Posts

27
Sep

Are you thinking of doing a Mini-IVF?

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Hi this is Dr. Rob Kiltz, founder and director of CNY Fertility Center with locations in Syracuse, Rochester and Albany, NY.  We recently had a client ask us about whether or not we do “mini-IVF”.  The question was about the protocols and whether we use  Clomid, Letrozole, injectables, or do we use just FSH, or both FSH and LH. Many people may be interested in this type of IVF cycle so we wanted to share the information to all, on our website. If you have questions about your journey to fertility please don’t hesitate to call us toll free at 800.539.9870, request a phone or in-office consultation or send us your questions here.

Mini-IVF is a term of minimal stimulation.  Invitro Fertilization (IVF) was 1st started with no stimulation (natural cycle, 1 egg) and the pregnancy rates were much lower per cycle.  Over time, protocols were developed using gonadotropins,  FSH (follicle stimulating hormone), LH and medications like Pergonal, Repronex, Gonal-F,  Follistim, Bravelle & Menopur .  These are injectable medications that stimulate the ovary to mature multiple eggs.   On average we are getting 6-10 eggs which means more embryos.  This means a higher chance of pregnancy but at the same time a higher chance of multiples.

By using minimal stimulation, so either Clomid (a pill) which stimulates 1 or 2 eggs at a time, or Letrozole which is similar to Clomid but does not have the same anti-estrogenic effects (it is also not authorized by the manufacturer to be used this way, but many Reproductive Endocrinologists are using Letrozole), there is some success to be obtained by the 1 or 2 or 3 eggs that are retrieved.  In a similar fashion, Clomid or Letrozole would be used day 3-7 of the cycle and then monitoring would happen between day 8 and day 10 of the cycle with ultrasound and blood testing.  When the lead follicle is 18-22 mm in size and an endometrial lining of about 7mm or greater, HCG 10000 units or Ovidrel 250 units is used to stimulate the release of the egg, then 36 hours later egg retrieval is performed in the office.

Now gonadotropins can also be added to that, along with Cetrotide or Ganirelix, to prevent premature release of the eggs.  And this may have a slightly improved number of eggs without the same high-cost because the biggest issue is the expense of the gonadotropins and using mini-IVF (that’s low- dose gonadotropins, or Clomid/ Letrazole)  you can reduce the cost significantly.
The protocol is basically either low-dose gonadotropins with a natural cycle, and beginning on day 2 or 3 of the cycle with 37 to 75 units of gonadotropins with Cetrotide or Ganirelix beginning about day 5 to 7 of the cycle when the lead follicles are about 12 mm and ultrasound monitoring and blood testing so that when the eggs are 16 – 18 mm, HCG or Ovidrel is used to stimulate release and the egg retrieval is performed similar to the standard IVF.

These are all performed at CNY Fertility Centers, yet they are not our predominant protocols, but all are possible and based on your individual needs and can be utilized in the process.
~~~
Dr. Rob Kiltz

8
Jul

April's Journey to Fertility: Now and Next

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April is a CNY Fertility Center patient and has been on her journey to fertility for approximately two and a half years. April will share candid stories and a unique perspective on the fertility challenges many women and couples face. CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY.
Week 55: Now and Next
Norman Lear, producer of many popular television shows including All in the Family said, “I’m interested in now and next,” during his recent interview on Sunday Morning. What a great perspective, I thought to myself.  If we simply focus on what is happening now, we are living in the moment. If we focus on what is happening next we must let go of what has happened before.
Letting go of our past experiences can be extremely difficult! As my husband and I head into our next IVF cycle, I want to focus on the now and next because focusing on our past cycles will not make the next cycle a success. I need to simply let go of our past fertility challenges. I need to feel as if the next cycle is a fresh start, and in many ways each cycle is a fresh start. Our reproductive cycles vary each month as do our emotions, general physical health and overall perspective. Even the egg and sperm quality differ from month to month!
Our cancelled IVF cycle, especially since we made it as far as the egg retrieval, was devastating. No sugarcoating can change the array of overwhelming and heart-wrenching emotions both my husband and I experienced during that cycle, and I am sure you have experienced many emotions as well. However, we must remember that history does not determine the future. In fact, knowing what has and has not worked in the past gives both the doctors and patients a deeper knowledge about what will lead to success.
Fertility treatment is challenging, but focusing on what is happening now and what will be happening can be empowering and even comforting. What fears do you need to let go of? Sometimes I repeat a simple phrase to myself whenever a fearful or negative thought creeps into my consciousness: This does not service my higher purpose, and I release whatever does not serve my higher purpose. (Kristen Magnacca suggested this to me, and I have found this affirmation consistently helpful.)
What negative patterns interfere with your higher purpose and what can you begin to simply release away in thought so that you can feel empowered, confident, and content in spirit?
Looking ahead,
April all Year
Click here to read April’s blog including all of her previous articles.

18
Jun

April's Journey to Fertility: Adjustments

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April is a CNY Fertility Center patient and has been on her journey to fertility for approximately two and a half years. April will share candid stories and a unique perspective on the fertility challenges many women and couples face. CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY.
Week 52: Adjustments
As I was speaking to a friend the other day about what my husband and I are doing next in terms of fertility treatments, I mentioned how I was simply nervous about the outcome of another IVF cycle (which we are not ready for quite yet). Her response to my worry was so insightful I knew I had to share her wisdom with all of you! She simply stated, “No matter what happens you have to adjust. You have already adjusted to not having your baby in the way you thought you would. Then you adjusted to fertility treatment and you even adjusted after the last IVF didn’t work. And when you become pregnant, that will be an adjustment, too.
I remember thinking about how correct she was! I know that no matter what, I will adjust and move forward; I already have in so many ways. My belief is that you have had to do some adjusting, too. Although we would prefer to have life go exactly as planned, being able to adjust to life’s plan for us is vital to anyone’s happiness.
My husband always reads my articles when they are posted to the website. (No, he does not get to read them ahead of time, even if he helps generate any of the week’s material) He sometimes comments about how I recognize others’ abilities in my blog, and then asks me if I recognize my own achievements and/or capabilities. My friend, Katie, helped me to see that no matter what happens I will adjust and continue to move forward on my journey to motherhood. Please consider your own ability to adjust and move forward because I am sure that you, too, have already made many adjustments of your own!
Continuing to adjust,
April all Year
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Click here to read April’s blog including all of her previous articles.

2
Jun

IVF After 40 years of age – 2010 update

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This information is provided by CNY Fertility Center, where patients are accepted for IVF with no precondition or age cutoff. We offer patients who are in the older age group comprehensive information about their options to start, or add to their family. CNY Fertility Center provides quality, low-cost infertility treatments and IVF care with locations Rochester, Syracuse and Albany New York.
More than half of women over 40 years of age have difficulty conceiving, while others are still fertile. Patients who are over 40 and infertile are seen in IVF centers and tend to have lower success rates with treatments (using their own eggs) than younger women do.
Many women are delaying childbearing until later in life. Until an individual or couple tries to conceive, they don’t know if they fall until the fertile or unfertile category. Laboratory predictors of outcomes like FSH levels, follicle counts, and other ovarian reserve indicators are not absolute in dictating treatment success or failure. Most women over 40 have one or more indicators of a potentially low prognosis.
Two recent papers have reported detailed information for specific age categories. From Egypt, over 200 women aged 40 and above were evaluated for IVF outcomes. As women increased in age, their treatment cycles were more likely to be canceled due to a lack of ovarian response. Miscarriages were 40-67% of clinical pregnancies. The live birth rate for those who made it to egg retrieval was 11% in 40 year olds, 7.5% in 41, 5% age 42, 2% at age 43, and under 1% at age 44 and 45. (Hourvitz et al )
A study in Israel evaluated 842 patients ages 42 plus, between 1998 and 2006. Clinical pregnancy rates per cycle were 7.7, 5.4 and 1.9% for 42, 43 and 44 years old respectively. Many of these pregnancies resulted in miscarriages. Only one IVF cycle in patients aged 44 years resulted in delivery. None of the 54 cycles performed in women of 45 years or older resulted in a pregnancy. A marked decline in clinical pregnancy and delivery rates, accompanied by an increase in spontaneous abortion rates, was found in patients >42 years old (Serour et al).
Results at CNY for 2007 were 12.5% live births per egg retrieval in the 41-42 year group and no deliveries in the 43 and 44 year olds in that year. In 2008, 8% of 41 and 42 year olds who had retrieval had a baby. Above age 42, about 2% of women succeeded in having a birth.
It is often a challenging decision whether or not to use donor eggs or sperm to create a family. Many people desire a child who is genetically related to both parents. Men see a much lower decline in fertility with age, and technologies including IVF and ICSI can increase pregnancy rates for couples where the man has a severely low sperm count.
When maternal age is an issue, it is helpful to remember that the statistics apply to a group of patients. They are general predictors for 100 women. No one can say what an individual’s results will be. CNY Fertility Center helps couples make every reasonable effort to create a biological child, but also offers patients other options for their family building including donor eggs, donor sperm and donor embryos.
It is important to recognize that the use of donor eggs is a high success back up plan. This alternative has delivery rates close to 50%. Many couples where the woman’s age is over 40 will initially try an IVF cycle using their own eggs. Success can come with persistence and positive mental attitude. Among those who are unsuccessful with their own eggs, many move on to using donor eggs for the baby of their dreams. Using a combination of options is often the best plan.
References
A Hourvitz1,2, MD Ronit Machtinger2, MD Ettie Maman, MD Micha Baum, MD, PROF Jehoshua Dor, MD Jacob Levron Assisted reproduction in women over 40 years of age: how old is too old?
Reproductive BioMedicine Online 2009 http://www.rbmonline.com/Article/3872
[e-pub ahead of print on 24 August 2009]
Serour, G et al Analysis of IVF in … women aged 40 years and above. Fertil Steril In press 2010

9
Feb

Birds, Bees and Bunnies: The Biology of IVF – Part 3 (Sperm & Embryos)

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This article discusses the basic biology behind the process of In Vitro Fertilization (IVF) and may be helpful to couples who plan to undergo IVF. Technical terms may be found in a glossary at www.fertilitylifelines.com.
CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY. CNY Fertility Center offers couples and individuals affordable fertility treatments including low cost IVF (In Vitro Fertilization) by our experienced and caring staff.

Sperm penetration and fusion, cortical granule reaction, from www.Wikipedia.com
Once one sperm has penetrated, the cortical granule reaction causes a shield to slam shut just inside the egg membrane within microseconds. This prevents the entry of another sperm. If this system fails and two sperm enter, there are two sets of male chromosomes.  This is called polyspermy and actually is observed commonly in the IVF lab. Three pronuclei, a sign that an entire extra set of chromosomes is present is a fatal flaw.

In IVF, in cases of low sperm numbers when the sperm function is inadequate for this task, delicate micromanipulation tools are brought to bear. Using methods developed by cell biologists, the embryologist sits before controls like joysticks on a video game. Imagine threading a bit of angel hair into a speck of dust and you will be able to understand how intracytoplasmic sperm injection (ICSI) is done. Now a daily part of the armamentarium of highly skilled IVF embryologists, it is nonetheless an amazing advance.

ICSI, intracytoplasmic sperm injection. From www.cht.nhs.uk
 
After fertilization, in the incubator, the pronuclei can be seen on day one. On the first day after insemination, the IVF embryologist looks for the two pronuclei as an indicator that fertilization has occurred. Further scrutiny of these under high magnification gives clues as to the future.  Lynnette Scott PhD in Boston among others has developed a system of predicting outcomes based on the tiny nucleoli in the pronuclei. If they line up in an orderly manner the embryos may progress. If they are disorganized there is a good chance development will be impaired.

Pronuclei.
On day three the embryos are 5-8 cells

8 cells
Sometimes embryos are cultured to day 5 at the blastocyst stage
Assisted hatching is done to assist the hatching of the blastocyst through the zona

Normal zona

Thin zona

Laser ICSI used to breach the zona, as used for assisted hatching, from www.hamiltonthorne.com


 
Blastocyst
Counting the chromosomes in the pregnancy tissue is recommended if a miscarriage occurs after IVF. This test can be performed in a genetics laboratory on miscarriage tissue in order to determine if one of these errors caused the loss. When aneuploidy is found in the tissue by chromosome testing, we are reassured that the loss was not due to a disease in the mother.
In IVF a common occurrence is the early pregnancy which attaches and produces a positive test, but then dies within a few days. Because we only know there is a pregnancy by looking at a biochemical reaction, the pregnancy test, this event is called a biochemical pregnancy. Most of these unfortunate occurrences are due to aneuploidy also. Implantation occurs, HCG hormone is produced but often the progesterone level is low, the HCG hormone does not rise and over the first week of the pregnancy it is apparent that the pregnancy is in danger, and then the hormone levels go down over the following week. In essence this may be considered a microscopic miscarriage. A tiny defective implanted embryo is lost which contained placental cells and usually had no fetal development at all.
 
References
Thomas FH and Vanderhayden .  Oocyte growth and developmental competence in In –vitro Maturation Of Human Oocytes Tan, Chian, Bucket eds. pages 1-15  Informa UK 2007
Harris, Sarah E and Picton HM. Metabolism of follicles and oocytes during growth and maturation. IBID  page 15-36.
Written by Joe B Massey MD
Additional references provided on request.
Related Articles
Birds, Bees and Bunnies: The Biology of IVF – Part 1
Birds, Bees and Bunnies: The Biology of IVF – Part 2 (Eggs!)

9
Feb

Birds, Bees and Bunnies: The Biology of IVF – Part 2 (Eggs!)

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This article discusses the basic biology behind the process of In Vitro Fertilization (IVF) and may be helpful to couples who plan to undergo IVF. Technical terms may be found in a glossary at www.fertilitylifelines.com.

CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY. CNY Fertility Center offers couples and individuals affordable fertility treatments including low cost IVF (In Vitro Fertilization) by our experienced and caring staff.
Now let’s look at the details of the process from the perspective of the biology of reproduction. How does a woman conceive? Only 5% of all the eggs harvested in IVF treatments result in a baby.  Many of the errors which arise can be traced back to the egg. The most obvious example of this is the well known adverse influence of advanced age of the woman. In many instances an egg from a 40 year old will look great under the microscope, but it is doomed from the start by genetic errors. Please refer to a separate article on IVF and age of the woman. The resting egg within the primary follicle is surrounded by a single layer of cells, the granulosa cells. Selected follicles grow to become secondary or antral follicles in a phase called initial recruitment. This occurs before the woman even has a period. Then suddenly a new phase of recruitment begins with the onset of the menstrual cycle.  Much research has been directed at the signals which initiate the selection of about 20 follicles to suddenly begin to grow at once. As yet this signal is not clearly identified. But in any case, independent of gonadotropins, this cohort of follicles does emerge. As they grow they do become sensitive to the gondadotropin (gonad /growth)follicle stimulating hormone, FSH. In IVF, added gonadotropin will be given by injection to promote the growth of these follicles.

Primary follicle
The granulosa cells multiply and as the follicle develops, fluid is secreted forming an antrum which can be visualized on ultrasound as it reaches about 2 mm in size. Counting the number of these antral follicles can be predictive of the numbers of eggs retrieved in IVF cycles.

Secondary or antral follicle surrounded by granulosa cells. From www.dkiimages.com
About half of the antral follicles will result in an egg in the laboratory during IVF. The numbers will vary from one month to another, but typically within a narrow range. One does not see the antral follicle count jump from 3 to 15 in one month.   There is no amount of drugs which can force more follicles to develop than there are antral follicles. The limit is really set at the beginning of the cycle.  Counting the antral follicles is probably more valid than the measurement of blood FSH on day 3, in evaluation of fertility potential.

Mitochondria from www.nsf.org
Another problem which can arise as the cytoplasm begins to mature relates to the tiny energy factories themselves, the mitochondria. Yes, those were in your biology book too. The mitochondrial numbers increase enormously from about 10,000 in the primordial egg, to several hundred thousand in the mature egg.  The mitochondria are the tiny engines which burn or oxidize fuel and produce energy for the egg. In older women, eggs may have low numbers of mitochondria.  This may be an aspect of the eggs’ incompetence. Attempts in the past to restore mitochondria by injection of healthy cytoplasm from egg donors have not been successful.    For complex reasons this research area is not being pursued.
The all important FSH hormone stimulates the development of the cumulus cells which are tightly bound to the egg and provide nutrients and molecular signals. These assist in rapid growth of the egg cell from 35 to 90-120 microns in diameter as it acquires the proteins and RNA which will be utilized in fertilization and development.
In IVF, the immature egg is easily recognized by the presence of the nucleus (germinal vesicle). Once it disappears, we know that maturation is occurring.

Germinal Vesicle Egg
In the meantime, a tiny amount of LH is required to initiate the breakdown of the nucleus, (germinal vesicle breakdown) which marks the beginning of nuclear maturation and the egg evolves to the stage known as Metaphase I.
 

MI egg
The development of the nucleus must be coordinated with simultaneous development of the cytoplasm. Estrogen provided through the cumulus cells helps to activate or suppresses selected genes in the cytoplasm. These lead to the maturation steps required. Just the right amount of estrogen is needed, and this hormone production becomes the marker used for follicular development. Daily blood tests can indicate indirectly that the follicles are producing estrogen well or not so well.
The other ovarian hormone, progesterone is involved in egg membrane and cytoplasmic maturation as well (Chian review). If there is a surge of LH, the process of luteinization can begin in the follicle, causing production of rising progesterone levels. Too much progesterone from premature luteinization can occur and this causes atresia of the eggs and all is lost. This is the reason in IVF the pituitary gland is usually suppressed by the agonists or antagonists.  See further discussion of antagonists at www.fertilitylifelines.com and elsewhere on this website.

Simultaneously, one other element of maturation occurs at the level of the membrane around the egg. Cytoplasmic maturation coincides with one more element. The membrane surrounding the cytoplasm has to mature. Most amazing at the submicroscopic level is the critical cortical granule release system. When one sperm enters the egg, this system instantly solidifies the membrane and prevents entry of another sperm.

Granulosa cells communicate with the egg by tiny projections which create an intimate relationship. These cells must remain attached to the immature egg so that nourishing factors are transmitted which promote the development of the cytoplasm. The cytoplasm, the bulk of the egg, contains the submicroscopic mitochondria and other organelles. The maturation of the organelles must occur hand in hand with the maturation of the nucleus. IVF patients will recognize the cytoplasm as the major part of the egg, the place where sperm are inserted with a needle in intracytoplasmic sperm injection, ICSI.

Later, when the egg is mature, the granulosa cells are washed off with an enzymatic solution.  Then we can grasp the egg with a pipette and inject a single sperm (ICSI). This will be covered later.

These connections are not a one way street from cumulus cell to the egg. The egg in turn is controlling or influencing the functions of the rapidly expanding group of surrounding granulosa cells. It is sending signals which promote the very development of the follicle which expands eventually to approximately 2 cm. Some of the cells are morphed into theca cells, and later will be called on to produce progesterone.  This dynamic expansion has no rival in the body. The rapid development of the needed blood supply is another of the diverse and intricate responses required.

During stimulation in IVF, high doses of FSH and sometimes LH are used to recruit multiple follicles and aid in their maturation. For many years there has been concern that gonadotropin stimulation and the effect on the oocytes could be a factor which limits the success of IVF (Paulson et al 1991). The blood supply is impaired by crowding of follicles when we stimulate for IVF. Low oxygen within the follicle leads to lower oocyte competence in some of the eggs. This is one disadvantage of ovarian stimulation (Von Blerkom 1997)
Van Blerkom ( 1997) and Munne  (1997) suggested that drug stimulations might predispose to chromosomal abnormalities in the human embryo. Jackson et al (1998) asserted that accelerated ovulation induction response was linked to abnormal nuclear formation which resulted in embryos with a defect called multinucleation.

On the other hand there have been many studies reassuring us that the outcomes of IVF are not revealing an epidemic of abnormal babies. Furthermore, reassuring results were noted recently in a comparison of stimulated vs natural cycle derived oocytes (Zeibe et al, 2004). Most likely these embryos which become impaired are falling by the wayside and never implant.
But let’s get back to the biology of the cumulus-egg complex. In addition to links to the cytoplasm,   there is an active two way communication from the cumulus involving nutrients and signals to the nucleus to begin its required maturation steps. This begins the process which results in the transition of the nucleus from the packed short chromosomes of the germinal vesicle of the most immature egg, to the metaphase II mature structure which is ready for fertilization.

In the natural cycle, the dominant follicle produces androgens (Anderiesz, and Trounson, 1995) which cause atresia, a type of cell death of the remaining follicle and eggs.  Additionally, the rising level of estrogen signaling through the inhibin-based feedback mechanism tells the pituitary gland to reduce the level of FSH which reaches the smaller follicles. These follicles are thus deprived of the stimulation they need to continue to grow.  Thus in most cycles after the largest follicle is about 14 mm, only one egg retains the competence to become fertilized and develop. The concept of acquiring healthy eggs for in vitro maturation (IVM) rests on appropriate harvesting of oocytes after maturation has begun and before atresia has begun. In any egg retrieval, there are likely to be one or more eggs which are atretic.

Atretic egg
Once the follicles have been recruited, the stimulation by FSH is necessary for continued growth. But the timing and amount of FSH can be critical (Thomas and Vanderhayden). Premature stimulation can interfere with egg competence including errors in the chromosomes.

In IVF, ovarian stimulation overrides the influence of the dominant follicle. We promote the continued development of all the follicles by giving FSH in huge doses relative to the amount naturally produced by the pituitary.  This is called stimulation or hyperstimulation of the ovaries and is a key to IVF.

An important function of the granulosa cells as they relate to IVF is the fact that these little cells are powerful factories producing estrogen. As mentioned earlier this is need to promote the development of the egg. The healthy follicles produce one particular type of estrogen called estradiol in science language, but called E-2 in the IVF clinic. Normal follicles produce dramatically increasing amounts. Unhealthy follicles produce less. The total amount of E-2 can be measured in the blood as an indicator of the response and health of the follicle. This indicator ultimately reflects on the health of the eggs.  Additionally too much estrogen being produced can be an indicator of the possibility of ovarian hyperstimulation, a dangerous syndrome in about two per cent of IVF cases.

As the egg matures the chromosomes numbers are reduced to half of an adult cell and the egg is ready to receive a contribution of DNA or genetic material from the sperm.

The final trigger for resumption of nuclear maturation and competence in IVF treatment is the result of the surge of LH like activity provided by its chemical cousin, HCG. Suddenly the close bond between the granulosa cells and the follicle are broken. The egg in cumulus is preparing to be cast off down the tube to meet a sperm and the final nuclear development occurs as the magical metaphase II stage is quickly reached. At this point the egg has half the copies it will need as it has cast off 23 copies of its DNA into the polar body. The observation of the polar body is the sign of maturity is welcomed in the IVF lab as the signal that the nucleus has reached this stage.

Mature egg with granulosa cells in IVF
Egg with granulosa from www.vetmed.auburn.edu

 

Sperm from WWW.3dscience.com
 
 

MII, as seen in the IVF laboratory with prominent polar body


M II with nuclear material in the polar body and nucleus (blue) from www.reproduction-online.com
In the IVF lab the ideal egg is the metaphase II which is abbreviated MII using roman numerals, “M two’s” as we call them. The polar body is easily seen once the granulosa cells have been stripped away.

If the first cell division goes awry, the wrong number of chromosomes results. The errors in general are known as aneuploidy. One possibility is that the egg retains one chromosome too many. This is called trisomy, three of one set of chromosomes. Down’s syndrome is caused by triploidy of the number 21 chromosome for example. Many miscarriages are due to trisomies of certain chromosomes. Another derangement of numbers is monosomy (one /chromosome), in which the egg is left with one copy of the pair required for normal reproduction and development. Turner ’s syndrome and some miscarriages are due to monosomy.
Often fertilization can be accomplished by simply allowing the sperm and eggs to mix in vitro. The other prominent structure in the egg is the zona pellucida (clear zone) or jelly coat, which must be traversed by the sperm and usually does so with ease in natural fertilization. The natural process is depicted in a clip graphically: www.health.howstuffworks.com/human-reproduction10.htm

Related Articles
Birds, Bees and Bunnies: The Biology of IVF – Part 1
Birds, Bees and Bunnies: The Biology of IVF – Part 3 (Sperm & Embryos)

9
Feb

Birds, Bees and Bunnies: The Biology of IVF – Part 1

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This article discusses the basic biology behind the process of In Vitro Fertilization (IVF) and may be helpful to couples who plan to undergo IVF. Technical terms may be found in a glossary at www.fertilitylifelines.com.

CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY. CNY Fertility Center offers couples and individuals affordable fertility treatments including low cost IVF (In Vitro Fertilization) by our experienced and caring staff.
In the high school classroom, perhaps we giggled a bit about these slightly embarrassing topics. Now that we are trying to get pregnant we need to pay attention.  The story of reproduction is fascinating and complex and the more we know the more we can understand some of the terms used in IVF clinics which affect our outcomes.

In nature, for most women, the production of a single egg each month is automatic. The hormone changes required are treated lightly here.  In IVF, we must go to enormous lengths to be able to obtain this precious cell (the egg) in the laboratory.  More of the story can be found in articles on how the gonadotropin hormones work and how egg retrieval is done, elsewhere on this web site.

We begin with consideration of the egg, which measures a tenth of a millimeter, is barely visible, but is the largest and most complex single human cell. It provides the energy and structure to form a healthy embryo which can develop into a baby composed of a few trillion cells.  A perfectly competent egg is ready to be fertilized and develop to the 4 cell stage with a little help from the sperm. The sperm will provide 23 chromosomes, half of the genes and the centriole, critical to organize cell division. But (as some would argue, typical of the man), there is no energy provided by the sperm nor is there any follow-up responsibility. The leading contributions for assuring a next generation must depend on the egg.

The tiny egg which has been resting in the ovary for 20-40 years must suddenly, within weeks, awaken, mature and develop the ability to combine with the sperm and divide.  Rapid and complex changes give the egg competence to do these tasks.  The more we know about the complexities of the process it seems amazing that it ever works. Indeed, too often it does not.  There is much inefficiency in reproduction, especially in humans. The development of the eggs, the fertilization process, and early development often fail in nature. Even the most fertile young woman has about a 20% chance to conceive in one cycle.  Throughout evolution this has turned out to be just fine for the human species. Other animals are different. Famously the rabbit produces several eggs each month, and to make sure the timing is right the female bunny, the doe, ovulates by reflex after intercourse. Pregnancy follows automatically. Considering our behavior, it is a good thing that this is not the case in humans.

However the good luck of the bunny is not helpful to infertility patients, who are often frustrated with the low percentages which can be less than 5% per cycle.  They have to spend time and money to improve their conception possibilities. In fact after IVF, ongoing healthy pregnancy rates can be in the range of 40% in one month.  There is much technology involved to produce multiple eggs and embryos.
Related Articles

Birds, Bees and Bunnies: The Biology of IVF – Part 2 (Eggs!)
Birds, Bees and Bunnies: The Biology of IVF – Part 3 (Sperm & Embryos)

1
Feb

A Reason to Give

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Have you ever wanted to help another family, but didn’t know where to begin?  The Donor Program, PRIDE (PRegnancy Initiated with Donated Eggs) at CNY Fertility Center is a wonderful place to begin.  We have established an easy and personal program to help you through the steps of egg donation.  There are many reasons to donate your eggs to another woman but regardless of why you choose to give, know that we will be there to support you.

Many of our donors have had beautiful, close experiences with children.  Whether they have children of their own or they come from a large family of siblings, there is an appreciation of the love and bond of parenthood.  Through egg donation you would be able to create that same experience for another woman.  Most of our patients have been trying for at least one year to conceive, and some as many as ten.  They had always planned on having a family of their own, but never imagined they would be faced with the devastating news that they would not conceive with their own eggs.  Whatever the reason for their infertility, without donor eggs these patients will never carry and deliver a child of their own.  In their hearts they know they will be wonderful parents and give their children the world, but unfortunately they have not been able to achieve this dream.  Your gift of egg donation would make this dream a reality.  The beauty of this program is that the recipient will also be able to carry the child, and experience those special nine months, delivery, and breastfeeding if they wish.  For some women, this is a dream come true.

Through egg donation, you would be able to change the lives of a deserving, and loving family.  You would be giving them the ultimate gift, life.  While your reasons to donate are personal, know that someone will be forever grateful for your decision.
If you would like further information about the Donor Program at CNY Fertility Center, please explore our website further and contact one of our Donor Coordinators: http://cnyfertility.com/donor-gametes/donor-oocytes/
If you have familiarized yourself with the program and would like to pursue egg donation, follow this link to the Donor Portal and further instructions: http://cnyfertility.com/2010/01/22/cny-fertility-center-donor-portal/

Or contact Kari Gardner directly at the Syracuse Office by calling toll free 800.539.9870 or emailing her at kgardner@cnyfertility.com.

21
Jan

Solo Mothers

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IVF in single women with donor eggs and donor sperm
CNY Fertility Center has locations in Syracuse, NY Albany, NY and Rochester, NY. Fertility treatments are affordable and include low cost IVF (In Vitro Fertilization). Our caring and experienced staff provides confidential treatments for heterosexual couples, same sex couples and  unmarried individuals who are looking to conceive. CNY Fertility Center offers donor eggs, donor sperm and donor embryos. In this article we will explore the options for solo mothers using donor eggs and sperm IVF to create their family.

There is virtually no method for trying to conceive which has not been explored in this day of increasingly progressive options. There can be many different match ups between the sources of the sperm and eggs, thanks to the structure of the IVF technique. It seems that where there is a will, there is a way.

Over the past 20 years, the new class of “solo mothers” has emerged. This is an example of the strength of the drive for reproduction, despite seemingly overwhelming odds. One study focused on 11 single Israeli women who required both eggs and sperm from anonymous sources. These women’s biological clocks had indeed run out, as their average age was 46. Prior to treatment, these women were intensively interviewed regarding issues of older parenting and the living adjustments that would have to be made.

In most countries, it is only financially stable women with college educations who choose to become mothers in this fashion. In pro-baby Israel, the national health care system actually encourages this further, as it provides infertility treatment for producing up to two children up to the maternal age of 51, without regard to marital status. Out of the small Israeli study group, three women had not attended college.  Upon follow-up, socio-emotional development and mother-child relationships seemed satisfactory. All the women reported the highest possible levels of satisfaction with parenthood.

Several of these women were working full time; however, they were depending on extended families and day care facilities during those hours. Interestingly, the lack of a genetic bond did not seem to be a concern for the women: The gestational bond seemed quite strong and was distinguished from adoptive situations. This information may be of help to others considering egg donations.

It is known that IVF can produce multiple births, and this may carry some health risks for the children. In the small Israeli study, one set of twins had suboptimal health after a premature birth.  Certainly this risk is an important one to remember, if a single parent. The amount of work and time involved may be greater than “normal,” if circumstances such as this arise. Replacement of single embryos is a consideration for women in this situation. And that might mean an increase in the number of attempts to have a child; therefore, it might increase IVF cost.

Methods of low cost IVF can be applied in the pursuit of conception for the single woman. Egg donors may have low gonadotropin stimulation for fresh cycle therapy. Egg banks using frozen eggs are also now a realistic option to pursue. This is because the splitting of batches of donated eggs among two or more recipients lowers the cost of IVF.

There is debate on what to tell the child. Concerns have been raised about the previous secrecy involved and much increased openness with the children has been advocated. This and other related topics are covered in a recent book by Angela Best Boss and Evelina Sterling. It is of note that the writers provide a professional counseling service at www.myfertilityplan.com.   Also we recommend the referenced article published in Women’s Health on a related topic.

References:
Best-Boss, Angie and Sterling, Evelina. Having Your Baby through Egg Donation  2005.
Kirkamn M.  Egg and embryo donation and the meaning of motherhood.  Women’s Health 2003; 38: 1-18.
Landau R et al. Older single mothers and IVF with sperm and egg donation. Fertil Steril 2008; 90: 576-583

21
Jan

Embryo Transfer – Day 3 versus Day 5

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CNY Fertility Center has locations in Syracuse, NY Albany, NY and Rochester, NY. CNY Fertility offers affordable fertility treatments including low cost IVF (In Vitro Fertilization). Patients often have questions about the day that their embryos will be transferred back to their uterus following their IVF procedure. This article is a quick summary of the history and advantages of both Day 3 and Day 5 embryo transfers.
Until about 10 years ago, all embryos were routinely placed in the uterus on day 3 of the cycle. Embryos are then at the 6-8 cell stage.

(8 celled embryo – Day 3)
Culture methods then emerged which allowed healthy embryos to continue developing to day 5, the blastocyst stage which has several attractive features.  Most importantly it allows some of the embryos which are doomed to failure due to internal defects to fall by the wayside as they arrest and do not continue to develop. Thus the more hardy embryos are self selecting and the rate of implantation of each embryo is higher.  Culturing embryos out to the blastocyst stage reduced the number of embryos that were transferred back as well, reducing the incidence of multiple gestations.

(Blastocyst stage embryo – Day 5)
Initially it seemed as this was applied in IVF practice, that the ability to choose the more robust embryos by self selection in this manner would raise pregnancy rates. In a common scenario, the choice if a patient had 5 embryos available for transfer, all about equal in quality on inspection under the microscope, the option would be to replace 3 embryos on day 3 or two on day 5. It was hoped that the day 5 embryo transfer would yield higher results for the IVF patient. This has not turned out to be the case. It is however true that the number of triplets is reduced by use of the day 5 strategy, which is an important option to consider when the risk of multiples is paramount.

Success Stories

27
Sep

Are you thinking of doing a Mini-IVF?

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Hi this is Dr. Rob Kiltz, founder and director of CNY Fertility Center with locations in Syracuse, Rochester and Albany, NY.  We recently had a client ask us about whether or not we do “mini-IVF”.  The question was about the protocols and whether we use  Clomid, Letrozole, injectables, or do we use just FSH, or both FSH and LH. Many people may be interested in this type of IVF cycle so we wanted to share the information to all, on our website. If you have questions about your journey to fertility please don’t hesitate to call us toll free at 800.539.9870, request a phone or in-office consultation or send us your questions here.

Mini-IVF is a term of minimal stimulation.  Invitro Fertilization (IVF) was 1st started with no stimulation (natural cycle, 1 egg) and the pregnancy rates were much lower per cycle.  Over time, protocols were developed using gonadotropins,  FSH (follicle stimulating hormone), LH and medications like Pergonal, Repronex, Gonal-F,  Follistim, Bravelle & Menopur .  These are injectable medications that stimulate the ovary to mature multiple eggs.   On average we are getting 6-10 eggs which means more embryos.  This means a higher chance of pregnancy but at the same time a higher chance of multiples.

By using minimal stimulation, so either Clomid (a pill) which stimulates 1 or 2 eggs at a time, or Letrozole which is similar to Clomid but does not have the same anti-estrogenic effects (it is also not authorized by the manufacturer to be used this way, but many Reproductive Endocrinologists are using Letrozole), there is some success to be obtained by the 1 or 2 or 3 eggs that are retrieved.  In a similar fashion, Clomid or Letrozole would be used day 3-7 of the cycle and then monitoring would happen between day 8 and day 10 of the cycle with ultrasound and blood testing.  When the lead follicle is 18-22 mm in size and an endometrial lining of about 7mm or greater, HCG 10000 units or Ovidrel 250 units is used to stimulate the release of the egg, then 36 hours later egg retrieval is performed in the office.

Now gonadotropins can also be added to that, along with Cetrotide or Ganirelix, to prevent premature release of the eggs.  And this may have a slightly improved number of eggs without the same high-cost because the biggest issue is the expense of the gonadotropins and using mini-IVF (that’s low- dose gonadotropins, or Clomid/ Letrazole)  you can reduce the cost significantly.
The protocol is basically either low-dose gonadotropins with a natural cycle, and beginning on day 2 or 3 of the cycle with 37 to 75 units of gonadotropins with Cetrotide or Ganirelix beginning about day 5 to 7 of the cycle when the lead follicles are about 12 mm and ultrasound monitoring and blood testing so that when the eggs are 16 – 18 mm, HCG or Ovidrel is used to stimulate release and the egg retrieval is performed similar to the standard IVF.

These are all performed at CNY Fertility Centers, yet they are not our predominant protocols, but all are possible and based on your individual needs and can be utilized in the process.
~~~
Dr. Rob Kiltz

8
Jul

April's Journey to Fertility: Now and Next

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April is a CNY Fertility Center patient and has been on her journey to fertility for approximately two and a half years. April will share candid stories and a unique perspective on the fertility challenges many women and couples face. CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY.
Week 55: Now and Next
Norman Lear, producer of many popular television shows including All in the Family said, “I’m interested in now and next,” during his recent interview on Sunday Morning. What a great perspective, I thought to myself.  If we simply focus on what is happening now, we are living in the moment. If we focus on what is happening next we must let go of what has happened before.
Letting go of our past experiences can be extremely difficult! As my husband and I head into our next IVF cycle, I want to focus on the now and next because focusing on our past cycles will not make the next cycle a success. I need to simply let go of our past fertility challenges. I need to feel as if the next cycle is a fresh start, and in many ways each cycle is a fresh start. Our reproductive cycles vary each month as do our emotions, general physical health and overall perspective. Even the egg and sperm quality differ from month to month!
Our cancelled IVF cycle, especially since we made it as far as the egg retrieval, was devastating. No sugarcoating can change the array of overwhelming and heart-wrenching emotions both my husband and I experienced during that cycle, and I am sure you have experienced many emotions as well. However, we must remember that history does not determine the future. In fact, knowing what has and has not worked in the past gives both the doctors and patients a deeper knowledge about what will lead to success.
Fertility treatment is challenging, but focusing on what is happening now and what will be happening can be empowering and even comforting. What fears do you need to let go of? Sometimes I repeat a simple phrase to myself whenever a fearful or negative thought creeps into my consciousness: This does not service my higher purpose, and I release whatever does not serve my higher purpose. (Kristen Magnacca suggested this to me, and I have found this affirmation consistently helpful.)
What negative patterns interfere with your higher purpose and what can you begin to simply release away in thought so that you can feel empowered, confident, and content in spirit?
Looking ahead,
April all Year
Click here to read April’s blog including all of her previous articles.

18
Jun

April's Journey to Fertility: Adjustments

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April is a CNY Fertility Center patient and has been on her journey to fertility for approximately two and a half years. April will share candid stories and a unique perspective on the fertility challenges many women and couples face. CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY.
Week 52: Adjustments
As I was speaking to a friend the other day about what my husband and I are doing next in terms of fertility treatments, I mentioned how I was simply nervous about the outcome of another IVF cycle (which we are not ready for quite yet). Her response to my worry was so insightful I knew I had to share her wisdom with all of you! She simply stated, “No matter what happens you have to adjust. You have already adjusted to not having your baby in the way you thought you would. Then you adjusted to fertility treatment and you even adjusted after the last IVF didn’t work. And when you become pregnant, that will be an adjustment, too.
I remember thinking about how correct she was! I know that no matter what, I will adjust and move forward; I already have in so many ways. My belief is that you have had to do some adjusting, too. Although we would prefer to have life go exactly as planned, being able to adjust to life’s plan for us is vital to anyone’s happiness.
My husband always reads my articles when they are posted to the website. (No, he does not get to read them ahead of time, even if he helps generate any of the week’s material) He sometimes comments about how I recognize others’ abilities in my blog, and then asks me if I recognize my own achievements and/or capabilities. My friend, Katie, helped me to see that no matter what happens I will adjust and continue to move forward on my journey to motherhood. Please consider your own ability to adjust and move forward because I am sure that you, too, have already made many adjustments of your own!
Continuing to adjust,
April all Year
{{hrule}}

Click here to read April’s blog including all of her previous articles.

2
Jun

IVF After 40 years of age – 2010 update

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This information is provided by CNY Fertility Center, where patients are accepted for IVF with no precondition or age cutoff. We offer patients who are in the older age group comprehensive information about their options to start, or add to their family. CNY Fertility Center provides quality, low-cost infertility treatments and IVF care with locations Rochester, Syracuse and Albany New York.
More than half of women over 40 years of age have difficulty conceiving, while others are still fertile. Patients who are over 40 and infertile are seen in IVF centers and tend to have lower success rates with treatments (using their own eggs) than younger women do.
Many women are delaying childbearing until later in life. Until an individual or couple tries to conceive, they don’t know if they fall until the fertile or unfertile category. Laboratory predictors of outcomes like FSH levels, follicle counts, and other ovarian reserve indicators are not absolute in dictating treatment success or failure. Most women over 40 have one or more indicators of a potentially low prognosis.
Two recent papers have reported detailed information for specific age categories. From Egypt, over 200 women aged 40 and above were evaluated for IVF outcomes. As women increased in age, their treatment cycles were more likely to be canceled due to a lack of ovarian response. Miscarriages were 40-67% of clinical pregnancies. The live birth rate for those who made it to egg retrieval was 11% in 40 year olds, 7.5% in 41, 5% age 42, 2% at age 43, and under 1% at age 44 and 45. (Hourvitz et al )
A study in Israel evaluated 842 patients ages 42 plus, between 1998 and 2006. Clinical pregnancy rates per cycle were 7.7, 5.4 and 1.9% for 42, 43 and 44 years old respectively. Many of these pregnancies resulted in miscarriages. Only one IVF cycle in patients aged 44 years resulted in delivery. None of the 54 cycles performed in women of 45 years or older resulted in a pregnancy. A marked decline in clinical pregnancy and delivery rates, accompanied by an increase in spontaneous abortion rates, was found in patients >42 years old (Serour et al).
Results at CNY for 2007 were 12.5% live births per egg retrieval in the 41-42 year group and no deliveries in the 43 and 44 year olds in that year. In 2008, 8% of 41 and 42 year olds who had retrieval had a baby. Above age 42, about 2% of women succeeded in having a birth.
It is often a challenging decision whether or not to use donor eggs or sperm to create a family. Many people desire a child who is genetically related to both parents. Men see a much lower decline in fertility with age, and technologies including IVF and ICSI can increase pregnancy rates for couples where the man has a severely low sperm count.
When maternal age is an issue, it is helpful to remember that the statistics apply to a group of patients. They are general predictors for 100 women. No one can say what an individual’s results will be. CNY Fertility Center helps couples make every reasonable effort to create a biological child, but also offers patients other options for their family building including donor eggs, donor sperm and donor embryos.
It is important to recognize that the use of donor eggs is a high success back up plan. This alternative has delivery rates close to 50%. Many couples where the woman’s age is over 40 will initially try an IVF cycle using their own eggs. Success can come with persistence and positive mental attitude. Among those who are unsuccessful with their own eggs, many move on to using donor eggs for the baby of their dreams. Using a combination of options is often the best plan.
References
A Hourvitz1,2, MD Ronit Machtinger2, MD Ettie Maman, MD Micha Baum, MD, PROF Jehoshua Dor, MD Jacob Levron Assisted reproduction in women over 40 years of age: how old is too old?
Reproductive BioMedicine Online 2009 http://www.rbmonline.com/Article/3872
[e-pub ahead of print on 24 August 2009]
Serour, G et al Analysis of IVF in … women aged 40 years and above. Fertil Steril In press 2010

9
Feb

Birds, Bees and Bunnies: The Biology of IVF – Part 3 (Sperm & Embryos)

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This article discusses the basic biology behind the process of In Vitro Fertilization (IVF) and may be helpful to couples who plan to undergo IVF. Technical terms may be found in a glossary at www.fertilitylifelines.com.
CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY. CNY Fertility Center offers couples and individuals affordable fertility treatments including low cost IVF (In Vitro Fertilization) by our experienced and caring staff.

Sperm penetration and fusion, cortical granule reaction, from www.Wikipedia.com
Once one sperm has penetrated, the cortical granule reaction causes a shield to slam shut just inside the egg membrane within microseconds. This prevents the entry of another sperm. If this system fails and two sperm enter, there are two sets of male chromosomes.  This is called polyspermy and actually is observed commonly in the IVF lab. Three pronuclei, a sign that an entire extra set of chromosomes is present is a fatal flaw.

In IVF, in cases of low sperm numbers when the sperm function is inadequate for this task, delicate micromanipulation tools are brought to bear. Using methods developed by cell biologists, the embryologist sits before controls like joysticks on a video game. Imagine threading a bit of angel hair into a speck of dust and you will be able to understand how intracytoplasmic sperm injection (ICSI) is done. Now a daily part of the armamentarium of highly skilled IVF embryologists, it is nonetheless an amazing advance.

ICSI, intracytoplasmic sperm injection. From www.cht.nhs.uk
 
After fertilization, in the incubator, the pronuclei can be seen on day one. On the first day after insemination, the IVF embryologist looks for the two pronuclei as an indicator that fertilization has occurred. Further scrutiny of these under high magnification gives clues as to the future.  Lynnette Scott PhD in Boston among others has developed a system of predicting outcomes based on the tiny nucleoli in the pronuclei. If they line up in an orderly manner the embryos may progress. If they are disorganized there is a good chance development will be impaired.

Pronuclei.
On day three the embryos are 5-8 cells

8 cells
Sometimes embryos are cultured to day 5 at the blastocyst stage
Assisted hatching is done to assist the hatching of the blastocyst through the zona

Normal zona

Thin zona

Laser ICSI used to breach the zona, as used for assisted hatching, from www.hamiltonthorne.com


 
Blastocyst
Counting the chromosomes in the pregnancy tissue is recommended if a miscarriage occurs after IVF. This test can be performed in a genetics laboratory on miscarriage tissue in order to determine if one of these errors caused the loss. When aneuploidy is found in the tissue by chromosome testing, we are reassured that the loss was not due to a disease in the mother.
In IVF a common occurrence is the early pregnancy which attaches and produces a positive test, but then dies within a few days. Because we only know there is a pregnancy by looking at a biochemical reaction, the pregnancy test, this event is called a biochemical pregnancy. Most of these unfortunate occurrences are due to aneuploidy also. Implantation occurs, HCG hormone is produced but often the progesterone level is low, the HCG hormone does not rise and over the first week of the pregnancy it is apparent that the pregnancy is in danger, and then the hormone levels go down over the following week. In essence this may be considered a microscopic miscarriage. A tiny defective implanted embryo is lost which contained placental cells and usually had no fetal development at all.
 
References
Thomas FH and Vanderhayden .  Oocyte growth and developmental competence in In –vitro Maturation Of Human Oocytes Tan, Chian, Bucket eds. pages 1-15  Informa UK 2007
Harris, Sarah E and Picton HM. Metabolism of follicles and oocytes during growth and maturation. IBID  page 15-36.
Written by Joe B Massey MD
Additional references provided on request.
Related Articles
Birds, Bees and Bunnies: The Biology of IVF – Part 1
Birds, Bees and Bunnies: The Biology of IVF – Part 2 (Eggs!)

9
Feb

Birds, Bees and Bunnies: The Biology of IVF – Part 2 (Eggs!)

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This article discusses the basic biology behind the process of In Vitro Fertilization (IVF) and may be helpful to couples who plan to undergo IVF. Technical terms may be found in a glossary at www.fertilitylifelines.com.

CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY. CNY Fertility Center offers couples and individuals affordable fertility treatments including low cost IVF (In Vitro Fertilization) by our experienced and caring staff.
Now let’s look at the details of the process from the perspective of the biology of reproduction. How does a woman conceive? Only 5% of all the eggs harvested in IVF treatments result in a baby.  Many of the errors which arise can be traced back to the egg. The most obvious example of this is the well known adverse influence of advanced age of the woman. In many instances an egg from a 40 year old will look great under the microscope, but it is doomed from the start by genetic errors. Please refer to a separate article on IVF and age of the woman. The resting egg within the primary follicle is surrounded by a single layer of cells, the granulosa cells. Selected follicles grow to become secondary or antral follicles in a phase called initial recruitment. This occurs before the woman even has a period. Then suddenly a new phase of recruitment begins with the onset of the menstrual cycle.  Much research has been directed at the signals which initiate the selection of about 20 follicles to suddenly begin to grow at once. As yet this signal is not clearly identified. But in any case, independent of gonadotropins, this cohort of follicles does emerge. As they grow they do become sensitive to the gondadotropin (gonad /growth)follicle stimulating hormone, FSH. In IVF, added gonadotropin will be given by injection to promote the growth of these follicles.

Primary follicle
The granulosa cells multiply and as the follicle develops, fluid is secreted forming an antrum which can be visualized on ultrasound as it reaches about 2 mm in size. Counting the number of these antral follicles can be predictive of the numbers of eggs retrieved in IVF cycles.

Secondary or antral follicle surrounded by granulosa cells. From www.dkiimages.com
About half of the antral follicles will result in an egg in the laboratory during IVF. The numbers will vary from one month to another, but typically within a narrow range. One does not see the antral follicle count jump from 3 to 15 in one month.   There is no amount of drugs which can force more follicles to develop than there are antral follicles. The limit is really set at the beginning of the cycle.  Counting the antral follicles is probably more valid than the measurement of blood FSH on day 3, in evaluation of fertility potential.

Mitochondria from www.nsf.org
Another problem which can arise as the cytoplasm begins to mature relates to the tiny energy factories themselves, the mitochondria. Yes, those were in your biology book too. The mitochondrial numbers increase enormously from about 10,000 in the primordial egg, to several hundred thousand in the mature egg.  The mitochondria are the tiny engines which burn or oxidize fuel and produce energy for the egg. In older women, eggs may have low numbers of mitochondria.  This may be an aspect of the eggs’ incompetence. Attempts in the past to restore mitochondria by injection of healthy cytoplasm from egg donors have not been successful.    For complex reasons this research area is not being pursued.
The all important FSH hormone stimulates the development of the cumulus cells which are tightly bound to the egg and provide nutrients and molecular signals. These assist in rapid growth of the egg cell from 35 to 90-120 microns in diameter as it acquires the proteins and RNA which will be utilized in fertilization and development.
In IVF, the immature egg is easily recognized by the presence of the nucleus (germinal vesicle). Once it disappears, we know that maturation is occurring.

Germinal Vesicle Egg
In the meantime, a tiny amount of LH is required to initiate the breakdown of the nucleus, (germinal vesicle breakdown) which marks the beginning of nuclear maturation and the egg evolves to the stage known as Metaphase I.
 

MI egg
The development of the nucleus must be coordinated with simultaneous development of the cytoplasm. Estrogen provided through the cumulus cells helps to activate or suppresses selected genes in the cytoplasm. These lead to the maturation steps required. Just the right amount of estrogen is needed, and this hormone production becomes the marker used for follicular development. Daily blood tests can indicate indirectly that the follicles are producing estrogen well or not so well.
The other ovarian hormone, progesterone is involved in egg membrane and cytoplasmic maturation as well (Chian review). If there is a surge of LH, the process of luteinization can begin in the follicle, causing production of rising progesterone levels. Too much progesterone from premature luteinization can occur and this causes atresia of the eggs and all is lost. This is the reason in IVF the pituitary gland is usually suppressed by the agonists or antagonists.  See further discussion of antagonists at www.fertilitylifelines.com and elsewhere on this website.

Simultaneously, one other element of maturation occurs at the level of the membrane around the egg. Cytoplasmic maturation coincides with one more element. The membrane surrounding the cytoplasm has to mature. Most amazing at the submicroscopic level is the critical cortical granule release system. When one sperm enters the egg, this system instantly solidifies the membrane and prevents entry of another sperm.

Granulosa cells communicate with the egg by tiny projections which create an intimate relationship. These cells must remain attached to the immature egg so that nourishing factors are transmitted which promote the development of the cytoplasm. The cytoplasm, the bulk of the egg, contains the submicroscopic mitochondria and other organelles. The maturation of the organelles must occur hand in hand with the maturation of the nucleus. IVF patients will recognize the cytoplasm as the major part of the egg, the place where sperm are inserted with a needle in intracytoplasmic sperm injection, ICSI.

Later, when the egg is mature, the granulosa cells are washed off with an enzymatic solution.  Then we can grasp the egg with a pipette and inject a single sperm (ICSI). This will be covered later.

These connections are not a one way street from cumulus cell to the egg. The egg in turn is controlling or influencing the functions of the rapidly expanding group of surrounding granulosa cells. It is sending signals which promote the very development of the follicle which expands eventually to approximately 2 cm. Some of the cells are morphed into theca cells, and later will be called on to produce progesterone.  This dynamic expansion has no rival in the body. The rapid development of the needed blood supply is another of the diverse and intricate responses required.

During stimulation in IVF, high doses of FSH and sometimes LH are used to recruit multiple follicles and aid in their maturation. For many years there has been concern that gonadotropin stimulation and the effect on the oocytes could be a factor which limits the success of IVF (Paulson et al 1991). The blood supply is impaired by crowding of follicles when we stimulate for IVF. Low oxygen within the follicle leads to lower oocyte competence in some of the eggs. This is one disadvantage of ovarian stimulation (Von Blerkom 1997)
Van Blerkom ( 1997) and Munne  (1997) suggested that drug stimulations might predispose to chromosomal abnormalities in the human embryo. Jackson et al (1998) asserted that accelerated ovulation induction response was linked to abnormal nuclear formation which resulted in embryos with a defect called multinucleation.

On the other hand there have been many studies reassuring us that the outcomes of IVF are not revealing an epidemic of abnormal babies. Furthermore, reassuring results were noted recently in a comparison of stimulated vs natural cycle derived oocytes (Zeibe et al, 2004). Most likely these embryos which become impaired are falling by the wayside and never implant.
But let’s get back to the biology of the cumulus-egg complex. In addition to links to the cytoplasm,   there is an active two way communication from the cumulus involving nutrients and signals to the nucleus to begin its required maturation steps. This begins the process which results in the transition of the nucleus from the packed short chromosomes of the germinal vesicle of the most immature egg, to the metaphase II mature structure which is ready for fertilization.

In the natural cycle, the dominant follicle produces androgens (Anderiesz, and Trounson, 1995) which cause atresia, a type of cell death of the remaining follicle and eggs.  Additionally, the rising level of estrogen signaling through the inhibin-based feedback mechanism tells the pituitary gland to reduce the level of FSH which reaches the smaller follicles. These follicles are thus deprived of the stimulation they need to continue to grow.  Thus in most cycles after the largest follicle is about 14 mm, only one egg retains the competence to become fertilized and develop. The concept of acquiring healthy eggs for in vitro maturation (IVM) rests on appropriate harvesting of oocytes after maturation has begun and before atresia has begun. In any egg retrieval, there are likely to be one or more eggs which are atretic.

Atretic egg
Once the follicles have been recruited, the stimulation by FSH is necessary for continued growth. But the timing and amount of FSH can be critical (Thomas and Vanderhayden). Premature stimulation can interfere with egg competence including errors in the chromosomes.

In IVF, ovarian stimulation overrides the influence of the dominant follicle. We promote the continued development of all the follicles by giving FSH in huge doses relative to the amount naturally produced by the pituitary.  This is called stimulation or hyperstimulation of the ovaries and is a key to IVF.

An important function of the granulosa cells as they relate to IVF is the fact that these little cells are powerful factories producing estrogen. As mentioned earlier this is need to promote the development of the egg. The healthy follicles produce one particular type of estrogen called estradiol in science language, but called E-2 in the IVF clinic. Normal follicles produce dramatically increasing amounts. Unhealthy follicles produce less. The total amount of E-2 can be measured in the blood as an indicator of the response and health of the follicle. This indicator ultimately reflects on the health of the eggs.  Additionally too much estrogen being produced can be an indicator of the possibility of ovarian hyperstimulation, a dangerous syndrome in about two per cent of IVF cases.

As the egg matures the chromosomes numbers are reduced to half of an adult cell and the egg is ready to receive a contribution of DNA or genetic material from the sperm.

The final trigger for resumption of nuclear maturation and competence in IVF treatment is the result of the surge of LH like activity provided by its chemical cousin, HCG. Suddenly the close bond between the granulosa cells and the follicle are broken. The egg in cumulus is preparing to be cast off down the tube to meet a sperm and the final nuclear development occurs as the magical metaphase II stage is quickly reached. At this point the egg has half the copies it will need as it has cast off 23 copies of its DNA into the polar body. The observation of the polar body is the sign of maturity is welcomed in the IVF lab as the signal that the nucleus has reached this stage.

Mature egg with granulosa cells in IVF
Egg with granulosa from www.vetmed.auburn.edu

 

Sperm from WWW.3dscience.com
 
 

MII, as seen in the IVF laboratory with prominent polar body


M II with nuclear material in the polar body and nucleus (blue) from www.reproduction-online.com
In the IVF lab the ideal egg is the metaphase II which is abbreviated MII using roman numerals, “M two’s” as we call them. The polar body is easily seen once the granulosa cells have been stripped away.

If the first cell division goes awry, the wrong number of chromosomes results. The errors in general are known as aneuploidy. One possibility is that the egg retains one chromosome too many. This is called trisomy, three of one set of chromosomes. Down’s syndrome is caused by triploidy of the number 21 chromosome for example. Many miscarriages are due to trisomies of certain chromosomes. Another derangement of numbers is monosomy (one /chromosome), in which the egg is left with one copy of the pair required for normal reproduction and development. Turner ’s syndrome and some miscarriages are due to monosomy.
Often fertilization can be accomplished by simply allowing the sperm and eggs to mix in vitro. The other prominent structure in the egg is the zona pellucida (clear zone) or jelly coat, which must be traversed by the sperm and usually does so with ease in natural fertilization. The natural process is depicted in a clip graphically: www.health.howstuffworks.com/human-reproduction10.htm

Related Articles
Birds, Bees and Bunnies: The Biology of IVF – Part 1
Birds, Bees and Bunnies: The Biology of IVF – Part 3 (Sperm & Embryos)

9
Feb

Birds, Bees and Bunnies: The Biology of IVF – Part 1

by

This article discusses the basic biology behind the process of In Vitro Fertilization (IVF) and may be helpful to couples who plan to undergo IVF. Technical terms may be found in a glossary at www.fertilitylifelines.com.

CNY Fertility Center has locations in Syracuse, Albany and Rochester, NY. CNY Fertility Center offers couples and individuals affordable fertility treatments including low cost IVF (In Vitro Fertilization) by our experienced and caring staff.
In the high school classroom, perhaps we giggled a bit about these slightly embarrassing topics. Now that we are trying to get pregnant we need to pay attention.  The story of reproduction is fascinating and complex and the more we know the more we can understand some of the terms used in IVF clinics which affect our outcomes.

In nature, for most women, the production of a single egg each month is automatic. The hormone changes required are treated lightly here.  In IVF, we must go to enormous lengths to be able to obtain this precious cell (the egg) in the laboratory.  More of the story can be found in articles on how the gonadotropin hormones work and how egg retrieval is done, elsewhere on this web site.

We begin with consideration of the egg, which measures a tenth of a millimeter, is barely visible, but is the largest and most complex single human cell. It provides the energy and structure to form a healthy embryo which can develop into a baby composed of a few trillion cells.  A perfectly competent egg is ready to be fertilized and develop to the 4 cell stage with a little help from the sperm. The sperm will provide 23 chromosomes, half of the genes and the centriole, critical to organize cell division. But (as some would argue, typical of the man), there is no energy provided by the sperm nor is there any follow-up responsibility. The leading contributions for assuring a next generation must depend on the egg.

The tiny egg which has been resting in the ovary for 20-40 years must suddenly, within weeks, awaken, mature and develop the ability to combine with the sperm and divide.  Rapid and complex changes give the egg competence to do these tasks.  The more we know about the complexities of the process it seems amazing that it ever works. Indeed, too often it does not.  There is much inefficiency in reproduction, especially in humans. The development of the eggs, the fertilization process, and early development often fail in nature. Even the most fertile young woman has about a 20% chance to conceive in one cycle.  Throughout evolution this has turned out to be just fine for the human species. Other animals are different. Famously the rabbit produces several eggs each month, and to make sure the timing is right the female bunny, the doe, ovulates by reflex after intercourse. Pregnancy follows automatically. Considering our behavior, it is a good thing that this is not the case in humans.

However the good luck of the bunny is not helpful to infertility patients, who are often frustrated with the low percentages which can be less than 5% per cycle.  They have to spend time and money to improve their conception possibilities. In fact after IVF, ongoing healthy pregnancy rates can be in the range of 40% in one month.  There is much technology involved to produce multiple eggs and embryos.
Related Articles

Birds, Bees and Bunnies: The Biology of IVF – Part 2 (Eggs!)
Birds, Bees and Bunnies: The Biology of IVF – Part 3 (Sperm & Embryos)

1
Feb

A Reason to Give

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Have you ever wanted to help another family, but didn’t know where to begin?  The Donor Program, PRIDE (PRegnancy Initiated with Donated Eggs) at CNY Fertility Center is a wonderful place to begin.  We have established an easy and personal program to help you through the steps of egg donation.  There are many reasons to donate your eggs to another woman but regardless of why you choose to give, know that we will be there to support you.

Many of our donors have had beautiful, close experiences with children.  Whether they have children of their own or they come from a large family of siblings, there is an appreciation of the love and bond of parenthood.  Through egg donation you would be able to create that same experience for another woman.  Most of our patients have been trying for at least one year to conceive, and some as many as ten.  They had always planned on having a family of their own, but never imagined they would be faced with the devastating news that they would not conceive with their own eggs.  Whatever the reason for their infertility, without donor eggs these patients will never carry and deliver a child of their own.  In their hearts they know they will be wonderful parents and give their children the world, but unfortunately they have not been able to achieve this dream.  Your gift of egg donation would make this dream a reality.  The beauty of this program is that the recipient will also be able to carry the child, and experience those special nine months, delivery, and breastfeeding if they wish.  For some women, this is a dream come true.

Through egg donation, you would be able to change the lives of a deserving, and loving family.  You would be giving them the ultimate gift, life.  While your reasons to donate are personal, know that someone will be forever grateful for your decision.
If you would like further information about the Donor Program at CNY Fertility Center, please explore our website further and contact one of our Donor Coordinators: http://cnyfertility.com/donor-gametes/donor-oocytes/
If you have familiarized yourself with the program and would like to pursue egg donation, follow this link to the Donor Portal and further instructions: http://cnyfertility.com/2010/01/22/cny-fertility-center-donor-portal/

Or contact Kari Gardner directly at the Syracuse Office by calling toll free 800.539.9870 or emailing her at kgardner@cnyfertility.com.

21
Jan

Solo Mothers

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IVF in single women with donor eggs and donor sperm
CNY Fertility Center has locations in Syracuse, NY Albany, NY and Rochester, NY. Fertility treatments are affordable and include low cost IVF (In Vitro Fertilization). Our caring and experienced staff provides confidential treatments for heterosexual couples, same sex couples and  unmarried individuals who are looking to conceive. CNY Fertility Center offers donor eggs, donor sperm and donor embryos. In this article we will explore the options for solo mothers using donor eggs and sperm IVF to create their family.

There is virtually no method for trying to conceive which has not been explored in this day of increasingly progressive options. There can be many different match ups between the sources of the sperm and eggs, thanks to the structure of the IVF technique. It seems that where there is a will, there is a way.

Over the past 20 years, the new class of “solo mothers” has emerged. This is an example of the strength of the drive for reproduction, despite seemingly overwhelming odds. One study focused on 11 single Israeli women who required both eggs and sperm from anonymous sources. These women’s biological clocks had indeed run out, as their average age was 46. Prior to treatment, these women were intensively interviewed regarding issues of older parenting and the living adjustments that would have to be made.

In most countries, it is only financially stable women with college educations who choose to become mothers in this fashion. In pro-baby Israel, the national health care system actually encourages this further, as it provides infertility treatment for producing up to two children up to the maternal age of 51, without regard to marital status. Out of the small Israeli study group, three women had not attended college.  Upon follow-up, socio-emotional development and mother-child relationships seemed satisfactory. All the women reported the highest possible levels of satisfaction with parenthood.

Several of these women were working full time; however, they were depending on extended families and day care facilities during those hours. Interestingly, the lack of a genetic bond did not seem to be a concern for the women: The gestational bond seemed quite strong and was distinguished from adoptive situations. This information may be of help to others considering egg donations.

It is known that IVF can produce multiple births, and this may carry some health risks for the children. In the small Israeli study, one set of twins had suboptimal health after a premature birth.  Certainly this risk is an important one to remember, if a single parent. The amount of work and time involved may be greater than “normal,” if circumstances such as this arise. Replacement of single embryos is a consideration for women in this situation. And that might mean an increase in the number of attempts to have a child; therefore, it might increase IVF cost.

Methods of low cost IVF can be applied in the pursuit of conception for the single woman. Egg donors may have low gonadotropin stimulation for fresh cycle therapy. Egg banks using frozen eggs are also now a realistic option to pursue. This is because the splitting of batches of donated eggs among two or more recipients lowers the cost of IVF.

There is debate on what to tell the child. Concerns have been raised about the previous secrecy involved and much increased openness with the children has been advocated. This and other related topics are covered in a recent book by Angela Best Boss and Evelina Sterling. It is of note that the writers provide a professional counseling service at www.myfertilityplan.com.   Also we recommend the referenced article published in Women’s Health on a related topic.

References:
Best-Boss, Angie and Sterling, Evelina. Having Your Baby through Egg Donation  2005.
Kirkamn M.  Egg and embryo donation and the meaning of motherhood.  Women’s Health 2003; 38: 1-18.
Landau R et al. Older single mothers and IVF with sperm and egg donation. Fertil Steril 2008; 90: 576-583

21
Jan

Embryo Transfer – Day 3 versus Day 5

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CNY Fertility Center has locations in Syracuse, NY Albany, NY and Rochester, NY. CNY Fertility offers affordable fertility treatments including low cost IVF (In Vitro Fertilization). Patients often have questions about the day that their embryos will be transferred back to their uterus following their IVF procedure. This article is a quick summary of the history and advantages of both Day 3 and Day 5 embryo transfers.
Until about 10 years ago, all embryos were routinely placed in the uterus on day 3 of the cycle. Embryos are then at the 6-8 cell stage.

(8 celled embryo – Day 3)
Culture methods then emerged which allowed healthy embryos to continue developing to day 5, the blastocyst stage which has several attractive features.  Most importantly it allows some of the embryos which are doomed to failure due to internal defects to fall by the wayside as they arrest and do not continue to develop. Thus the more hardy embryos are self selecting and the rate of implantation of each embryo is higher.  Culturing embryos out to the blastocyst stage reduced the number of embryos that were transferred back as well, reducing the incidence of multiple gestations.

(Blastocyst stage embryo – Day 5)
Initially it seemed as this was applied in IVF practice, that the ability to choose the more robust embryos by self selection in this manner would raise pregnancy rates. In a common scenario, the choice if a patient had 5 embryos available for transfer, all about equal in quality on inspection under the microscope, the option would be to replace 3 embryos on day 3 or two on day 5. It was hoped that the day 5 embryo transfer would yield higher results for the IVF patient. This has not turned out to be the case. It is however true that the number of triplets is reduced by use of the day 5 strategy, which is an important option to consider when the risk of multiples is paramount.