Dr. Sher Blog

Official blog of Dr. Geoffrey Sher

Premature Luteinization (“the premature LH surge): Why it Happens and how it can be Prevented

by Dr. Geoffrey Sher on March 24, 2016

Premature luteinization (“premature LH surge”) occurs when prior to the planned initiation of the hCG trigger, a progressive rise in LH, irreversibly compromises follicle and egg development and maturation. It is not a sporadic isolated event. It comes as a culmination of a series ovarian events, occurring mostly in susceptible women (i.e. usually older women and those with diminished ovarian reserve. It is more likely to occur when the protocol used for ovarian stimulation has failed to maintain LH activity at a low level prior to and throughout the ovarian stimulation process.  Once it occurs in any given stimulation cycle it cannot be switched off by changing the stimulation in progress or by administering GnRH antagonists (e.g. Ganirelix/Cetrotide/Orgalutron) midway in the cycle in the hope that this could rescue the eggs under development. It is my opinion, once premature luteinization commences, the cycle is doomed and outcome is doomed to fail. The condition increases the likelihood of premature ovulation, failed release of eggs during needle-guided egg retrieval (so called “empty follicle syndrome” and the incidence of egg/embryo “incompetence” (chromosomal aneuploidy).

This situation is most commonly seen in older women and in women who have severely diminished ovarian reserve.  In many cases its effect can be prevented through implementation of strategic and individualized protocols for controlled ovarian stimulation (COS) coupled with optimizing the type, timing and dosage of the “hCG trigger shot.”

Normally, following optimal ovarian stimulation, the “trigger shot” is given for the purpose of it initiating meiosis (reproductive division) that is intended to halve the number of chromosomes from 46 to 23 within 32-36 hours. The hCG trigger also enables the egg to signal the “cumulus cells” that bind it firmly to the inner wall of the follicle (through enzymatic activity), to loosen or disperse, so that the egg can detach and readily be captured at egg retrieval (ER).

Older women, and women with diminished ovarian reserve, tend to have more biologically active LH in circulation. LH causes production of male hormone (androgens, predominantly testosterone), by ovarian connective tissue (stroma/theca). A little testosterone is needed for optimal follicle development and for FSH-induced ovogenesis (egg development). Too much LH activity compromises the latter, and eggs so affected are far more likely to be aneuploid following meiosis.

Women with the above mentioned conditions often have increased LH activity and are thus more likely to produce excessive ovarian testosterone. It follows that sustained, premature elevations in LH or premature luteinization (often referred to as a “premature LH surge”) will prejudice egg development. Such compromised eggs are much more likely to end up being complex aneuploid following the administration of the hCG trigger, leading to fruitless attempts at retrieval and the so called “empty follicle syndrome.”

The developing eggs of women who have increased LH activity (older women, and women with diminished ovarian reserve) are inordinately vulnerable to the effects of protracted exposure to LH-induced ovarian testosterone. Because of this, the administration of medications that provoke further pituitary LH release (e.g., clomiphene and Letrozole), drugs that contain LH or hCG (e.g., Menopur), or protocols of ovarian stimulation that provoke increased exposure to the woman’s own pituitary LH (e.g., “flare-agonist protocols”) and the use of “late pituitary blockade” (antagonist) protocols can be prejudicial.

The importance of individualizing COS protocol selection, precision with regard to the dosage and type of hCG trigger used, and the timing of its administration in such cases cannot be overstated. The ideal dosage of urinary-derived hCG (hCG-u) such as Novarel, Pregnyl and Profasi is 10,000U. When recombinant DNA-derived hCG (hCG-r) such as Ovidrel is used, the optimal dosage is 500mcg. A lower dosage of hCG or Ovidrel can, by compromising meiosis, increase the risk of egg aneuploidy, and thus of IVF outcome.

Share this post:

18 comments

Leave A Reply
  • Mark - December 2, 2016 reply

    I read on your site that a risk of clomiphene is that it can cause LH to rise too far at the start of and during ovarian stimulation. What do you refer to by the start of ovarian stimulation in my case? The IVF clinic my 39 year old wife and I attend gave her 50mg of clomiphene from the 3rd day after her period for 10 days, and also gave her 150mg injection of Gonal-F (follitropin alfa for injection) on alternate days 3 or 4 times before ovulation, partly overlapping the clomiphene pills. We do not know what her LH levels were on the 3rd day since her period as the clinic didn’t measure them, but blood tests show that her LH levels about four days before her period were between 4 and 8 (I think the units are mlU/ml). What should her LH levels be on the 3rd day after her period and on the day’s just before ovulation?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 2, 2016 reply

    I would imagine the levels were unaltered befor the clomiphene but after that I imagine they would have risen dramatically.

    Respectfully, in my opinion the type of protocol you were on is not optimal because of the likely impact it would have on LH-induced ovarian testosterone and thus on egg development.

    Geoff Sher

    Mark - December 3, 2016 reply

    Sorry, I made a key typo in my previous mail. I meant to say:
    … blood tests show that her LH levels from four days to two days before Ovulation (not period) ranged between 4 and 8 in each cycle/extraction (I think the units are mlU/ml).
    Are LH levels in this range too high during this time of the cycle? Thank you in advance.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 3, 2016 reply

    Not really!

    Geoff Sher

    Mark - December 13, 2016

    Thank you. Is it safe to assume that her LH was below this level (recorded at four and two days before ovulation) at the time she started the Clomid 50mg course on Day 3 after her period?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 13, 2016

    I cannot say!

    Geoff Sher

    Mark - December 13, 2016

    Sorry; I posted this under the wrong thread: Hopefully this will land in the correct place: What factors could make the LH level a few days after her period (before she took clomid) be equal to or above the LH level on Day 13, or 14 (after 10 days of taking the drug) ?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 13, 2016

    There might, independent of the clomiphene have been high endogenous (self indsuced) LH. This is often seen in women with diminished ovarian reserve (DOR) or polycystic ovarian syndrome (PCOS).

    Geoff Sher

    Mark - December 22, 2016 reply

    Thank you. I am sorry, my earlier question about range was a bit unclear: I should have been more specific: does an LH reading of 7–8mlU/ml at 3.5 days before ovulation count as a premature LH surge?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 23, 2016 reply

    That is not a surge…but in my opinion is on the high side!

    Geoff Sher

    Mark - December 25, 2016

    Is this relative? For example, is LH rising from 4mlU/ml on Day 3 to 7.5mlU/ml at 3.5days before ovulation likely to be worse than LH rising from 5.5mlU/ml on Day 3 to 7.5mlU/ml at 3.5days before ovulation?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 25, 2016

    Not really much difference but the LH of 7.5 is on the high side.

    Geoff Sher

  • Cinthia - October 6, 2016 reply

    Good afternoon doctor, does being with progynova (valerate estradiiol) 3 Days before period and continued 5 days through he period acts like An agonist to prevent fsh rise? I did that in my last cycle to prevent dominant follicle but doesnt work and my ovaries wasnt supressed is that a thing that occurs only to old women?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - October 6, 2016 reply

    It is not fully adequate for that purpose in my opinion.

    Geoff Sher

  • Anna - May 3, 2016 reply

    Dr. Sher, I have been plagued with the issue of premature luteinization ever since I commenced my ivf journey. I have used mostly estrogen priming-antagonistic protocols sometimes with added clomid for the first 5 days of stims. My typical cycle has baseline LH ~4.5, P4~ 0.9. After 4 days of stims, I have seen my LH values at 8, 11 and as high as 18. P4 values at always over 1 throughout stimming with P4 at 2.6 before stimming. Does that, in your opinion, contitute premature surge. To me it seems like it is indeed premature rise in LH and P4. Some of my cycles have resulted in poor fertilization although I do have three day 6 blasts frozen to show from one of these compromised cycles. My RE (who happens to be one among the celebrated REs) refuses to acknowledge the phenomena of premature surge and that it has anything to do with our poor outcomes (since I have FSH that ranges from 10-15) it is easily blamed on my ovaries). But when I do a little looking, the poor outcome associated with this phenmena is all over the internet. I have 3 specific questions regarding this:
    1. What exactly are the LH and P4 values in any stim cycle to call it premature surge levels? What is the exact definition
    2. Why is it not given the importance by even the top of the line REs, when they clearly see poor outcomes associated with it? Is it because it happens in older women where it is hugely convenient to blame the age rather than question the protocol? which bring me to my 3rd question
    3. Is there a fix? A protocol that fixes the premature surge problem? In my case the use of lupron has led to poor quality as compared to antagonists.
    I am a 40 year old trying since I was 30. Me and husband are otherwise healthy individuals with no known issues other than my raised FSH (highest being 15) which has stayed fairly constant all these years. In all my more than 10 years of trying, I have been having this problem and “they” don’t have a clue. Am I being right in accepting that- regardless of her age, there is place for a woman with lowered reserve in the stimulation-IVF world?

    Have you seen success with your conversion protocol in such women?

    Thanks so much for being out on the internet for the likes of us seeking information!!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - May 3, 2016 reply

    1. What exactly are the LH and P4 values in any stim cycle to call it premature surge levels? What is the exact definition

    A: An LH of >4MIU/ml and a progesterone of >2ng/ml would be bothersome

    2. Why is it not given the importance by even the top of the line REs, when they clearly see poor outcomes associated with it? Is it because it happens in older women where it is hugely convenient to blame the age rather than question the protocol? which bring me to my 3rd question

    A: I cannot answer that question, but those that ignore this real issue, will in my opinion, not solve your kind of problem.

    3. Is there a fix? A protocol that fixes the premature surge problem? In my case the use of lupron has led to poor quality as compared to antagonists.

    A: In my opinion, You need a modified, long pituitary down-regulation protocol. I would use an agonist/antagonist conversion protocol with human growth hormone (HGH) augmentation and would suggest (for your consideration) Staggered IVF with embryo banking of PGS (next generation gene sequencing)-normal blastocysts, to make hay while the sun may still be shining.

    Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly

    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    • Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
    • Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
    • Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • Implications of “Empty Follicle Syndrome and “Premature Luteinization”
    • Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
    • The Fundamental Requirements For Achieving Optimal IVF Success

    I invite you to arrange to have a Skype or an in-person consultation with me to discuss your case in detail. If you are interested, please contact Julie Dahan, at:

    Email: Julied@sherivf.com

    OR

    Phone: 702-533-2691

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

    Geoff Sher

  • Dada - April 5, 2016 reply

    Dear dr Sher,
    I find your posts very informative and helpful.
    Here is my situation: I am 44 years old, had one pregnancy 2.5 years ago, but miscarried at 10th week of gestation. Since then I couldn’t achieve pregnancy naturally, nor with IVF treatments.
    My first IVF treatment was so called soft protocol: Clomiphene 50 mg twice a day for 4 days starting on day 3 of cycle + Merional 150 IU for 5 days starting on day 3 + and Orgalutran 0.25 mg for 3 days starting on day 6 (on day 8 of cycle I got only Orgalutran and in the evening Ovitrelle 0.250 mg as a trigger shot). This resulted in 7 follicles, just two eggs, both fertilized and embryos transferred on day 2, but no pregnancy.
    Second treatment was short protocol: Fostimon 3 x 75 IU for 5 days starting on day 2 of cycle, and then Merional 75 IU + Cetrotide 0.25 for the next 2 days. In the evening of day 8 of cycle (day 7 of stimulation!!!), I got Pregnyl 10 000 IU. This resulted in 9 follicles, 6 eggs retrieved, 5 fertilized, 3 embryos transferred on day 3, two vitrified. Again no pregnancy. It appears that my follicles grow rapidly and unevenly – after 5 days of Fostimon there were two 18 mm follicles, the rest were pretty smaller and endometrial thickness was 10 mm.
    Third IVF was also short protocol: Puregon 100 IU + Merional 75 IU for 5 days starting on day 2 of cycle, next 3 days Merional 3 x 75 IU + Orgalutran 0.25 mg, Ovitrelle 0.250 mg was administered next morning (day 9 of stimulation, day 10 of cycle) at 6 am (because of the evening egg retrieval schedule), yet, I got one last Orgalutran shot later that day (after trigger shot!). After 5 days of stimulation endometrial thickness was 10 mm and ultrasound showed 9 follicles – right ovary had 3 x 12-15 mm, 10 mm, 9 mm, and left ovary had 2 x 12-15 mm, 10 mm, 4 mm. On day 8 endometrial thickness was 11.2 mm, and again, two leading follicles reached 20 mm. In the end 5 eggs retrieved, only two fertilized, transferred on day 2, no pregnancy.
    Fourth, and the last one, was long protocol: Microgynon starting on day 5 of cycle, overlapping with Suprefact 0.4 ml starting on day 12 of Microgynon. I took Microginon for 21 days. On day 14 of Suprefact, LH level was 1.06 mlU/ml, and E2 was 7.45 pg/ml. However, my stimulation didn’t start until day 17 of Suprefact, because my RE had to go to some conference, and she said it didn’t matter if it starts 3 days later. So, on day 17 of Suprefact, I started with 2 x Merional 75 IU for the next two days, then 3 x Merional 75 IU for 6 days, and finally on the day 9 of stimulation 2 x Merional 75 IU. E2 was checked on day 6 of stimulation (but blood was drawn before sixth shot) and it was 194 pg/ml, endometrial thicknes was 7.4 mm, right ovary had already 18 mm follicle, and 4 x 12-14 mm, left ovary had 3 x 11 mm. On day 8 endometrial thickness was 12 mm and on day 9 it was 14.4 mm (E2 was not checked!). The biggest follicle was 24 mm and the rest of them (9 follicles total) were 12-18 mm. That evening I had trigger shot (Ovitrelle 0.250 mg). Only 3 eggs retrieved, two fertilized, PGS was done and it showed that both embryos were aneuploid. Biologist said that the cells were multiplying too quick, and that never happened before.
    What puzzles me in this last IVF is low E2 level on day 6 (194), but thick (too thick?) endometrium on day 9 (14mm). In your opinion, did suppression lasted longer than necessary? My LH level was already low after 14 days of Suprefact, could it be that LH component in Merional acted too aggressively? Is that the cause of rapid growth in all four of my IVF’s? I understand that too rapid growth of follicles affects their quality, and that is why I hesitate to try FET with embryos from my second IVF (stimulation took only 7 days, and no PGS was done before freezing) .
    I am well aware of my age, but still feel like every ER was missing the right stimulation protocol for me. There were always “empty follicles”, but after reading your posts I doubt that dosage of trigger shots were sufficient. We changed three clinics, even went abroad (we live in central Europe), but nobody uses your A/ACP approach. Unfortunately, it is virtually impossible for us to come to any of your clinics.
    I have ovulatory cycles 29-32 days with corpus luteum, antral follicle count in spontaneous cycles is higher than before IVF procedures, usually 7 per ovary (prior to 2nd and 3rd IVF I was on Primolut-Nor and 4th included Microgynon). Before pregnancy my AMH was 2.54 ng/ml, now it’s 1.97 ng/ml, FSH 3.4 IU/l, LH 3.3 IU/l, PRL 378 mlU/L Progesterone 1.5 nmol/l, but E2 181.5 pg/ml. My E2 levels were perfect before pregnancy and miscarriage, but then it started to elevate steadily. (Some say it’s the Hashimoto’s that causes Estrogen dominance. After m/c I found out that I have elevated ATPO, but TSH levels were ok till recently (6 months). Now I take Euthyrox 50 mcg a day.).
    I apologize for such an extensive comment/question. I would really appreciate your feedback!
    Thank you!
    Dada

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 5, 2016 reply

    Dear Dada,

    Respectfully, at 44Y, you really should be considering IVF with egg donation preferentially.

    However, if as I suspect is the case, you are not willing to consider OD, then again, very respectfully, In my opinion, the protocols used for stimulation in your case are not ideal. Please read the articles listed below and you will fully understand why I take this position. Remember, the protocol used for ovarian stimulation is pivotal and even more important the older the woman and the amount of ovarian reserve.

    In my opinion, you need a modified, robust, long pituitary down-regulation protocol. I would use an agonist/antagonist conversion protocol with human growth hormone (HGH) augmentation and would recommend Staggered IVF with embryo banking of PGS (next generation gene sequencing)-normal blastocysts, to make hay while the sun still shines.
    Please visit my new Blog at o to http://goo.gl/4hvjoP , find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    • Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
    • Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
    • Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • IVF Failure and Implantation Dysfunction: The Role of Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Why did my IVF Fail
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • How Many Embryos Should be Transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF

    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

    Geoff Sher
    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

    Geoff Sher

Ask a question or post a comment