Case Report: Woman with Diminished Ovarian Reserve (DOR) and Age-related Secondary Infertility whose Husband has Autoimmune Infertility Following Vasectomy Reversal

Juanita, a 42y old who, between 2003 and 2007, had delivered 3 children in a prior relationship. Carlos, her new partner of 3 years, had 3 children through spontaneous conception, in a prior relationship. He had undergone vasectomy in 2004 and had a surgical reversal performed in 2015. Although he was never tested for antisperm antibodies, Carlos’s 70%-80% sperm agglutination suggests that he had such. Clearly the only treatment for the latter is IVF/ICSI. Juanita was found to have an antimullerian hormone (AMH) blood level if 0.28ng/ml (i.e. severely diminished ovarian reserve-DOR). Given Carlos’s severe male factor, Juanita’s age and her DOR, it became self-evident that IVF with intracytoplasmic sperm injection (ICSI) was required ASAP.

After seven (7) ovarian stimulations with 6 egg retrievals and Preimplantation Genetic Testing (PGT), no chromosomally normal (euploid/” competent”) blastocysts were propagated. There were however, 4 aneuploid blastocysts, each of which had a single autosomal chromosomal defect (autosomal monosomy and autosomal trisomy). In such cases the potential exists for such embryos to harbor a combination of both normal cells alongside abnormal one’s. Such embryos are termed “mosaic”. Some “mosaic” embryos autocorrect in-utero and go on to propagate healthy babies. Thus, the couple elected to have all 4 “potentially mosaic” blastocysts transferred to Juanita’s uterus. Juanita conceived but sadly produced an empty gestational sac (blighted ovum).

A.Diminished Ovarian Reserve older women and those with DOR:

Although the poor-quality eggs/embryos propagated by Juanita could be explained on the basis of her advanced age and her DOR alone, it is my opinion, that the protocols used for ovarian stimulation were not optimal. I believe it to be suboptimal to use clomiphene alone, or in combination with gonadotropins for IVF in older women and those who (regardless of age, have DOR. The use of clomiphene increases pituitary LH production/release which in turn significantly induces excessive ovarian male hormone (predominantly testosterone) production. While some testosterone is needed for follicle/egg development, it is my opinion that too much ovarian testosterone compromises egg quality and increases the occurrence of egg numerical chromosomal aberrations (aneuploidy). And, aneuploid eggs will invariably propagate aneuploid (incompetent) embryos. For this reason, I never recommend clomiphene to older women and those with DOR who are inordinately at risk of producing aneuploid eggs.  You see, 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. 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  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.

B.A recommended stimulation protocol:

“Going forward, unless Juanita and Carlos wish to consider switching to IVF with egg donation, I recommend a change in their protocol for ovarian stimulation protocol to a robust Agonist/antagonist Conversion Protocol (A/ACP) with Human Growth Hormone (HGH) augmentation and Banking of euploid blastocysts for future dispensation.”  

 

Treatment commences on day 1-5 of a selected menstrual cycle, with a pack of monophasic (balanced) birth control pills-BCP (e.g. Orthonovum 1/35, Desogen, Marvelon, Lo-Estrin or Lo-Ovral). The duration of time on the BCP is not that relevant (provided that it is used as recommended here) and can vary from 10-60 days. Since women taking the BCP are at a slightly increased risk of developing thromboembolism (venous blood clots capable of dislodging and traveling to vital organs), I recommend that they take 81mg aspirin orally, daily while taking the BCP. This should significantly reduce the risk of thromboembolism. Thereupon, the BCP is overlapped with daily subcutaneous (SC) injections of a gonadotropin releasing hormone -agonist (GnRHa) such as Leuprolide (0.5mg (10U) or /Superfact/Buserelin/amino peptidyl) for a period of 3 days, at which point the BCP is discontinued. The dosage of Leuprolide is reduced to 0.25 mg. (5units) daily and this is continued until the onset of vaginal bleeding (usually within 4-7 days of stopping the BCP). Once bleeding starts or if it is delayed beyond 7 days, a vaginal ultrasound examination + a blood estradiol (E2) measurement should be done to rule out the existence of a functional ovarian cyst. Should a cyst be present, it is my preference that this be drained through transvaginal needle aspiration performed under local anesthesia (paracervical nerve block). In my experience this will result in menstruation within a few days. At the time of bleeding, the baseline blood [E2] should measure <70pg/ml or <200Pmol/L). If not, daily ultrasound and blood [E2] assessments need to be done until these parameters are fulfilled.  At this point, gonadotropin therapy is commenced and the GnRHa is supplanted with daily SC injections of 250mcg, GnRH-antagonist (e.g. Ganirelix/Cetrotide/Orgalutron).  Both are continued until the intramuscular administration of the hCG ‘trigger”, >7days later, using 10,000U Pregnyl/Profasi/Novarel or 500mcg Ovidrel/Ovitrelle).

 

Gonadotropin administration is as follows: FSH-recombinant (FSHr), 600U, [Follistim/ Gonal-F/ Puregon/Fostimon] daily SC injections should ideally commence (along with GnRH antagonist administration) on the 1st or 2nd day of bleeding (designated cycle day 2 -CD2) or as soon as possible (but under no circumstances more than 7 days following the onset of bleeding). Unless otherwise specified, the daily dosage of FSHr is reduced to 350U on CD3. This regimen is maintained until the day of the hCG “trigger”. Menotropin (Menopur/Merional), 75U (one vial) SC is added to the mix, from CD3. This is continued (along with the with the FSHr), to the day of the hCG “trigger”. Daily follicle ultrasound and plasma estradiol [E2] monitoring commences on CD 8 (the 7th day of gonadotropin administration) and continues until the day of the hCG “trigger”.

 

The timing of the hCG “Trigger is based more upon the US measurement of mean follicular dimensions (size) than the blood [E2]. This is because when a GnRH antagonist is administered from early on and throughout the stimulation phase blood estradiol levels often understate true ovarian estrogen production, often being lower than anticipated based upon the number and size of the follicles. Accordingly, measured [E2] values are often “falsely/deceptively low”. This is one of the reasons that I tend to shy away from using the A/ACP in woman with high ovarian reserve (“high responders”) who are often at risk of developing dangerous life-threatening complications associated with Severe Ovarian Hyperstimulation Syndrome (OHSS) and in whom the accurate measurement of  [E2] is often a central to planning a safe treatment strategy.

 

All patients undergoing an Embryo Transfer (ET) commence prophylactic, oral antibiotics (Ciprofloxin 500mg BID or Doxycycline 100mg twice daily) from CD8 or CD9. This is continued for 10 days. Such patients receive 1 mg from CD2 through the pregnancy or until pregnancy is discounted.

 

I recommend that patients all undergoing ET receive an oral corticosteroids (e.g. dexamethasone 0.75 mg) daily from the commencement of GnRHa therapy. This daily dosage is maintained until the 2nd blood pregnancy hCG testy. Thereafter:

  1. In the event of  a failed IVF, dexamethasone therapy is reduced to 0.75 mg every alternate day for one week and is then discontinued.
  2. Women who conceive and have positive blood beta-hCG, pregnancy tests continue to take the oral dexamethasone daily until the 8th week of pregnancy. Thereupon the dexamethasone dosage is reduced to 0.75 mg every alternate day for two weeks, whereupon it is discontinued.

 

I selectively recommend to many of my patients that they have daily injections of 0.4mg Human Growth Hormone-HGH (Saizen/Omnitrope) commencing with the initiation of GnRHa, until the hCG “trigger”.

 

Commencing 5-6 days prior to anticipated blastocyst transfer (fresh embryo transfer-ET or Frozen Embryo Transfer-FET), I recommend the following hormonal support:

    1. Progesterone in oil (PIO) intramuscular(gluteal) injections (50 mg IM daily). Until the 2nd blood Beta hCG (the 1st beta hCG test is done 8 days after blastocyst transfer ER and the  2nd Beta hCG, 2 days)
  1. If pregnancy test is negative, discontinue PIO.
  2. If the pregnancy hCG blood levels rise appropriately over 2-4 days, continue the PIO injections until the 10th week of pregnancy.
    1. A combined PIO (50 mg)/Estradiol Valerate (1 mg) vaginal suppository is used daily. Commencing on the day following embryo transfer (ET) and continued until the 10th week of pregnancy (or as soon as a beta hCG test/ ultrasound exam rules out a viable gestation).
    2.  Alternative regimen for patients who cannot tolerate intramuscular progesterone:. Two vaginal applications of Crinone 8% is administered daily, starting 5-6 days prior to ET/FET until blood pregnancy test.  The day following the ET/FET an estradiol valerate 2mg vaginal suppository is inserted and this is repeated daily until blood pregnancy tests confirm or rule out a viable gestation.

I will update you as this couple progresses through further IVF treatment.

2 Comments

Shruthi

I am 33 year old and have DOR. Amh 0.1 and fsh 14 . After taking 75 mg dhea per day for 6 weeks as we my endocrinologist advise. Now my period stoped with one day scanty flow past two months. Now I stoped taking dhea as I think it has messed up my periods. Before taking dhea my periods have beennormal with 30 day cycle. Please advise what I should I do to get my periods back to normal. Thank you.

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Dr. Geoffrey Sher

The big question here is whether you are now entering a “premature menopause”. It would be helpful to repeat the AMH and also to have a basal FSH and LH level measured.

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, and/or biological activity, of LH. This can result in excessive ovarian male hormone (predominantly testosterone) production. This 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, www. SherIVF.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

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ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

Patients are encouraged to share the information I provide, with their treating Physicians and/or to avail themselves of my personal hands-on services, provided through batched IVF cycles that I conduct every 3 months at Los Angeles IVF (LAIVF) Clinic, Century City, Los Angeles, CA.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

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Geoff Sher

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