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Difficult stimulation

Dear Colleague, 

I would like some advice with regards to the management of a patient with a difficult problem. Age 28, P0 G0, BMI 18, she never menstruates except in response to the oral contraceptive. Hormone profile TSH and T4 normal, LH 25 iu/l, FSH 8 iu/l, E2 122 pmols/litre, 17 OH Prog 0.9 ngh/ml, prog 0.5 ngm. Above all CD 3, AMH 36 ngm/ml, FAC approx 30 bilateral.

In January 2015 I made a diagnosis of PCOS. In February, I started OH with 75 Gonal F for 9 days. No response, therefore increased to 112 for further 5 days. No response, cycle cancelled. In March 2015, I used Femara 5 mg po daily for 5 days, no response. I then thought that she may need some LH because she may be a patient of hypo/hypo. April 2015, commenced stimulation with 150 iu Pergovaris daily. After 15 days of stimulation, she developed many follicles on both sides, approx 40 on each side. I triggered with Agonist 0.4 ml step to be repeated 12 hours later. Oocyte harvesting performed 36 hours later. All follicles empty on one side and zero oocytes found.

I then thought there may have been a problem with her taking the trigger injection.  I then repeated the Agonist injection as above and scheduled egg harvesting 36 hours later from the contralateral side. Approximately 40 follicles were aspirated with no oocyte found.

In August 2015 I again started COH this time with Menopur 112.5 iu. After 7 days there was no response and I increased the dose to 150 iu. There was an excellent response and on stimulation day 21 there were many mature follicles, possibly 40-50 on each side. I decided to trigger as before with Agonist and aspirated one side only and found no follicles. I then repeated the Agonist trigger with 1500 iu of HCG. I aspirated the other side 36 hours later and found one mature oocyte with 3 GVs out of 25 follicles. She is now back for another cycle and wants to proceed.

I don't know how to proceed and would appreciate some help, my greatest fear here obviously being OHSS.

Thanking you in advance.
Dr. GH Mohamed Sandton Fertility Center Johannesburg

View Answers

Answer by Robert F Casper

Hi all,
I think she needs to be checked for an LHCGR mutation.

Best

Robert F Casper MD
Professor, Division of Reproductive Sciences
University of Toronto
Senior Scientist Lunenfeld-Tanenbaum Research Institute
Scientific Director, TRIO IVF
Medical Director, Insception-Lifebank Cord Blood Bank

Answer by Norbert Gleicher, MD

I cannot make a recommendation without knowing the female's androgen profile. My suspicion is that she is what we now have come to call a hypoandrogenic PCOS. If I am correct, she will not show the typically high teftstosterone levels of a PCOS patient but will show normal or even low testosterone and relatively high SHBG. Should that be confirmed, you will see improvements in her response to stimulation once her testosterone levels increase after DHEA supplementation for 6-8 weeks and her SHBG level has come down.
I would like to know her current free (FT) and total testosterone (TT), DHEA, DHEAS, SHBG, morning cortisol and morning ACTH levels.
Best regards,
Norbert
_____________________________________
Norbert Gleicher, MD
Medical Director and Chief Scientist, The CHR
President, Foundation for Reproductive Medicine
Professor (Adjunct) The Rockefeller University

Further test results

Dear Colleague,
Thank all so much for your valuble input. Here are the results of some tests done which i hope will clarify a difficult problem
Total Testosterone 1.5nmols/l [Ref <1.97]
SHBG 122.60nmols/l  [Ref 11.7-137.2]
Free Testosterone 1.2  [Ref not detected to 10.4]
DHEA 4.19umols/l  [Ref 2.6 -13.9]
Cortisol 303nmols/l  [Ref 101-535 MORNING]
ACTH 12.2pg/ml  [REF <46]
I hope i can get some recommendation on future stimulation protocol..
My own feeling is to stimulate with menopur 112,5 to 150 IU daily , trigger with 250 ugms ovidrell and freeze all.
I have commenced DHEA as recommended by Dr Gleicher
Thank you in anticipation
Dr GH Mohamed, Sandton Fertility Center, Johannesbur South Africa

Answer by Norbert Gleicher, MD

As you can see, androgen and SHBG levels are as I expected them to be: Free T is extremely low, DHEA is also quite low and SHBG is quite high. My prediction is that you hopefully will see the SHBG falling under 80 once the DHEA supplementation takes effect. I would retest her after 6-8 weeks of DHEA. If SHBG has declined, she will be ready for cycle stimulation with her next menses. Please do not stop her DHEA supplementation until she has a positive hCG. We would stimulate her with a short microdose agonist cycle, starting on day-2 of menses. Please do not use anything suppressive on her ovaries; i.e., no OCPs, no long agonists and no antagonists. We recommend that you decide on the gonadotropin dosage based on her AMH/AFC at stimulation start. Please split that dosage between FSH (~66%) and hMG (~ 33%). We also suggest you prime the patient with estradiol for the last 10 days of her preceding luteal phase.
Good luck, and best regards,
Norbert

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