Case Report: Patient with Repeated IVF Failures, Diminished Ovarian Reserve (DOR) and Autoimmune Hypothyroidism (Hashimoto’s Disease)

Beryl, 39y and her husband Jack is 36y presented with a history of 5 years of infertility. They had failed 2 attempts at IVF (both in 2918). Beryl had normal regular, ovulatory menstrual cycles. She had hypothyroidism caused by an autoimmune process, secondary to the presence of antithyroid antibodies (Hashimoto’s disease). She had a laparoscopy done about 18 months prior and was found to have a normal uterus and patent Fallopian tubes. A concomitantly performed hysteroscopy (to examine her uterine cavity), revealed no evidence of endo-uterine pathology. About 5 years prior she had been found to have unexplained hyperprolactinemia (raised blood prolactin). A pituitary MRI revealed no evidence of a pituitary tumor. Heather had significantly diminished ovarian reserve (DOR) with an AMH=0.7ng/ml and basal blood FSH level of 13.5MIU/ml (elevated). Jack had normal sperm function and had proven fertility by having initiated 2 pregnancies before, in a prior relationship.

For both her IVF attempts, Beryl initiated ovarian stimulation using “flare protocols” where treatment with a GnRH agonist (Lupron) and recombinant FSH (400U Gonal-F) and menotropin (75U Menopur) were all started together at the onset of menstruation and continued throughout the 9th day (cycle #1) and 12th day (cycle #2) of ovarian stimulation. She developed 7 follicles in her 1st attempted IVF and 9 in her 2nd. Her peak blood estradiol levels reached 1100pg/ml and 1340pg/ml in cycles #1 & 2, respectively. Her endometrial lining was adequate and measured >9mm (normal) in cycles 1 &2. She was given 250mcg of recombinant hCG (Ovidrel) as a “trigger” in both cases. Beryl underwent transvaginal ultrasound needle guided egg retrievals. Three mature (MII) eggs were extracted in Cycle# 1 and 4 in cycle #2. Fertilization was conducted using intracytoplasmic sperm injection (ICSI). In both cycles, two blastocysts developed by day-6 post-ICSI. These were transferred but she did not conceive on either occasion.

Opinion:

First: The protocol used for ovarian stimulation was in my opinion, not optimal. Here is why: Women who (regardless of age) have DOR 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”.  “Flare”  protocols should thus, preferably not be used in women who have DOR since the GnRH-agonist (Lupron) immediately expunges LH (in large amount) , from the pituitary gland and promptly initiates overproduction and release  ovarian male hormones (e.g. testosterone).Similarly, the amount/dosage of certain fertility drugs that contain LH/hCG (e.g. Menopur) can negatively 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

With the Agonist/antagonist Conversion Protocol (A/ACP), 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 Lupron (0.5mg (10U for a period of 3 days, at which point the BCP is discontinued. The dosage of Lupron 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: Six hundred units(600U) of recombinant FSH (Follistim or Gonal-F) is administered daily by SC injections commencing 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)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.

Egg retrieval is followed by intracytoplasmic sperm injection of each mature (MII) egg. These are then cultured to blastocyst. Those embryos reaching blastocyst by no later than day 6 post-ER are biopsied for PGS.

Subsequent Frozen Embryo Transfer (FET): The results of PGS should be back within 2 weeks at which time this is discussed with the patient and arrangements are made for the transfer of 1-2 blastocysts to the uterus during a subsequent frozen embryo transfer (FET) cycle.

Second, the Autoimmune Hypothyroidism (Hashimoto’s disease): Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e. infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroid antibodies such as in Beryl’s case.  Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment.

Third, The Hyperprolactinemia: it is likely that hypothyroidism caused the elevation in prolactin. I say this because treatment with thyroid hormone replacement brought the level down to normal. and the fact that the level reduced post TH treatment, would support this view.

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