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Fertility in 2023: latest advances in Reproductive Medicine

Dr Oliver Pack
Fertility Specialist

Category:
Advanced Maternal Age, Donor Eggs, Genetics PGS / PGT-A, IVF Abroad

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From this video you will find out:
  • What treatment options and solutions are there for women of advanced maternal age?
  • How can PGT-A work, and when is it recommended?
  • How does ovarian & endometrial rejuvenation work?
  • What kind of treatment options are available for single women and lesbian couples?
  • What are the newest advances in Reproductive Medicine?

Fertility in 2023: latest advances in Reproductive Medicine

In this webinar, Dr Oliver Pack, Fertility Specialist discussed all the latest advances in reproductive medicine in 2023. Dr Pack talked about  PGT-A, advanced maternal age, egg donation, fertility preservation, and ovarian reservation. He has covered the techniques applied in treatments and some ongoing investigations into experimental treatments.

Starting with a brief overview of Reproductive Medicine and fertility treatments in Spain. Based on data from 2020, Spain ranks as the third country with the highest number of fertility treatments. India and Turkey hold the first and second positions, respectively. One of the primary reasons Spain is relatively advanced in this field is due to the significant volume of people who come here for treatment, particularly for egg donation. Spain is a popular destination for egg donation treatments, attracting patients from around the world due to its high success rates.

Currently, around 9% of pregnancies are achieved through ART. Couples typically undergo IVF due to male-factor infertility, female-factor infertility, or a combination of both. Male factor infertility can often be resolved through techniques such as intracytoplasmic sperm injection (ICSI), which has been in use for many years and is highly efficient in addressing sperm-related issues.

On the other hand, resolving female factor infertility is more challenging as it depends on various causes. It is not uncommon for multiple factors to contribute to the inability to conceive, including issues with fertilization, implantation, and early-stage embryo development during the first trimester. Pinpointing a single cause can be difficult, and even if implantation fails, identifying all contributing factors can be a complex task.
Approximately 30% of infertility cases have a mixed origin involving both male and female factors. Furthermore, 40% of treatments are related to advanced maternal age, which is a significant concern. The age of the female partner plays a crucial role in fertility, as women produce eggs that are the same age as they are. This leads to challenges in both egg quality and quantity, as the ovarian reserve diminishes over time, and eggs cannot be regenerated. The number of viable eggs decreases each month, with only one dominant follicle growing and potentially being fertilized. Advanced age in women, typically considered to be over 40, significantly impacts the chances of success. The window of opportunity to achieve pregnancy becomes narrower as women approach their late 30s and early 40s, and beyond the age of 45, the chances of natural conception become nearly impossible.

Considering these factors, it is essential to focus on the age of the eggs rather than the age of the woman. Egg donation is a viable solution for women over 40 and even up to the age of 50, as it resolves the issue of diminished egg quality and quantity. However, for women who are 38 or younger, there are still chances of success with their eggs, although the quality of the embryos may be a concern.

Advanced maternal age – solutions

Preimplantation Genetic Testing for Aneuploidy (PGT-A) can help identify embryos with missing or additional chromosomes, providing insight into their potential to develop into a healthy babies. However, it’s important to note that PGT-A does not determine the overall health of the future child; it focuses solely on chromosomal abnormalities. The detection of abnormal embryos allows for their exclusion from the transfer process, reducing the risk of unsuccessful implantation or the birth of a baby with certain chromosomal disorders.

In cases where blastocysts (embryos at the stage of development on day five) cannot be obtained, couples often seek egg donation as a solution. Statistics show that couples who pursue egg donation in Spain have typically undergone five failed IVF cycles before seeking this option. The reasons for IVF failures can vary, ranging from a lack of viable embryos to cancelled procedures due to inadequate follicle growth. Each step in the IVF process presents uncertainties, from follicle response to egg quality, fertilization, embryo development, and successful implantation. The goal is to reach the blastocyst stage, as embryos at this stage have a higher chance of successful development. However, even if a blastocyst is achieved, there is still a significant question of chromosomal health, which can be addressed through PGT-A.

In summary, while there is still a chance of success with IVF for women over 38, the probability decreases as age advances. Embryos obtained from older women are more likely to have chromosomal abnormalities, impacting their ability to develop into healthy babies. For couples pursuing IVF with such embryos, the success rates remain relatively high if a euploid (chromosomally normal) embryo is transferred. However, even in these cases, success rates do not exceed 60% for live births.

The success rate for assisted reproductive technologies (ART) is around 60%, which is not bad considering the viewpoint of embryos. However, the problem lies in women older than 42, where it becomes challenging to find a euploid embryo. Even if one is obtained, there might only be one. In such cases, we consider egg donation.

Egg Donation: For couples facing these challenges, egg donation is a viable solution. Spain, known as one of the meccas for egg donation, offers numerous donors who provide high-quality eggs. This allows for the production of many high-quality blastocysts with a high rate of successful implantation and live births, ranging from 45-50%. The advantage of using donor eggs is that if one cycle fails, another attempt can easily be made. Egg donation provides a nearly 100% solution for age-related issues such as low egg reserve and poor egg quality.

Ovarian Rejuvenation: In cases where egg donation is not an option or is not accepted by couples for personal or religious reasons, ovarian rejuvenation is an experimental treatment that can be considered. This treatment involves injecting platelet-rich plasma (PRP) into the ovaries to stimulate follicle growth and possibly achieve a higher number of eggs. However, the effectiveness of ovarian rejuvenation varies, and it strongly depends on factors such as egg reserve, quality, and age. Clinical trials are currently underway to determine its true efficacy.

Fertility Preservation: Fertility preservation, specifically freezing eggs, is highly recommended for women. Ideally, it should be done before the age of 37 when the egg reserve starts to decline rapidly (although it starts to decline at 35). Freezing eggs later than 37 presents challenges due to lower egg quantity and quality. Additionally, it’s important to consider that around 30% of frozen eggs may be lost during the thawing process. To ensure a good chance of success in the future, it is advisable to have at least 15 frozen eggs when a woman is under 37.

New family models: In recent years, there has been an increase in new family models, such as single women choosing to become mothers and same-sex couples. For single women, embryo donation or egg donation is often the best treatment option, especially if they are over 40. In same-sex couples, the reciprocal IVF method (ROPA) is commonly used, where one partner undergoes ovarian stimulation to retrieve her eggs, which are then fertilized with donor sperm. The other partner receives the embryo and carries the pregnancy.

New Advances in Reproductive Medicine

Customized stimulation protocols have become a significant advancement in reproductive medicine. These protocols take into account factors like follicle count and AMH level, which are strongly related to age. The timing and type of stimulation are individualized decisions, and there is no general protocol that applies to everyone. Technological advances, including time-lapse imaging of embryo development, artificial intelligence for embryo grading, and advanced diagnostic tests, have improved the success rates of ART.

Treating Male Factor Infertility: Male factor infertility is a common issue, and various techniques can be used to address it. In cases where sperm quality is affected, methods such as magnetic cell sorting, sperm selection based on fragmentation rates and apoptosis, and advanced spermogram analysis can be employed to separate and select good-quality sperm.

In conclusion, the field of reproductive medicine has made significant advancements, offering solutions such as egg donation, ovarian rejuvenation (still experimental), and fertility preservation. New family models, including single women and same-sex couples, can benefit from these treatments. Customized stimulation protocols, advanced diagnostic tests, and techniques for treating.

Advancements in Reproductive Medicine & Innovative Techniques

Identifying the window of implantation (WOI)

Endometrial receptivity tests are genetic tests that analyze the cells of the uterine lining to determine the degree of receptivity. Biopsies are routinely performed, especially when the first embryo transfer has failed. The test provides valuable information about the optimal timing for embryo transfer, which is typically five days after starting progesterone. However, receptivity can vary, following a curve of increasing receptivity, reaching a peak, and then decreasing. By assessing receptivity, we can adjust the timing of progesterone in the natural cycle, increasing the chances of a successful transfer.

Immunological Testing

In addition to endometrial receptivity tests, we also conduct immunological testing, specifically for natural killer cells (KIR) and lymphocytes. We examine different cell types involved in the immune response against the embryo. Additionally, we perform HLA-C genotyping, which analyzes the compatibility between the receptors on natural killer cells and antigens on the embryo’s surface. Certain combinations of HLA-C types may not be compatible, potentially impacting pregnancy success rates. While these findings are not yet proven, they offer insights into potential factors affecting fertility.

Artificial Intelligence (AI) Applications

Artificial intelligence is making its way into reproductive medicine as well. AI technology is being used to analyze embryo development and structure, assisting embryologists in embryo selection. By assessing images of embryos, AI systems can contribute to the identification of high-quality embryos, complementing the expertise of embryologists. Although AI’s role is currently limited to embryo selection, there is potential for future applications, including sperm selection. As AI continues to advance, it may become an even more valuable tool in reproductive medicine.

Conclusion

These advancements in reproductive medicine demonstrate the integration of technology to improve success rates and enhance patient outcomes. From endometrial receptivity testing to immunological analysis and the use of AI, these techniques offer a comprehensive approach to addressing infertility issues. While AI is still in its early stages in this field, its potential impact is promising. With ongoing research and development, we can expect further innovations that will continue to revolutionize reproductive medicine.

- Questions and Answers

What is the upper age limit for fertility rejuvenation?

There is currently no specific age limit for fertility rejuvenation. The effectiveness of fertility rejuvenation treatments depends on individual factors, and it is challenging to determine which women it can benefit. The success rate of fertility rejuvenation is still relatively low, with only around one-third of patients experiencing improved outcomes. Even in cases where more eggs are obtained, it does not guarantee the development of high-quality embryos or successful pregnancies. Further research and investigation are needed in this field to gain a better understanding of its potential.

My latest IVF at age 36 resulted in 21 eggs, 10 blastocysts, and 10 fertilized (ICSI) and after rPGT-A – there were 3 euploid embryos. Is this a satisfactory result? How might this increase the potential of pregnancy and live birth?

3 euploids are not a guarantee to have a baby, but chances are really good with 3 embryos. I would say that in 1 of the 3 attempts you will be successful, around 80%. 36 is also a very good age, quality is still conserved. She has also got 21 eggs and a very high blastocyst rate, with 10 blastocysts from 22 eggs. 3 euploids is a slightly low euploidy rate. Statistically, it would be around 60%, this is only 33%. However, it’s still an amazing cycle.

With embryo donation? Do you know the age of the woman when the embryo was created?

Yes, embryo donation follows the same rules as egg donation and sperm donation. The rule is that the donor woman has to be under 35, and the donor has to be under 50. This is required by law, regardless of whether the embryo has already been generated or if we are generating it for the patient. The age of the woman is one of the data points that the patient will receive once she is pregnant and reaches the end of the first trimester. This information is important for the gynaecologist to know because when they want to do the first-trimester screening for Down syndrome, age is one of the parameters that enter into the equation. It doesn’t matter when the embryo was created because the embryo is frozen in liquid nitrogen. The time of freezing does not negatively affect the quality of the embryo. So it doesn’t matter, and it’s not something that we reveal. The only data we reveal about the parents of the embryo is the age.

Could blastocysts that are euploids have implantation or development issues due to sperm DNA fragmentation, or does PGT testing reduce the likelihood of this being an issue?

When an embryo is euploid, it’s supposed to carry 4 to 6 chromosomes in the cells, so it has the best possible success for implantation and live birth rates. DNA fragmentation, which refers to the fragmentation rate of sperm DNA, can have a negative impact on the implantation rate and the chances of the embryo being viable. However, once we have the result from the PGT-A confirming that the embryo is euploid, it doesn’t matter whether the sperm was fragmented or not. This will still be a very good embryo, and euploid embryos are the best embryos we can get. They have lower abortion rates and slightly higher success rates in live births. It also strongly depends on maternal age, but what is clear is that the chance of having a miscarriage is reduced.

It seems to be increasingly common to culture embryos until day 7, especially for couples with fewer embryos. What is your opinion on culturing embryos to this day?

This practice varies depending on the specific laboratory culture and composition. Some cultures may slow down the embryo’s development, resulting in the blastocyst stage being reached on day 7 instead of day 6. While day 7 transfers have been reported, it’s important to note that in our clinic, the maximum time an embryo stays in culture is still day 6. If an embryo does not develop into a good blastocyst by day 6, it will not be selected for freezing as it is considered of lower quality. This is our clinic’s protocol, and we do not require 7 days to reach the blastocyst stage.

I have secondary infertility and underwent egg donation, resulting in 2 euploid embryos. However, the first transfer was unsuccessful, what can I do to improve my chances for the second transfer?

When it comes to implantation, the term “challenge” does not imply that pregnancy cannot be achieved. It simply highlights that successful implantation is a significant hurdle for every embryo. Even with a high-quality embryo, successful implantation is a complex process that involves various factors, cell types, and interactions among cytokines. While we are still in the early stages of understanding implantation fully, we have observed cases where numerous perfectly prepared linings fail to support embryo implantation. Similarly, some women have achieved success with their first transfer but face failure with subsequent attempts using the same embryos and lining preparation protocol. The reasons behind these outcomes remain unknown. Roughly speaking, the chances of success for each transfer are around 50%, possibly slightly higher if the embryo is of high quality. To improve the chances of the second transfer, it is crucial to ensure that the uterine lining is well-prepared. Factors such as the timing and duration of progesterone administration play a crucial role. The lining thickness should be at least six millimetres, and its structure should be optimal. In cases where it is the last remaining embryo, considering a hysteroscopy is advisable to rule out any issues that may not be visible on scans, such as polyps, fibroids, adhesions, or micro polyps. Additionally, an endometrial biopsy can provide insights into the window of implantation and the ideal duration of progesterone supplementation. Analyzing natural killer (NK) cells can also be helpful in ruling out chronic endometritis, as these conditions can negatively impact implantation. In summary, if it’s your last remaining embryo, it is essential to consider both a hysteroscopy and an endometrial biopsy to increase the chances of success.

Does your clinic offer any technological advances or advice in cases of recurrent miscarriages with your own eggs and donor eggs?

In cases of recurrent miscarriage, the reasons why embryos that have started implantation stop developing the placenta are often related to placentation issues. Rarely, malformations in the uterus, such as a septum or atrophic lining can contribute to miscarriages. There are also certain conditions and autoimmune diseases that increase the risk of miscarriage. However, in many cases, the causes of miscarriage and non-implementation are similar. To determine the underlying causes, tests such as endometrial biopsy and hysteroscopy are necessary. These tests help rule out issues related to the uterus and lining. Additionally, a thrombophilia screening is recommended to assess the risk of thrombosis. This extensive blood test is typically ordered by clinics specializing in recurrent miscarriages. Finding the cause of recurrent miscarriage often requires ruling out various factors.

Can people apply to be part of an upcoming clinical trial?

Yes, when conducting a clinical trial, we offer participation to all eligible patients. However, at the moment, I cannot provide specific data on when the trial will start. As mentioned before, we are planning trials on ovarian rejuvenation and endometrial rejuvenation, where platelet-rich plasma (PRP) is utilized. PRP has shown promising results in endometrial rejuvenation based on our experience and that of our colleagues over the past five years. Although time constraints have limited our research, we are planning a clinical trial for endometrial rejuvenation. If a patient meets the specific criteria for the trial, they can participate. However, they would need to be a patient at our clinic, and the trial must have already begun.

How do embryo grades relate when all embryos are euploid? Is grade still taken into account when choosing which one to transfer? If not, how do you choose?

Yes, we still consider embryo quality when all embryos are euploid. However, we prioritize morphological criteria less when embryos are euploid. Quality is still taken into account, but it is not as significant as the embryo being euploid. For example, a 5AA embryo may be considered better than a 3BC embryo. Quality remains an important factor, but euploidy has a higher priority.

Does the father being much younger than the mother (27/43) increase the chances of live birth?

Not significantly. As I mentioned earlier, sperm quality is generally maintained until the age of 45. We do not observe a significant difference in sperm quality between a 20-year-old and a 45-year-old. The negative impact of sperm quality becomes noticeable when the man is over 50 or 55. At that point, we may see fewer embryos, lower-quality embryos, and a lower euploidy rate during preimplantation genetic testing for aneuploidy (PGT-A). However, there is no significant effect on live birth before the age of 50.

I am 35, I have low ovarian reserve secondary to endometriosis and poor response. They have had good fertilization rates but created only 4 blastocysts in total and experienced 3 failed transfers. Should we request PGT-A?

In this case, the person is 35 years old, and for young individuals, we do not recommend PGT-A as much because the chances of having euploid embryos are higher. PGT-A has limitations as well. We can only analyze a small number of cells, usually five or six, which are taken from the trophectoderm, not the inner cell mass (ICM) of the embryo. If the PGT-A result indicates aneuploidy, which means the embryo is abnormal, it will be discarded as it is not allowed for transfer. However, it is possible that the embryo had mosaic cells, with the ICM containing normal cells. This becomes a problem when the embryo’s overall quality is considered good, as it is expected to be at the age of 35. We also don’t use PGT-A extensively in donor cycles for similar reasons. Statistically, there isn’t a significant difference between doing PGT-A and not doing it when the eggs come from young donors under 35, as in the case of the individual asking the question. Therefore, I agree with the colleague who recommended not doing PGT-A. Out of the 4 blastocysts created, 2 may have been mosaic embryos, which can still result in a healthy baby. Mosaicism means that the embryo has a mix of both normal and abnormal cells. If you select only the normal cells, you may transfer the embryo, and it can still lead to a healthy baby, albeit with a slightly higher risk of miscarriage.

I have had 7 donor egg blastocyst transfers within 6 cycles, but there has been no sign of implantation. None of the embryos have been tested, and I didn’t have an ERA test, my clinic does not believe in this test. Besides the tests mentioned and immunology tests, are there any other investigations I could consider?

For cases where multiple embryo transfers have failed to implant, we usually prioritize the endometrial biopsy and hysteroscopy as important tests. These exams help analyze the endometrium and rule out chronic endometritis or the presence of plasma cells. However, even with these tests, we sometimes struggle to find the key to success. In such cases, we may consider endometrial rejuvenation. Endometrial rejuvenation involves introducing platelet-rich plasma (PRP) into the uterine cavity during a hysteroscopy. This procedure has shown success in cases where multiple embryos have failed to implant. While it’s not a guaranteed solution, it has shown promising results in certain situations. We reserve this option for patients who have experienced multiple implantation failures. We plan to conduct trials soon to further prove its efficiency.

What impact does a cyst have on the IVF cycle and why does it form?

If there is a large cyst, it can occupy space and hinder the growth of other follicles. However, the impact depends on various factors, such as the size and location of the cyst. In some cases, we may choose to puncture the cyst, while in others, we leave it as it is. The decision depends on the number of follicles and the specific circumstances. It’s challenging to give a precise answer without directly examining the cyst.

Is a chemical pregnancy with a euploid embryo a good sign of a future ongoing pregnancy?

Yes, especially for women who have never been pregnant before, a chemical pregnancy is an encouraging sign. It demonstrates the ability to conceive, which is a significant step in the treatment process. While there are no guarantees, having a strong embryo, especially a euploid one, increases the chances of a future ongoing pregnancy.

I’d like to ask about performing PGT-A at the age of 43. I have been advised not to undergo PGT-A to avoid potential damage to the only viable embryo. What are your thoughts?

As mentioned earlier, there is a possibility of discarding an embryo that could have resulted in a successful pregnancy. However, there is an important consideration. Some chromosomal abnormalities, such as trisomy 21 or trisomy 18, are not detectable until the end of the first trimester. Therefore, I usually recommend performing PGT-A even if there is only one embryo, especially for women over 38. In the case of a 42 or 43-year-old, I would definitely recommend considering PGT-A.

I have Hashimoto’s and will be undergoing my first donor egg transfer this year. I’m concerned about implantation failure, even though my lining has been good on all scans. I’m worried about the impact of autoimmune issues. What can I do to prepare my body for the transfer and make my lining receptive?

Hashimoto’s is a common autoimmune disease, and its prevalence is not a coincidence. Unfortunately, there are no specific treatments to avoid or mitigate the negative impact that Hashimoto’s and other autoimmune diseases have on implantation failure. One approach is measuring the antibodies and their levels, but there is no evidence that reducing antibody levels helps in any significant way. For patients with autoimmune issues, I recommend doing a biopsy even before the first transfer. This allows us to detect any alterations in natural killer cells and T-helper cells, and the medication used to treat these alterations may also help reduce the impact of Hashimoto’s. However, it’s important to understand that there is no definitive treatment for this. Patients with Hashimoto’s may require more transfers compared to those without autoimmune diseases and a normal uterus. Typically, a woman without autoimmune diseases and a normal uterus may need 2 to 3 transfers to achieve a successful pregnancy through egg donation. However, for women with Hashimoto’s, I usually recommend a treatment plan with a guarantee of 5 or more attempts, including the transfer of up to 5 embryos. It may take a little longer, but success is still possible.

Can high TH1 and TH2 cytokine levels as well as NK cells activity in the blood reduce the chances of successful implantation and achieving an ongoing pregnancy?

We no longer determine these levels in the blood. There is no significant relationship between the levels in the blood and the levels in the uterus. Instead, we focus on evaluating NK cell activity and other cell types, such as TH1, TH2, TH17, T Regulators, and B cells, through an endometrial biopsy. This biopsy provides more reliable information because it is where the embryo will implant and interact with these cells. NK cells, for example, derive their name from their function in killing viruses in the blood. However, their function in the blood is unrelated to implantation, so there is no need to determine NK cells in the blood anymore.

If I want to try with my own eggs but have premature ovarian failure, FSH level over 100, AMH of 0.5, AFC of 1, and no cycles without hormone replacement therapy (HRT). Would you try a particular stimulation protocol? I am 37.

Based on the given information, it appears to be a very complicated case. With an AMH of 0.5, indicating a very low egg reserve, even ovarian rejuvenation with PRP treatment is unlikely to be helpful. It would be necessary to thoroughly examine the patient’s case, including conducting a detailed analysis and assessing the presence of follicles, before providing a definitive recommendation. However, if it is determined that there is only one follicle or no follicles at all, the chances of success would be very low. In such a situation, I would advise against attempting treatment with the patient’s own eggs.

Is celiac disease an autoimmune disorder, and does it impact outcomes in egg donation?

Yes, celiac disease is an autoimmune disorder, and there is some evidence that it might have an impact on outcomes in egg donation. We also determine the antibodies for celiac disease, so it is possible to assess its presence.

Does the oocyte quality is directly related to the woman’s age?

It is strongly correlated. As women age, the quality of their eggs tends to decline. There is no direct test to stimulate the growth of good quality eggs. Nature naturally selects the best eggs, and follicles that grow better have a higher chance of containing good quality eggs. In fertility treatments, we aim to use lower doses of hormones to encourage better egg quality by allowing the follicles to grow selectively.

Is there a test to determine the quality of the eggs?

The quality of eggs is observed during the cycle once the eggs have been retrieved. We assess the percentage of eggs that fertilize, the percentage that develop into blastocysts, and the percentage of euploid embryos during preimplantation genetic testing for aneuploidy (PGT-A). These tests provide insights into the quality of the eggs. However, there is no way to determine egg quality before the cycle. Age is strongly associated with egg quality, so we can estimate the quality based on statistical correlations.

Is there a test to determine the cycle in which a good quality egg will ovulate?

In IVF, we aim to prevent ovulation by using agonists or antagonists to suppress the luteinizing hormone (LH) surge. This ensures that we retrieve the eggs shortly before the patient would naturally ovulate. The trigger injection is administered once the eggs have reached a certain size and are deemed mature. Eggs are retrieved 36 hours after the trigger injection to capture them before ovulation occurs. So, in a way, the timing of egg retrieval is determined by preventing ovulation.
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Authors
Dr Oliver Pack

Dr Oliver Pack

Dr Oliver Pack was born in Solingen, Germany. In 1994, he travelled to Spain to start his medical studies. In 1999, he obtained his title from the Universidad de Salamanca. Soon after, he started his General Practitioner specialisation at the General Hospital of Alicante. His interest in closeness to the patient and personalised treatment motivated him to specialise in Reproductive Medicine. In 2018, he became part of IVF Spain's medical team.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.