The science of (in)fertility

The 2 main roads leading to infertility (apart from anatomical issues like uterine issues or blocked tubes) are:

1.     Declining egg quality/number
2.     Factors that hinder implantation or the development of the baby (autoimmune or clotting factors)

The decline in egg quality may occur by three very different ways:
  • Biochemical aging: Herein, the egg has metabolic issues; it divides poorly and often does poorly in IVF. People with this issue hit menopause earlier. Importantly, this problem is correlated with the antral follicle count, and women with this issue present with diminished ovarian reserve (DOR).
  • Ovarian aging: Herein, the eggs may have no metabolic issues, even at an advanced maternal age. They may grow well in IVF, and women with this issue are often found to hit menopause much later. Yet, something is wonky with the meiotic process, and they produce eggs with aneuploidy or more subtle genetic abnormalities. Importantly, this need not correlate with the antral follicle count, and women with this issue do not present with a diminished ovarian reserve. Indeed, they may have a great antral follicle count/AMH/FSH. Women with this issue could present with unexplained infertility or recurrent pregnancy loss (RPL).
  •  Polycystic ovarian syndrome: This is a syndrome characterized by hormonal imbalance. The hormonal imbalance is attributed to insulin resistance. In other words, PCOS is related to Type 2 diabetes. Many women with PCOS cannot ovulate because the hormonal regulation is out of sync. Some other women with PCOS do ovulate, but can have other issues.

Working your way around biochemical aging (i.e., DOR):
To reiterate, when you have a DOR, it means that the issue is biochemical aging: these eggs may be metabolically poor: their capacity to keep dividing has been compromised. In women of an advanced maternal age, this goes hand in hand with ovarian aging, where the chromosomal division is also compromised. 
Diagnosing DOR: One important point on determining ovarian reserve: FSH and Estradiol, the gold standards for many years have been proven to be inaccurate in certain cases. A woman might have normal FSH and have a DOR diagnosis. The only reliable marker for ovarian reserve is your antral follicle count(AFC). AMH is used as a marker for your AFC, but the problem is AMH can vary based on your vitamin D levels, and hence is not reliable.
Treating DOR: There is very little one can do when you have a diminished ovarian reserve. You can try to coax the best response possible from the few remaining eggs using supplements (See the CCRM cocktail thread). 

Working your way around ovarian aging (unexplained infertility or RPL)
Diagnosing Ovarian aging: As previously stated, this is the most difficult to diagnose, because everything could check out as absolutely normal. You have to make the diagnosis based on what happens to you, and not any laboratory tests.
So your embryos are genetically abnormal, but you have no way of figuring it out, just by looking at the embryo after IVF. What happens when the uterus sees an abnormal embryo that can divide very well? Does it implant? A really interesting study found that the uterus of fertile women may reject genetically abnormal embryos, while that of some other women (with recurrent pregnancy loss) may accept such embryos. Based on this, women with ovarian aging along could hypothetically be divided into two groups:
 Group 1: Has difficulties getting pregnant because the uterus rejects the abnormal embryos
Dealing with RPL combined with the super fertility:
You cannot fix what is messed up with the chromosomal division process, because nobody knows what causes it. You can deal with this situation in one of 3 ways:

1)   Rely on luck to find your one good embryo: After 3 failed pregnancies, I did not have what it took to keep hoping for luck, but many people have gone on to have healthy children by this route.

2)   Do IVF, and do a day-5 biopsy of your embryos, followed by chromosomal microarray analysis to test all chromosomes. I've written very lengthy blogposts on this topic (see the first of the two here), but basically, to sum up all that: If done by a competent clinic, this does not damage your embryos, and can give you comprehensive answers about how many of your embryos are normal (note that only around 50-60% of day 5 blastocysts of healthy young women are normal). It can help you decide if the time has come to give up on your eggs. Or more happily, it can help identify the 1-2 normal embryos.
Some things to keep in mind: 
Do not go for a day-3 (cleavage stage) biopsy. This can damage your embryos, and cannot catch mosaicism (where some cells are normal but others are not). In addition, this process is flawed in that some embryos that test as normal on day 5 and go on to make healthy babies were found to test as abnormal on day 3.
Do not go in for FISH testing as the genetic test to detect aneuploidy.  
If your clinic offers a Day-3 Biopsy and FISH, don’t stick with them.

3)    Do IVF and go for surrogacy: The key here is that the discriminatory uterus of the surrogate may help in selecting the few good embryos you have (This is highly speculatory on my part: I base this on the fact that I got pregnant almost every time, even with embryos that were genetically abnormal; However, 2 surrogates rejected 4 out of my 5 "high-grade" embryos before getting pregnant with one embryo).

Working your way around PCOS
Diagnosing PCOS: Different women can have only certain or all features, which is why it can be often missed in diagnosis. You need to fulfill atleast 2 or 3 of these requirements to suspect PCOS. 
Physical characteristics: Weight gain, hirsutism (abundant, thick facial hair, courtesy an excess of male hormones), dark patches of skin, acne, ovulatory issues (never have periods or rarely get one)polycystic ovaries (high AFC) on ultrasound.
In Blood: Increased Day-3 LH to FSH ratio (normal is 1), increased androgens (DHEAS, Testosterone), increased insulin resistance, increased AMH.
Sometimes PCOS can go undiagnosed for years. Take my case for example: I am skinny (never put on weight), have only slightly thick facial hair but nothing about it screams classical hirsutism, and ovulate like clockwork. I also have no insulin resistance, increased testosterone, or a high LH:FSH ratio. In short, I have almost no cause to suspect PCOS. But what I do have is high AMH, polycystic ovaries and my DHEAS is mildly elevated. Enough to get me treated for PCOS? I tried both myo-inositol and metformin, and the myo-inositol seems to have helped.
One thing about PCOS though- women with this syndrome, in certain cases, could have a longer lasting ovarian reserve- this is because depletion of eggs occurs at a slower rate- more details here.
Interestingly, there seems to be a link with PCOS and autoimmune hypothyroidism (see below): both interfere with pregnancy and when a lot of women have these 2 seemingly unrelated issues together, it is a little intriguing.

PCOS treatments:
1.   Metformin: This is a drug used to treat insulin resistance in type 2 diabetes, a condition where you are producing more than enough insulin, your body just stops using it efficiently. Recently it has come to light that in some mysterious manner,  PCOS can happen because you have issues with insulin resistance. Treatment with metformin can reduce many of the manifestations of PCOS, can make women start ovulating again, can decrease the male hormones that cause the hair thickening, and can decrease antral follicle counts and AMH. Note : Not all women with PCOS have detectable insulin resistance, but even in the ones that have no resistance, metformin, in some mysterious way, can help.
2.   Myo-insoitol: This is naturally found in the body, and plays a very ill-understood role in the insulin resistance that is responsible for PCOS. Importantly, people are finding that though they do not understand its mechanisms of action, it is a miracle supplement for a subset of women with PCOS, in that it can induce ovulation and fix some of the other PCOS symptoms. It can also improve egg quality during IVF. This supplement is part of CCRM regimen. See my post of myo-inositol and its affects. Overall, what seems to be best is a combination of myo-insoitol and a closely related molecule, D-chiro insoitol. This is marketed as "INOFOLIC combi." However, this one is hard to find, and myo-insoitol + foloc acid alone seems to be almost as effective. This one is available easily as "Pregntitude."

Vitamin D Deficiency
This is fairly common given that most people spend very little time in the sun, nowhere close to what nature intended us to be doing.  There is increasing evidence that deficiency in this can contribute to infertility. I've got a few labeled posts on the subject, you can start with this one.
The mechanisms by which vitamin D can contribute to baby-creating are many, and it works on different levels. We don't even know a fraction of these, but progress is being made here.
  • Vitamin D and AMH:  The AMH gene has a mechanism by which it can be turned on by Vitamin D. This is a novel and interesting finding ----what does it mean? Does it mean that, if you are vitamin D deficient, your AMH levels could be falsely low? My story does seem to suggest this is true.  My other markers for ovarian reserve(Day 3 FSH/E2, antral follicle count) had come back with excellent results. When we finally tested AMH, it was far too low to fit in with my other tests. In this same blood test, I had also found out that I was Vitamin D deficient. So I went looking for a connection between the two, and I found what I mentioned above. So I first tried to correct my vitamin D3 deficiency and then retested AMH and it was like magic- Vitamin D3 had increased 4 fold, and so had AMH! I've been in correspondence with doctors to conduct clinical trials examining this-- we will see what comes out of it! UPDATE: Yeah, its true, and has been scientifically shown in this study.
  • Vitamin D, PCOS and Insulin resistanceIt is baffling that PCOS, a  hormonal dysregulation syndrome, appears to stem primarily from insulin resistance. Many women who have PCOS also are Vitamin D deficient (one study put this number as high as about 40%). Is there a link between these 3 things? Do women get PCOS maybe because they do not have enough D? I have wondered about this, but did not see a logical link until today, when a study that mentioned that Vitamin D could help correct insulin resistance. Fascinating stuff, really--- do people get vitamin D deficient first, then develop insulin resistance culminating ultimately in PCOS? Note that this is not obviously the case all the time-- like I've said before, there are multiple roads leading to PCOS; this is just possibly one of them.
  • Vitamin D has directly been shown to be necessary for a gene involved in implantation-the original paper is here.
  • Low vitamin D levels are definitely associated with autoimmunity. Antiphospholipid sydrome (APS) is one of the more common immune causes of infertility. This paper links APS and Vitamin D3 deficiency.
  • Vitamin D deficiency earlier in pregnancy is correlated with a higher risk for preeclampsia. 
  • Vitamin D deficiency is a risk factor for spontaneous pre-term birth.
  • Vitamin D deficiency now looks like a risk factor for Autism 
  • Vitamin D and fetal programming:Vitamin D induces more than 3,000 genes, many of which have a role in fetal development . Interestingly, in later life, children of mothers with low vitamin D serum levels during pregnancy suffer more often from chronic diseases such as wheezing and asthma, schizophrenia , multiple sclerosis , type 1 diabetes mellitus and insulin resistance. 
  • Vitamin D deficiency is also implicated in Male factor infertility.

About 90% of people with infertility are also vitamin D deficient. Checking for deficiency and correcting it is a smart way to go.


Hypothyroidism and Infertility
There is a lot of controversy and debate over what constitutes a normal range for TSH. The old normal range of TSH was 0.4-4 (the previous upper limit was 5). The new revised normal range of TSH is 0.3-3. Beware, your doctor may be a dinosaur that still follows the old guidelines.
There are two risk groups of people with thyroid issues, the ones with high TSH and the one ones with high TSH and the autoantibodies. The latter group is at higher risk. There are 2 theories of how this could contribute to infertility/miscarriage. a) there is a paucity of thyroid hormone available to the developing baby or b) the anti-thyroid antibodies are representative of a too active immune system, which could be attacking the embryo, or the preventing implantation, or cause issues later in pregnancy. This is a great review on the topic, to take to your doctor.
What constitutes high TSH? Having a TSH level higher than 2.5 is apparently a risk factor for miscarriage even if you are antibody negative, though the risk only doubles, going to 6.1 %.
Other possible consequences of having high TSH- your child could be at higher risk of developing ADHD.
Higher TSH has also been linked to lower cognitive function. My take on both studies is that they do not make terribly strong cases for it, though a very slight detriment is definitely plausible.
Summary on thyroid issues:
  • If you have TSH levels over 2.5, you should get tested for anti-thyroid autoantibodies (ATA). Since 10% (approximately) of the population has this anyway, it is a good thing to rule out.
  • If you do have ATA, here is a list of stuff to take which could possibly help deal with the issue.  Selenium is reported to lower anti-thyroid antibody titers. Becoming Vitamin D replete also is supposed to help.
  •  While conceiving, err on the side of caution- if you are fround to have highish TSH (I'd say over 2), find a competent endocrinologist who will manage it so it stays around 1. This is accomplished by giving you the thyroid hormone T4.
Overall, I think getting a clear picture at the getgo is crucial. Overall, if you do not have age-related or uterine-structure related IF, then ruling out the unholy trinity of PCOS, Hypothyroidism and a vitamin D deficiency is the next logical step: this trio is probably the cause for a significant portion of IF cases, along with exploring male factor IF, which is not covered here.
Antral follicles early in your cycle (ultrasound)
FSH, LH, prolactin (day 3 blood tests)
AMH, Testosterone/DHEA (Fasting blood tests are preferred)
Vitamin D (low in about 40% of women with PCOS, and 91% of infertile women) (blood test at any point in your cycle)
TSH and Anti-thyroid peroxidase antibodies (seen in around 10% of the population) (blood test at any point in your cycle)

In summary:

Diagnosing DOR is straightforward, but deciding what to do next is never easy.  
If you are of an advanced maternal age, you may be dealing with both biochemical aging (DOR) and ovarian ageing. If you want to try to succeed with your own eggs, give it your best shot with IVF while taking supplements (see the post on the CCRM supplement list).

If you are young, do not appear to have DOR or PCOS, then you may have a case of early onset ovarian aging. Diagnosing this is difficult and will take a very long time, because there is no way to figure it out by lab testing. All you may have to go on is either an inability to get pregnant (which some people may also attribute to a hostile uterine environment) or recurrent pregnancy loss: see the section on the 3 ways to proceed in this scenario.

Diagnosing and dealing with PCOS is fairly straightforward. However, if neither metformin nor myo-inositol in combination with ovulation-inducing drugs works for you, then it is more difficult.

I would love to get your feedback on all this information. Please comment/ask questions!


    1. Jay, I just had my Vitamin D level checked and am waiting for the results.

    2. Whitney, I kind of hope you come back deficient, because then you atleast have something you can 'fix'. Not being able to identify what is the problem really sucks.

    3. Thanks for posting this - Vitamin D3 has been the main cause for MANY MANY health issues I've had. And studies and countless tests ... i've gone undiagnosed and had case studies done on me. In short, it's the sever Vit D3 deficiency that made me feel that way. 100-101 fevers for 5 years. Infiltrate on lung - went away after D3 supplement and after 2-3 years of scans, bone marrow biopsies, lung biopsy etc.. Docs don't always test for D3 soooo I'm hoping this helps bring awareness to other ppl. It's a simple blood test and it can be fixed!! I take 8000 IU's / day (drop form)

    4. Jay - thank you for commenting on my blog- I love you for taking the time, energy and resources to research and document all of your findings for us.

      I did have my Vitamin D levels checked a while agao and I was low...I have been a substancial dosage since and my levels are finally back in range. I am not using cheapie suppelemtns, I am on 5000iu and my levels appear to be in range again. Thannk you for pointing this out.

      The inflammation stuff is new to me, so I am going to be doing a ton more research on it- I'll be reading more of your blog and whatever else I can get my hands on. I am trying to figure out what tests I can take and what treatments I can use to help get my body healthy again.

      Thanks again for your comments and support.

    5. Oh my gosh, you're a wealth of knowledge I'm so glad I happened upon your blog! (I saw your very in depth response about Finn's tumor and clicked over).

      Thanks to a bout with melanoma, I have been out of the sun and slathered in SPF for years which resulted in a Vitamin D deficiency (obviously) but I NEVER would have thought that it would have contributed to my fertility issues.

      My core "issue" was that my endometrial lining is too thin to sustain a pregnancy which they could never quite figure out but I was pushing them to find out if it was correlated to some really weird results I had with my shbg and testosterone levels.

      Luckily, despite a >6mm lining we were able to conceive and have a successful pregnancy but the issues for TTC2.0 are already on the horizon.

      You've given me some great resources to check out! THANK YOU!

    6. Love you. Thanks to you, I realized my vit-D is too low. I'm currently working to correct it. Baby Dust to you. Thank you for sharing.

    7. Hi, my husband and I have been ttc for almost 2 years. I've had 2 m/c in the past year and am desperate to figure out bloodwork came back normal and now i'm scheduled to have an hsg test in the next week or 2. I had to beg my gynecologist to put an order through for my Vitamin D levels. Finally she did and they are low (18L). Do you think this could be why I've been miscarrying? Should I still do the HSG testing?? Thanks for any help/advice!

    8. Sorry for the delayed response, I just saw this comment. The answer is discussed on this post

    9. Thanks so much for posting this information. I also have normal fsh, e2 numbers, but a very low AMH .17. We just found this out today and are heartbroken, but hoping that a d3 test will confirm that is the issue. If nothing else, at least it's hope.

    10. Very interesting. I actually have had low vitamin D in the past and my doctor recommended taking a supplement. I'm not sure why or when I stopped taking it, but I am curious now if I should start again...

    11. Found you through ICOMLEAVWE. Love the list of tesst every woman should get. Fortunately I am not shy but I had to advocate very strongly for all those tests, which I got. BUT one I would add to this list is to get the guy tested. No one ever thinks to check the man but it can be a factor in 40% of IF cases.

    12. I just love your blog, specially the scientific information! (i'm a scientist to) I'm not TTC yet, but I then I'll ask for every test in this list.

    13. Thanks for this. My RE tests for TSH, but nothing else thyroid related. My TSH was "within normal range" according to him, but I went to an endocrinologist for a second opionon and she was convinced it was high enough to be a cause for concern. She actually wants me to take 3-6 months off TTC to allow the synthroid to do it's job. I will see what my RE thinks about this. But it is shocking that their opinions can be so different.

    14. MMMsecret...doctors are people of strong and difficult-to-sway opinions and too many of them do not keep up with the latest findings in science. Its kind of hard to decide who is right, but at the end of the day, its best to err on the side of caution. Your endocrinologist is obviously familiar with all the literature cited above, you are in good hands.

      I think 1-2 months should be enough for the T4 to do its job. I also urge you to get your vitamin D levels tested and treated if necessary (talk to your endo about this, if she questions this, just ask her to run a "pubmed" search on 'thyroid and vitamin D', and also take selinium if you are anti-TPO ab positive.

    15. Thanks for pointing this out. It takes so long to really compile good research. My TSH is 2.83...I'll have to ask my RE what he thinks.

    16. Jay, I also am a scientist (albeit a social scientist!), and I, too, spend a great deal of time reviewing medical literature to enhance my fertility. It is both empowering and shocking due to the misinformation floating around out there. Thanks for the information! K.

    17. Ok so I have a new TSH of 2.68 and my Vit D is 35. Thoughts?

    18. Mrs Green Grass, I think your D3 is just fine. I'd probably supplement with a small dose- like maybe 600 IU/day just to raise it a notch, but I do not think anything more is necessary. Basically, however, your TSH is consistently slightly over 2.5, and will increase if you get pregnant.

      In this area, I'd get tested for anti-thyroid antibodies. I'd also find an endocrinologist who is willing to treat you with T4 hormone, to bring your TSH to around 1 for the next round of conception. From my experience, a lot of REs toss aside the study where it shows that a low TSH is ideal for conception and lowers risk for certain issues in pregnancy, but endocrinologists take those studies more seriously.

      See a blog by a person in a similar situation below.

    19. Nice post!! keep it up!!Female infertility is an extremely sensitive issue and is increasing in India due to numerous reasons. These are hormonal problems, scarred ovaries, premature menopause, and follicle problems etc. its quite difficult to select best female fertility supplement in Availability of many fertility treatments.

    20. I agree with you, but I'm curious: The most common objection I hear from people I know who are pro-life is that an impotent couple who wants a child can get the embryo implanted in herself. I maintain that it's wrong, but the recourse I fall back into is natural law theory when asked to explain (which is perfectly fine, but in my experience not that convincing). So are there any more concrete reasons to explain why that's wrong? Here i suggest peoples to go INDIA for IVF surrogacy, then you must search for Surrogacy India, Surrogate mother India, IVF India, IVF clinic India & IVF cost india. I found Go Surrogacy for this treatment in India. Hope you also like these.

    21. male fertility is very sensitive issue in india.Now, you can enhance your fertility by specifically designed, doctor approved and scientifically validated male fertility supplements.

    22. I am much pleased with your work. You put very helpful information. I just want to thank you for sharing your information and your blog is simple but attractive.
      Treatment of Infertility

    23. The info on links between PCOS & Vitamin D deficiency is so interesting. I haven't read that anywhere else, but my wife experiences both. No matter how much Vitamin D supplement she takes, she's still always a little deficient.

    24. Good topic and it elaborates all the process very clearly and share it to all infertile parents how to check their fertility and what checkups must be done to prove it.

      Infertility Solutions