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.

  1. 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.
  2. 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”.

Recommendations:

  • 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.

2 Comments

Sarah

Hello,
I have had 2 early miscarriages and 1 chemical at the age of 39. I just turned 40 and finished my first IVF cycle..out of 16 retrieved, 8 fertilized, I got 1 blast. What would be your best advice/protocol
moving forward? I have AMH around 1.2, FSH 13 (only checked once) . Part tee has slightly slow motility but good sperm count.

reply
Dr. Geoffrey Sher

You have diminished ovarian reserve (DOR). This in combination with advancing age presents a challenge.

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. diminished ovarian reserve (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

Please visit my 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

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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.

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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