#352 ‒ Female fertility: optimizing reproductive health, diagnosing and treating infertility and PCOS, and understanding the IVF process | Paula Amato, M.D.
Dr. Paula Amato, an expert in reproductive endocrinology, discusses female fertility, covering the menstrual cycle, causes of infertility (like PCOS and fallopian tube issues), and treatment options including IVF, genetic testing, and egg freezing. She also touches on lifestyle factors and future innovations.
Deep Dive Analysis
20 Topic Outline
Introduction to Female Fertility and Egg Reserve
Hormonal Regulation of the Menstrual Cycle and Ovulation
Chromosomal Abnormalities and Miscarriage Causes
The Journey of Conception: Fertilization to Implantation
Defining and Diagnosing Infertility
Impact of STDs and Fallopian Tube Damage on Fertility
Understanding Polycystic Ovary Syndrome (PCOS)
Treating PCOS for Non-Conception Goals
PCOS Treatment for Conception: Oral Medications
Barriers to Informed Fertility Care and Access
Intrauterine Insemination (IUI) Process and Success Rates
Evolution and Process of In Vitro Fertilization (IVF)
IVF Lab Procedures: Fertilization and Embryo Culture
Genetic Testing and Embryo Selection in IVF
Embryo Transfer and Pregnancy Support in IVF
Egg Donation as a Fertility Option
Choosing the Right IVF Clinic: Key Considerations
Egg Freezing for Fertility Preservation
Future of Fertility: Research and Emerging Technologies
Lifestyle Factors and Supplements for Fertility
7 Key Concepts
Atresia
The natural process by which most eggs in a woman's ovaries die. This leads to a significant reduction in egg count from birth (around 2 million) to the onset of menstruation (around 400,000).
Aneuploidy
An abnormal number of chromosomes in a cell, such as an egg or a fertilized embryo. The majority (up to 90%) of early miscarriages are attributed to aneuploidy, often resulting from errors during the egg's meiotic division.
Polycystic Ovary Syndrome (PCOS)
A common hormonal condition affecting 6-8% of women, characterized by irregular periods, elevated androgen levels (leading to symptoms like acne or excess hair growth), and frequently associated with insulin resistance. It often impairs regular ovulation.
Ovarian Hyperstimulation Syndrome (OHSS)
A rare but serious complication of fertility treatments where the ovaries become excessively stimulated, leading to enlargement and fluid shifts. Careful monitoring and dose adjustments of fertility medications are used to minimize this risk.
Vitrification
A specialized, rapid freezing technique used in IVF to cryopreserve embryos and eggs. This method prevents the formation of damaging ice crystals, resulting in high survival rates for thawed cells compared to older slow-freezing methods.
In Vitro Gametogenesis (IVG)
An experimental reproductive technology aiming to generate functional eggs and sperm from somatic cells, such as skin cells, through cellular reprogramming. If successful, it could offer new fertility options for individuals with no viable gametes.
Mitochondrial Replacement Therapy
A technique designed to prevent the transmission of mitochondrial diseases or improve egg quality in older women. It involves transferring the nucleus from an egg with problematic mitochondria (or from an older egg) into a donor egg that has had its nucleus removed but retains healthy mitochondria.
12 Questions Answered
Women are born with a finite number of eggs, about 2 million, which reduces to around 400,000 by the time menstruation begins due to a process called atresia.
The vast majority, close to 90% of first-trimester miscarriages, are due to chromosomal abnormalities (aneuploidy) in the embryo, often stemming from errors during egg development.
Infertility is defined as trying to conceive through unprotected intercourse for about a year without success for women under 35, or after six months for women over 35. Earlier consultation is advised if there are known fertility concerns like irregular cycles.
STDs like gonorrhea and chlamydia can ascend to the fallopian tubes, causing scarring and blockage, which interferes with the egg and sperm meeting and increases the risk of ectopic pregnancy.
PCOS is characterized by irregular periods, signs of high androgen levels (like acne or excess hair growth), and often obesity or being overweight. Most women with PCOS also exhibit insulin resistance.
Unregulated cycles in PCOS can lead to the uterine lining overgrowing, which can become hyperplastic and, in worst-case scenarios, lead to cancer. Hormonal treatments help shed the lining or suppress its growth.
IUI success rates depend heavily on the female partner's age; it can be 20-25% per cycle for women in their twenties, 10-15% for women over 35, and only 1-5% for women over 40.
A fully loaded IVF cycle, including genetic testing, is approximately $20,000 per cycle.
Egg freezing offers optionality for women who want to delay childbearing. The "sweet spot" for freezing eggs is typically in the early to mid-30s, as it offers a good balance between egg quality/quantity and the likelihood of needing to use them later.
Red flags include poor communication with staff, limited access to the actual doctor, or a clinic that pushes expensive add-ons like genetic testing without a thorough discussion of pros and cons.
While rarely the sole cause of infertility, lifestyle factors like diet, stress, sleep, and exercise can exacerbate fertility issues. Promoting overall health through a healthy diet (e.g., Mediterranean), stress coping mechanisms, adequate sleep, and moderate exercise generally supports fertility.
Extreme exercise can lead to irregular or absent menstrual periods (amenorrhea) due to a condition called Relative Energy Deficiency in Sport (REDS), where the body conserves energy by shutting down reproductive function, thereby impacting ovulation and fertility.
23 Actionable Insights
1. Monitor menstrual cycle health early
Pay attention to your menstrual cycle health (regularity, pain, heaviness) from a young age, and don’t wait until you’re trying to conceive to address any irregularities. Menstrual cycles are a marker of overall health, and early detection of issues can prevent future fertility problems and other health complications.
2. Address cycle irregularities early
If you are a young woman (teens or twenties) experiencing any irregularity in your menstrual cycle, seek medical evaluation promptly. Early intervention can help prevent or mitigate future infertility problems and other health issues.
3. Seek fertility help sooner with irregular cycles
If you suspect a fertility problem, especially if you have irregular menstrual cycles or symptoms of polycystic ovary syndrome (PCOS), consult a healthcare provider sooner than the standard one-year waiting period for infertility diagnosis. This allows for earlier intervention and assessment of potential underlying issues.
4. Don’t blame yourself for early miscarriage
If you experience an early miscarriage, understand that it’s highly likely (greater than 90% chance) due to a chromosomal abnormality and not something you did wrong, such as consuming too much coffee or being under stress. This understanding can help alleviate self-blame and emotional distress.
5. Men should get semen analysis periodically
Men should consider assessing their semen analysis periodically, even if not actively trying to conceive. This can serve as an important marker for other underlying health problems.
6. Adopt healthy lifestyle for fertility
Embrace general healthy lifestyle factors, including a healthy diet, exercise, and good sleep, as these promote overall health and can positively impact fertility. While rarely the sole cause of infertility, these habits can mitigate factors that exacerbate it.
7. Follow a Mediterranean diet for fertility
Adopt a Mediterranean diet, rich in fruits, vegetables, whole grains, and protein primarily from fish and olive oil. This diet is palatable, reasonably healthy, and generally recommended for overall well-being, which extends to fertility.
8. Maintain a healthy weight for fertility
Maintain a healthy body weight, avoiding both being overweight/obese and severely underweight. Both extremes can negatively impact fertility by disrupting ovulation and menstrual cycles.
9. Avoid extreme exercise impacting cycles
Avoid extreme levels of exercise that cause changes in your menstrual cycle, such as periods stopping altogether (amenorrhea). Extreme exercise can lead to Relative Energy Deficiency in Sport (RED-S), signaling to the body that there isn’t enough energy to support a pregnancy, thereby impairing ovulation and fertility.
10. Develop stress coping mechanisms
Actively find and practice coping mechanisms for stress, such as exercise, meditation, or mindfulness, as stress can negatively impact fertility and overall health. Personalized strategies are effective in managing stress.
11. Supplement to correct nutrient deficiencies
Supplement with iron if deficient, take folic acid when trying to get pregnant, and consider vitamin D if you live in areas prone to deficiency. Correcting known deficiencies and ensuring adequate folic acid intake are important for overall health and pregnancy preparation.
12. Stop GLP-1 agonists before pregnancy
If you are trying to conceive, you should stop taking GLP-1 agonists (e.g., semaglutide, tirzepatide) for at least two months prior to attempting pregnancy. There is currently no data on their safety during pregnancy, and it’s a current recommendation to avoid potential unknown risks.
13. Weight loss helps PCOS symptoms
If you have Polycystic Ovary Syndrome (PCOS) and are overweight or obese, prioritize weight loss through a healthy diet and lifestyle. Weight loss helps alleviate all symptoms of PCOS, regardless of whether you are trying to conceive.
14. Freeze eggs in early to mid-30s
If you anticipate delaying childbearing, consider freezing your eggs in your early to mid-30s. This age range is considered the ‘sweet spot’ where it’s most cost-effective, as it’s before the significant decline in egg quality and increases the likelihood of needing them later.
15. Freeze 10-20 eggs in your 30s
If you are in your 30s and decide to freeze your eggs, aim to retrieve and freeze 10 to 20 eggs to provide a decent chance of success. Understand that younger age may require fewer eggs due to higher quality, but no guarantees exist.
16. Seek testing after two consecutive miscarriages
If a woman experiences two miscarriages in a row, she should seek additional medical testing. This warrants investigation into potential underlying causes that might be treatable, even if chromosomal abnormalities are the most common reason for early losses.
17. Research IVF clinic success rates
When considering IVF, research clinic-specific success rates by visiting sart.org (Society of Assisted Reproductive Technology) to compare clinics in your area. This allows for an informed decision based on objective data, though population differences between clinics should be considered.
18. Choose high-volume IVF clinics
Select an IVF clinic that performs a sufficient volume of cycles, ideally more than 100 cycles per year. Higher volume clinics generally indicate more experience and potentially better outcomes.
19. Inquire about clinic philosophy on add-ons
When interviewing an IVF doctor, ask about their philosophy on protocols and add-ons like genetic testing. Ensure they discuss pros and cons and allow patient autonomy in decision-making, rather than pushing unnecessary treatments.
20. Prioritize clear clinic communication
Pay attention to the quality and smoothness of communication with clinic staff (nurses, coordinators) when evaluating an IVF clinic. Poor communication can add significant stress to an already demanding process.
21. Evaluate patient reviews cautiously
When looking at patient reviews or word-of-mouth recommendations for IVF clinics, take them with a grain of salt. Not all positive experiences are reported, leading to a potentially unrepresentative view of a clinic’s overall quality.
22. Consider academic IVF centers
When choosing an IVF clinic, consider academic centers, as their missions often include education and research, which can contribute to high-quality care. However, several excellent private clinics also exist.
23. Avoid rapamycin when trying to conceive
Do not take rapamycin if you are trying to conceive. Animal data on its effect on fertility is mixed, and its safety and efficacy in humans for fertility extension are not established, with potential for harm.
7 Key Quotes
Most of the time, only the chromosomally normal embryos are the ones that implant and continue to develop.
Paula Amato
Definitely the majority of them, probably close to 90% of them [first trimester miscarriages are due to aneuploidy].
Paula Amato
I feel like I'm saying that a lot about women's health. We don't know exactly what causes it because we're not investing enough in women's research.
Paula Amato
The lab is almost more important than what we do because there's just more variability.
Paula Amato
You basically want to normalize the thing. And you definitely want to be the ones to tell them, and you don't want them to find out by some other means, like somebody contacts them on 23andMe or something like that.
Paula Amato
The lifestyle factors that promote health are generally the same lifestyle factors that promote fertility.
Paula Amato
Your periods are also a marker [of health].
Paula Amato
3 Protocols
PCOS Ovulation Induction Protocol (Letrozole)
Paula Amato- Induce a withdrawal bleed by giving progesterone (e.g., 5-10 mg medroxyprogesterone acetate or 200 mg micronized progesterone) for 7-10 days.
- Consider the first day of full bleeding as Day 1 of the cycle.
- Take Letrozole (Femara) for five days, typically from Day 3 to Day 7 of the cycle.
- Perform an ultrasound around Day 12 of the cycle to assess follicle growth and response.
- If ovulation occurs and pregnancy is not achieved, continue for up to three consecutive cycles before re-evaluating the treatment plan.
Intrauterine Insemination (IUI) Protocol
Paula Amato- Female partner takes oral fertility medication (e.g., Clomid or Letrozole) to stimulate the ovaries to release more than one egg (superovulation).
- Track ovulation using LH monitoring (urine tests) or ultrasound to determine the timing of the LH surge.
- Administer a precise HCG injection (typically 5,000 units) to trigger ovulation.
- On the day of anticipated ovulation, the male partner provides a sperm sample (or donor sperm is prepared).
- Process the sperm sample in the lab to concentrate the best sperm in a small volume.
- Place the processed sperm directly into the uterus through the cervix using a thin catheter.
In Vitro Fertilization (IVF) Cycle Protocol
Paula Amato- Perform initial screening tests on both partners, including blood tests, a semen analysis, and an ultrasound to assess the woman's egg number.
- The woman typically starts on birth control pills for a couple of weeks to suppress the ovaries and synchronize follicle growth.
- Stop birth control pills and begin daily injectable gonadotropins (primarily FSH with some LH) for approximately 8-12 days to stimulate multiple follicles to grow.
- Administer a GnRH antagonist during the stimulation phase to prevent a premature LH surge and spontaneous ovulation.
- Undergo regular ultrasound monitoring and estradiol blood level checks every few days to track follicle growth and adjust medication doses.
- Once follicles reach a mature size, administer a precise HCG trigger shot (36 hours before retrieval) to induce final egg maturation.
- Perform egg retrieval under IV sedation, guiding a 16-gauge needle through the vagina into the ovaries to aspirate fluid and eggs from the mature follicles.
- In the lab, retrieved eggs are inseminated with sperm (either via conventional IVF or Intracytoplasmic Sperm Injection (ICSI) for male factor or to maximize fertilization rates).
- Fertilized eggs (now embryos) are cultured in a Petri dish for 5-6 days until they reach the blastocyst stage.
- (Optional) Biopsy a few cells from blastocyst-stage embryos for genetic testing (e.g., aneuploidy screening) and then freeze the embryos using vitrification while awaiting test results.
- Prepare the woman's uterus for transfer by timing it with her natural cycle or using a controlled hormonal program to ensure the uterine lining is sufficiently thick (7-10 mm).
- Thaw one selected embryo (if frozen) and transfer it into the uterus, approximately 1.5-2 cm from the top, using a catheter guided by abdominal ultrasound.
- Provide supplemental progesterone to support the uterine lining and maintain the early pregnancy.
- Perform a pregnancy test 12-14 days after the embryo transfer.