Ask Our Doctors – Archive
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the doctors.
Hi Dr. Sher, I am doing long lupron which started on cd21, what day of my period would you start stims? Thanks
Ideally ..the sooner the better (Day 1-4).
Geoff Sher
Hi Dr. Sher,
I recently had a natural modified ivf cycle. On egg collection day the follicle measured 24mm, which the consultant said was “a little big.” Anyway they collected the egg, but when the stripped it back they said it was empty and said something about a leak???
Could this bad egg be due to a late trigger?
Respectfully, this wasm likely a luteinized unruptured follicle.
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.
Geoff Sher
Hello Dr. Sher,
I have read many of your articles on DOR and short luteal phase – thank you so much! I have found them very helpful. I am hoping you can give me your thoughts on IVF protocol based on my situation. I am 36, AMH is 1.05, AFC was 7 total at baseline, and FSH is 8 so I have been diagnosed with DOR. I also have a short luteal phase (7-8 days) and we conceived our 2 year old using progesterone after ovulation and until 10 weeks of pregnancy. My husband also has a low morphology of 1%. We decided to start IVF after trying for baby #2 for a year with no success. For my first IVF cycle, I did estrogen priming until my period started then clomid for five days before moving to menopur and gonal-f, before adding cetrotide for 5-6 days. The trigger was HCG and two doses of lupron. I was also on dexamethasone throughout the 12 days of stims. We were happy to retreive 18 eggs but only 10 were mature (all fertilized with ICSI), three made it to blast on day 6 and we have one PGD normal embryo which we will transfer next month. While I am trying to be positive, I am realistic that we may have to do another IVF cycle. I’ve read that you don’t recommend clomid or menopur for DOR protocol. What would you change next time to get more blasts/ higher quality eggs? Do you believe that IVF is the right solution for my situation? I should also note that I was on a prenatal, fish oil, vit D and CoQ10 for two months prior to retrieval. Thank you and best regards.
In my opinion, against the backdrop of age and diminished ovarian reserve (DOR), the protocol used for ovarian stimulation is one of the most important drivers of egg “competence” (quality) and the number, yielded.
Women who (regardless of age) have DOR have a reduced potential for IVF success. Much of this is due to the fact that such women tend to have increased production of LH biological activity which can result in excessive LH-induced ovarian male hormone (predominantly testosterone) production which in turn can have a deleterious effect on egg/embryo “competency”.
While it is presently not possible by any means, to reverse the effect of DOR, certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), can in my opinion, make matters worse. Similarly, the amount/dosage of certain fertility drugs that contain LH/hCG (e.g. Menopur) can have a negative effect on the development of the eggs of older women and those who have DOR and should be limited.I try to avoid using such protocols/regimes (especially) in women with DOR, favoring instead the use of the agonist/antagonist conversion protocol (A/ACP), a modified, long pituitary down-regulation regime, augmented by adding supplementary human growth hormone (HGH). I further recommend that such women be offered access to embryo banking of PGS (next generation gene sequencing/NGS)-selected normal blastocysts, the subsequent selective transfer of which by allowing them to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” could significantly enhance the opportunity to achieve a viable pregnancy
Please visit my new Blog on this very site, https://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
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
• 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.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
• Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• 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?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
• 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 Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally Abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• 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
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
• IVF Egg Donation: A Comprehensive Overview
If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .
Geoffrey Sher MD
___________________________________________________________________
ADDENDUM:
IVF AND DIMINISHED OVARIAN RESERVE (DOR): A RATIONAL BASIS FOR SELECTING THE OPTIMAL PROTOCOL FOR OVARIAN STIMULATION
Geoffrey Sher MD
When it comes to the selection of ovarian stimulation protocols for older women and those who have DOR there is in my opinion, no justification for the use of a “one size fits all” or “recipe approach”. I firmly believe that the time has arrived to reflect seriously on an individualized selection of ovarian stimulation protocols that would optimize egg/embryo quality, rather than simply trying to maximize the total egg yield.
A woman is born with all the eggs she will ever have. The quality as well as the number of eggs in her ovaries (ovarian reserve) usually begins to decline in the mid- 30’s, becoming more pronounced as she ages beyond 35Y. Typically, very few women retain normal fertility by the time they enter their 40s. It is essential to note that there is no known method by which reverse these age-related effects. There is also an inevitable decline in the number of eggs present in the ovaries.
Maturation is a conclusive developmental event, designed to fine tune biological systems so as to optimize function. But optimal maturation cannot take place in a vacuum. Without exception, it requires prior, orderly development of numerous preliminary molecular-biological systems. In the case of the egg, optimal development (ovogenesis) requires a perfect functional interaction of countless intracellular microsystems, all designed to effect and regulate orderly chromosomal segregation during reproductive division (meiosis). It follows that factors that are capable of influencing such preovulatory molecular nuclear-cytoplasmic events, will profoundly influence the ultimate numerical chromosomal integrity of the mature egg, which in turn will largely determine embryo “competency”.
A woman is born with all the eggs she will ever have. After birth, there is a progressive decline in the number of eggs present in her ovaries. Following puberty and the onset of regular ovulation, numerous eggs are used up each cycle. Over time, the woman’s the egg population declines below a theoretical threshold (which probably varies from woman to woman). This is the point beyond which the hypothalamus and pituitary gland, progressively increases its production and output of FSH in a futile attempt to reawaken follicle and egg production. Once this threshold is crossed there occurs a progressive reduction in cyclical ovarian follicle development, manifesting as a reduction in antral follicle count (AFC), a slow but steady rise in basal FSH (>9.0MIU/ml), an increase in the biologic activity (and later in the overall production) of LH and a progressive decline in ovarian production of antimullerian hormone (AMH) below the normal value of 2ng/ml (or 15pmol/L). This reduction in AMH coincides with the onset of diminishing ovarian reserve (DOR). While AFC and basal FS/LH levels are relatively good indicators of ovarian reserve, it is the AMH level that is by far the most reliable. Once the AMH level falls below 1.5 ng/ml (11pmol/l) it suggests that the severity of DOR is significant, to the point that it will likely significantly, adversely affect the yield of follicles and eggs following ovarian stimulation. And, once the AMH falls below 0.5ng/ml (<4pmol/L) the DOR should be regarded as advanced and that total ovarian egg depletion is likely to occur within 6months-3 years.
Physiologically, in response to LH, the connective tissue surrounding ovarian follicles, produces male hormones ( predominantly testosterone) which is conveyed to the granulosa cells that line the inside of follicles where FSH induces enzymatic activity that converts it to estradiol. While a small amount of LH-induced testosterone is essential for orderly follicle and egg development, overexposure to testosterone can be decidedly detrimental leading to dysfunctional follicle and egg development, increasing the likelihood of egg (and thus embryo) aneuploidy and thus, a reduced chance of a successful pregnancy. Typically, women with DOR, older women and those with polycystic ovarian syndrome – (PCOS) have increased LH activity, often leading to exaggerated ovarian testosterone activity which can compromise IVF outcome.
The above serves to clarify why it is my opinion that the use of drugs which increase pituitary LH output (e.g. clomiphene and Letrozole) should preferably be avoided in older women and those who have with DOR/PCOS/older women in such cases, why “flare-agonist (Lupron/Buserelin/Superfact) protocols that dramatically increase pituitary LH release should also be avoided and why the amount of LH/hCG containing drugs (e.g. Menopur) should be curtailed. I hold that women with DOR should preferentially receive robust dosages of FSH-dominant gonadotropins (e.g. Follistim/Gonal-F/Puregon).
Older women and those with DOR often have increased LH-induced ovarian testosterone. The only way to minimize such deleterious influences is to control LH prior to and during the cycle. It follows that the use of low-dosage stimulation protocols (mini-IVF) and natural cycle (NC)- IVF where elevated LH is NOT addressed, are best avoided.
I propose that aggressive, individualized and strategically designed FSH-dominant and LH-regulated protocol for ovarian stimulation should be used in women with DOR. Such stimulated IVF cycles should in my opinion also best augmented with PGS testing of blastocysts, followed by the selective transfer of chromosomally competent (euploid) blastocysts.
.
Hi Dr. Sher-
What are the chances of pregnancy using our only PGS-normal embryo and transferred to a surrogate? We have had repeated implantation failure, DOR, male factor infertility, and alloimmune dysfunction and are leaning towards using a surrogate to increase our chances. Do you think this is wise?
Thanks, Sophia
Hello Dr. Sher,
I have reached out to Tina to schedule a Skype consult and just waiting to hear back. I will be starting my 13th egg Retrevial in October. I really would like a second opinion. I am so scared that my time is almost over at 39 years of age. Thank you.
Jenny Garrison
I will bring this to her attention so we can interact via Skype…soon!
Geoff Sher