Why are my ovaries unresponsive to stimulation drugs ?

Every infertile couple , when they start their IVF cycle , are full of hopes. They are excited that they are pursuing an infertility treatment which gives them a very high chance of success - and , for some , it is also a last resort for having a baby !  As they go through each and every step of an IVF cycle , they are tormented with different emotions -  excitement , confusion , despair , happiness , sadness and what not ! But for some women , their excitement comes to a crushing halt during the very first step of IVF - their ovaries simply do not respond to the stimulation drugs which are used to grow multiple follicles. When follicles don't grow there is no chance of harvesting eggs - their journey sadly ends before it even begins ! This situation is more painful than a failed IVF  , because ,  for some ,  this can also mean the end of their baby making journey ! Why do ovaries become unresponsive to stimulation drugs ? Can this situation be overcome ?

There are three possible reasons for having  unresponsive ovaries :

1. Poor or diminished ovarian reserve
2. Use of sub - optimal concentration of stimulation drugs ( gonodotropins )
3. FSH insensitivity

Poor ovarian reserve

Aging is the main reason for having a poor ovarian reserve. All the eggs a women harbors in her ovaries are created when she was in her mother's womb . To start with ( at around 6 months of gestational age ) ,  a woman's ovaries contain approximately 7 million eggs .  But at birth , only 1 - 3 million eggs remain , other eggs are lost even before she is born due to a process called follicular atresia ( a self - destructive process ) . Follicular atresia continues as a woman grows , and hence the number of eggs in her ovaries continue to decreases drastically. By the time she reaches puberty , only 300 , 000 - 400 , 000 eggs are left. When she reaches menopause ( the normal age for menopause is around 50 years for most women )  , her ovaries might contain around 1000 eggs.  Many older women ( > 40 years ) , who undergo IVF , might find that their ovaries are no more responsive to stimulation drugs because their ovarian reserve is extremely poor . As the women approach menopause ( even 10 years before menopause ) the quantity and quality of eggs decreases , drastically.  The follicles ( the structures that contain egg )  present in the ovaries also lose their ability to grow in response to FSH ( because they become refractory to the action of FSH ) . As a result , older women find that their ovaries respond very poorly to stimulation drugs leading to poor egg yield , or they might also experience complete lack of follicle growth . This often comes as a cruel shock ,  because , aging of the ovaries are not as obvious as aging of other visible body parts , and hence no one are really aware about it . For example , we are very much aware of our greying hair and skin wrinkles , but we rarely think about our ovaries , and the changes that happens in them , as we age  . Many women are ignorant about their fertile years  , they think , having a regular menstrual cycle indicates all is well with their reproductive system ! Many even think , if they look young for their age , their ovaries remain young , too ( sadly that's not the case ! ) Older ovaries are most of the time unresponsive to stimulation drugs ,  and there is nothing one can really do to make them sensitive to gonodotropins.

Unfortunately , 10 % of young women can also have ovaries which are much older than their actual chronological age. For example , a women can be 25 years old , and can have ovaries which behave like that of 40 year old women's. This is a very unfortunate happening. There can be many reasons for this , like , chemotherapy , smoking , ovarian surgery leading to the loss of majority of ovarian tissues , autoimmune diseases ,  some genetic defects like fragile X syndrome , etc. These women's ovaries might also become unresponsive to stimulation ( FSH) .

Women who have poor ovarian reserve can be identified using a couple of blood tests , such as , measuring their FSH , e2 and inhibin B levels on day 3 of their menstrual cycle  ,  or measuring a hormone in blood , called AMH. Counting antral follicles present on ovaries using an ultrasound probe , during their earlier phase of menstrual cycle also gives a rough idea of their ability to respond to stimulation drugs. But the ultimate proof of their ovaries' ability to respond to stimulation drugs can only be assessed during an IVF cycle . A woman who fails to grow more than 3 follicles with maximum amount of FSH ( 450 IU ) ,  (  and whose e2 is less than 300 pg / ml for a single follicle or less than 500 pg / ml for 3 follicles  ) , for a minimum stimulation period of 9 days , are classified as poor responders.

Use of sub - optimal dose of gonodotropins

The antral follicles carry receptors for FSH in their granulosa cells.  During IVF , the FSH that is used ,  bind to these receptors and help in the growth of follicles. Since , FSH is used in supranatural amounts during IVF  , it rescues most of the antral follicles which will be otherwise lost due to atresia. The sensitivity of follicles to FSH varies with age. Normally , older women need more FSH to rescue maximum number of antral follicles from degenerating when compared to that of a young age woman. In other words , young women's ovaries are much sensitive to FSH and hence they need less FSH to initiate the growth of  maximum number of antral follicles. The usual starting dose of FSH is 150 miu for women aged 25 - 30 , 225 miu for women upto 35 years of age , and above 300 miu for women above 35 years of age. If lower doses of FSH are used for older women , their ovaries fail to respond to FSH. Hence an optimal concentration of FSH is necessary to make the ovaries respond effectively to stimulation drugs.

For example , I responded very poorly to stimulation drugs during my first few IVF cycles. During my first IVF cycle my AMH was 4.5 ng / ml. Because of my high AMH , and because of the fact that I was diagnosed with PCOD , the doctor wanted to be extremely careful. I was 28 years then and the doctor started me with 150 miu of gonal F . Even though my FSH dose was increased gradually during the stimulation period , at the end of the cycle , I had only 3 follicles that were growing and I got only one embryo  ! That was a disaster and I was heart broken. I thought I would have lots of eggs because of my age and PCOD diagnosis.  Now , when I look back , I could guess what might be the reasons for my ovaries ' poor response to FSH - high AMH and insulin resistance ( insulin acts as a co - gonodotropin ) could be the possible reasons which can lead to poor response if the starting FSH dose is not high enough !

Although , PCOD patients are hyper responders to stimulation drugs , getting most of their FSH - sensitive antral follicles growing depends a lot on the initial dose of gonodotropin that is used.  If the initial FSH dose used was too small , many PCOD patients tend to respond very poorly. A recent publication talks about the effect of high circulating AMH affecting the FSH sensitivity of antral follicles. They found that , higher the AMH level , higher starting doses of FSH are needed to create an optimal ovarian response. High AMH levels make the ovaries resistant to stimulation drugs and hence higher doses of FSH is needed to overcome FSH resistance  ( http://www.ncbi.nlm.nih.gov/pubmed/24341292 )

So , not only old age but also having PCOD can make ovaries resistant to the action of FSH. Hence , determining and administering optimal FSH dose is essential to make the ovaries responsive to stimulation.

FSH insensitivity

There is a genetic condition called hypergonodotropic hypogonodism. It is an endocrine disorder where the ovaries are resistant to the actions of FSH. This happens because of a mutation ( genetic defect ) in the FSH receptor ( to which FSH binds and initiates it's action ). As a result , FSH cannot act on the receptors that are found on the granulosa cells of follicles. Because of the lack of FSH action , no follicles could be grown ! The ovaries will not respond to stimulation drugs and at present there are no cures for it !

Alternative Medicine Versus Western Medicine for IVF patients – Friend or Foe ?

This article is the brainchild of Dr.Malpani. Thank you Dr for giving me permission to reproduce it in my blog!

Indians were unaware of western medicines up to until three centuries ago. Ayurveda, a form of traditional and alternative medicine was practised in India for centuries. Infertile couples in olden days were treated by Ayurvedic or Unani medical practitioners by using plant-based medicines and, in addition, they provided life-style advices too. Undoubtedly, such medical practices are very effective for some forms of infertility and many infertile couples would have achieved their dream of starting a family via using them. When some couples found no luck with such treatments, they sought the help of the supernatural power to give them a baby; many went from temple to temple in search of God’s grace! Since knowledge about the functioning of the reproductive system and its defects were very much limited during that time, infertile couples at one point of time had to accept their fate and move on with life. Many resorted to adoption as a means of enjoying parenthood and some remarried so that they got a chance to propagate their genes and made sure their generation didn’t end prematurely!  

Times have changed today. Since the practice of Ayurvedic medicine was done by word of mouth during ancient days and is vigilantly guarded among families, the enormous knowledge our ancestors possessed about different curative plant compounds, their mode of preparation and the principle behind such practices are eventually lost! Although there are medical schools which teach Ayurveda, there are very few Ayurvedic practitioners existing in India today. Western medicine being based on strong scientific-evidence and rationality, gained importance eventually and is widely followed in today’s India. With improvement in biomedical research and the knowledge gained thereof, ground-breaking discoveries have emerged in the field of reproductive medicine. As a result, modern age infertile couples have enormous treatment options to deal with any kind of infertility problem. With patience and persistence most infertile couples can hope that their dream of having a baby will become a reality!

But the ironical truth is, even today, many infertile couples feel uncomfortable to use western medical advancements that are available in the field of reproductive medicine. The reasons are twofold: many western medicine based infertility treatments are costly and not everyone could afford to spend so much, as a result, many resort to traditional medical practices like Ayurveda or Unani (which are comparatively much cheaper) even though the chance of success is very low or even nonexistent for many infertility ailments using such traditional approach. The other reason is that, unfortunately, still many Indians believe that western medicine is evil and pose many unpleasant side-effects. Especially if you have a granny at home who never went to a modern hospital and managed all her and her family illnesses using traditional medicine, the first advice you receive will be to seek the help of an Ayurvedic medical practitioner for your infertility problem! Some even depend on “faith healers” like “witch doctors” to cure their infertility problem.

So, if you are faced with infertility problem what will you do? If IVF patients depend on such alternative medicine for improving their chance of success, does it make sense? How do doctors who practice western medicine view it when their patients depend on alternative therapies to cure their infertility problem or to improve their chance of success?  Although alternative medicine is practiced world-wide, a lot of infertility specialists are not always happy when patients depend on such treatments. They feel that the patients are being fooled by these primitive systems of healthcare and they pity them for wasting their precious reproductive period by following treatments, which they think, are fruitless.

Doctors who practice western medicine spend many years in medical school, acquiring their degrees. They then work hard at acquiring practical experience in a hospital, so that they can get a license to practice medicine. IVF doctors study for as long as 10 years before they can hang out their shingle as IVF specialists. Not only are they proud of their expertise and experience, they naturally want to guard their domain jealously. They have a low opinion about alternative medicine and its practitioners because they are poorly trained and they acquire a degree in as little as 6 months. Many IVF doctors feel that such degrees are of no value and are just a “license to kill”. Also, they often have a superiority complex, because only western medicine has modern technology (such as vaginal ultrasound scans and endoscopy) at their disposal, to make an accurate diagnosis, based on which they can recommend the right course of treatment on a scientific basis. They think that alternative medicine practitioners do not have the same depth and breadth of training as they posses and many doctors feel that alternative medicine clinics are encroaching on their territory. They look down on these doctors as being quacks, who have no effective therapeutic interventions to offer because they lack any evidence to prove their efficacy.

On the other hand, many alternative medicine practitioners are equally happy to bad-mouth infertility specialists who practice western medicine. They scare their patients by telling them that IVF is “artificial” and the babies born out of IVF are “weak” or abnormal. While some envy the high income an IVF doctor gets, others genuinely believe that the holistic options which they offer have a higher success rate. They feel that IVF is like band-aid therapy, and does not attempt to fix the underlying problems in the infertile couples.

As a result of this conflict between the doctors who practice western medicine and alternative medicine, patients end up getting confused as to which is the reliable argument. In order to try their luck, they shuttle back and forth between these two medical practitioners and finally get frustrated with the treatment process and many end up sacrificing their dreams of a baby being born to them. If this is the case, how should a responsible doctor react? What advice should they give their patients?

We need to remember that many infertile couples will actively seek out alternative medicine options, even when undergoing treatment for IVF. These options are highly respected by their family elders and deeply rooted in their culture. They are also much less expensive. Hence they believe quite logically that even if they have not been proven to help, they will not cause any harm (although this is not true)! This is why they want to cover all possible bases and try them out, to ensure that they have not left any stone unturned in their baby chase. There are tons of anecdotal success stories of women who have conceived after taking a particular herbal concoction; and this, even as the scientific base of alternative medicine is not always strong.

Doctors who practice western medicine must understand that unless and until they take into account the cultural healing beliefs of the patients and learn to incorporate them within their treatment regimen in a rational way, it is impossible to achieve patient satisfaction. Improved patient satisfaction will lead to better compliance to therapy. Cultural competency of the healthcare provider is very important to help patients get the best medical care and also to be successful in one’s own medical profession.

Alternative medical practitioners should also understand the limitation of the treatment they can offer to an infertile couple and encourage them to seek appropriate infertility treatment from western medical practitioners when needed. After all, a patient with a blocked fallopian tube cannot be cured with Ayurveda and Unani medicines. Giving patients false hope and wasting their precious fertile period is very unethical on their part.

Every infertile couple has to decide wisely about their treatment options. Of course, there are some problems which can be cured by alternative therapies (for example anovulation due to PCOD!). But there are problems like low sperm count, blocked fallopian tubes and much more which cannot be cured using herbal concoctions. A well-educated patient will know for sure which treatment should be opted for, after analyzing their medical problem. It is also wise to find a balance, for example when you are going through IVF and if your alternative medicine practitioner advices you to take a herbal potion which he might think will help create a healthy environment for embryo implantation or which might balance your hormones, then it is nothing wrong in trying it, provided such advice is given by a reputed practitioner who is not a quack. Please do not believe in the claims of mushrooming internet sites which are claiming to provide you with herbal therapy to make your IVF a success. First, you will never know if what they are providing you will be of benefit and the next concern is, it should not harm you or your IVF cycle. Remember, many herbal medicines carry the risk of being contaminated with heavy metals!

Rather than taking a confrontationist approach, patients would find it a lot easier if IVF doctors and alternative medicine practitioners could learn to work together for the wellbeing of the patient.