There is a high likelihood that aside from the age factor impacting egg quality, your severely diminished ovarian reserve sets you up fro what is known as “premature Luteinization”. This is particularly more likely if the protocol used for ovarian stimulation is not optimally fashioned.
- ADDRESSING ADVANCING AGE AND DIMINISHING OVARIAN RESERVE (DOR) IN IVF
Understanding the impact of age and ovarian reserve on the success of in vitro fertilization (IVF) is crucial when it comes to reproductive health. This article aims to simplify and clarify these concepts, emphasizing their significance in the selection of ovarian stimulation protocols for IVF. By providing you with this information, we hope to shed light on the importance of considering these factors and making informed decisions regarding fertility treatments.
- The Role of Eggs in Chromosomal Integrity: In the process of creating a healthy embryo, it is primarily the egg that determines the chromosomal integrity, which is crucial for the embryo’s competency. A competent egg possesses a normal karyotype, increasing the chances of developing into a healthy baby. It’s important to note that not all eggs are competent, and the incidence of irregular chromosome numbers (aneuploidy) increases with age.
- Meiosis and Fertilization: Following the initiation of the LH surge or the hCG trigger shot, the egg undergoes a process called meiosis, halving its chromosomes to 23. During this process, a structure called the polar body is expelled from the egg, while the remaining chromosomes are retained. The mature sperm, also undergoing meiosis, contributes 23 chromosomes. Fertilization occurs when these chromosomes combine, resulting in a euploid embryo with 46 chromosomes. Only euploid embryos are competent and capable of developing into healthy babies.
- The Significance of Embryo Ploidy: Embryo ploidy, referring to the numerical chromosomal integrity, is a critical factor in determining embryo competency. Aneuploid embryos, which have an irregular number of chromosomes, are often incompetent and unable to propagate healthy pregnancies. Failed nidation, miscarriages, and chromosomal birth defects can be linked to embryo ploidy issues. Both egg and sperm aneuploidy can contribute, but egg aneuploidy is usually the primary cause.
- Embryo Development and Competency: Embryos that develop too slowly or too quickly, have abnormal cell counts, contain debris or fragments, or fail to reach the blastocyst stage are often aneuploid and incompetent. Monitoring these developmental aspects can provide valuable insights into embryo competency.
- Diminished Ovarian Reserve (DOR): As women advance in their reproductive age, the number of remaining eggs in the ovaries decreases. Diminished ovarian reserve (DOR) occurs when the egg count falls below a certain threshold, making it more challenging to respond to fertility drugs effectively. This condition is often indicated by specific hormone levels, such as elevated FSH and decreased AMH. DOR can affect women over 40, but it can also occur in younger
Why IVF should be regarded as treatment of choice for older women an those who have diminished ovarian reserve ( DOR):
Understanding the following factors will go a long way in helping you to make an informed decision and thereby improve the chances of a successful IVF outcome.
- Age and Ovarian Reserve: Chronological age plays a vital role in determining the quality of eggs and embryos. As women age, there is an increased risk of aneuploidy (abnormal chromosome numbers) in eggs and embryos, leading to reduced competency. Additionally, women with declining ovarian reserve (DOR), regardless of their age, are more likely to have aneuploid eggs/embryos. Therefore, it is crucial to address age-related factors and ovarian reserve to enhance IVF success.
- Excessive Luteinizing Hormone (LH) and Testosterone Effects: In women with DOR, their ovaries and developing eggs are susceptible to the adverse effects of excessive LH, which stimulates the overproduction of male hormones like testosterone. While some testosterone promotes healthy follicle growth and egg development, an excess of testosterone has a negative impact. Therefore, in older women or those with DOR, ovarian stimulation protocols that down-regulate LH activity before starting gonadotropins are necessary to improve egg/embryo quality and IVF outcomes.
- Individualized Ovarian Stimulation Protocols: Although age is a significant factor in aneuploidy, it is possible to prevent further decline in egg/embryo competency by tailoring ovarian stimulation protocols. Here are my preferred protocols for women with relatively normal ovarian reserve:
- Conventional Long Pituitary Down Regulation Protocol:
- Begin birth control pills (BCP) early in the cycle for at least 10 days.
- Three days before stopping BCP, overlap with an agonist like Lupron for three days.
- Continue daily Lupron until menstruation begins.
- Conduct ultrasound and blood estradiol measurements to assess ovarian status.
- Administer FSH-dominant gonadotropin along with Menopur for stimulation.
- Monitor follicle development through ultrasound and blood estradiol measurements.
- Trigger egg maturation using hCG injection, followed by egg retrieval.
- Agonist/Antagonist Conversion Protocol (A/ACP):
- Similar to the conventional long down regulation protocol but replace the agonist with a GnRH antagonist from the onset of post-BCP menstruation until the trigger day.
- Consider adding supplementary human growth hormone (HGH) for women with DOR.
- Consider using “priming” with estrogen prior to gonadotropin administration
- Protocols to Avoid for Older Women or Those with DOR: Certain ovarian stimulation protocols may not be suitable for older women or those with declining ovarian reserve:
- Microdose agonist “flare” protocols
- High dosages of LH-containing fertility drugs such as Menopur
- Testosterone-based supplementation
- DHEA supplementation
- Clomiphene citrate or Letrozole
- Low-dosage hCG triggering or agonist triggering for women with DOR
Preimplantation Genetic Screening/Testing(PGS/T): PGS/T is a valuable tool for identifying chromosomal abnormalities in eggs and embryos. By selecting the most competent (euploid) embryos, PGS/T significantly improves the success of IVF, especially in older women or those with DOR.
Understanding the impact of advancing age and declining ovarian reserve on IVF outcomes is essential when making decisions about fertility treatments. Age-related factors can affect egg quality and increase the likelihood of aneuploid embryos with resultant IVF failure. Diminished ovarian reserve (DOR) further complicates the process. By considering these factors, you can make informed choices and work closely with fertility specialists to optimize your chances of success. Remember, knowledge is power, and being aware of these aspects empowers you to take control of your reproductive journey.
- Premature Luteinization: A Hurdle in Ovarian Stimulation
Premature luteinization, is a condition where a progressive increase in LH (luteinizing hormone) disrupts the development and maturation of follicles and eggs before the planned hCG trigger is initiated. This phenomenon is not an isolated occurrence; it results from a series of ovarian events, often affecting susceptible women, particularly older women and those with diminished ovarian reserve (DOR). It is more likely to happen when the ovarian stimulation protocol fails to keep LH levels low throughout the stimulation process.
Once premature luteinization sets in during a stimulation cycle, it cannot be reversed by altering the ongoing stimulation or by administering GnRH antagonists like Ganirelix, Cetrotide, or Orgalutron midway through the cycle in the hope of rescuing the developing eggs. Unfortunately, once it starts, the cycle is likely to fail. This condition raises the risk of premature ovulation, unsuccessful egg retrieval (referred to as “empty follicle syndrome”), and the occurrence of chromosomal abnormalities in eggs and embryos.
This issue is most commonly observed in older women and those with severe DOR. However, its impact can be mitigated through personalized and strategic protocols for controlled ovarian stimulation (COS), along with optimizing the type, timing, and dosage of the “hCG trigger shot.”
Typically, the “trigger shot” is administered after optimal ovarian stimulation to initiate meiosis (reproductive division) within 36- 40 hours, reducing the chromosome count from 46 to 23. Additionally, it enables the egg to detach from the follicle wall for easy retrieval.
Older women and those with DOR tend to have higher levels of biologically active LH, which promotes the production of excessive male hormones ( predominantly, testosterone) by ovarian connective tissue. A controlled amount of testosterone is necessary for healthy follicle development and egg development ( oogenesis) induced by FSH (follicle-stimulating hormone). Excessive LH activity can result in overproduction of ovarian testosterone, compromising oogenesis and leading to a higher likelihood of chromosomal abnormalities in eggs following meiosis.
Women with increased LH activity due to age or DOR are particularly vulnerable to the effects of prolonged exposure to LH-induced ovarian testosterone. Medications or protocols that further stimulate pituitary LH release, contain LH or hCG, or promote increased exposure to the woman’s own pituitary LH can be detrimental.
To address this issue effectively, it is crucial to tailor COS protocols, choose the appropriate hCG trigger dosage and type, and administer it at the right time. For urinary-derived hCG (such as Novarel, Pregnyl, and Profasi), 10,000U is the ideal dosage. When using recombinant DNA-derived hCG (like Ovidrel), 500mcg is recommended. Using lower dosages can increase the risk of egg chromosomal abnormalities and affect the overall outcome of IVF treatments.
