CASE REPORT #1: Advancing age, Diminished Ovarian Reserve (DOR) + Male Infertility Geoffrey Sher MD Case History: Mary D. (42y) and her husband, Chris (43y) recently had a SKYPE consultation with me. The couple had been trying to have a baby for 1.5 years. Maria had been pregnant when she was 19 years of age and had an abortion without any subsequent complications. Aside from having had her gallbladder removed laparoscopically in 2015, she otherwise had an unremarkable medical history. Her family history was positive for high blood pressure (her mother and father); coronary vascular heart disease (her father) and Type II diabetes (her mother). A recent annual physical examination was absolutely normal. This included a PAP cervical smear and a mammogram which were both negative for malignant disease. Maria was tested for the number of eggs she still had left in her ovaries (ovarian reserve) by ich by way of her blood antimullerian hormone (AMH) level which was low at 0.2ng/ml (normal is >2.0ng/ml). This, and her markedly elevated basal follicle stimulating hormone (FSH) measurement of 29MIU/ml, (normal =<10MIU/ml) confirmed that she had severely diminished ovarian reserve (DOR), and that her ‘biological clock” was rapidly running out of time. A previously performed dye X-ray test (HSG) as well as a saline ultrasound examination (HSN) both indicated that her uterus was normal and her Fallopian tubes were open (patent). Chris had a reduced sperm count of 11 million per milliliter (normal is >20million per milliliter) with only 10% of his sperm being motile (normal = >40%), indicating moderately sever e male infertility. His blood FSH and testosterone levels were both in the normal range, indicating that it was unlikely to be a reversible problem. Maria had undergone five (5) failed attempts to conceive using artificial intrauterine insemination (IUI) after taking clomiphene (Clomid/Serophene), an oral fertility medication. Thereupon she twice underwent in-vitro fertilization. In her 1st IVF attempt, she used a modest dosage of injectable Fertility agents Follistim + Menopur). Five (5) eggs were extracted from her ovaries and these were fertilized through the injection of husband’s sperm directly into her eggs (intracytoplasmic sperm injection -ICSI). Two day-3 embryos were transferred to her uterus. The cycle was unsuccessful. In her 2ns cycle placed on a “low dosage” regime of fertility agents (i.e., Mini-IVF) using oral clomiphene + a low dosage of injectable gonadotropin (i.e. 75U Follistim). In this cycle, 3 eggs that were extracted. All failed to fertilize using ICSI. The couple sought advice how they should proceed: Analysis: There are several issues to consider.
- Maria has a combination of 2 serious factors that impact the biological clock namely, age and DOR. Both impact the number of available eggs as well as their “competency” . Bearing in mind that it is egg quality far more than sperm quality that impacts the likelihood of numerical chromosomal aberrations (aneuploidy) in the embryo. Simply stated, advancing age is likely, the most critical factor impacting egg/embryo “competency”. At 42y of age, under the best of circumstances, only about 1 out of 10n eggs are likely to be chromosomally normal (euploid). This translates into a relatively poor likelihood of any given embryo being “competent” to propagate a viable pregnancy. Then to make matters worse, her DOR translates into fewer eggs being available to start with. With fewer eggs + increased age-related likelihood that resulting eggs/embryos will be “competent” (euploid, the chance of successful IVF is not great.
- Male factor: While Chris’ reduced sperm motility and compromised sperm structure (morphology) does not rule out a successful pregnancy, it undoubtedly adds another negative component which further reduces fertilization potential and increases the likelihood of any given embryo being aneuploid and “incompetent”.
- The Egg Donation option: Undoubtedly, IVF using egg donation is the most rational approach and would yield the best possible outcome. However, Mary and Chris were adamant that they wish to try with own eggs. Given this decision, it is imperative that every effort be made to optimize the chance of accessing euploid, “competent” embryos for transfer to the uterus.
- Selecting the optimal protocol for Controlled Ovarian Stimulation (COS) is central to success in any woman who has DOR and/or is over 40Y of age. In my opinion, the optimal COS protocol for ovarian stimulation in such cases, is one that does not overexpose developing eggs to excessive male hormone (predominantly Testosterone) because excessive ovarian testosterone (and other male hormones) can compromise egg development and thus also, embryo quality. Luteinizing hormone (LH), released from the pituitary gland and also present in certain fertility drugs such as Menopur and Merional activate ovarian connective tissue (stroma/theca) resulting in Testosterone production. Use of “flare” agonist (e.g. Lupron/Buserelin/Superfact/Aminopeptidyl) protocols, clomiphene or Letrozole administration (which expunges a large amount LH from the pituitary gland and the use of high dosages of LH/HCG containing fertility drugs such as Menopur and Merional should best be avoided in such cases. The injudicious adding of Testosterone or hCG (which acts on the ovary like LH) is also, in my opinion not advised. My advice would be to use a robust (high dosage modified long pituitary down-regulation protocol …the Agonist/Antagonist-Conversion Protocol -A/ACP (see elsewhere on this website for more information on the A/ACP). To this I would add Human Growth Hormone throughout the stimulation, in the hope that by enhancing mitochondrial function, egg quality might be enhanced.
- The Male Factor: It relatively unlikely that any specific treatment will improve Chris’ sperm quality. However, I would recommend that he undergo a Urologic examination be to evaluate for a collection of varicose veins in the scrotum (varicocele) and that a sperm culture be done to exclude infection. ICSI should be employed to optimize successful fertilization.
- Preimplantation Genetic Testing (PGT) and Embryo Banking: Because of Mary’s advanced age and her DOR, I recommend that the couple submit to several attempts at egg retrieval (ER) and that all blastocysts be biopsied for PG testing and that all euploid blastocysts be banked and stockpiled over time. Subsequently one (1) or at most 2) euploid blastocysts should selectively be transferred. Mary’s age and DOR mandates that the couple try to “make hay while the sun still shines”!
MOST IMPORTANTLY: TIME IS OF THE ESSENCE HERE!! ADDENDUM: I intend to follow this couple and will report on their progress as treatment is implemented.