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 Screening (PGS), 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.

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