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 !