-hypo-hypo vs PCO

The hormonal profile is clearly PCO with normal gonadotrophins in August including 1:1 ratio LH:FSH; in September this was nearly 3:1, more typical of PCO.

Ultrasound shows PCO pattern (normal volume ovaries) but I would like to see AMH. Without elevated AMH in young woman, the PCO pattern may not be relevant i.e. common incidental feature.

Many young women with underlying PCO ovaries, go through Hypo-hypo period during teens and early twenties; their neuro-endocrinology remains somewhat immature as well as leaving legacy of underdeveloped uterus (<15 sq cm on transverse area or < 25 cc volume on U/S). We have found such cases respond better after 3 months continuous oestrogen therapy e.g. Progynova 2-4mg tds).

In current day, we never use gonadotrophins in ovulation induction in any case with AMH ≥ 20 pm/l (2.8 ng/ml) outside IVF.

For your patient, consider period of pre-estrogenisation.

Then increase Clomid to 50mg bd or use my preferred agent Tamoxifen 20mg bd.

With follicle > 16mm, Trigger with Ovidrel X2 amps (~10,000 Pregnyl) or X3 amps.

Can safely use higher doses of Tamoxifen but all difficult cases best managed in IVF setting where gonadotrophins can be used, developing many follicles and raising E2 levels higher.

From about 20 similar cases I have seen over 37 yrs, I believe the E2 threshold for LH surge and hypothalamic responsiveness needs to be higher than normal.

My former Registrar Adam Balen was studying this phenomenon with Howard Jacobs under the title "attenuation of GnRH', when I was at Bourn-Hallam in 1989-92). I will copy him herewith for his contribution.

John Yovich,
PIVET Medical Centre & Cairns Fertility Centre, Australia

Answer by Dom de Ziegler

An interesting case.
A PCOS who does respond too well despite being young.
Her LH/FSH ratio is <1, suggesting that she entered a low gonadotrpin phase sometimes seen in PCOS.
Her response to CC is insufficient. hCG was picked up in the blood 7 and 10 days later, which is to be expected.
I believe she's likely to respond better to FSH/hMG only. We start them w/ a typical step up protocol, with a start dose of 50IU:day, increasing by 25IU after 7 days of no response.
One question however, what was her AMH level?
I hope it helps
Dom de Ziegler, MD, France

Answer by Seang Lin Tan

Further to Gabor and John Yovich's responses, if those approaches don't work, I'll try modified nat cycle IVF IVM, trigger at 12-14 with hCG 10000 + buserelin 1000 to augment FSH rise as well and OPU 38 hours later with Steiner-Tan needle. I've had similar cases over the years, and IVM often works. Seang Lin
Seang Lin Tan, Canada

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