When you read about the human body, it might not be that easy for you to learn. You have many questions which you encounter during your studies but sometimes they remain unaddressed. With this article, we will present some of the most frequent and common questions which are raised by the Fellowship in Infertility and Reproductive Medicine in India. We have answered some of the most relevant questions.
What is the action of CC, of clomiphene citrate? Yes, it fools the pituitary, doesn’t it?
It results in an environment wherein despite having a low amount of estrogen, there is not low estrogen; rather, it gives an indication of low levels of estrogen to the hypothalamic-pituitary region that occupies these receptors, thereby causing a spike in the level of FSH.
What happens when it is provided for five days and when it is provided for a longer time period? What does the pituitary secrete?
It gives out FSH and also gives out LH.
This is why the basal level of LH increases while the FSH levels keep on rising. The continuous rise in FSH works out to be rather effective since it ends up recruiting more follicles; however, one needs to remember that along with the rise in FSH, there is a simultaneous rise in LH.
What happens if you give clomiphene for five days and what if you give clomiphene longer?
They do very different things. If you increase the duration of clomiphene administration, you will prolong the period when your body keeps high FSH levels, but you will also keep higher LH levels. Now, I wonder how many of you are familiar with 2007 article, which comes from Japan.
However, what happens in the Japanese is that they use a lot of clomiphene for their mild stimulation cycles and what this has proved to them is that although there is an increase of LH with the use of clomiphene, it is not associated with an abrupt increase of LH. The LH increase in this whole group was just 2-3%, which is very low. What this doctor wants to know is if you use the clomiphene for only five days, is it causing any luteal phase defect? By largely means, luteal phase defect means the unruptured lutealized follicle. However, what we do not know is whether or not this leads to an unruptured lutealized follicle.
Does it affect luteal phase function?
Clomiphene appears to correct luteal phase function and clomiphene appears to cause luteal phase dysfunction as well. However, once again, this is not a very clear explanation and my understanding on the matter is quite simplistic because if in cases where you prescribe clomiphene and find that there are low levels of progesterone seven days after ovulation, even after the trigger, you should rethink the use of that drug.
Once again, if we talk about the Legros paper where clomiphene is compared to letrozole, then the point to note is that when the drugs are compared for giving spontaneous ovulation and letrozole is better than clomiphene in terms of spontaneous ovulation. The rate of women not having spontaneous ovulation in case of clomiphene is around 10-15%. In that case, there is something that needs to be looked into. The way of action of the gonadotrophins is totally different from clomiphene.
If we use clomiphene and IVF, what happens in the endometrium?
The endometrial dysfunction or the side effect of clomiphene is encountered in about 15-20% of cases. Certainly, this affects the implantation, and in such cases, pregnancies are almost impossible when considering the induction of ovulation. Secondly, if one considers the article that I presented, which focuses on the endometrial receptivity genes that are present, then it is clear that clomiphene decreases endometrial receptivity of at least three genes.
So again, if you have a look at it, what would I do? I would prefer that if I use clomiphene in the IVF cycles, I would prefer to freeze the embryos. I used it mainly in poor responders and I want people to have a rethink about how they treat poor responders. Egg donation is simple.
It doesn’t require thinking when you move a poor responder into egg donation. A woman often opts for egg donation for lack of funds and secondly, to keep a relationship going. Sometimes think differently.
I have seen at least 30 women out of those who were asked to go for egg donation who managed to conceive and have a baby, just looking at different protocols which can treat egg donors.
Is stimulation in the presence of an unruptured luteinized follicle? The question raised here is whether the follicles are unruptured and continue to be on day two and three, can we proceed with stimulation? My opinion regarding CIS is totally contrary to that of many others.
Textbooks are here to help you. The textbooks are not there to dictate everything for you and my suggestion here is to find out what is the source of CIS. If CIS is a luteal CIS, it can produce progesterone and yes, in case of a fresh cycle, its impact is evident by reduced pregnancy rates. However, one simple thing is to go ahead and perform Doppler test on the CIS as well as progesterone test. If progesterone level in your body is low initially in the cycle and Doppler test results show that CIS is almost collapsed, then start your stimulation. There is really no reason why we delay treatments for the CIS and my opinion about CIS in IVF treatment is quite different. I would rather like to know what kind of CIS this is, whether CIS gets stimulated or not and whether it is compressing the rest of the follicles.
Is it a good practice? Should we do the scan before an IUI after an HCG trigger to confirm we’re doing a post ovulatory IUI?
In my opinion, one can come across several options that may lead to additional work in reproductive medicine. One of such options is conducting unnecessary tests. An estrogen test or progesterone test during the first days of the menstrual cycle usually leads to thinking too much and doing nothing. That is exactly what you will find yourself in. I would recommend that you do not conduct any scans. The only thing that you need to do is give the trigger and have a seven-day progesterone. If your progesterone is low, something else is going on. However, now all the evidence in nature is pointing to section intercourse prior to ovulation. In addition, I would say that if you are considering conducting the IUI, you need to conduct it 24 to 36 hours after giving the trigger. The question that arises in your case is why we should check whether the trigger works in 36 hours. It does not.
It can work up to 37 hours, 38 hours and sometimes 40 hours. Also, what you may be seeing is a corpus luteum that has formed but has not collapsed. I would suggest that we leave doing it because the actions then are more worrisome because you would not know what to do.
You would continue giving her more HCG and doing an IUI again. Also, look at the endometrium. The endometrium starts changing with the progesterone effect.
If you are still worried, do a progesterone on the day of IUI and you will see a slightly rise of progesterone. If you look at the analog studies, the analog studies do indicate that progesterone levels rise after giving the analog trigger within 24 hours. That is something to be considered.
When do we repeat AMH after a variant surgery?
Always do an AMH before surgery.
- One, a medical legal value.
- Secondly, it gives you very good insight into what the surgery should be.
If you are a surgeon and you do not do AMH, no matter how well a law is formed, when you have a patient with premature menopause, you do not have any leg to stand on. I would recommend that you do not operate and take out ovaries without an AMH test before operation. It would be better for you to know the number of follicles left. Moreover, this advice should be given to patients. You can tell them that your reserve of eggs is low. Any procedure that you perform is going to influence your ovarian reserve. For instance, the endometrial cyst that enlarges also influences the ovarian reserve negatively.
Which one do you choose?
This is what you will discuss with your patients. When should you measure AMH? Not right after surgery because I don’t believe in doing that. Why? Look at what they did in the literature on ovarian drilling. What happened in the literature of ovarian drilling was that AMH level dropped fast after ovarian drilling and started rising. I would rather see it clearer in three months’ time.
Endometrial receptivity in IUI?
In one of the discussions that Dr. Bahadur suggested, he proposed to puncture the endometrium like an endometrial scratch while stimulating. I did a discussion on endometrial scratch in IUI and these studies have very poor power. These studies are highly incomplete and do not give us the correct results.
I will be very honest when I say that we don’t have the right answer at all. It would be suggested by me that we don’t do any scratch in the cycle where there is no proper study.
Case Study
It is a 38-year-old female case of premature ovarian failure and desire to conceive. She has conceived naturally 1 year back and has a baby. She planned to undergo egg donation. Her FSH level was 60. Her LH level was 35.62. Ovaries could not be visualized in either of the ovaries. Eggs were retrieved from a donor and the cycle was initiated. In the first cycle, she needed 60 mg of oral tablets and two applications of Estraderm gel per day. Even after that, her endometrium was 6 mm. The treatment was started, and then in the next cycle, Proganova was started at 6 mm orally and also with estrogen gel. After one-two days of menses, she was taking 16 mg of Proganova tablets and gel per day. Despite that, on day 11, her endometrial was 6 mm. It was increased to 18 mg a day along with twice daily estrogen gel. However, on day 15, she presented with bleeding. The question is, how do you prepare her for a frozen embryo replacement cycle?
There is one point I have to clarify. Oral estrogen is not a fantastic drug. Look at the dosage of estrogen taken, 16 to 18 mg. A dose of more than 8 mg Proganova rarely works. One has to consider the problem of the endometrial lining. Consider menopause, and consider the size of the uterus. I will not encourage any woman who had undergone menopause, with increased FSH-LH levels and decreased E2 levels and reduced uterus size. This is how the endometrium becomes extremely thin. Less than 1 mm. I believe that building the endometrial lining is something that takes time. Remember that many of the receptors have disappeared. Oral estrogen might not be an appropriate way of proceeding. I am not sure about the effectiveness of estrogen gel since its absorption is irregular. Many countries do not use estrogen gel. Americans switch to subcutaneous endometrial estrogen, whereas Europeans go for the patches.
What would I do in this case?
- The first option would be when you are using patches and hence transfer to patches. Once every three days, 100 micrograms of Everol and that keeps increasing the size of the endometrium over about six weeks. Increase it, monitor the endometrial size, allow a withdrawal bleeding and repeat this process of increasing the endometrium two or three times and then you can use 2 mg of Proganova and patches. In many instances, I have seen this approach perform better in producing the right endometrium than going directly into treatment. Two things are sure in this instance. One, oral estrogen does not work.
- Secondly, there is the issue with the endometrium. Instead of insisting on the use of a surrogate, I would advise that common things be done commonly. The patient does not tolerate estrogen very well. Therefore, the estrogen should be stopped and patches should be used instead of gels.
Starting stimulation in PCOS without withdrawal bleeding?
In cases where the ovaries are quiescent and the endometrium is thin, stimulation can be started without waiting for the withdrawal bleeding induced by progesterone. Nevertheless, in some cases, the onset of stimulation through the use of clomiphene or retrosol causes onset of bleeding. Will not such late shedding of endometrium pose problems to its development? Endometrium that is thin; what will it shed? It is suggested that do not worry about it. What prevents the bleeding? Forget all the medicines. What prevents bleeding in nature? Growth of the follicle, oestrogen as growth factors.
Exactly the same thing would happen. As the follicle starts building, as follicle recruitment starts, estrogen levels will start rising and then you will see the endometrium building up. Do not worry. I think this is commonly seen and the endometrium often builds up.
Now, which is the best training institute for Fellowship in Reproductive Medicine in India?
The query to this answer depends on your requirement. Medline Academics provides an answer to all of your queries. This institute that is headed by Padma Shri Prof. Dr. Kamini A. Rao offers courses in reproductive medicine in both the modes of hybrid as well as full-time course. These courses are even more valuable since the course curriculum has been developed by some of the leading faculties in the field of reproductive medicine. Moreover, Medline Academics is also affiliated to some of the leading universities, which is recognized across India.
According to the latest ART Bill, it has become necessary to have a fellowship degree in reproductive medicine or to have a certificate of 50 OPU’s to start an ART Clinic Level 1. In that clinic, “Dr. Kamini Rao Hospital” which is the clinical department of “Medline Academics” conducts training program of fertility specialists every month. This hospital is the best for infertility treatment in Bangalore.
It takes a lot of bravery to pose questions and say that I need clarification. We all should continue learning. I am a reader, and I read an article each day since I have to learn as well. I feel there isn’t anybody in this world who knows everything. There is nothing wrong with posing queries. Provided you pose your queries to me with detailed history and without incomplete questions, I will do my level best to answer those questions. Provided I do not know about the particular topic, I will read and get back to you with information on the topic. This would help us in improving our method of sharing knowledge. The knowledge is not confined to closed doors and secrets in the conferences alone.
