Tuesday, July 3, 2012

A Step By Step Guide To The IVF Process: Step One -- Stimulation

Dear Readers,

This is the second part in the series I have begun to help answer what In Vitro Fertilization (IVF) is and how it works with my world-wide Blog audience. What you read here is what I also provide my patients with on a daily basis. I plan on going into some detail but in a way that is understandable to the normal (lay) audience, and not the medical or scientific one. I hope that this will not only clarify what you will go through, but explain why things are done a certain way and what the goals of each step are. I also want to convey that IVF is actually a replacement for some of the “natural” steps required to get pregnant and not some miraculous high tech fertility treatment that gets patients pregnant artificially, as many think it is. It is somewhat of a miracle that we can do as much as we can, but there are still lots of things/steps that we cannot do or influence. I hope this discussion will benefit you. This series will be posted over the next few weeks in installments.


As explained in the natural process, the first step in your body is for the hypothalamus and pituitary to send a hormone to the ovary to stimulate the growth of a follicle and maturation of the egg within.

The hypothalamus sends a hormone called GnRH or gonadotropin releasing hormone to the pituitary. This in turn, causes the pituitary to give off follicle stimulating hormone (FSH) and a little luteinizing hormone (LH). For now, I won’t go into detail regarding LH since it is not as important in this stage of the process. The FSH, or follicle stimulating hormone, stimulates the growth of a follicle, hence the name. The ovaries already have all the follicles they are going to have from birth. These follicles are in a dormant state until they are stimulated. In a natural cycle, several follicles are stimulated but only one is designated to grow to ovulation. The FSH goes through the blood stream and makes its way to the ovary. The ovary then picks up this hormone from the blood. It then processes the hormone and a follicle grows causing the production of estradiol and progesterone, and maturing the egg within. The egg is normally in an immature state in the dormant follicle.

In the IVF process, we take over the function of the hypothalamus and pituitary. In fact, we shut down the natural process so that we can control how the process goes and to help with timing. Timing is critical in IVF, as it is in the natural process. Many programs use birth control pills to shut down the ovaries and thereby shut down the hypothalamic-pituitary axis. Some clinics use leuprolide acetate or Lupron, Synarel or a similar drug, to shut down this axis. These drugs are known as GnRH (gonadotropin releasing hormone) agonists which is essentially adding GnRH but the brain monitors the levels of this hormone and if it reaches a certain threshold, shuts down production in the hypothalamus. Using Lupron from the luteal phase of the previous cycle is known as the “long protocol”. Some programs will go into IVF directly from an natural menstrual cycles and this is sometimes called “Natural cycle” IVF.

As I was explaining, in the IVF process we take over this step by giving FSH and LH hormone directly. These are known as injectable fertility drugs, but in actuality are not “fertility” drugs but merely the hormones your body would naturally produce to induce follicle growth in the ovary but at a higher dosage. So in reality, these drugs don’t increase your fertility or make you more fertile, they actually just give you more of an opportunity to become pregnant. Some of the medication used in IVF, such as Gonal-f or Follistim are now recombitant, or genetically produced FSH (in the old days, all FSH used to be natural FSH that was extracted from elderly women’s urine). These medications are pure FSH and have no LH within. There are other medications such as Pergonal, Menopur, Repronex that contain both FSH and LH. These are still derived from urine. Some clinics will use only FSH but most will use a “mixed” protocol, meaning they use both an FSH only drug in combination with an FSH/LH drug taken together.

The amount of medication given is what determines how many follicles your ovaries grow, and is dependent on how aggressive your doctor wants to be, i.e. how many follicles they want to try to get, and how well he/she thinks your ovaries are functioning or going to respond to the stimulation. We call the latter “ovarian reserve”. A younger patient will usually, but not always, have a very good ovarian reserve and therefore require less medication, whereas as a woman ages, her ovaries become more resistant or less likely to pick up the FSH from the blood, i.e. decreased ovarian reserve. Logically you can see that if the ovaries are more responsive, less medication is required and vice versa. The best way to picture this, as I explain to my patients, is to imagine a golf “wuffle” ball. If you don’t know golf, this is a practice ball with lots of holes in it so that it doesn’t fly far. Imagine that all the holes are open and you put the ball in a bowl of fluid (which is the FSH). The wuffle ball readily admits the fluid into its center. Now imagine that you block off most of the holes in the ball. You can see that less fluid gets into the ball (you also have to imagine that you have a time limit as to how long the ball gets to sit in the bowl of fluid). That is ovarian resistance. No matter how much drug you give, the ovary will only pick up as much FSH as it can and thereby only stimulate as well as it is going to stimulate. There is no technology that can change this. That leads to a lower ovarian response to the stimulation, and less follicles and eggs to work with. It is called “ovarian resistance” once stimulation has been attempted and only a few follicles grow. That is different from “ovarian reserve” which is the anticipated ovarian response or ovarian response potential before stimulation. “Ovarian resistance” is what you see once the stimulation is done and the ovary does not stimulate well.

The stimulation step is important because part of the success of IVF is an enhanced statistical chance by having lots of eggs to work with. Take for instance, if you have one dice and you want the number five. You have a 1 in 6 chance with each roll of the dice. Of course, your chances increase with rolling the dice more times, which is a different statistical chance and the statistic that changes as you attempt IVF repetitively. But taking just one roll into consideration, as in one IVF cycle, your chance is 1 in 6. Now, if you add three, four or five dices to that one roll, you can see that you have increased your chances 3, 4 or 5 fold. That is the same with each IVF cycle. In a natural cycle, you give off only one egg, so if that egg doesn’t go through each step perfectly, you don’t get pregnant. IVF increases your chances of pregnancy by accomplishing more of the steps of the process for you, but more importantly, you still need to have a perfect egg that forms a perfect embryo. If you only have one egg, the chances of having a perfect egg are significantly decreased. It increases by having more eggs to work with. That is how IVF increases your chances of pregnancy statistically. So the goal of stimulation is to try to maximize the number of eggs that you have available in order to increase your chances of getting/finding the perfect egg/embryo.

Now there is a caveat to this. You don’t necessarily want too many eggs because over stimulation can not only cause a major illness, but the egg quality may suffer. This is where the “art” of IVF lies. It is up to the doctor to try to make an educated guess as to how much stimulation would be ideal for each patient. Under-stimulate and you decrease the chances. Over-stimulate and you also decrease the chances, as well as, risk making the patient sick. Doctors get better at making this decision through experience. And this is part of what makes each doctor and each clinic different.

We will continue this discussion soon with the next installment, "Step Two: Follicle Growth and Egg Maturation". Thank you for joining me today!

Edward J. Ramirez, M.D. F.A.C.O.G.
Medical Director, Monterey Bay IVF
Monterey, CA


  1. Hi Dr. Ramirez-

    I just happened across your blog this week, and it's been enormously helpful for me! I'd like to submit a question, but can not for the life of me find any information regarding how to do so. I'm sure it's right under my nose and I'm just missing it, but can you please enlighten me?


    1. Hi Erin,

      You got it right. Just ask your question via the comments section.

  2. Excellent! Thanks so much for your thoughts on my situation:

    Hi there-

    I just turned 34 and was recently diagnosed with diminished ovarian reserve, on the basis of my low AMH (.81). All of my other CD3 blood work looked good (FSH 8, LH 5.9, Prolactin 10, DHEA 1.540,
    Testosterone .5 (free), 24 (total).

    I have hypothyroidism and have been treating it with Synthroid for 18 months. A 50 mcg dose consistently kept my TSH between 2.5 and 2.7, which my OB previously said was perfectly fine for trying to conceive. However, after meeting with a new GP recently, she informed me that getting it below 2 would be optimal, and raised my dose to 75 mcg, which I've now been taking for 2 weeks.

    My husband recently had a semen analysis, and the results are good according to my OB: Count 48 million/mL, Motility 74%, pH 8.1, Morphology 41%.

    I have been pregnant once before, in the summer of 2011. This pregnancy happened easily, the first month we stopped preventing.

    Unfortunately, we learned at 11 weeks that it was a partial molar pregnancy and I immediately underwent a D&C. My hCG resolved to negative after 6 weeks, and was confirmed negative for three months afterward.

    My husband and I started trying to conceive in December and have been trying for 7 cycles, with no luck yet. I've been temping/charting for 6 months, and know that I ovulate predictably each month between CD15 and 17. We do an excellent job of timing sex, and my luteal phase is 12 to 13 days.

    I tend to experience 2-5 days of very light spotting (really, just pink/brown tinged cervical fluid) prior to my actual menstruation. Likewise, I tend to experience an additional 2-5 days of this very light spotting afterward. My actual menstruation typically lasts 2 to 2.5 days and is quite light, whereas prior to my PMP and D&C, I would typically experience 4-5 full days of flow and very little spotting. Because of these menstrual changes, I underwent an HSG in April to determine whether I might be experiencing Asherman's Syndrome. The radiologist and my OB both agree that anatomically, everything is great: no sign of adhesions, polyps or fibroids, and both tubes are wide open.

    My questions for you are in my next comment:

    1. Hi Erin,

      I see that you have had some testing done but not a complete evaluation. From what you have described, you are ovulating, your tubes are open and the sperm is normal. Your FSH is elevated and your AMH is decreased which both indicate decreased ovarian reserve. This is only pertinent if you undergo stimulation for treatment. It also means that you may have a shorter time to become pregnant but that time is not predictable (it could be years). Since you've been pregnant before, your chances of getting pregnant again are good.

      Your thyroid is too high. As your GP stated it should be lower to maximize pregnancy. We prefer it to be under 2.0.

      The tests you should have now would be laparoscopy, mid-lutal phase progesterone, end cycle endometrial biopsy for dating and a pelvic ultrasound to look at the ovaries and uterus. This would complete the evaluation.

  3. 1. Is it possible that I can still get pregnant 100% naturally with an AMH of .81? If so, how might you characterize the odds? Would you recommend that I have an antral follicle count?

    2. My OB recommended that I take 100mg of Clomid on CD3-7 during my next cycle. My understanding is that this will encourage my ovaries to produce more follicles and potentially more eggs, thereby increasing the odds that ONE of them will be fertilized and implant. Does this sound right to you? Is there anything else I need to know about the use of Clomid in women who already ovulate? Should I be concerned about it further diminishing my ovarian reserve, since I’ll (in theory) ovulate more eggs each cycle?

    3. Would I be a good candidate for Letrazole or Tamoxafin? I'm very concerned about the negative side effects of Clomid - particularly the effect it has on cervical fluid and uterine lining, because these are both things I tend to think I may already have a slight problem with. I tried using Mucinex to improve the quality of my CF for a few cycles, but there was no noticeable change, so I discontinued use. My concerns about my uterine lining are based only on the fact that my period has been much shorter and lighter since my PMP/D&C, and to date, I have not had an ultrasound at any point in my cycle to measure it. Likewise, I have not yet had my progesterone checked to determine whether that might play a role in the light spotting I'm experiencing for several days prior to my period.

    4. If I DO use Clomid, would I benefit from estrogen supplementation from CD7 through ovulation and/or progesterone supplementation after ovulation?

    5. Is there anything I can do to improve my egg quality, in terms of diet and/or supplements? Aside from a high-quality prenatal vitamin and Synthroid, I do not take any other vitamins/supplements/medications, and honestly, I tend to be quite skeptical of the vitamin and supplement industry. I'm not opposed to taking those that show significant promise in empirical studies, but I'd prefer not to take anything and everything recommended on a wing and a prayer that it just might work for me. I'm particularly interested in what your thoughts are on DHEA, CoQ10, Royal Jelly, Wheatgrass and Maca Root, all of which seem to be quite popular amongst women who are experiencing sub-fertility or infertility.

    6. Would you recommend that I undergo laproscopy to check for endometriosis? I've just recently begun to learn a bit about it and between my low AMH, hypothyroidism and the sciatica I experience every month in conjunction with my period, I'm concerned that this may be an issue for me.

    Finally, I will be meeting with a Reproductive Endocrinologist soon, and am curious as to whether you might have any words of wisdom and/or questions you'd suggest I ask.

    Thanks so much, I really appreciate any insights you can provide!

    1. Hello Again Erin,

      What a long letter. Let me try to give you some short and succinct answers.

      First, I think seeing an infertility specialist is the way to go at this point. Time is of the essence for you. No sense in wasting it with practitioners that can't take you through all levels of evaluation or treatment.

      FSH, AMH and AFC are all means to see whether or not you would stimulate well with fertility meds and whether time is an issue. It is not predictable how much time is left, nor what the prognosis is. It does indicate that you should be more aggressive and not waste time.

      I can't answer the Clomid question entirely in this forum. I have written extensively on Clomid in this blog so you will need to look them up. The reasoning behind using Clomid in you is correct. It is to "superovulate" you which is to increase the number of follicles formed and the number of eggs ovulated to increase the chances of one getting to the tube and fertilizing. Clomid is commonly used with minimum side effects if used properly.

      I'm afraid I'm going to have to stop here. This answer is already too long as it is.

      Good Luck

    2. You may also want to look up one of my earlier blog posts: "Infertility Evaluation ABC's", where I go into detail what you should expect and be asking when you see an infertility specialist. http://womenshealthandfertility.blogspot.com/2008/03/infertility-evaluation-abcs.html

  4. Hi Dr.edward

    I have been married for 41/2 years now,we have been planning for kid from past 2 years first it was an issue with me for irregular period and i got operated for ovarian cysts and got all my eggs dissolved.we changed many doctor.finally my hubby got his sperm test his mobility rate is very less and active sperm count is 4ml.we both are just 30 years now recently we came to know he got sugar and high BP also.
    Finally we decided to go for IVF.when doing the IVF my hubby activate sperm count was very less still doctor took chance and did IVF.after the 8days of eggs inserted i started bleeding i called my doctor even she was shocked and she increase the dose of progesterone from 1 to 2.its been 3 days i am bleeding its very little but still what are chances for postive result.
    my doctor sd its all most negative she gave us only 10% chances of being postive.

    1. Hello Coral,

      There is always a chance of pregnancy even with early bleeding (see "Bleeding after Embryo Transfer). You won't know for sure until you have a pregnancy test done so until then, keep up the hope.

      Good Luck

    2. Thanxs Dr.Edward,
      As you Advised I went and meet my doctor.she told me that we will wait till july 10 that would be my 13 day after IVF and do the pregnancy test ,as of now she can't tell me anything.
      Just told me to believe god.

  5. Thanks so much Dr. Ramirez. I really appreciate your insights. It's really wonderful that you dedicate time to sharing information in this forum. :)

  6. I love your blog. It is great having the support of people that have been through all this before. We are having treatment with this company for IVF.

  7. Very informative review! Can't wait to read more of your blogs. Its just great to read quality reviews. Just keep it coming. :)

    genf20 plus fundamental review

  8. Hello Dr. Ramirez,

    I am 36 years old diagnosed with "Unexplained infertility'" after a complete evaluation by a reproductive endocrinologist. I am currently in a 'two week wait' after my second iui. This is my first iui using follistim and ovidrel. I had 6 follicles at my baseline exam but only two mature follicles at my mid cycle scan. My boyfriend had 45 million motile sperm after wash. My question to you is how many iui's do you recommend before coming to resolve or moving on to ivf? We have been 'not trying not preventing' for two years and undergoing fertility treatment for 1 year. Before trying iui, my boyfriend and I have done 6 cycles using timed intetcourse with clomid and ovidrel. Thanks so much for taking time out of your own schedule to answer questions about infertility.

    1. Studies show that most women will become pregnant within 4 IUI cycles. After that, the pregnancy rate drops drastically. Therefore, I counsel my patients to try four cycles and if it fails, they should proceed with IVF.

  9. Hello Dr.Edward,
    In July 2012, I had IVF done which was negative,i was thinking of going IUI this month would that be any help for us because before IVF i have gone through only IUI cycle.I am really not understanding where is the problem me or my husband.

  10. Dr. Edward,
    I am 40. My follicles are growing unevenly and I only have 5-7 total. I am paying or everything out of pocket and can only afford one cycle. Is it worth canceling and trying again hoping for a larger number? Or just go through with this one given my age?

    1. Certainly there is the option of cancelling and hoping that the ovaries do better the next cycle, but you need to consider this. The goal with IVF in older patients is to try to find the one perfect egg still left in the ovaries. There is no way to predict when you will find that egg. It could be in this group or another group. Since at age 40 there aren't many perfect eggs left, you have to decide if you want to take the chance that the perfect egg might be in this group.

      The alternative would be to not just scrap the cycle, but same from the cost of the major part of the IVF, which is the retrieval procedure and embryological procedures by converting to an IUI. At 40 years old, I would certainly allow an IUI even if there is 5-7 eggs that ovulate because the chances of finding more than one good egg is low.

      Good Luck

  11. Hi was just browsing and came across this blog great info.. im on day 15 of stims high dose i have 4.6amh and after todays scan have 1 dominent 16mm folicle 1 at 11mm and maybe 5 small ones. Ive been given 2 more days on stimms then another scan before dr decides to go ahead with retrieval or not. Is this good enough to take chance on in your opinion although i probably will go ahead given choice but just wanted to ask someone experienced. Thanks mk

  12. Dear Dr.Ramirez

    Hello ! this is coral from India.we hope you guys are fine.I wrote about me almost an year age,again i am here.
    i am 31 years old married for 6 years now.try to conceive from past 3 years.i have changed many doctor.
    first my issue was irregular periods,took medicines of it,for sometime it was fine still could not conceive,then i started treatment to conceive first i was under gone the operation of laparoscopy for ovary insist because doctor said they were 4-5 eggs growing in tube.even after 6 months i could not conceive went of IUI one cycle.meanwhile my husband got sugar and when we did his test we got know that his sperm count is very low 10 and activate cells are less then 30%.
    After an year we changed the doctor and went though IVF in june 2012 the day we planned for the IVF his count was 14 but the day the operation was done his count reduced to 4,still doctor took chance and did IVF so it was afailure.

    yesterday after an year i went to doctor to check the status she again suggested us to go for IVF or ICSI but want to know whether that would help us.
    Please Note:my husband is in sales so lot of stress in there,he even drinks alcohol and we hardly meet.

    Waiting for ur reply

    1. If there is a sperm problem, ICSI is highly recommended at the time of IVF. Based on what you've told me, I'm surprised that your doctor did not do this in the first IVF cycle. Knowing that there are many sub-standard IVF clinics in India, I would suggest that you consider a different one than the one you are going to. Find one that has high pregnancy rates and they can show you.

  13. Hello Dr. Ramirez,

    I found your blog very informative and thank you for sharing your knowledge so openly.

    I am 43 yrs old with 2 miscarriages due to chromosome issue. Couple months ago, I decided to give IVF a try and today I learned that did not work for me. During my stimulation phase, I only had 3 follicles and only two were large, 18, and 20 day of HCG. My Dr told me that one of the two was not mature and the other didn't make it. I have lots of questions but let me start asking once a cycle is started, if the respond to medication is not good, should my Dr have changed medication or dosage? I stayed on the same med throughout the cycle and wonder different medication would have worked better. I also asked my Dr if I should try another cycle and her respond was that I was on the maximum dosage already.

    Thank you for your time in advance.

    1. If you were already on the maximum amount of medication (total FSH of 600IU), then increasing the dosage is of no value, nor changing brands of medication (they all work the same). Your response is characteristic of "decreased ovarian reserve" or "low responder" which is what we see in older patients. The ovaries just don't work as well as you get older. However, keep in mind that every cycle is a new cycle and the ovaries may respond differently with different cycles, so there is still hope. You also have to keep in mind, however, that the chances of pregnancy, even with IVF, at 43 are low. You are trying to be the exception to the rule.

  14. How long from the first day of starting the drugs for stimulation does it usually take til the eggs are ready to be retrieved...on average?

  15. Hello doctor
    I love ur column and thank you for the details given in the beginning. Me and husband are going for ivf this month.i m on gonal-f from last 5 days. Today is 8th day of cycle and my folicles are 1.1,1.1,.8 on my right and .8 on my left with couple of other folicles. Am I doing ok? My doc told me to start cetrotide from tmrw morning. I have standing job.5 hrs per day with little lifting. Is it ok? Do I need to take days off and rest at home coz medicines are pretty strong and 5 hrs standing jjob I get tired. Does diet make any difference, I meant do I need to go on a specific diet in ivf?

    Thank you doc



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