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Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)

by Dr. Geoffrey Sher on November 23, 2015

Ovarian reserve is the term used to describe the extent of a woman’s ovarian egg supply. Diminished ovarian reserve (DOR) refers to a reduction in the total number of eggs left in the ovaries such that resistance builds to ovarian stimulation with fertility drugs. With progressively diminishing ovarian reserve, an ever increasing amount of fertility drugs is required to stimulate optimal follicle and egg development. This reduction in the woman’s egg supply is inevitably accompanied by a progressive egg depletion and when the eggs run out, the woman enters menopause.

The precise point at which the onset of diminishing ovarian reserve can be diagnosed based upon blood tests is inexact. However, it usually coincides with an elevation in basal follicle stimulating hormone (FSH) level (measured on day 2-4 of the menstrual cycle) above >9.0 MIU/ml and an antimullerian hormone (AMH) level of less than 2.0 ng/ml or <15 pmol/L). As the FSH rises above 10 MIU/ml and the AMH drops below 1.0 ng/ml or <8 pmol/l) DOR becomes ever more clinically apparent, and by the time the basal FSH blood level rises above >15 MIU/ml and the blood AMH concentration falls below 0.5 ng/ml or 5 pmol/l, the degree of DOR is likely to be so severe as to render the likelihood of a “fresh” IVF cycle (using own eggs) resulting in a viable pregnancy very low indeed. In such cases, either IVF with egg donation or “staggered IVF” with “embryo banking” of vitrified PGS selected blastocysts should be given preferential consideration (see below).

Causes of Diminished Ovarian Reserve (DOR):  Biochemical evidence of DOR usually first appears about 5-8 years prior to the onset of menopause, which in the vast majority of American women occurs between the age of 40 and 55. When it occurs prior to age 40 it is referred to as “premature menopause.”  DOR occurs because of an age related “wear and tear” which progressively erodes the woman’s ovarian egg supply; It can be hastened in onset by pathologic states such as severe endometriosis and/or chronic pelvic inflammatory disease that directly destroy ovarian tissue or compromise blood flow to the ovaries; post-surgical pelvic scarring and adhesions that strangulate ovarian blood supply can exact a similar toll. Exposure to radiation therapy and/or the use of certain anti-cancer drugs can also destroy ovarian egg bearing tissue resulting in DOR and premature menopause. Finally, genetic/chromosomal factors can sometimes result in the premature onset of DOR and menopause. Presently there is nothing that can be done to slow down or reverse DOR.

The effect of advancing age on egg competency/quality: Advancing age, aside from being responsible for DOR is inevitably and invariably accompanied by progressively declining egg “competency” (quality) which is primarily due a progressive increase in the percentage of eggs that have an irregular number of chromosomes (aneuploidy). Just consider the fact that in women in their early 30’s the incidence of egg aneuploidy is about 50%, but by the time they reach their mid-forties, more than 90% of their eggs will be aneuploid. Aneuploid eggs will, upon fertilization, invariably produce embryos that likewise are aneuploid and thus “incompetent” (incapable of propagating viable, healthy pregnancies). Such aneuploid embryos either arrest during cell division, cause early pregnancy loss, or result in chromosomal birth defects such as Down syndrome.

The role of ovarian male hormones (mainly testosterone) on egg/embryo development and “competency”: A certain concentration of ovarian male hormone (androgens), predominantly testosterone, is absolutely essential for adequate follicle growth and egg development to take place. Complete absence in production of ovarian testosterone will virtually preclude healthy egg production and result in poor quality embryos. Simply stated, some testosterone is necessary for FSH to induce optimal follicle and egg development. However, too much ovarian testosterone can, in my opinion, seriously compromise egg development and increase the likelihood of egg/embryo aneuploidy. There must be a balance.

The importance of controlling ovarian exposure to testosterone during ovarian stimulation: The production of ovarian testosterone is dependent upon the influence of luteinizing hormone (LH) which in turn is primarily derived from pituitary gland production. However, LH can also be found in certain fertility hormones (gonadotropins) such as Menopur and Luveris. Thus in cases where “long”  ovarian down-regulation protocols (that involve the administration of GnRH-agonists such as Lupron/Buserelin or GnRH-antagonists such as Ganirelix/Cetrotide that are capable of completely blocking the production or release of LH) are used, along with purified “recombinant” FSH gonadotropins such as Puregon/Gonal-F/Follistim (which contain virtually no LH), it is  essential to expose the developing follicles to some testosterone by adding LH activity in the form of Menopur, Luveris or hCG supplementation. Alternatively, a small amount of testosterone may be added to the mix. In so doing, follicle and egg development can be optimized and embryo quality enhanced.

To reiterate, in my opinion, it is essential to understand that the presence of too much ovarian testosterone can be harmful to egg development/quality and follicular development. Accordingly, optimal ovarian stimulation requires that a balance be struck when it comes to exposure to LH or supplementary testosterone. This is especially important when it comes to stimulating the ovaries of older women and those with DOR who already tend to have increased biological LH activity and whose follicles and eggs are particularly vulnerable to the damaging influence of excessive male hormones (testosterone). It is for this reason that when it comes to choosing an ovarian stimulation protocol for my IVF patients, I tend to avoid any/all protocols that cause increased pituitary LH production (“Flare” protocols and use of  clomiphene and Letrozole).

How should ovarian stimulation be approached in women with DOR?  Since advancing age adversely impacts both egg quality and ovarian reserve, there is a tendency to lump these two variables (DOR and egg quality) together. This misses a critical point: while in most cases, the two variables are tied with age, there are many instances where a younger woman has DOR, but because of her relative youth, those eggs will not necessarily suffer inherent quality deficit brought about primarily by age. Thus, in contrast with an older woman with the same degree of DOR, a younger counterpart would be better capable of yielding “competent” eggs. This is why I tend to recommend egg donation to older women with severe DOR, while I often advise younger women with DOR to opt for “Staggered IVF” with selective “embryo banking” of PGS-selected blastocysts.

What about mini-IVF or Natural Cycle IVF for women with DOR? It is quite understandable that many women with DOR are easily persuaded that less (or no) ovarian stimulation offers a more “natural” and less “stressful” approach on eggs than a robust, high gonadotropin-based, long-pituitary down regulation approach. This, in my opinion is a fallacy and can compromise rather than benefit IVF outcome in such cases.  Even in young women in their early or mid-30’s, the IVF success rate per fresh “natural” or “mini”  IVF cycle is much lower (<15%)  than that which can be achieved through the use of conventional long down-regulation protocols, where the anticipated success is at least double this rate (30%). Mini-IVF is usually conducted using clomiphene or Femara, alone or in combination with Menopur, all of which is associated with the production of excessive LH-induced ovarian testosterone. Furthermore, low dosage stimulation will result in fewer eggs being available, thus further reducing the odds of IVF success per egg retrieval conducted. Natural cycle IVF is in my opinion also not in the best interest of women with DOR, because with such an approach, nothing is done to control the exaggerated production of LH by the woman’s own pituitary gland.

Augmenting ovarian response to gonadotropins in women with DOR:

  1. There is data to suggest that selective administration of human growth hormone (HGH) to women with DOR and possibly those with egg quality issues, could benefit egg development and maturation by augmenting mitochondrial energy generation that drives DNA synthesis. While the high cost of HGH can be a burden for most women, it is certainly well worth considering in certain cases.
  2. Estrogen priming before the onset of and during ovarian stimulation is another approach that was pioneered at SIRM. We reported on a distinct benefit using this approach in women with severely diminished ovarian reserve. Estrogen is believed to prime FSH receptors in the follicle granulosa cells and thereby might enhance response to ovarian stimulation.
  3. Anecdotal evidence suggests that certain nutritional supplements, such as folic acid and antioxidants (especially Coenzyme Q) enhance egg development and maturation. While more data is needed to support this contention, it is also true that such supplements do no harm whatsoever. Also they are low cost, so there is really no harm using them.
  4.  DHEA has been touted as being capable of enhancing egg quality and ovarian response. However, there is no convincing evidence of any such benefit in my opinion. Besides, DHEA is readily metabolized to testosterone in the ovaries and as stated, many older women and those with DOR are more vulnerable to over-exposure to ovarian testosterone, I believe that the indiscriminate use of DHEA in such cases can be potentially harmful to such women.
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  • Dr. Geoffrey Sher

    Dr. Geoffrey Sher - February 4, 2017 reply

    Hi Smini,

    I would need much more information to comment authoritatively,

    Might I suggest that you call or email Julie Dahan, my patient concierge. She could guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
    Julie Dahan
    • Email: Julied@sherivf.com
    • Phone: 702-533-2691
     800-780-7437

    Geoff Sher

    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.

  • JS - October 17, 2016 reply

    Hi Dr. Sher,
    I hope you’re well. I am 39, have low AMH (.15-.2) since first being tested at age 37, have had 3 failed IUI cycles, and 1 canceled IVF cycle due to only one small follicle (15mm, L ovary tends to be most productive). Canceled IVF cycle included BCP/androderm patches prior to 375-400u Follistim, Menopur, with HGH. During those 4 cycles, my best response was 3 small follicles during an IUI cycle, largest one measuring 18mm. Acupuncture initially with my first 3 IUI cycles. My husband is 45 and has relatively healthy sperm (8-10million, some low motility). 5 months ago I had a robotic myomectomy to remove a subserosal fibroid, an endometrioma from my right ovary, and a few spots of mild endometriosis were found and cleaned. This past month, an US showed 6 follicles on both L and R ovaries and we once again tried naturally. This month, I took Clomid and only had 1 large (15mm on day 13) follicle and a few small ones. Normal HSG, small cervical opening. In order to get to retrieval for an IVF cycle, I need to have at least 3 large follicles. I’d like to at least get to retrieval so we can know more about my egg quality. What would you suggest? I’ve also had mild UC since age 30, so I wonder about immune issues as well. Have you successfully treated anyone with similar issues?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - October 17, 2016 reply

    The older a woman becomes, the more likely it is that her eggs will be chromosomally/genetically “incompetent” (not have the potential upon being fertilized and transferred, to result in a viable pregnancy). That is why, the likelihood of failure to conceive, miscarrying and of giving birth to a chromosomally defective child (e.g. with Down Syndrome) increases with the woman’s advancing age. In addition, as women age beyond 35Y there is commonly a progressive diminution in the number of eggs left in the ovaries, i.e. diminished ovarian reserve (DOR). So it is that older women as well as those 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 age-related effect on the woman’s “biological clock, certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), can 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 older women and those 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 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, 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
    • 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
    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
    800-780-7437

    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.

  • Stephanie - April 13, 2016 reply

    Hello!
    I hope this question finds you well! My husband and I are entering another fertility journey. We have a 4 year old daughter (conceived naturally our first month off birth control) and a one year old son (conceived through IVF using the estrogen priming protocol at SHER St. Louis). We would absolutely love to add a third child to our family. Recently my blood test were run again and I fall in the category of DOR. I am 33 years old, have only one ovary (I lost my L ovary and tube secondary to ovarian torsion 12 years ago) and my AMH is .6, FSH 11.6. Do you recommend using DHEA or proceeding with IVF treatment. I am trying to be hopeful because IVF was successful for us last time, but also want to be realistic about our prognosis. Lastly, can having only one ovary skew my AMH/FSH numbers? Thank you for your time. I truly appreciate it.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 13, 2016 reply

    Hi Stephanie!

    Congratulations. The doctors at SIRM-St Louis are outstanding. I worked there with Dr Molina Dayal and loved it. She is highly talented/competent and a real class act.

    I would not use DHEA. It converts to testosterone in the ovaries and too much ovarian testosterone is not good for theeggs/embryos.

    Good luck and G-d bless!

    Geoff Sher

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