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Endometriosis Presenting as “Unexplained Infertility”

by Dr. Geoffrey Sher on August 17, 2018

Background: “Jamie” consulted with me when she was 34 years of age, after 3 years of failed treatment and a diagnosis of “unexplained infertility.” A laparoscopy had revealed her to have mild (Stage 1) endometriosis, which was ablated at the time of surgery. She had undergone 3 IUI procedures, using clomiphene citrate in the first two procedures and Letrozole in the last one. In all cases she developed between 5-8 follicles and triggered with 10,000 units of hCG. Ovulation occurred uniformly throughout, but she failed to conceive. She then moved on to In Vitro Fertilization (still with her previous clinic), and over the course of 18 months, she underwent 3 failed IVF attempts. In each case she was stimulated with a modest, long pituitary down-regulation protocol involving the use of birth control pills, overlapped with an agonist (Lupron). Between 12 and 16 oocytes were recovered at egg retrieval, and following ICSI, she consistently produced between 2 and 5 blastocysts. Embryo transfers involving 2-3 blastocysts failed to achieve a pregnancy.

Our Treatment Approach: We performed immunologic testing on this patient and found her to have activated Natural Killer cells (NKa) by the K562 target cell test, as well as antiphospholipid antibodies (APA). We made a diagnosis of autoimmune implantation dysfunction and scheduled the patient for a frozen embryo transfer (FET) with her residual cryobanked blastocysts. We prepared her with twice-weekly injections of Delestrogen (6 mg) combined with 0.75 mg dexamethasone daily, and 30 mg Lovenox daily starting at the onset of her cycle.

Approximately 10 days prior to the anticipated FET she received an Intralipid (IL) infusion. At ET, we transferred 3 thawed blastocysts. Eight days later, her first beta hCG was 45, and 2 days afterward it had risen to 160. She thereupon received a second and final intralipid infusion. A subsequent ultrasound examination 3 weeks later revealed a healthy set of twins. She was weaned off the dexamethasone at 10 weeks gestation. The patient went on to give birth to healthy twins.

Commentary: This patient’s infertility was really not “unexplainable” it was simply undiagnosed. Clearly there was not an underlying egg/embryo issue at all. The reason she failed to conceive on her own (in spite of spontaneous and regular ovulation) and following IUI was almost certainly due to the fact that all women with endometriosis (regardless of severity) have an underlying toxic peritoneal factor that compromises fertilization as the eggs pass from the ovary (ies) to the sperm waiting in the fallopian tube(s).This reduces fertilization potential and therefore compromises fecundity. This toxic peritoneal factor is present in 100% of women with this condition and explains why the chance of having a baby is reduced 4-6 fold in women with even the mildest of endometriosis. Since the visual endometriotic deposits represent just a small percentage of those that are in the process of developing, neither surgery to remove such lesions nor fertility drugs with or without IUI will likely significantly improve the baby rate per cycle (fecundity).

Furthermore, there was the issue of an immunologic implantation dysfunction (IID) as evidenced by NK cell activation and antiphospholipid antibodies. IID occurs in about 30% of women who have endometriosis, and when it is associated with NK cell activation, the chance of a successful pregnancy is very low. When we administered intralipid, heparin (Lovenox) and steroids (dexamethasone), down-regulated the activated uterine NK cells, and counteracted the influence of antiphospholipid antibodies, the patient readily conceived following FET.

The lesson, in this case, is that all women with endometriosis have diminished fecundity because of the consistent presence of a toxic pelvic environment that cannot be resolved through surgery or medical manipulation. Only IVF, by transferring the embryo directly to the uterus, can bypass this problem.

I do not mean to imply that all women with endometriosis will require IVF. In fact, for younger women who have associated ovulation dysfunction (which is not uncommon in women with endometriosis), fertility drugs can be tried. However, this will only deal with the ovulation dysfunction, but will not address the toxic peritoneal factor. Simply stated, women with mild to moderate endometriosis that conceive following the use of fertility drugs (with or without IUI), usually achieve this in spite of, rather than due to, such treatment. Ultimately, only IVF (which consistently bypasses the toxic pelvic environment), will address this problem.

Since 1/3 of women with endometriosis will have an IID which will prevent implantation, even IVF will fail unless this problem is dealt with through down-regulation of NK cell activity and treatment of often associated anti-phospholipid antibodies (as was done in this case).

In summary, normally ovulating women with endometriosis-associated infertility who are under the age of 35 years, should consider timed intercourse (using home ovulation testing).If this fails to result in a pregnancy, IVF will in all likelihood be required. For women who do not ovulate normally, fertility drugs can be used to correct this problem, but when such treatment is implemented, it must be done with the full understanding that ovulation induction will not reverse the toxic peritoneal effect. Ultimately, IVF might still be needed.

For women over the age of 35 and those with diminished ovarian reserve (cases where time is of the essence), IVF treatment should, in my opinion, be the first line of attack.

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  • Sofia Matos - August 18, 2018 reply

    Dear Dr. Sher,

    Firstly I would like to thank you for the help you are giving to infertile couples via this blog. I will be exceptionally honored to receive your reply.

    I’m 34, trying to conceive for 2 years without success. I don’t have any children and I’m afraid I never will. These have been the most difficult times of my life.

    This year I was diagnosed with DOR (AFC 3-4), extensive recto-vaginal endometriosis (even though I don’t have any pain) and Adenomyosis (the anterior wall of the uterus is larger – JZ is 12mm). The ovaries seem to be Ok, but they are smaller than usual. I will undergo a laparoscopy in September to remove the endometriosis and attempt to conceive again. I am taking levothyroxine to correct a slight hypothyroidism (TSH usually around 3.5). My blood tests:
    TSH: 1.553, AMH: 0.97, FSH: 10.81, LH: 8.03, CA-125: 9, Anti-TPO: 31, Anti-TG: 20, Ferritin: 33, Rheumatoid Factor: 9, Anti-Cardiolipin IgG: 0.9, Anti-Cardiolipin IgM: 1.5, Vitamin D: 76.7 ng/ml, DHEA-S: 68 ug/dL, Total Testosterone: 21, ANA: 1/80, C-Reactive Protein: 0.09

    DHEA and Testosterone seem to be low for my age.

    I have done a lot of research in the past year and I have more doubts than certainties. I selected a few questions that I hope you can help me with:
    1- What do you think is the primary reason why I’m not getting pregnant? DOR, Endometriosis or Adenomyosis?
    2- Do you think I should spend some time trying naturally after the laparoscopy or should I move to IVF immediately?
    3- Is it expectable that the oocyte quality will improve after the laparoscopy?
    4- Should I be worried with my Adenomyosis? I have read that JZ is higher than 10mm implies a very low probability of implantation: https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/aogs.13158
    5- I am considering supplementing with Ubiquinol (100mg/d), Pycnogenol (100mg/d), DHEA (75 mg/d), Resveratrol (100 or 200mg/d) and Melatonin (3mg/d for IVF); which ones do you think are beneficial and which ones may be counterproductive?
    6- In particular, I find it intriguing that CHR recommends DHEA for DOR and you argue that DHEA/Testosterone has a detrimental effect; how can this be so black and white?
    7- Can DHEA further fuel my Adenomyosis?
    8- What is in your opinion the best IVF protocol for me? My doctor seems to favor the Antagonist (Elonva + Menopur) because he thinks the ovaries may not respond to stimulation if we use the long Agonist protocol, but I read that it is bad for Endometriosis (https://www.ncbi.nlm.nih.gov/pubmed/28970135) and really bad for Adenomyosis (https://europepmc.org/abstract/med/25736122), and from the discussions in your blog I believe you don’t like Menopur for DOR either; I met a previous patient of my doctor that had exactly the same problems as I do and this protocol failed the first time (2 poor quality oocytes) and the 2nd time after supplementation with DHEA and Ubiquinol there were 2 good quality oocytes that yielded a grade A embryo but it didn’t implant;
    9- In this paper regarding Adenomyosis https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/aogs.13158 the authors recommend the following: “In women with diminished ovarian reserve, immediate IVF or ICSI with long protocol or oocyte retrieval can be followed by frozen embryo transfer after GnRH‐a treatment is performed.”; do you agree?

    Thank you so much for your time and help.

    Sofia

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - August 19, 2018 reply

    These are all issues that require lengthy responses..that cannot be appropriately addressed here. We need to talk…see below.

    Women who (regardless of age) have diminished ovarian reserve (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, 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.

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